Single Cell Transcriptomic Profiling of -Associated Hypertrophic Cardiomyopathy Across Species Reveals Conservation of Biological Process But Not Gene Expression.

Background: Hypertrophic cardiomyopathy (HCM) is a common heritable heart disease where the most frequently associated mutations occur in the myosin-binding protein C () sarcomere-associated gene. HCM is also a common veterinary clinical problem in certain cat breeds such as Maine Coons and Ragdolls, also most associated with mutations in . Mouse models of HCM in which mutations are introduced recapitulate some, but not all, features of human HCM.

Mineralocorticoid Receptor in Endothelial Cells Contributes to VEGF Receptor Inhibitor-Induced Vascular and Kidney Damage.

Background: Vascular endothelial growth factor receptor inhibitors (VEGFRis) improve cancer patient survival by inhibiting tumor angiogenesis. However, VEGFRis induce treatment-limiting hypertension which has been associated with impaired vascular endothelial cell (EC) function and kidney damage. The mineralocorticoid receptor (MR) regulates blood pressure via effects on the vasculature and the kidney.

Identifying mitigating strategies for endothelial cell dysfunction and hypertension in response to VEGF receptor inhibitors.

Vascular endothelial growth factor receptor inhibitors (VEGFRis) improve cancer survival but are associated with treatment-limiting hypertension, often attributed to endothelial cell (EC) dysfunction. Using phosphoproteomic profiling of VEGFRi-treated ECs, drugs were screened for mitigators of VEGFRi-induced EC dysfunction and validated in primary aortic ECs, mice, and canine cancer patients. VEGFRi treatment significantly raised systolic blood pressure (SBP) and increased markers of endothelial and renal dysfunction in mice and canine cancer patients.

CD14 is a decision-maker between Fas-mediated death and inflammation.

Signaling through classical death receptor Fas was mainly appreciated as a pro-death pathway until recent reports characterized pro-inflammatory outcomes of Fas-mediated activation in pathological contexts. How Fas signaling can switch to pro-inflammatory activation is poorly understood. Herein, we report that in macrophages and neutrophils, the Toll-like receptor (TLR) adapter CD14 determines the inflammatory output of Fas-mediated signaling.

Non-canonical autophosphorylation of RIPK1 drives timely pyroptosis to control Yersinia infection.

Caspase-8-dependent pyroptosis has been shown to mediate host protection from Yersinia infection. For this mode of cell death, the kinase activity of receptor-interacting protein kinase 1 (RIPK1) is required, but the autophosphorylation sites required to drive caspase-8 activation have not been determined. Here, we show that non-canonical autophosphorylation of RIPK1 at threonine 169 (T169) is necessary for caspase-8-mediated pyroptosis.

Dynasore modulates store-operated calcium entry and mitochondrial calcium release in corneal epithelial cells.

Dysregulation of calcium homeostasis can precipitate a cascade of pathological events that lead to tissue damage and cell death. Dynasore is a small molecule that inhibits endocytosis by targeting classic dynamins. In a previous study, we showed that dynasore can protect human corneal epithelial cells from damage due to tert-butyl hydroperoxide (tBHP) exposure by restoring cellular calcium (Ca) homeostasis.

Blocking HXA-mediated neutrophil elastase release during lung infection limits pulmonary epithelial barrier disruption and bacteremia.

(), a leading cause of community-acquired pneumonia, can spread from the lung into the bloodstream to cause septicemia and meningitis, with a concomitant three-fold increase in mortality. Limitations in vaccine efficacy and a rise in antimicrobial resistance have spurred searches for host-directed therapies that target pathogenic immune processes. Polymorphonuclear leukocytes (PMNs) are essential for infection control but can also promote tissue damage and pathogen spread.

KDM2B is required for ribosome biogenesis and its depletion unequally affects mRNA translation.

KDM2B is a JmjC domain lysine demethylase, which promotes cell immortalization, stem cell self-renewal and tumorigenesis. Here we employed a multi-omics strategy to address its role in ribosome biogenesis and mRNA translation. These processes are required to sustain cell proliferation, an important cancer hallmark.

Transmission of reduced levels of miR-34/449 from sperm to preimplantation embryos is a key step in the transgenerational epigenetic inheritance of the effects of paternal chronic social instability stress.

The transgenerational effects of exposing male mice to chronic social instability (CSI) stress are associated with decreased sperm levels of multiple members of the miR-34/449 family that persist after their mating through preimplantation embryo (PIE) development. Here we demonstrate the importance of these miRNA changes by showing that restoring miR-34c levels in PIEs derived from CSI stressed males prevents elevated anxiety and defective sociability normally found specifically in their adult female offspring. It also restores, at least partially, levels of sperm miR-34/449 normally reduced in their male offspring who transmit these sex-specific traits to their offspring.

Vital role for primary healthcare providers: urgent need to educate the community about daily nutritional self-care to support immune function and maintain health.

The importance of self-care to improve health and social well-being is well recognised. Nevertheless, there remains a need to encourage people to better understand how their body works, and how to keep it healthy. Because of its important role, part of this understanding should be based on why the immune system must be supported.

ACKR3 Proximity Labeling Identifies Novel G protein- and β-arrestin-independent GPCR Interacting Proteins.

The canonical paradigm of GPCR signaling recognizes G proteins and β-arrestins as the two primary transducers that promote GPCR signaling. Recent evidence suggests the atypical chemokine receptor 3 (ACKR3) does not couple to G proteins, and β-arrestins are dispensable for some of its functions. Here, we employed proximity labeling to identify proteins that interact with ACKR3 in cells devoid of β-arrestin.

Traumatic brain injury disrupts state-dependent functional cortical connectivity in a mouse model.

Traumatic brain injury (TBI) is the leading cause of death in young people and can cause cognitive and motor dysfunction and disruptions in functional connectivity between brain regions. In human TBI patients and rodent models of TBI, functional connectivity is decreased after injury. Recovery of connectivity after TBI is associated with improved cognition and memory, suggesting an important link between connectivity and functional outcome.

Borrelia burgdorferi initiates early transcriptional re-programming in macrophages that supports long-term suppression of inflammation.

Borrelia burgdorferi (Bb), the causative agent of Lyme disease, establishes a long-term infection and leads to disease manifestations that are the result of host immune responses to the pathogen. Inflammatory manifestations resolve spontaneously despite continued bacterial presence, suggesting inflammatory cells become less responsive over time. This is mimicked by in vitro repeated stimulations, resulting in tolerance, a phenotypic subset of innate immune memory.

Powassan Virus Infections: A Systematic Review of Published Cases.

Background: Powassan virus is an emerging neurotropic arbovirus transmitted by the tick This systematic review was conducted to aggregate data on its clinical manifestations, diagnostic findings, and complications.

Methods: PubMed was searched until August 2023 using the term "Powassan", to identify all published cases of Powassan virus infections, as per PRISMA guidelines.

Results: Among the 380 abstracts identified, 45 studies describing 84 cases (70 adult, 14 pediatric) were included.

Transcriptional regulation of amino acid metabolism by KDM2B, in the context of ncPRC1.1 and in concert with MYC and ATF4.

Introduction: KDM2B encodes a JmjC domain-containing histone lysine demethylase, which functions as an oncogene in several types of tumors, including TNBC. This study was initiated to address the cancer relevance of the results of our earlier work, which had shown that overexpression of KDM2B renders mouse embryonic fibroblasts (MEFs) resistant to oxidative stress by regulating antioxidant mechanisms.

Methods: We mainly employed a multi-omics strategy consisting of RNA-Seq, quantitative TMT proteomics, Mass-spectrometry-based global metabolomics, ATAC-Seq and ChIP-seq, to explore the role of KDM2B in the resistance to oxidative stress and intermediary metabolism.

Pore-forming activity of pneumolysin disrupts the paracellular localization of the epithelial adherens junction protein E-cadherin.

a common cause of community-acquired bacterial pneumonia, can cross the respiratory epithelial barrier to cause lethal septicemia and meningitis. pore-forming toxin pneumolysin (PLY) triggers robust neutrophil (PMN) infiltration that promotes bacterial transepithelial migration and disseminated disease in mice. Apical infection of polarized respiratory epithelial monolayers by at a multiplicity of infection (MOI) of 20 resulted in recruitment of PMNs, loss of 50% of the monolayer, and PMN-dependent bacterial translocation.

Roles unveiled for membrane-associated mucins at the ocular surface using a Muc4 knockout mouse model.

Membrane-associated mucins (MAMs) are proposed to play critical roles at the ocular surface; however, in vivo evidence has been lacking. Here we investigate these roles by phenotyping of a Muc4 KO mouse. Histochemical analysis for expression of the beta-galactosidase transgene replacing Muc4 revealed a spiraling ribbon pattern across the corneal epithelium, consistent with centripetal cell migration from the limbus.

Transcriptional regulation of amino acid metabolism by KDM2B, in the context of ncPRC1.1 and in concert with MYC and ATF4.

Introduction: KDM2B encodes a JmjC domain-containing histone lysine demethylase, which functions as an oncogene in several types of tumors, including TNBC. This study was initiated to address the cancer relevance of the results of our earlier work, which had shown that overexpression of KDM2B renders mouse embryonic fibroblasts (MEFs) resistant to oxidative stress by regulating antioxidant mechanisms.

Methods: We mainly employed a multi-omics strategy consisting of RNA-Seq, quantitative TMT proteomics, Mass-spectrometry-based global metabolomics, ATAC-Seq and ChIP-seq, to explore the role of KDM2B in the resistance to oxidative stress and intermediary metabolism.

Differential Efficacy of Small Molecules Dynasore and Mdivi-1 for the Treatment of Dry Eye Epitheliopathy or as a Countermeasure for Nitrogen Mustard Exposure of the Ocular Surface.

The ocular surface comprises the wet mucosal epithelia of the cornea and conjunctiva, the associated glands, and the overlying tear film. Epitheliopathy is the common pathologic outcome when the ocular surface is subjected to oxidative stress. Whether different stresses act via the same or different mechanisms is not known.

Longitudinal study evaluating post-ICU syndrome differences between acute care surgery and trauma SICU survivors.

Background: Post-intensive care unit (ICU) syndrome (PICS) occurs at an exorbitant rate in surgical ICU (SICU) survivors. It remains unknown if critical illness due to trauma versus acute care surgery (ACS) may represent different pathophysiologic entities. In this longitudinal study, we determined if admission criteria in a cohort of trauma and ACS patients were associated with differences in the occurrence of PICS.

Increasing diversity, equity, and inclusion in the fields of nutrition and obesity: A roadmap to equity in academia.

Research shows that a diverse faculty improves academic, clinical, and research outcomes in higher education. Despite that, persons in minority groups, usually categorized by race or ethnicity, are underrepresented in academia (URiA). The Nutrition Obesity Research Centers (NORCs), supported by the NIDDK, hosted workshops on five separate days in September and October 2020.

Cortical Parvalbumin-Positive Interneuron Development and Function Are Altered in the APC Conditional Knockout Mouse Model of Infantile and Epileptic Spasms Syndrome.

Infantile and epileptic spasms syndrome (IESS) is a childhood epilepsy syndrome characterized by infantile or late-onset spasms, abnormal neonatal EEG, and epilepsy. Few treatments exist for IESS, clinical outcomes are poor, and the molecular and circuit-level etiologies of IESS are not well understood. Multiple human IESS risk genes are linked to Wnt/β-catenin signaling, a pathway that controls developmental transcriptional programs and promotes glutamatergic excitation via β-catenin's role as a synaptic scaffold.

Neutrophils and macrophages drive TNF-induced lethality via TRIF/CD14-mediated responses.

TNF mediates a variety of biological processes including cellular proliferation, inflammatory responses, and cell death and is therefore associated with numerous pathologies including autoinflammatory diseases and septic shock. The inflammatory and cell death responses to TNF have been studied extensively downstream of TNF-R1 and are believed to rely on the formation of proinflammatory complex I and prodeath complex II, respectively. We recently identified a similar multimeric complex downstream of TLR4, termed the TRIFosome, that regulates inflammation and cell death in response to LPS or .