bcRflow: a Nextflow pipeline for characterizing B cell receptor repertoires from non-targeted transcriptomic data.

B cells play a critical role in the adaptive recognition of foreign antigens through diverse receptor generation. While targeted immune sequencing methods are commonly used to profile B cell receptors (BCRs), they have limitations in cost and tissue availability. Analyzing B cell receptor profiling from non-targeted transcriptomics data is a promising alternative, but a systematic pipeline integrating tools for accurate immune repertoire extraction is lacking.

Carotid body denervation improves hyperglycemia in obese mice.

The carotid bodies (CBs) have been implicated in glucose abnormalities in obesity via elevation of activity of the sympathetic nervous system. Obesity-induced hypertension is mediated by insulin receptor (INSR) signaling and by leptin, which binds to the leptin receptor (LEPR) in CB and activates transient receptor potential channel subfamily M member 7 (TRPM7). We hypothesize that in mice with diet-induced obesity, hyperglycemia, glucose intolerance, and insulin resistance will be attenuated by the CB denervation (carotid sinus nerve dissection, CSND) and by knockdown of , and gene expression in CB.

Epigenetic Reprogramming Drives Epithelial Disruption in Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) remains a major public health challenge that contributes greatly to mortality and morbidity worldwide. Although it has long been recognized that the epithelium is altered in COPD, there has been little focus on targeting it to modify the disease course. Therefore, mechanisms that disrupt epithelial cell function in patients with COPD are poorly understood.

Exercise-primed extracellular vesicles improve cell-matrix adhesion and chondrocyte health.

Extracellular vesicles (EVs) have been suggested to transmit the health-promoting effects of exercise throughout the body. Yet, the mechanisms by which beneficial information is transmitted from extracellular vesicles to recipient cells are poorly understood, precluding a holistic understanding of how exercise promotes cellular and tissue health. In this study, using articular cartilage as a model, we introduced a network medicine paradigm to simulate how exercise facilitates communication between circulating EVs and chondrocytes, the cells resident in articular cartilage.

Age-related matrix stiffening epigenetically regulates α-Klotho expression and compromises chondrocyte integrity.

Extracellular matrix stiffening is a quintessential feature of cartilage aging, a leading cause of knee osteoarthritis. Yet, the downstream molecular and cellular consequences of age-related biophysical alterations are poorly understood. Here, we show that epigenetic regulation of α-Klotho represents a novel mechanosensitive mechanism by which the aged extracellular matrix influences chondrocyte physiology.

TRPM7 channels regulate breathing during sleep in obesity by acting peripherally in the carotid bodies.

Sleep-disordered breathing (SDB) affects over 50% of obese individuals. Exaggerated hypoxic chemoreflex is a cardinal trait of SDB in obesity. We have shown that leptin acts in the carotid bodies (CB) to augment chemoreflex and that leptin activates the transient receptor potential melastatin 7 (TRPM7) channel.

Blood DNA Methylation and Incident Coronary Heart Disease: Evidence From the Strong Heart Study.

Importance: American Indian communities experience a high burden of coronary heart disease (CHD). Strategies are needed to identify individuals at risk and implement preventive interventions.

Objective: To investigate the association of blood DNA methylation (DNAm) with incident CHD using a large number of methylation sites (cytosine-phosphate-guanine [CpG]) in a single model.

Pharmacological and Genetic Blockade of in the Carotid Body Treats Obesity-Induced Hypertension.

[Figure: see text].

Leptin Induces Epigenetic Regulation of Transient Receptor Potential Melastatin 7 in Rat Adrenal Pheochromocytoma Cells.

Obesity elevates the plasma level of leptin, which has been associated with hypertension. Our recent studies in mice demonstrated that leptin increases blood pressure by activating the carotid sinus nerve, which transmits the chemosensory input from carotid bodies (CBs) to the medullary centers, and that the effect of leptin is mediated via (TRP [transient receptor potential] melastatin 7) channels in CB glomus cells. We also found that overexpression and promoter demethylation in CBs correlate positively with the hyperleptinemia and leptin receptor overexpression in CBs.

Multigenerational Epigenetic Regulation of Allergic Diseases: Utilizing an Experimental Dust Mite-Induced Asthma Model.

Environmental exposures have been linked to increased asthma risk, particularly during pregnancy and in early life. Here we use a mouse model of allergic lung disease to examine the effects of pre- and perinatal house dust mite (HDM) allergen exposure on offspring phenotypic and transcriptional outcomes in three generations. We show that maternal HDM exposure (F0) acts synergistically with adult HDM exposure, leading to enhanced airway hyperresponsiveness (AHR) and lung inflammation when compared to mice exposed solely in adulthood.

A Nonlinear Relation Between Maternal Red Blood Cell Manganese Concentrations and Child Blood Pressure at Age 6-12 y: A Prospective Birth Cohort Study.

Background: Although manganese (Mn) is an essential trace element and a common component of most multivitamins on the market, an adverse effect on blood pressure (BP) has been reported in adults. In addition, the longitudinal relation between prenatal Mn status and childhood BP is still unknown.

Objective: This study investigated the association between prenatal Mn concentrations and risk of elevated BP at ages 3-12 y.

Prenatal exposure to mercury and precocious puberty: a prospective birth cohort study.

Study Question: Is in utero exposure to mercury associated with the risk of precocious puberty?

Summary Answer: Prenatal exposure to high levels of mercury was associated with increased risk of precocious puberty, which was strengthened by concomitant maternal cardiometabolic conditions and adverse birth outcomes.

What Is Known Already: The developing fetus is sensitive to mercury, a well-known endocrine disruptor which impacts the endocrine and reproductive system.

Study Design, Size, Duration: This study included 1512 mother-child pairs from the Boston Birth Cohort, a longitudinal cohort which recruited at birth and followed prospectively up to 21 years of age.

DNA methylation and adiposity phenotypes: an epigenome-wide association study among adults in the Strong Heart Study.

Background: Elevated adiposity is often posited by medical and public health researchers to be a risk factor associated with cardiovascular disease, diabetes, and other diseases. These health challenges are now thought to be reflected in epigenetic modifications to DNA molecules, such as DNA methylation, which can alter gene expression.

Methods: Here we report the results of three Epigenome Wide Association Studies (EWAS) in which we assessed the differential methylation of DNA (obtained from peripheral blood) associated with three adiposity phenotypes (BMI, waist circumference, and impedance-measured percent body fat) among American Indian adult participants in the Strong Heart Study.

Genome-wide association study identifies a novel maternal gene × stress interaction associated with spontaneous preterm birth.

Background: Maternal stress is potentially a modifiable risk factor for spontaneous preterm birth (sPTB). However, epidemiologic findings on the maternal stress-sPTB relationship have been inconsistent.

Methods: To investigate whether the maternal stress-sPTB associations may be modified by genetic susceptibility, we performed genome-wide gene × stress interaction analyses in 1490 African-American women from the Boston Birth cohort who delivered term (n = 1033) or preterm (n = 457) infants.

Arsenic Directs Stem Cell Fate by Imparting Notch Signaling Into the Extracellular Matrix Niche.

Compromise of skeletal muscle metabolism and composition may underlie the etiology of cardiovascular and metabolic disease risk from environmental arsenic exposures. We reported that arsenic impairs muscle maintenance and regeneration by inducing maladaptive mitochondrial phenotypes in muscle stem cells (MuSC), connective tissue fibroblasts (CTF), and myofibers. We also found that arsenic imparts a dysfunctional memory in the extracellular matrix (ECM) that disrupts the MuSC niche and is sufficient to favor the expansion and differentiation of fibrogenic MuSC subpopulations.

Locus-Specific Differential DNA Methylation and Urinary Arsenic: An Epigenome-Wide Association Study in Blood among Adults with Low-to-Moderate Arsenic Exposure.

Background: Chronic exposure to arsenic (As), a human toxicant and carcinogen, remains a global public health problem. Health risks persist after As exposure has ended, suggesting epigenetic dysregulation as a mechanistic link between exposure and health outcomes.

Objectives: We investigated the association between total urinary As and locus-specific DNA methylation in the Strong Heart Study, a cohort of American Indian adults with low-to-moderate As exposure [total urinary As, creatinine: 11.

Cadmium, Smoking, and Human Blood DNA Methylation Profiles in Adults from the Strong Heart Study.

Background: The epigenetic effects of individual environmental toxicants in tobacco remain largely unexplored. Cadmium (Cd) has been associated with smoking-related health effects, and its concentration in tobacco smoke is higher in comparison with other metals.

Objectives: We studied the association of Cd and smoking exposures with human blood DNA methylation (DNAm) profiles.

Role of Isocitrate Dehydrogenase 2 on DNA Hydroxymethylation in Human Airway Smooth Muscle Cells.

Global DNA hydroxymethylation mediated by the TET (ten-eleven translocation) enzyme was induced in allergen-induced airway hyperresponsiveness in mouse lung tissues and specifically in isolated airway smooth muscle (ASM) cells. TET is an α-ketoglutarate (α-KG)-dependent enzyme, and the production of α-KG is catalyzed by IDH (isocitrate dehydrogenase). However, the role of IDH in the regulation of DNA hydroxymethylation in ASM cells is unknown.

Leptin Induces Hypertension Acting on Transient Receptor Potential Melastatin 7 Channel in the Carotid Body.

Rationale: Obesity leads to resistant hypertension and mechanisms are poorly understood, but high plasma levels of leptin have been implicated. Leptin increases blood pressure acting both centrally in the dorsomedial hypothalamus and peripherally. Sites of the peripheral hypertensive effect of leptin have not been identified.

Can social support during pregnancy affect maternal DNA methylation? Findings from a cohort of African-Americans.

Background: While stress and the absence of social support during pregnancy have been linked to poor health outcomes, the underlying biological mechanisms are unclear.

Methods: We examined whether adverse experiences during pregnancy alter DNA methylation (DNAm) in maternal epigenomes. Analyses included 250 African-American mothers from the Boston Birth Cohort.

Estrogen down regulates COMT transcription via promoter DNA methylation in human breast cancer cells.

Catechol-O-methyltransferase (COMT) acts as a 'gate-keeper' to prevent DNA damage during estrogen metabolism. Both experimental and epidemiological studies suggest the role of COMT in pathogenesis of human breast cancer (BCa). It was previously reported that inhibition of COMT enzyme activity in estradiol-treated human breast epithelial carcinoma-derived MCF-7 cells caused increased oxidative DNA damage and formation of mutagenic depurinating adducts.

Mitochondria are a substrate of cellular memory.

Cellular memory underlies cellular identity, and thus constitutes a unifying mechanism of genetic disposition, environmental influences, and cellular adaptation. Here, we demonstrate that enduring physicochemical changes of mitochondrial networks invoked by transient stress, a phenomenon we term 'mitoengrams', underlie the transgenerational persistence of epigenetically scripted cellular behavior. Using C2C12 myogenic stem-like cells, we show that stress memory elicited by transient, low-level arsenite exposure is stored within a self-renewing subpopulation of progeny cells in a mitochondrial-dependent fashion.

Biological sex affects vaccine efficacy and protection against influenza in mice.

Biological sex affects adaptive immune responses, which could impact influenza infection and vaccine efficacy. Infection of mice with 2009 H1N1 induced antibody responses, CD4 T cell and CD8 T cell memory responses that were greater in females than males; both sexes, however, were equally protected against secondary challenge with an H1N1 drift variant virus. To test whether greater antibody in females is sufficient for protection against influenza, males and females were immunized with an inactivated H1N1 vaccine that induced predominantly antibody-mediated immunity.

Leptin acts in the carotid bodies to increase minute ventilation during wakefulness and sleep and augment the hypoxic ventilatory response.

Key Points: Leptin is a potent respiratory stimulant. A long functional isoform of leptin receptor, LepR , was detected in the carotid body (CB), a key peripheral hypoxia sensor. However, the effect of leptin on minute ventilation (V ) and the hypoxic ventilatory response (HVR) has not been sufficiently studied.

Maternal smoking during pregnancy and cord blood DNA methylation: new insight on sex differences and effect modification by maternal folate levels.

Maternal smoking during pregnancy may affect newborn DNA methylation (DNAm). However, little is known about how these associations vary by a newborn's sex and/or maternal nutrition. To fill in this research gap, we investigated epigenome-wide DNAm associations with maternal smoking during pregnancy in African American mother-newborn pairs.