Scalable and efficient DNA sequencing analysis on different compute infrastructures aiding variant discovery.

DNA variation analysis has become indispensable in many aspects of modern biomedicine, most prominently in the comparison of normal and tumor samples. Thousands of samples are collected in local sequencing efforts and public databases requiring highly scalable, portable, and automated workflows for streamlined processing. Here, we present nf-core/sarek 3, a well-established, comprehensive variant calling and annotation pipeline for germline and somatic samples.

Sequencing by avidity enables high accuracy with low reagent consumption.

We present avidity sequencing, a sequencing chemistry that separately optimizes the processes of stepping along a DNA template and that of identifying each nucleotide within the template. Nucleotide identification uses multivalent nucleotide ligands on dye-labeled cores to form polymerase-polymer-nucleotide complexes bound to clonal copies of DNA targets. These polymer-nucleotide substrates, termed avidites, decrease the required concentration of reporting nucleotides from micromolar to nanomolar and yield negligible dissociation rates.

mlf-core: a framework for deterministic machine learning.

Motivation: Machine learning has shown extensive growth in recent years and is now routinely applied to sensitive areas. To allow appropriate verification of predictive models before deployment, models must be deterministic. Solely fixing all random seeds is not sufficient for deterministic machine learning, as major machine learning libraries default to the usage of nondeterministic algorithms based on atomic operations.

Immune cell profiles of patients with interstitial cystitis/bladder pain syndrome.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a disorder characterized by bladder pain upon filling which severely affects quality of life. Clinical presentation can vary. Local inflammatory events typify the clinical presentation of IC/BPS patients with Hunner lesions (IC/BPS-HL).

Coronary vasodilation mediated by T cells expressing choline acetyltransferase.

CD4 T cells expressing choline acetyltransferase (ChAT) have recently been shown to cause a drop in systemic blood pressure when infused into mice. The aim of this study was to determine if ChAT-expressing T cells could regulate coronary vascular reactivity. Preconstricted segments of epicardial and intramyocardial porcine coronary arteries relaxed in response to Jurkat T cells (JT) that overexpressed ChAT (JT cells).

Extracellular Superoxide Dismutase (EC-SOD) Regulates Gene Methylation and Cardiac Fibrosis During Chronic Hypoxic Stress.

Chronic hypoxic stress induces epigenetic modifications mainly DNA methylation in cardiac fibroblasts, inactivating tumor suppressor genes (RASSF1A) and activating kinases (ERK1/2) leading to fibroblast proliferation and cardiac fibrosis. The Ras/ERK signaling pathway is an intracellular signal transduction critically involved in fibroblast proliferation. RASSF1A functions through its effect on downstream ERK1/2.

Female-Specific Association of Plasma N-Terminal Pro-Brain Natriuretic Peptide With Organ Dysfunction and Prognosis in Sepsis: A Retrospective Study.

Objectives: The plasma level of N-terminal pro-brain natriuretic peptide is regulated by sex hormones. It has been controversial whether N-terminal pro-brain natriuretic peptide is a prognosis marker for sepsis. The aim of this study is to examine the sex-dependent association of plasma N-terminal pro-brain natriuretic peptide with organ dysfunction and mortality of sepsis patients.

Contribution of Connexin Hemichannels to the Pathogenesis of Acute Lung Injury.

Connexin (Cx) family members form hemichannels (HCs) and gap junctions (GJs). Biological functions of Cx HCs have not been adequately characterized due to the inability to selectively target HCs or GJs. Recently, we developed a 6-mer peptide mimetic (P5) of the first extracellular loop of Cx43 and showed that it can block the permeability of HCs but not GJs formed by Cx43.

Development of a biomarker mortality risk model in acute respiratory distress syndrome.

Background: There is a compelling unmet medical need for biomarker-based models to risk-stratify patients with acute respiratory distress syndrome. Effective stratification would optimize participant selection for clinical trial enrollment by focusing on those most likely to benefit from new interventions. Our objective was to develop a prognostic, biomarker-based model for predicting mortality in adult patients with acute respiratory distress syndrome.

Cerebrospinal fluid macrophage migration inhibitory factor: a potential predictor of cerebral vasospasm and clinical outcome after aneurysmal subarachnoid hemorrhage.

Objective: In patients with aneurysmal subarachnoid hemorrhage (aSAH), poor outcomes have been shown to be correlated with subsequent cerebral vasospasm (CV) and delayed cerebral ischemia (DCI). The identification of novel biomarkers may aid in the prediction of which patients are vulnerable to developing vasospasm, cerebral ischemia, and neurological deterioration.

Methods: In this prospective clinical study at North Shore University Hospital, patients with aSAH or normal pressure hydrocephalus (NPH) with external ventricular drains were enrolled.

Correction: MIF inhibition enhances pulmonary angiogenesis and lung development in congenital diaphragmatic hernia.

In the original version of this article, the name of the author "Kamesh Ayasolla" was incorrectly given as "Kamesh Ayyasola". This has now been corrected to "Kamesh Ayasolla" in both the PDF and HTML versions of the article.

MIF inhibition enhances pulmonary angiogenesis and lung development in congenital diaphragmatic hernia.

Background: Congenital diaphragmatic hernia (CDH) is a complex birth anomaly with significant mortality and morbidity. Lung hypoplasia and persistent pulmonary hypertension (PPHN) limit survival in CDH. Macrophage migration inhibitory factor (MIF), a key regulator of innate immunity, is involved in hypoxia-induced vascular remodeling and PPHN.

D-dopachrome tautomerase predicts outcome but not the development of acute kidney injury after orthotopic liver transplantation.

Background: Elevated concentrations of D-dopachrome tautomerase (D-DT) were associated with adverse outcome in various clinical settings. However, no study assessed D-DT concentrations in patients requiring orthotopic liver transplantation (OLT). The aim of this observational study was to measure serum D-DT concentrations in patients undergoing OLT and associate D-DT with survival and acute kidney injury (AKI).

Macrophage migration inhibitory factor (MIF) in the development and progression of pulmonary arterial hypertension.

Macrophage migration inhibitory factor (MIF) has been described as a pro-inflammatory cytokine and regulator of neuro-endocrine function. It plays an important upstream role in the inflammatory cascade by promoting the release of other inflammatory cytokines such as TNF-alpha and IL-6, ultimately triggering a chronic inflammatory immune response. As lungs can synthesize and release MIF, many studies have investigated the potential role of MIF as a biomarker in assessment of patients with pulmonary arterial hypertension (PAH) and using anti-MIFs as a new therapeutic modality for PAH.

Sputum Detection of Predisposing Genetic Mutations in Women with Pulmonary Nontuberculous Mycobacterial Disease.

Nontuberculous mycobacterial lung disease (NTM), including Mycobacterium avium complex (MAC), is a growing health problem in North America and worldwide. Little is known about the molecular alterations occurring in the tissue microenvironment during NTM pathogenesis. Utilizing next generation sequencing, we sequenced sputum and matched lymphocyte DNA in 15 MAC patients for a panel of 19 genes known to harbor cancer susceptibility associated mutations.

Rux largely restores lungs in Iraq PM-exposed mice, Up-regulating regulatory T-cells (Tregs).

Background Military personnel post-deployment to Iraq and Afghanistan have noted new-onset respiratory illness. This study's primary objective was to further develop an animal model of Iraq Afghanistan War Lung Injury (IAW-LI) and to test a novel class of anti-injury drug called RuX. Methods Particulate Matter (PM) samples were obtained in Iraq then characterized by spectromicroscopy.

Selective inhibition of endothelial NF-κB signaling attenuates chronic intermittent hypoxia-induced atherosclerosis in mice.

Background And Aims: Chronic intermittent hypoxia (CIH) exposure causes atherosclerosis, although the underlying mechanisms are poorly understood. This study defines the role of endothelial intrinsic NF-κB signaling in the atherogenic response to CIH.

Methods: We created ApoE-EC mice that are deficient in the apolipoprotein E gene (ApoE) and overexpress an I-κBα mutant (I-κBmt) selectively in endothelial cells.

Immunomodulation by Mesenchymal Stromal Cells and Their Clinical Applications.

Mesenchymal stromal cells (MSCs) are multipotent progenitor cells that can be isolated and expanded from various sources. MSCs modulate the function of immune cells, including T and B lymphocytes, dendritic cells, and natural killer cells. An understanding of the interaction between MSCs and the inflammatory microenvironment will provide critical information in revealing the precise mechanisms involved in MSCs-mediated therapeutic effects, and for designing more practical protocols for the clinical use of these cells.

Hypoxia-induced activation of specific members of the NF-kB family and its relevance to pulmonary vascular remodeling.

Background And Objective: Pulmonary Hypertension (pH) is a chronic progressive disease. Endothelial cells (EC) play a central and critical role in the initiation and progression of pH. The NF-κB family (NF-κB1 (p50/p105), NF-κB2 (p52/p100), RelA (p65), RelB, and C-Rel) regulates a wide array of genes involved in inflammatory responses, cell proliferation, and survival.

Enhanced Mortality to Metastatic Bladder Cancer Cell Line MB49 in Vasoactive Intestinal Peptide Gene Knockout Mice.

To identify if the absence of the vasoactive intestinal peptide (VIP) gene enhances susceptibility to death from metastatic bladder cancer, two strains of mice were injected with MB49 murine bladder cancer cells. The growth and spread of the cancer was measured over a period of 4 weeks in C57BL/6 mice and 5 weeks in VIP knockout (KO) mice. A Kaplan-Meier plot was constructed to compare control C57BL/6 mice and C57BL/6 mice with MB49 vs.

Comparison of macrophage migration inhibitory factor and neutrophil gelatinase-associated lipocalin-2 to predict acute kidney injury after liver transplantation: An observational pilot study.

Introduction: Several biomarkers have been suggested as early predictors of acute kidney injury (AKI) after orthotopic liver transplantation (OLT). Neutrophil gelatinase-associated lipocalin-2 (NGAL) appears to be a promising predictor of AKI after OLT, but the clinical benefit remains to be proven. Recently, systemic macrophage migration inhibitory factor (MIF) has been proposed as early indicator for requirement of renal replacement therapy after OLT.

Age-Related Changes in Immunological and Physiological Responses Following Pulmonary Challenge.

This review examines the current status of knowledge of sepsis and pneumonia in the elderly population and how the dynamics of the pulmonary challenge affects outcome and consequences. Led by an unprecedented shift in demographics, where a larger proportion of the population will reach an older age, clinical and experimental research shows that aging is associated with certain pulmonary changes, but it is during infectious insult of the lungs, as in the case of pneumonia, that the age-related differences in responsiveness and endurance become obvious and lead to a worse outcome than in the younger population. This review points to the neutrophil, and the endothelium as important players in understanding age-associated changes in responsiveness to infectious challenge of the lung.

Graft-derived macrophage migration inhibitory factor correlates with hepatocellular injury in patients undergoing liver transplantation.

Unlabelled: Experimental studies suggest that macrophage migration inhibitory factor (MIF) mediates ischemia/reperfusion injury during liver transplantation. This study assessed whether human liver grafts release MIF during preservation, and whether the release of MIF is proportional to the extent of hepatocellular injury. Additionally, the association between MIF and early allograft dysfunction (EAD) after liver transplantation was evaluated.

Regulation of angiopoietin-2 secretion from human pulmonary microvascular endothelial cells.

Introduction: Sepsis is characterized by dysregulated systemic inflammation and cytokine storm. Angiopoietin-2 (Ang-2) is known to closely correlate with severity of sepsis-related acute lung injury and mortality. The aim of this study was to clarify the mechanisms involved in Ang-2 secretion to better understand the pathophysiology of sepsis.