Rapid cyclic stretching induces a synthetic, proinflammatory phenotype in cultured human intestinal smooth muscle, with the potential to alter signaling to adjacent bowel cells.

Background And Aims: Bowel smooth muscle experiences mechanical stress constantly during normal function, and pathologic mechanical stressors in disease states. We tested the hypothesis that pathologic mechanical stress could alter transcription to induce smooth muscle phenotypic class switching.

Methods: Primary human intestinal smooth muscle cells (HISMCs), seeded on electrospun aligned poly-ε-caprolactone nano-fibrous scaffolds, were subjected to pathologic, high frequency (1 Hz) uniaxial 3% cyclic stretch (loaded) or kept unloaded in culture for 6 hours.

Neuroimmune Crossroads: The Interplay of the Enteric Nervous System and Intestinal Macrophages in Gut Homeostasis and Disease.

A defining unique characteristic of the gut immune system is its ability to respond effectively to foreign pathogens while mitigating unnecessary inflammation. Intestinal macrophages serve as the cornerstone of this balancing act, acting uniquely as both the sword and shield in the gut microenvironment. The GI tract is densely innervated by the enteric nervous system (ENS), the intrinsic nervous system of the gut.

The longitudinal behavioral effects of acute exposure to galactic cosmic radiation in female C57BL/6J mice: Implications for deep space missions, female crews, and potential antioxidant countermeasures.

Galactic cosmic radiation (GCR) is an unavoidable risk to astronauts that may affect mission success. Male rodents exposed to 33-beam-GCR (33-GCR) show short-term cognitive deficits but reports on female rodents and long-term assessment are lacking. We asked: What are the longitudinal behavioral effects of 33-GCR on female mice? Also, can an antioxidant/anti-inflammatory compound (CDDO-EA) mitigate the impact of 33-GCR? Mature (6-month-old) C57BL/6J female mice received CDDO-EA (400 μg/g of food) or a control diet (vehicle, Veh) for 5 days and Sham-irradiation (IRR) or whole-body 33-GCR (0.

Spatially resolved multiomics on the neuronal effects induced by spaceflight in mice.

Impairment of the central nervous system (CNS) poses a significant health risk for astronauts during long-duration space missions. In this study, we employed an innovative approach by integrating single-cell multiomics (transcriptomics and chromatin accessibility) with spatial transcriptomics to elucidate the impact of spaceflight on the mouse brain in female mice. Our comparative analysis between ground control and spaceflight-exposed animals revealed significant alterations in essential brain processes including neurogenesis, synaptogenesis and synaptic transmission, particularly affecting the cortex, hippocampus, striatum and neuroendocrine structures.

Molecular mechanisms linking missense ACTG2 mutations to visceral myopathy.

Visceral myopathy is a life-threatening disease characterized by muscle weakness in the bowel, bladder, and uterus. Mutations in smooth muscle γ-actin (ACTG2) are the most common cause of the disease, but the mechanisms by which the mutations alter muscle function are unknown. Here, we examined four prevalent ACTG2 mutations (R40C, R148C, R178C, and R257C) that cause different disease severity and are spread throughout the actin fold.

Developmental and behavioral phenotypes of pediatric patients with PTEN hamartoma tumor syndrome.

Our study characterized the neurodevelopmental spectrum of individuals with PTEN Hamartoma Tumor Syndrome (PHTS), a syndrome that predisposes to both neurodevelopmental phenotypes and cancer risk. We aim to better understand life-impacting neurodevelopmental features of PHTS. Our study recruited 20 children/adolescents with PHTS, who were then administered assessments for autism spectrum disorder (ASD) and other neurocognitive measures, including assessment of IQ, executive and adaptive functioning, and health-related quality of life.

A Matched-Pair Analysis of Gross Motor Skills of 3- to 5-Year-Old Children With and Without a Chronic Physical Illness.

Purpose: The purpose of this study was to compare the gross motor skills of children with a chronic physical illness with those of their healthy peers.

Methods: Data for children with a chronic physical illness come from the Multimorbidity in Children and Youth Across the Life Course study, and data from children without a physical illness come from the Health Outcomes and Physical Activity in Preschoolers study. Multimorbidity in Children and Youth Across the Life Course and Health Outcomes and Physical Activity in Preschoolers included children ages 3-5 years and administered the Peabody Development Motor Scales-second edition.

Sequencing Reveals miRNAs Enriched in the Developing Mouse Enteric Nervous System.

The enteric nervous system (ENS) is an essential network of neurons and glia in the bowel wall. Defects in ENS development can result in Hirschsprung disease (HSCR), a life-threatening condition characterized by severe constipation, abdominal distention, bilious vomiting, and failure to thrive. A growing body of literature connects HSCR to alterations in miRNA expression, but there are limited data on the normal miRNA landscape in the developing ENS.

Alarm burden and the nursing care environment: a 213-hospital cross-sectional study.

Background: High rates of medical device alarms in hospitals are a well-documented threat to patient safety. Little is known about organisational features that may be associated with nurses' experience of alarm burden.

Aims: To evaluate the association between nurse-reported alarm burden, appraisals of patient safety, quality of care and hospital characteristics.

Back To Basics: Theory of Thrombus Formation and Potential Implications for Therapies?

Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common and potentially fatal condition. Despite existing treatments, recurrence rates and complications remain high. Understanding the pathophysiology of thrombus formation is crucial for developing effective therapies.

Loss of Baz1b in mice causes perinatal lethality, growth failure, and variable multi-system outcomes.

BAZ1B is one of 25-27 coding genes deleted in canonical Williams syndrome, a multi-system disorder causing slow growth, vascular stenosis, and gastrointestinal complaints, including constipation. BAZ1B is involved in (among other processes) chromatin organization, DNA damage repair, and mitosis, suggesting reduced BAZ1B may contribute to Williams syndrome symptoms. In mice, loss of Baz1b causes early neonatal death.

Multi-disciplinary Insights from the First European Forum on Visceral Myopathy 2022 Meeting.

Visceral myopathy is a rare, life-threatening disease linked to identified genetic mutations in 60% of cases. Mostly due to the dearth of knowledge regarding its pathogenesis, effective treatments are lacking. The disease is most commonly diagnosed in children with recurrent or persistent disabling episodes of functional intestinal obstruction, which can be life threatening, often requiring long-term parenteral or specialized enteral nutritional support.

Generation of CHOPe003-A ESC line to study an ACTG2 variant affecting smooth muscle development and function.

Dysfunction of visceral smooth muscle ("visceral myopathy") impairs bowel, bladder, and uterine function. Symptoms of this life-threatening condition include massive intestinal distension with slow transit, vomiting, feeding intolerance, growth failure, poor bladder emptying, and difficult vaginal delivery. The most common genetic cause of visceral myopathy is a heterozygous point mutation (R257C) in gamma smooth muscle actin (ACTG2).

Generation of CHOPi012-A iPSC line from a patient with visceral myopathy-related chronic intestinal pseudo-obstruction.

Visceral myopathies are debilitating conditions characterized by dysfunction of smooth muscle in visceral organs (bowel, bladder, and uterus). Individuals affected by visceral myopathy experience feeding difficulties, growth failure, life-threatening abdominal distension, and may depend on intravenous nutrition for survival. Unfortunately, our limited understanding of the pathophysiology of visceral myopathies means that current therapies remain supportive, with no mechanism-based treatments.

Oxidative stress induces lysosomal membrane permeabilization and ceramide accumulation in retinal pigment epithelial cells.

Oxidative stress has been implicated in the pathogenesis of age-related macular degeneration, the leading cause of blindness in older adults, with retinal pigment epithelium (RPE) cells playing a key role. To better understand the cytotoxic mechanisms underlying oxidative stress, we used cell culture and mouse models of iron overload, as iron can catalyze reactive oxygen species formation in the RPE. Iron-loading of cultured induced pluripotent stem cell-derived RPE cells increased lysosomal abundance, impaired proteolysis and reduced the activity of a subset of lysosomal enzymes, including lysosomal acid lipase (LIPA) and acid sphingomyelinase (SMPD1).

Single-cell RNA-sequencing of stria vascularis cells in the adult Slc26a4 mouse.

Background: The primary pathological alterations of Pendred syndrome are endolymphatic pH acidification and luminal enlargement of the inner ear. However, the molecular contributions of specific cell types remain poorly characterized. Therefore, we aimed to identify pH regulators in pendrin-expressing cells that may contribute to the homeostasis of endolymph pH and define the cellular pathogenic mechanisms that contribute to the dysregulation of cochlear endolymph pH in Slc26a4 mice.

Single Nucleus Sequencing of Human Colon Myenteric Plexus-Associated Visceral Smooth Muscle Cells, Platelet Derived Growth Factor Receptor Alpha Cells, and Interstitial Cells of Cajal.

Background And Aims: Smooth muscle cells (SMCs), interstitial cells of Cajal (ICCs), and platelet-derived growth factor receptor alpha (PDGFR+) cells (PCs) form a functional syncytium in the bowel known as the "SIP syncytium." The SIP syncytium works in concert with the enteric nervous system (ENS) to coordinate bowel motility. However, our understanding of individual cell types that form this syncytium and how they interact with each other remains limited, with no prior single-cell RNAseq analyses focused on human SIP syncytium cells.

Ridge Regression for Functional Form Identification of Continuous Predictors of Clinical Outcomes in Glomerular Disease.

Introduction: Penalized regression models can be used to identify and rank risk factors for poor quality of life or other outcomes. They often assume linear covariate associations, but the true associations may be nonlinear. There is no standard, automated method for determining optimal functional forms (shapes of relationships) between predictors and the outcome in high-dimensional data settings.

Dopamine, Immunity, and Disease.

The neurotransmitter dopamine is a key factor in central nervous system (CNS) function, regulating many processes including reward, movement, and cognition. Dopamine also regulates critical functions in peripheral organs, such as blood pressure, renal activity, and intestinal motility. Beyond these functions, a growing body of evidence indicates that dopamine is an important immunoregulatory factor.

Machine intelligence for radiation science: summary of the Radiation Research Society 67th annual meeting symposium.

The era of high-throughput techniques created big data in the medical field and research disciplines. Machine intelligence (MI) approaches can overcome critical limitations on how those large-scale data sets are processed, analyzed, and interpreted. The 67 Annual Meeting of the Radiation Research Society featured a symposium on MI approaches to highlight recent advancements in the radiation sciences and their clinical applications.

Mutation-agnostic RNA interference with engineered replacement rescues -related hearing loss.

Hearing loss is the most common sensory deficit, of which genetic etiologies are a frequent cause. Dominant and recessive mutations in , a gene encoding the pore-forming subunit of the hair cell mechanotransduction channel, cause DFNA36 and DFNB7/11, respectively, accounting for ∼2% of genetic hearing loss. Previous work has established the efficacy of mutation-targeted RNAi in treatment of murine models of autosomal dominant non-syndromic deafness.

A noradrenergic-hypothalamic neural substrate for stress-induced sleep disturbances.

In our daily life, we are exposed to uncontrollable and stressful events that disrupt our sleep. However, the underlying neural mechanisms deteriorating the quality of non-rapid eye movement sleep (NREMs) and REM sleep are largely unknown. Here, we show in mice that acute psychosocial stress disrupts sleep by increasing brief arousals (microarousals [MAs]), reducing sleep spindles, and impairing infraslow oscillations in the spindle band of the electroencephalogram during NREMs, while reducing REMs.

A solution to the long-standing problem of actin expression and purification.

Actin is the most abundant protein in the cytoplasm of eukaryotic cells and interacts with hundreds of proteins to perform essential functions, including cell motility and cytokinesis. Numerous diseases are caused by mutations in actin, but studying the biochemistry of actin mutants is difficult without a reliable method to obtain recombinant actin. Moreover, biochemical studies have typically used tissue-purified α-actin, whereas humans express six isoforms that are nearly identical but perform specialized functions and are difficult to obtain in isolation from natural sources.