Dalsgaardshah7466

In the last decade, activation of GPER1 has been shown to be important for lordosis and social cognition in females. In this review we will focus on several mechanisms that may contribute to sexually dimorphic behaviors including the colocalization of these estrogen receptors in the SBN, interplay between the signaling pathways activated by these different estrogen receptors, and the role of these receptors in development and the maintenance of the SBN, all of which remain underexplored.The phenotypic trait of high bone mass (HBM) is an excellent example of the nexus between common and rare disease genetics. HBM may arise from carriage of many 'high bone mineral density [BMD]'-associated alleles, and certainly the genetic architecture of individuals with HBM is enriched with high BMD variants identified through genome-wide association studies of BMD. HBM may also arise as a monogenic skeletal disorder, due to abnormalities in bone formation, bone resorption, and/or bone turnover. Individuals with monogenic disorders of HBM usually, though not invariably, have other skeletal abnormalities (such as mandible enlargement) and thus are best regarded as having a skeletal dysplasia rather than just isolated high BMD. A binary etiological division of HBM into polygenic vs. monogenic, however, would be excessively simplistic the phenotype of individuals carrying rare variants of large effect can still be modified by their common variant polygenic background, and by the environment. HBM disorders-whether predominantly polygenic or monogenic in origin-are not only interesting clinically and genetically they provide insights into bone processes that can be exploited therapeutically, with benefits both for individuals with these rare bone disorders and importantly for the many people affected by the commonest bone disease worldwide-i.e., osteoporosis. In this review we detail the genetic architecture of HBM; we provide a conceptual framework for considering HBM in the clinical context; and we discuss monogenic and polygenic causes of HBM with particular emphasis on anabolic causes of HBM.The chylomicronemia syndrome is characterized by severe hypertriglyceridemia and fasting chylomicronemia and predisposes affected individuals to acute pancreatitis. When due to very rare monogenic mutations in the genes encoding the enzyme, lipoprotein lipase, or its regulators, APOC2, APOA5, GPIHBP1, and LMF1, it is referred to as the familial chylomicronemia syndrome. Much more frequently, the chylomicronemia syndrome results from a cluster of minor genetic variants causing polygenic hypertriglyceridemia, which is exacerbated by conditions or medications which increase triglyceride levels beyond the saturation point of triglyceride removal systems. This situation is termed the multifactorial chylomicronemia syndrome. These aggravating factors include common conditions such as uncontrolled diabetes, overweight and obesity, alcohol excess, chronic kidney disease and pregnancy and several medications, including diuretics, non-selective beta blockers, estrogenic compounds, corticosteroids, protease inhibitors, vels. Several new pharmacotherapeutic agents are being tested that are likely to considerably improve treatment of hypertriglyceridemia in people at risk.Non-alcoholic fatty liver disease (NAFLD) is a spectrum of disorders, ranging from fatty liver to a more insulin resistant, inflammatory and fibrotic state collectively termed non-alcoholic steatohepatitis (NASH). In the United States, 30%-40% of the adult population has fatty liver and 3%-12% has NASH, making it a major public health concern. Consumption of diets high in fat, obesity and Type II diabetes (T2D) are well-established risk factors; however, there is a growing body of literature suggesting a role for the gut microbiome in the development and progression of NAFLD. The gut microbiota is separated from the body by a monolayer of intestinal epithelial cells (IECs) that line the small intestine and colon. The IEC layer is exposed to luminal contents, participates in selective uptake of nutrients and acts as a barrier to passive paracellular permeability of luminal contents through the expression of tight junctions (TJs) between adjacent IECs. A dysbiotic gut microbiome also leads to decreased gut barrier function by disrupting TJs and the gut vascular barrier (GVB), thus exposing the liver to microbial endotoxins. These endotoxins activate hepatic Toll-like receptors (TLRs), further promoting the progression of fatty liver to a more inflammatory and fibrotic NASH phenotype. This review will summarize major findings pertaining to aforementioned gut-liver interactions and its role in the pathophysiology of NAFLD.Subclinical hypothyroidism is a biochemical condition defined by elevated serum thyroid-stimulating hormone levels in the setting of normal levels of the peripheral thyroid hormones, thyroxine and triiodothyronine. Thyroid hormones act on the heart through various mechanisms and subclinical hypothyroidism has been associated with risk factors for cardiovascular disease, such as hypertension and dyslipidemia. MDL-28170 In addition, evidence from multiple studies supports an association between subclinical hypothyroidism and cardiovascular disease. However, the use of levothyroxine in subclinical hypothyroidism to reduce cardiovascular disease risk is not clearly beneficial. Treatment with levothyroxine may only provide benefit in certain subgroups, such as patients who are younger or at higher risk of cardiovascular disease. At present, most of the international societal guidelines advise that treatment decisions should be individualized based on patient age, degree of serum thyroid-stimulating hormone (TSH) elevation, symptoms, cardiovascular disease (CVD) risk, and other co-morbidities. Further study in this area is recommended.Increasing exercise capacity promotes healthy aging and is strongly associated with lower mortality rates. In this study, we analyzed skeletal muscle transcriptomics coupled to exercise performance in humans and rats to dissect the inherent and response components of aerobic exercise capacity. Using rat models selected for intrinsic and acquired aerobic capacity, we determined that the high aerobic capacity muscle transcriptome is associated with pathways for tissue oxygenation and vascularization. Conversely, the low capacity muscle transcriptome indicated immune response and metabolic dysfunction. Low response to training was associated with an inflammatory signature and revealed a potential link to circadian rhythm. Next, we applied bioinformatics tools to predict potential secreted factors (myokines). The predicted secretome profile for exercise capacity highlighted circulatory factors involved in lipid metabolism and the exercise response secretome was associated with extracellular matrix remodelling. Lastly, we utilized human muscle mitochondrial respiration and transcriptomics data to explore molecular mediators of exercise capacity and response across species.