545298 research outputs found
Sort by
Lack of maternal exposure to somatostatin leads to diet-induced insulin and leptin resistance in mouse male offspring.
Full text linkSomatostatin (Sst) is an inhibitory regulator of many hormones. The prenatal environment impacts an offsprings risk to type 2 diabetes in adulthood. However, the effect of maternal Sst deficiency on glucose and insulin metabolism in offspring and metabolic disease risk in their adult life has been poorly understood. The study was to investigate the impact of a lack of maternal Sst exposure in mouse male and female offspring on diet-induced changes in glucose metabolism and adiposity. Sst knockout offspring, SstKO born to the Sst-heterozygous dams or SstKO-MSD born to the Sst-homozygous dams were fed either a regular diet (CD) or a high-fat diet (HFD) at 3-week-old for 15 weeks. Body weight and blood glucose levels were monitored. Glucose and insulin tolerance tests were performed. Plasma hormone levels and gene expression in the hypothalamus were investigated. The results demonstrated that only male SstKO-MSD offspring developed obesity accompanied by severe insulin and leptin resistance after HFD challenge. Insulin secretion was reduced in both basal and oral glucose-challenged conditions in the CD-fed male SstKO-MSD mice. A reduced ratio of islet area to pancreas area was noted in SstKO-MSD mice in both sexes. Plasma levels of glucagon, Glp1 and Pyy were elevated in both male and female SstKO and SstKO-MSD mice. mRNA expression of leptin receptor, FoxO1, Npy and Agrp was downregulated in male SstKO-MSD mice. These results demonstrate that a lack of fetal somatostatin exposure impairs the islet development in offspring and increases risk of obesity, insulin resistance and leptin resistance later in life
The Systemic Inflammatory Response Syndrome and Predictors of Infection and Mortality in 1068 Critically Ill Newborn Foals.
Full text linkBACKGROUND: Sepsis has been defined in humans as the concurrent proven or suspected presence of microbial infection and the systemic inflammatory response syndrome (SIRS). Sepsis is the leading cause of morbidity and mortality in neonatal foals. The clinical utility of using SIRS or its individual components to predict infection and mortality in critically ill foals is currently unknown. OBJECTIVES: Assess the ability of history and signalment, clinical findings, laboratory results, and SIRS-related indices to predict infection and mortality in critically ill foals. ANIMALS: Retrospective, multi-center, cross-sectional study using a convenience sample of 1068 critically ill foals < 3 days of age admitted to 16 veterinary referral hospitals in 4 countries. METHODS: Data were retrieved from medical records. Infection was defined as the presence of bacteremia (positive blood culture) or clinical identification of an infected focus on admission. Univariate non-parametric and categorical methods, multivariate logistic regression, and classification tree methods were used for statistical analysis. RESULTS: Foal age at admission and presence of toxic neutrophils were independent predictors of infection, whereas SIRS-related indices were not predictive of infection. In-hospital mortality was 24%. Independent predictors for mortality were hypokinetic pulses, cold extremities, presence of seizures, blood L-lactate concentration > 6.0 mmol/L, and increased serum potassium and total bilirubin concentrations. CONCLUSIONS AND CLINICAL IMPORTANCE: The presence of infection in critically ill newborn foals was not predicted by SIRS indices. Cardiovascular dysfunction was strongly associated with mortality, suggesting that maintaining adequate perfusion and pulse pressure should be important treatment goals
Investigation of the Blood Microbiome in Horses With Fever of Unknown Origin.
Full text linkBACKGROUND: Fever of unknown origin (FUO) without a respiratory component is a frequent clinical presentation in horses. Multiple pathogens, both tick-borne and enteric, can be involved as etiologic agents. An additional potential mechanism is intestinal barrier dysfunction. OBJECTIVES: This case-control study aimed to detect and associate microbial taxa in blood with disease state. STUDY DESIGN: Areas known for a high prevalence of tick-borne diseases in humans were chosen to survey horses with FUO, which was defined as fever of 101.5°F or higher with no signs of respiratory illness or other recognisable diseases. Blood samples and clinical parameters were obtained from 52 FUO cases and also from matched controls from the same farms. An additional 23 febrile horses without matched controls were included. METHODS: Broadly targeted polymerase chain reaction (PCR) amplification directed at conserved sequence regions of bacterial 16S rRNA, parasite 18S rRNA, coronavirus RdRp and parvovirus NS1 was performed, followed by deep sequencing. To control for contamination and identify taxa unique to the cases, metagenomic sequences from the controls were subtracted from those of the cases, and additional targeted molecular testing was performed. Sera were also tested for antibodies to equine coronavirus. RESULTS: Over 60% of cases had intestinal microbial DNA circulating in the blood. Nineteen percent of cases were attributed to infection with Anaplasma phagocytophilum, of which two were subtyped as human-associated strains. A novel Erythroparvovirus was detected in two cases and two controls. Serum titres for equine coronavirus were elevated in some cases but not statistically different overall between the cases and controls. MAIN LIMITATIONS: Not all pathogens are expected to circulate in blood, which was the sole focus of this study. CONCLUSIONS: The presence of commensal gut microbes in blood of equine FUO cases is consistent with a compromised intestinal barrier, which is highlighted as a direction for future study
Small-diameter artery grafts engineered from pluripotent stem cells maintain 100% patency in an allogeneic rhesus macaque model.
Full text linkAutologous vascular grafts, the only clinically approved option for small-diameter (<6 mm) revascularizations, require invasive harvesting and have limited availability and variable quality. To address these challenges, we develop a 3-mm-diameter artery graft by using arterial endothelial cells (AECs) derived from pluripotent stem cells (PSCs). After establishing technologies for pure AEC generation and expanded polytetrafluoroethylene (ePTFE) graft coating, we engineer artery grafts by seeding the inner lumen of ePTFE vascular grafts with either major histocompatibility complex (MHC) mismatched unmodified-wild-type (MHC-WT) AECs or MHC class I/II double knockout (MHC-DKO) AECs. Their function is evaluated in a rhesus arterial interposition grafting model. MHC-WT grafts maintained 100% patency for 6 months, significantly better than naked and MHC-DKO grafts. Additionally, the endothelium of MHC-WT grafts is repopulated with host cells, supporting long-term patency. Collectively, our study demonstrates that PSC-derived MHC-WT artery grafts provide an unlimited homogenous resource for allogeneic arterial revascularization
A Small-Molecule TrkB/TrkC Ligand Promotes Neurogenesis and Behavioral Recovery Following Traumatic Brain Injury.
Full text linkTropomyosin receptor-kinase B (TrkB) and TrkC neurotrophin receptors promote neuronal growth and differentiation during the development and maintenance of structural integrity and plasticity in adult animals. Here, we test the hypotheses that activation of TrkB and TrkC will mitigate neuronal damage and loss, and behavioral deficits induced by traumatic brain injury (TBI). LM22B-10 (C10), a blood-brain barrier permeant small-molecule TrkB/TrkC co-activator, significantly increased proliferation, survival, and enhanced differentiation of neuronal progenitor cells in vitro. Following controlled cortical impact injury in rats, LM22B-10 administration increased the proliferation of doublecortin-expressing (DCX) cells in the hippocampus and significantly reduced cell death in the injured cortex. Interestingly, in studies of behavior, LM22B-10 promoted anxiety-like behavior and diminished spatial memory performance in the Barnes maze in sham-TBI animals but improved both of these behaviors in injured rats, a bimodal response suggesting the possibility that excess neurotrophic activity may be detrimental in uninjured animals but compensatory after injury. Thus, TrkB/TrkC agents may constitute a new therapeutic avenue for TBI but will require further study to determine safe and effective applications
Rare bilateral anatomical variation of the lateral thoracic artery: duplicated arteries with unique origins and pathways.
Full text linkThe lateral thoracic artery (LTA) is one of six main branches that originate from the axillary artery. The LTA has a textbook origin from the 2nd part of the axillary artery posterior to the pectoralis minor muscle. Contrary to the textbook origin, there are numerous reports of LTA variants that originate from the thoracoacromial artery, subscapular artery, and thoracodorsal artery, or even its duplication. This case report involves description of an additional unique duplicate variant of the LTA, bilaterally. The right duplicate LTA has its origin from the 3rd part of the axillary artery and then courses with the axillary sheath before coursing towards the breast. The right duplicate LTA variant also gives off two small subcutaneous branches in the medial upper arm. The left duplicate LTA has its origin from the brachial artery and courses directly to the breast through the axilla. Additional detail on the variants of the LTA could prove useful in surgical procedures that involve the lateral thorax, chest, and axilla and contribute to broader anatomical knowledge
Antioxidant-independent activities of alpha-tocopherol.
Full text linkAlpha-tocopherol (vitamin E) is a plant-derived dietary lipid that is essential for the health of most animals, including humans. Originally discovered as a fertility factor in rodents, the primary health-promoting properties of the vitamin in humans was shown to be protection of neuromuscular functions. Heritable vitamin E deficiency manifests in spinocerebellar ataxia that can be stabilized by timely supplementation with high-dose α-tocopherol. The molecular basis for α-tocopherols biological activities has been attributed primarily to the vitamins efficacy in preventing lipid peroxidation in membranes and lipoproteins, but the possibility that the vitamin possesses additional biological activities has been postulated and debated in the literature without conclusive resolution. We designed and synthesized a novel analog of α-tocopherol, 6-hydroxymethyl α-tocopherol (6-HMTC), which retains most of the vitamins structural, physical, and biochemical properties, yet lacks measurable radical-trapping antioxidant activity. 6-HMTC bound to the tocopherol transfer protein with high (nanomolar) affinity, like that of the natural vitamin, attesting to the analogs preservation of structural integrity. Yet, 6-HMTC did not inhibit lipid peroxidation or associated ferroptotic cell death. Notably, 6-HMTC modulated the expression of some genes in a manner essentially identical to that exhibited by α-tocopherol. These findings support the notion that α-tocopherol modulates gene expression via an antioxidant-independent mechanism
Functional Connectivity Analysis in Magnetic Resonance Imaging of Chronic Pain
Full text linkChronic pain disorders are among the top causes of global disability, presenting unique therapeutic challenges due to their complex pathophysiology and inherently subjective nature. Recent advances in non-invasive imaging, particularly magnetic resonance imaging (MRI), offer unprecedented opportunities to investigate the mechanisms underlying chronic pain conditions. This dissertation advances our understanding through three interconnected studies employing functional connectivity approaches: First, we develop a novel graph- theoretical model that predicts brain functional connectivity patterns from white matter structural architecture, providing insights into both healthy and diseased brain function. Second, using cross-decomposition analysis, we reveal previously uncharacterized relationships between distributed somatosensory patterns extracted from body map data and resting-state functional brain networks in chronic lower back pain patients. Finally, we extend functional connectivity principles to the knee, identifying distinct patterns of cartilage thickness change over 8 years that correlate with osteoarthritis progression and risk factors. Together, these works demonstrate the utility of connectivity-based approaches in understanding chronic pain across multiple biological scales
Reducing batch effects in single cell chromatin accessibility measurements by pooled transposition with MULTI-ATAC
Full text linkLarge-scale scATAC-seq experiments are challenging because of their costs, lengthy protocols, and confounding batch effects. Several sample multiplexing technologies aim to address these challenges, but do not remove batch effects introduced when performing transposition reactions in parallel. We demonstrate that sample-to-sample variability in nuclei-to-Tn5 ratios is a major cause of batch effects and develop MULTI-ATAC, a multiplexing method that pools samples prior to transposition, as a solution. MULTI-ATAC provides high accuracy in sample classification and doublet detection while eliminating batch effects associated with variable nucleus-to-Tn5 ratio. We illustrate the power of MULTI-ATAC by performing a 96-plex multiomic drug assay targeting epigenetic remodelers in a model of primary immune cell activation, uncovering tens of thousands of drug-responsive chromatin regions, cell-type specific effects, and potent differences between matched inhibitors and degraders. MULTI-ATAC therefore enables batch-free and scalable scATAC-seq workflows, providing deeper insights into complex biological processes and potential therapeutic targets
Functional Characterization of CSMD1, LRP1B, and the INK4/ARF Locus in Head and Neck Squamous Cell Carcinoma
Full text linkHead and neck squamous cell carcinoma (HNSCC) affects approximately 890,000 patients worldwide each year, primarily as a result of tobacco and alcohol use or infection with high-risk strains of human papillomavirus (HPV). Despite current therapeutic strategies including surgery, radiation, chemotherapy, immunotherapy, and targeted therapy, the mortality rate remains at approximately 50%. HNSCC tumors exhibit significant genetic heterogeneity, characterized by a high frequency of point mutations and somatic copy number alterations (CNAs). While numerous genomic loci affected by CNAs have been identified, their mechanistic contributions to tumorigenesis remain incompletely understood. Early and frequent genetic alterations in HNSCC include the loss of tumor suppressors within the INK4/ARF locus (9p21.3), particularly CDKN2A, in conjunction with TP53 mutations. The INK4/ARF locus contains several genetic elements, with point mutations predominantly targeting p16. However, about one-third of patient tumors exhibit homozygous deletions of the entire region, representing an additional mode of inactivation. In addition to INK4/ARF loss, two of the most commonly deleted loci in HNSCC involve CSMD1 (8p23.2) and LRP1B (2q22.1). Although these genes have been implicated as tumor suppressors in other cancers, their role in HNSCC is unclear. One of the major challenges in studying large-scale chromosomal deletions has been the difficulty of recreating them in an appropriate model system. Here, I describe two different approaches for generating large deletions (~1.7 kb – 1.2 Mb) in primary human keratinocytes using CRISPR/Cas9 via transfection and electroporation. These approaches enabled creating targeted deletions within CSMD1 and LRP1B, as well as performing a functional dissection of the INK4/ARF locus to evaluate the roles of its genetic elements and various gene inactivation mechanisms.
My results indicated that CSMD1 and LRP1B deletions were passenger events in the contexts examined, with no clear evidence supporting a pathogenic role in HNSCC tumorigenesis. I propose that alterations in these genes are more likely to represent common fragile sites. Furthermore, analysis of the INK4/ARF locus indicated that p16 was the essential tumor suppressor within this region, with point mutations and deletions exhibiting comparable biological outcomes. Additionally, there was no evidence that other genetic elements within the locus such as the regulatory domain (RD) element, p15, or p14 contribute to HNSCC tumorigenesis. These results have implications for future disease modeling as well as targeting the most critical pathways for therapeutic approaches