A study protocol to characterise pathophysiological and molecular markers of rheumatic heart disease and degenerative aortic stenosis using multiparametric cardiovascular imaging and multiomics techniques.

Introduction: Rheumatic heart disease (RHD), degenerative aortic stenosis (AS), and congenital valve diseases are prevalent in sub-Saharan Africa. Many knowledge gaps remain in understanding disease mechanisms, stratifying phenotypes, and prognostication. Therefore, we aimed to characterise patients through clinical profiling, imaging, histology, and molecular biomarkers to improve our understanding of the pathophysiology, diagnosis, and prognosis of RHD and AS.

ISG15 blocks cardiac glycolysis and ensures sufficient mitochondrial energy production during Coxsackievirus B3 infection.

Aims: Virus infection triggers inflammation and, may impose nutrient shortage to the heart. Supported by type I interferon (IFN) signalling, cardiomyocytes counteract infection by various effector processes, with the IFN-stimulated gene of 15 kDa (ISG15) system being intensively regulated and protein modification with ISG15 protecting mice Coxsackievirus B3 (CVB3) infection. The underlying molecular aspects how the ISG15 system affects the functional properties of respective protein substrates in the heart are unknown.

Dominance is common in mammals and is associated with trans-acting gene expression and alternative splicing.

Background: Dominance and other non-additive genetic effects arise from the interaction between alleles, and historically these phenomena play a major role in quantitative genetics. However, most genome-wide association studies (GWAS) assume alleles act additively.

Results: We systematically investigate both dominance-here representing any non-additive within-locus interaction-and additivity across 574 physiological and gene expression traits in three mammalian stocks: F2 intercross pigs, rat heterogeneous stock, and mice heterogeneous stock.

Effect of cardiopulmonary bypass on plasma and erythrocytes oxylipins.

Background: Oxylipins, the oxidative metabolites of polyunsaturated fatty acids (PUFAs), serve as key mediators of oxidative stress, inflammatory responses, and vasoactive reactions in vivo. Our previous work has established that hemodialysis affects both long chain fatty acids (LCFAs) and oxylipins in plasma and erythrocytes to varying degrees, which may be responsible for excess cardiovascular complications in end-stage renal disease. In this study, we aimed to determine changes in blood oxylipins during cardiopulmonary bypass (CPB) in patients undergoing cardiac surgery to identify novel biomarkers and potential metabolites of CPB-related complications.

Physics-Based Polymer Models to Probe Chromosome Structure in Single Molecules.

Human chromosomes have a complex 3D spatial organization in the cell nucleus, which comprises a hierarchy of physical interactions across genomic scales. Such an architecture serves important functional roles, as genes and their regulators have to physically interact to control gene regulation. However, the molecular mechanisms underlying the formation of those contacts remain poorly understood.

SPSB1-mediated inhibition of TGF-β receptor-II impairs myogenesis in inflammation.

Background: Sepsis-induced intensive care unit-acquired weakness (ICUAW) features profound muscle atrophy and attenuated muscle regeneration related to malfunctioning satellite cells. Transforming growth factor beta (TGF-β) is involved in both processes. We uncovered an increased expression of the TGF-β receptor II (TβRII)-inhibitor SPRY domain-containing and SOCS-box protein 1 (SPSB1) in skeletal muscle of septic mice.

Rbm8a deficiency causes hematopoietic defects by modulating Wnt/PCP signaling.

Defects in blood development frequently occur among syndromic congenital anomalies. Thrombocytopenia-Absent Radius (TAR) syndrome is a rare congenital condition with reduced platelets (hypomegakaryocytic thrombocytopenia) and forelimb anomalies, concurrent with more variable heart and kidney defects. TAR syndrome associates with hypomorphic gene function for that encodes a component of the exon junction complex involved in mRNA splicing, transport, and nonsense-mediated decay.

Multi-Omics Alleviates the Limitations of Panel Sequencing for Cancer Drug Response Prediction.

Comprehensive genomic profiling using cancer gene panels has been shown to improve treatment options for a variety of cancer types. However, genomic aberrations detected via such gene panels do not necessarily serve as strong predictors of drug sensitivity. In this study, using pharmacogenomics datasets of cell lines, patient-derived xenografts, and ex vivo treated fresh tumor specimens, we demonstrate that utilizing the transcriptome on top of gene panel features substantially improves drug response prediction performance in cancer.

PDGFRβ promotes oncogenic progression via STAT3/STAT5 hyperactivation in anaplastic large cell lymphoma.

Background: Anaplastic large cell lymphoma (ALCL) is an aggressive non-Hodgkin T cell lymphoma commonly driven by NPM-ALK. AP-1 transcription factors, cJUN and JUNb, act as downstream effectors of NPM-ALK and transcriptionally regulate PDGFRβ. Blocking PDGFRβ kinase activity with imatinib effectively reduces tumor burden and prolongs survival, although the downstream molecular mechanisms remain elusive.

Identification of novel genes whose expression in adipose tissue affects body fat mass and distribution: an RNA-Seq and Mendelian Randomization study.

Many studies have shown that abdominal adiposity is more strongly related to health risks than peripheral adiposity. However, the underlying pathways are still poorly understood. In this cross-sectional study using data from RNA-sequencing experiments and whole-body MRI scans of 200 participants in the EPIC-Potsdam cohort, our aim was to identify novel genes whose gene expression in subcutaneous adipose tissue has an effect on body fat mass (BFM) and body fat distribution (BFD).

Muscular myostatin gene expression and plasma concentrations are decreased in critically ill patients.

Background: The objective was to investigate the role of gene expression and plasma levels of the muscular protein myostatin in intensive care unit-acquired weakness (ICUAW). This was performed to evaluate a potential clinical and/or pathophysiological rationale of therapeutic myostatin inhibition.

Methods: A retrospective analysis from pooled data of two prospective studies to assess the dynamics of myostatin plasma concentrations (day 4, 8 and 14) and myostatin gene (MSTN) expression levels in skeletal muscle (day 15) was performed.

Temperature elevations can induce switches to homoclinic action potentials that alter neural encoding and synchronization.

Almost seventy years after the discovery of the mechanisms of action potential generation, some aspects of their computational consequences are still not fully understood. Based on mathematical modeling, we here explore a type of action potential dynamics - arising from a saddle-node homoclinic orbit bifurcation - that so far has received little attention. We show that this type of dynamics is to be expected by specific changes in common physiological parameters, like an elevation of temperature.

The Transcription Factor EB (TFEB) Sensitizes the Heart to Chronic Pressure Overload.

The transcription factor EB (TFEB) promotes protein degradation by the autophagy and lysosomal pathway (ALP) and overexpression of TFEB was suggested for the treatment of ALP-related diseases that often affect the heart. However, TFEB-mediated ALP induction may perturb cardiac stress response. We used adeno-associated viral vectors type 9 (AAV9) to overexpress TFEB (AAV9-Tfeb) or Luciferase-control (AAV9-Luc) in cardiomyocytes of 12-week-old male mice.

Hemodialysis and biotransformation of erythrocyte epoxy fatty acids in peripheral tissue.

Cardiovascular disease is the leading cause of mortality in patients with renal failure. Red blood cells (RBCs) are potential reservoirs for epoxy fatty acids (oxylipins) that regulate cardiovascular function. Hemoglobin exhibits pseudo-lipoxygenase activity in vitro.

Hidden Agenda - The Involvement of Endoplasmic Reticulum Stress and Unfolded Protein Response in Inflammation-Induced Muscle Wasting.

Critically ill patients at the intensive care unit (ICU) often develop a generalized weakness, called ICU-acquired weakness (ICUAW). A major contributor to ICUAW is muscle atrophy, a loss of skeletal muscle mass and function. Skeletal muscle assures almost all of the vital functions of our body.

The Physics of DNA Folding: Polymer Models and Phase-Separation.

Within cell nuclei, several biophysical processes occur in order to allow the correct activities of the genome such as transcription and gene regulation. To quantitatively investigate such processes, polymer physics models have been developed to unveil the molecular mechanisms underlying genome functions. Among these, phase-separation plays a key role since it controls gene activity and shapes chromatin spatial structure.

Polymer physics reveals a combinatorial code linking 3D chromatin architecture to 1D chromatin states.

The mammalian genome has a complex, functional 3D organization. However, it remains largely unknown how DNA contacts are orchestrated by chromatin organizers. Here, we infer from only Hi-C the cell-type-specific arrangement of DNA binding sites sufficient to recapitulate, through polymer physics, contact patterns genome wide.

Bioaccumulation of Blood Long-Chain Fatty Acids during Hemodialysis.

Long-chain fatty acids (LCFAs) serve as energy sources, components of cell membranes, and precursors for signaling molecules. Uremia alters LCFA metabolism so that the risk of cardiovascular events in chronic kidney disease (CKD) is increased. End-stage renal disease (ESRD) patients undergoing dialysis are particularly affected and their hemodialysis (HD) treatment could influence blood LCFA bioaccumulation and transformation.

Identification and validation of small molecule analytes in mouse plasma by liquid chromatography-tandem mass spectrometry: A case study of misidentification of a short-chain fatty acid with a ketone body.

Recently, there has been growing interest in short-chain fatty acids (SCFA) and ketone bodies (KB) due to their potential use as biomarkers of health and disease. For instance, these diet-related metabolites can be used to monitor and reduce the risk of immune response, diabetes, or cardiovascular diseases. Given the interest in these metabolites, different targeted metabolomic methods based on UPLC-MS/MS have been developed in recent years to detect and quantify SCFA and KB.