Refsgaardvelez1863

Deep and voluminous skin wounds are repaired with scars, by mobilization of fibroblasts and extracellular matrix from fascia, deep below the skin. The molecular trigger of this novel repair mechanism is incompletely understood. Eribulin Here we reveal that the gap junction alpha-1 protein (Connexin43, Cx43) is the key to patch repair of deep wounds. By combining full-thickness wound models with fibroblast lineage specific transgenic lines, we show Cx43 expression is substantially upregulated in specialized fibroblasts of the fascia deep beneath the skin that are responsible for scar formation. Using live imaging of fascia fibroblasts and fate tracing of the fascia extracellular matrix we show that Cx43 inhibition disrupts calcium oscillations in cultured fibroblasts and that this inhibits collective migration of fascia EPFs necessary to mobilize fascia matrix into open wounds. Cell-cell communication through Cx43 thus mediates matrix movement and scar formation, and is necessary for patch repair of voluminous wounds. These mechanistic findings have broad clinical implications toward treating fibrosis, aggravated scarring and impaired wound healing.

The effect of community-level factors on surgical outcomes has not been well examined. We sought to characterize differences in "textbook outcomes" (TO) relative to social vulnerability among Medicare beneficiaries who underwent operations for cancer.

Individuals who underwent operations for lung, esophageal, colon, or rectal cancer between 2013 and 2017 were identified using the Medicare database, which was merged with the CDC's Social Vulnerability Index (SVI). TO was defined as surgical episodes with the absence of complications, extended length of stay, readmission, and mortality. The association of SVI and TO was assessed using mixed-effects logistic regression.

Among 203,800 patients (colon, n= 113,929; lung, n= 70,642; rectal, n= 14,849; and esophageal, n= 4,380), median age was 75 years (interquartile range 70 to 80 years) and the overwhelming majority of patients was White (n= 184,989 [90.8%]). The overall incidence of TO was 56.1% (n= 114,393). The incidence of complications (low SVI 21.5% vs roughly one-half of Medicare beneficiaries achieved the composite optimal TO quality metric. Social vulnerability was associated with lower attainment of TO and an increased risk of adverse postoperative surgical outcomes after several common oncologic procedures. The effect of high SVI was most pronounced among minority patients.Nutraceutical polyphenol catechins in green tea oxidize H2S to polysulfides (PS) in buffer and in cells thereby conveying their cytoprotective effects. Here we measure H2S oxidation in buffer and HEK293 cells by over-the-counter nutraceuticals, blueberry, bilberry and cranberry, and by polyphenols, cyanadin (Cya), quercetin (Que), rosmarinic acid (RA) and resveratrol (Res). H2S and PS were measured with specific fluorophores, AzMc and SSP4 respectively, and thiosulfate (TS) production was measured in buffer using silver nanoparticles (AgNPs). All compounds increased polysulfide production from H2S in buffer and increased polysufides in cells. Decreasing oxygen from 100% to 21% and 0% progressively decreased PS production by Que and RA in buffer and Que decreased PS production in cells incubated in 5% O2 compared to 21% O2. Que, RA and Res, but not Cya, increased TS production from H2S in 21% O2 but not in 0% O2. Superoxide dismutase did not affect PS production from H2S by Que or TS production from H2S by Que, RA or Res, whereas catalase inhibited TS production by all three polyphenols. Conversely, these polyphenols only slightly reduce a mixed polysulfide (K2Sn) or thiosulfate to H2S in 0% O2. Collectively, our results suggest that polyphenols are autoxidized to a semiquinone radical and that this, in turn, oxidizes H2S to a thiyl radical from which polysulfides and thiosulfate derived. They also suggest that this is catalyzed by a semiquinone radical and it is independent of either superoxide or hydrogen peroxide concomitantly produced during polyphenol autoxidation. The polysulfides produced in these reactions are potent antioxidants and also initiate a variety of downstream cytoprotective effector mechanisms. It is also possible that H2S can be regenerated from the thiosulfate produced in these reactions by other cellular reductants and reused in subsequent reactions.Mediated by chaperon proteins, protein misfolding plays a crucial role in cancer pathogenesis. Chaperonin Containing TCP1 Subunit 3 (CCT3) is one of eight subunits forming eukaryotic chaperons that catalyzes correct folding of the proteins employed in cell division, proliferation, and apoptosis pathway. Moreover, CCT3 expression increases responsively with carcinogenesis. However, how CCT3 drives the cancerous process has not been documented. Here we probed the mechanistic and functional interactions between CCT3 and apoptotic pathways and cell stressors. First, we profiled CCT3 expression levels of different 16 cell lines and found that CCT3 expression levels of CRL-2329 and PC3 were significantly increased. Then, we suppressed CCT3 levels in CRL-2329 and PC3 lines by miR-24-3p, miR-128-3p, and miR-149-5p mimics, and measured apoptotic response of the cell lines to the knockdown of CCT3 by acridine orange/ethidium bromide and Annexin V/PI staining, cell-cycle and mitochondria membrane potential (MMP) analyse therapeutic strategy" through conventional cellular toxicity as well as energy withdrawal.'Artificial Intelligence' (AI) has recently had a profound impact on areas such as image and speech recognition, and this progress has already translated into practical applications. However, in the drug discovery field, such advances remains scarce, and one of the reasons is intrinsic to the data used. In this review, we discuss aspects of, and differences in, data from different domains, namely the image, speech, chemical, and biological domains, the amounts of data available, and how relevant they are to drug discovery. Improvements in the future are needed with respect to our understanding of biological systems, and the subsequent generation of practically relevant data in sufficient quantities, to truly advance the field of AI in drug discovery, to enable the discovery of novel chemistry, with novel modes of action, which shows desirable efficacy and safety in the clinic.An explosion of data has provided detailed information about organisms at the molecular level. For some traits, this information can accurately predict phenotype. However, knowledge of the underlying molecular networks often cannot be used to accurately predict higher order phenomena, such as the response to multiple stressors. This failure raises the question of whether methodological reductionism is sufficient to uncover predictable connections between molecules and phenotype. This question is explored in this paper by examining whether our understanding of the molecular responses to food limitation and pathogens in insects can be used to predict their combined effects. The molecular pathways underlying the response to starvation and pathogen attack in insects demonstrates the complexity of real-world physiological networks. Although known intracellular signaling pathways suggest that food restriction should enhance immune function, a reduction in food availability leads to an increase in some immune components, a decrease in others, and a complex effect on disease resistance in insects such as the caterpillar Manduca sexta. However, our inability to predict the effects of food restriction on disease resistance is likely due to our incomplete knowledge of the intra- and extracellular signaling pathways mediating the response to single or multiple stressors. Moving from molecules to organisms will require novel quantitative, integrative and experimental approaches (e.g. single cell RNAseq). Physiological networks are non-linear, dynamic, highly interconnected and replete with alternative pathways. However, that does not make them impossible to predict, given the appropriate experimental and analytical tools. Such tools are still under development. Therefore, given that molecular data sets are incomplete and analytical tools are still under development, it is premature to conclude that methodological reductionism cannot be used to predict phenotype.High consumption of fructose has paralleled an explosion in metabolic disorders including obesity and type 2 diabetes. Even more problematic, sustained consumption of fructose is perceived as a threat for brain function and development of neurological disorders. The action of fructose on peripheral organs is an excellent model to understand how systemic physiology impacts the brain. Given the recognized action of fructose on liver metabolism, here we discuss mechanisms by which fructose can impact the brain by interacting with liver and other organs. The interaction between peripheral and central mechanisms is a suitable target to reduce the pathophysiological consequences of neurological disorders.Cadmium (Cd) has been listed as one of the most toxic substances affecting numerous tissues/organs, including the immune system. Due to variations in studies examining Cd effects on the immune system (exposure regime, experimental systems, immune endpoint measured), data on Cd immunotoxicity in humans and experimental animals are inconsistent. link2 However, it is clear that Cd can affect cells of the immune system and can modulate some immune responses. Due to the complex nature of the immune system and its activities which are determined by multiple interactions, the underlying mechanisms involved in the immunotoxicity of this metal are still vague. Here, the current knowledge regarding the interaction of Cd with cells of the immune system, which may affect immune responses as well as potential mechanisms of consequent biological effects of such activities, is reviewed. Tissue injury caused by Cd-induced effects on innate cell activities depicts components of the immune system as mediators/effectors of Cd tissue toxicity. Cd-induced immune alterations, which may compromise host defense against pathogenic microorganisms and homeostatic reparative activities, stress this metal as an important health hazard.Spoilage of food by mycotoxigenic fungi poses a serious risk to food security throughout the world. In view of the negative effects of synthetic preservatives, essential oils (EOs) and their bioactive constituents are gaining momentum as suitable substitute to ensure food safety by controlling mycotoxins. However, despite their proven preservative potential against mycotoxins, the use of EOs/bioactive constituents in real food system is still restricted due to instability caused by abiotic factors and negative impact on organoleptic attributes after direct application. Nanoencapsulation in this regard could be a promising approach to address these problems, since the process can increase the stability of EOs/bioactive constituents, barricades their loss and considerably prevent their interaction with food matrices, thus preserving their original organoleptic qualities. link3 The aim of this review is to provide wider and up-to-date overview on recent advances in nanoencapsulation of EOs/bioactive constituents with the objective to control mycotoxin contamination in food system.