Sonnelambert7840

Several pathological manifestations in coronavirus disease 2019 (COVID-19), including thick mucus, poor mucociliary clearance, and bronchial wall thickening, overlap with cystic fibrosis disease patterns and may be indicative of "acquired" cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction. Indeed, tumor necrosis factor (TNF), a key cytokine driving COVID-19 pathogenesis, downregulates lung CFTR protein expression, providing a strong rationale that acquired CFTR dysfunction arises in the context of COVID-19 infection. In this perspective, we propose that CFTR therapeutics, which are safe and generally well-tolerated, may provide benefit to COVID-19 patients. Although CFTR therapeutics are currently only approved for treating cystic fibrosis, there are efforts to repurpose them for conditions with "acquired" CFTR dysfunction, for example, chronic obstructive pulmonary disease. In addition to targeting the primary lung pathology, CFTR therapeutics may possess value-added effects their anti-inflammatory properties may dampen exaggerated immune cell responses and promote cerebrovascular dilation; the latter aspect may offer some protection against COVID-19 related stroke.Here we present a model capable of self-healing and explore its ability to resolve pathological alterations in biological tissue. We derive a simple analytic model consisting of an agent representing a cell that exhibits anabolic or catabolic activity, and which interacts with its tissue substrate according to tissue stiffness. When perturbed, this system returns toward a stable fixed point, a process corresponding to self-healing. We implemented this agent-substrate mechanism numerically on a hexagonal elastic network representing biological tissue. Agents, representing fibroblasts, were placed on the network and allowed to migrate around while they remodeled the network elements according to their activity which was determined by the stiffnesses of network elements that each agent encountered during its random walk. Initial injury to the network was simulated by increasing the stiffness of a single central network element above baseline. This system also exhibits a fixed point represented by the uniform baseline state. During the approach to the fixed point, interactions between the agents and the network create a transient spatially extended halo of stiffer network elements around the site of initial injury, which aids in overall injury repair. Non-equilibrium constraints generated by persistent injury prohibit the network to return to baseline and results in progressive stiffening, mimicking the development of fibrosis. Additionally, reducing anabolic or catabolic rates delay self-healing, reminiscent of aging. Our model thus embodies what may be the simplest set of attributes required of a spatiotemporal self-healing system, and so may help understand altered self-healing in chronic fibrotic diseases and aging.Exposure to low ambient temperature imposes great challenge to human health. Epidemiological evidence has noted significantly elevated emergency admission and mortality rate in cold climate in many regions, in particular, adverse events in cardiovascular system. Cold stress is becoming one of the important risk factors for cardiovascular death. Through recent advance in echocardiography and myocardial histological techniques, both clinical and experimental experiments have unveiled that cold stress triggers a variety of pathological and pathophysiological injuries, including ventricular wall thickening, cardiac hypertrophy, elevated blood pressure, decreased cardiac function, and myocardial interstitial fibrosis. In order to examine the potential mechanism of action behind cold stress-induced cardiovascular anomalies, ample biochemical and molecular biological experiments have been conducted to denote a role for mitochondrial injury, intracellular Ca2+ dysregulation, generation of reactive oxygen species (ROS) and other superoxide, altered gene and protein profiles for apoptosis and autophagy, and increased adrenergic receptor sensitivity in cold stress-induced cardiovascular anomalies. These findings suggest that cold stress may damage the myocardium through mitochondrial injury, apoptosis, autophagy, metabolism, oxidative stress, and neuroendocrine pathways. Although the precise nature remains elusive for cold stress-induced cardiovascular dysfunction, endothelin (ET-A) receptor, endoplasmic reticulum (ER) stress, transient receptor potential vanilloid, mitochondrial-related protein including NRFs and UCP-2, ROS, Nrf2-Keap1 signaling pathway, Bcl-2/Bax, and lipoprotein lipase (LPL) signaling may all play a pivotal role. For myocardial injury evoked by cold stress, more comprehensive and in-depth mechanisms are warranted to better define the potential therapeutic options for cold stress-associated cardiovascular diseases.Increased wave reflection is an independent predictor of cardiovascular events, possibly due to effects on left ventricular (LV) function. We investigated the relationship between reflected waves in early systole, the forward decompression wave in mid-late systole and LV mechanical behavior. Invasively acquired ascending aortic velocity, pressure, and LV long and minor axes' dimensions were measured simultaneously in 11 anesthetized dogs during both control conditions and aortic occlusion to cause additional early wave reflection. Wave intensity analysis (WIA) was used to identify the arrival of the reflected wave and the onset of a forward decompression wave in mid-late systole. The arrival time of the reflected wave coincided with the time when minor axis shortening began to decline from its peak, even during aortic occlusion when this time is 12 ms earlier. The initial decline in long axis shortening corresponded to the time of the peak of the reflected wave. The forward decompression wave was consistently observed to have a slow and then rapid phase. The slow phase onset coincided with time of maximum shortening velocity of the long axis. The onset of the later larger rapid phase consistently coincided with an increased rate of deceleration of both axes during late systole. Forward decompression waves are generated by the LV when the long axis shortening velocity falls. Reflected wave arrival has a detrimental effect on LV function, particularly the minor axis. These observations lend support to suggestions that therapies directed toward reducing wave reflection may be of value in hypertension and cardiovascular disease.The clinical significance of diabetes arising in the setting of pancreatic disease (also known as diabetes of the exocrine pancreas, DEP) has drawn more attention in recent years. However, significant improvements still need to be made in the recognition, diagnosis and treatment of the disorder, and in the knowledge of the pathological mechanisms. The clinical course of DEP is different from type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). DEP develops in patients with previous existing exocrine pancreatic disorders which damage both exocrine and endocrine parts of pancreas, and lead to pancreas exocrine insufficiency (PEI) and malnutrition. Therefore, damage in various exocrine and endocrine cell types participating in glucose metabolism regulation likely contribute to the development of DEP. Due to the limited amount of clinical and experimental studies, the pathological mechanism of DEP is poorly defined. In fact, it still not entirely clear whether DEP represents a distinct pathologic entity or is a form of T2DM arising when β cell failure is accelerated by pancreatic disease. In this review, we include findings from related studies in T1DM and T2DM to highlight potential pathological mechanisms involved in initiation and progression of DEP, and to provide directions for future research studies.Chronic kidney disease is a major global health problem, as it affects 10% of the global population and kills millions of patients every year. It is therefore of the utmost importance to develop models that can help us to understand the pathogenesis of CKD and improve our therapeutic strategies. The discovery of human induced pluripotent stem cells (hiPSCs) and, more recently, the development of methods for the generation of 3D organoids, have opened the way for modeling human kidney development and disease in vitro, and testing new drugs directly on human tissue. In this review we will discuss the most recent advances in the field of kidney organoids for modeling disease, as well as the prospective applications of these models for drug screening. We will also emphasize the impact of CRISPR/cas9 genome engineering on the field, point out the current limitations of the existing organoid technologies, and discuss a set of technical developments that may help to overcome limitations and facilitate the incorporation of these exciting tools into basic biomedical research.Inhibition of myostatin- and activin-mediated SMAD2/3 signaling using ligand traps, such as soluble receptors, ligand-targeting propeptides and antibodies, or follistatin can increase skeletal muscle mass in healthy mice and ameliorate wasting in models of cancer cachexia and muscular dystrophy. selleck chemical However, clinical translation of these extracellular approaches targeting myostatin and activin has been hindered by the challenges of achieving efficacy without potential effects in other tissues. Toward the goal of developing tissue-specific myostatin/activin interventions, we explored the ability of transmembrane prostate androgen-induced (TMEPAI), an inhibitor of transforming growth factor-β (TGF-β1)-mediated SMAD2/3 signaling, to promote growth, and counter atrophy, in skeletal muscle. In this study, we show that TMEPAI can block activin A, activin B, myostatin and GDF-11 activity in vitro. To determine the physiological significance of TMEPAI, we employed Adeno-associated viral vector (AAV) delivery of a TMEPAI expression cassette to the muscles of healthy mice, which increased mass by as much as 30%, due to hypertrophy of muscle fibers. To demonstrate that TMEPAI mediates its effects via inhibition of the SMAD2/3 pathway, tibialis anterior (TA) muscles of mice were co-injected with AAV vectors expressing activin A and TMEPAI. In this setting, TMEPAI blocked skeletal muscle wasting driven by activin-induced phosphorylation of SMAD3. In a model of cancer cachexia associated with elevated circulating activin A, delivery of AAVTMEPAI into TA muscles of mice bearing C26 colon tumors ameliorated the muscle atrophy normally associated with cancer progression. Collectively, the findings indicate that muscle-directed TMEPAI gene delivery can inactivate the activin/myostatin-SMAD3 pathway to positively regulate muscle mass in healthy settings and models of disease.This study aims to investigate the embryo development potential of extending the culture of abnormally fertilized zygotes with no pronuclear (0PN), monopronuclear (1PN), and poor-quality day 3 embryos and to determine the associated clinical outcomes. This is a retrospective study performed between January 2014 and May 2018 at Jinhua People's Hospital. The normal developed embryos and the abnormal 0PN, 1PN, and poor-quality day 3 embryos were cultured to day 5 or 6 for embryo transfer. Clinical outcomes resulting from abnormal embryos and normally developed embryos were compared. A total of 6466 embryos (1542 0PN, 852 1PN, and 4072 poor-quality day 3 embryos) from 831 treatment cycles were cultured to the blastocyst stage. The total blastulation rate was 17.3% (1121/6466) with 18.2% in 0PN, 26.1% in 1PN, and 15.2% in poor-quality day 3 embryos. The rate for good-quality blastocyst formation was 9.5% (616/6466) with 11.2% in 0PN group, 14.8% in 1PN group, and 7.8% in poor-quality day 3 embryos, respectively. Blastulation rates of 0PN and 1PN derived from intracytoplasmic sperm injection (ICSI) were significantly lower compared with the in vitro fertilization group.