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This article has an associated First Person interview with the first author of the paper.Pancreatic β-cells are a critical cell type in the pathology of diabetes. Models of genetic syndromes featuring diabetes can provide novel mechanistic insights into regulation of β-cells in the context of disease. Myricetin We previously examined β-cell mass in models of two ciliopathies, Alström Syndrome (AS) and Bardet-Biedl Syndrome (BBS), which are similar in the presence of metabolic phenotypes, including obesity, but exhibit strikingly different rates of diabetes. Zebrafish models of these disorders show deficient β-cells with diabetes in AS models and an increased β-cells absent diabetes in BBS models, indicating β-cell generation or maintenance that correlates with disease prevalence. Using transcriptome analyses, differential expression of several exocrine pancreas proteases with directionality that was consistent with β-cell numbers were identified. Based on these lines of evidence, we hypothesized that pancreatic proteases directly impact β-cells. In the present study, we examined this possibility and found that pancreatic protease genes contribute to proper maintenance of normal β-cell numbers, proliferation in larval zebrafish, and regulation of AS and BBS β-cell phenotypes. Our data suggest that these proteins can be taken up directly by cultured β-cells and ex vivo murine islets, inducing proliferation in both. Endogenous uptake of pancreatic proteases by β-cells was confirmed in vivo using transgenic zebrafish and in intact murine pancreata. Taken together, these findings support a novel proliferative signaling role for exocrine pancreas proteases through interaction with endocrine β-cells.T-cell acute lymphoblastic leukemia (T-ALL) are aggressive hematological cancers with dismal outcomes, and are in need of new therapeutic options. Polycomb Repressor Complex 2 (PRC2) loss-of-function alterations were reported in pediatric T-ALL; yet their clinical relevance and functional consequences remain elusive. Here, we extensively analyzed PRC2 alterations in a large series of 218 adult T-ALL patients. We found that PRC2 genetic lesions are frequent events in T-ALL and are not restricted to ETP-ALL. PRC2 loss of function associates with activating mutations of the IL7R/JAK/STAT pathway. PRC2-altered T-ALL patients poorly respond to prednisone, have low bone marrow blast clearance, and persistent minimal residual disease. Furthermore, we identified that PRC2 loss of function profoundly reshapes the genetic and epigenetic landscapes, leading to the reactivation of stem cell programs that cooperate with Bromodomain and Extraterminal (BET) proteins to sustain T-ALL. This study identifies BET proteins as key mediators of the PRC2 loss of function-induced remodeling. Our data has uncovered a targetable vulnerability to BET inhibition that can be exploited to treat PRC2-altered T-ALL patients.
Due to the continued impact of coronovirus 2019 (COVID-19), residency programs were advised to offer virtual interviews in place of traditional in-person interviews for the 2021 match recruitment season. As a result, many pathology residency programs offered preinterview virtual open-house events to meet prospective applicants before the interview season. This article aims to understand applicants' perspective on those events during the residency recruitment season of 2020 to 2021.
We performed a cross-sectional survey-based study involving 95 pathology residency applicants.
Our results demonstrated that applicants generally have a positive perception of open house events; 91% found virtual open-house events beneficial, 63.2% attended open-house events for programs they were not considering applying to. Considering the high number of offered virtual open house events, 17% of applicants felt overwhelmed by attendance and 30% felt obligated to attend.
This brief report demonstrates the generally positive impact of these events.
This brief report demonstrates the generally positive impact of these events.Ozobranchus jantseanus is the largest metazoan known to survive in liquid nitrogen without pretreatment to date; however, the mechanism underlying this tolerance remains unclear. In this study, the first analyses of histological and morphological changes in normal, frozen, and dehydrated states were performed. Adults survived after direct placement in liquid nitrogen for 96 h, with a survival rate of approximately 86.7%. The leech could withstand rapid desiccation and its survival rate after rehydration was 100% when its water loss was below about 84.8%. After freezing, desiccation, and ethanol dehydration, the leech immediately formed a hemispherical shape. Particularly during drying, an obvious transparent glass-like substance was observed on surface. Scanning electron microscopy revealed many pores on the surface of the posterior sucker, creating a sponge-like structure, which may help to rapidly expel water, and a hemispherical shape may protect the internal organs by contraction and folding reconstruction in the anterior-posterior direction. A substantial amount of mucopolysaccharides on the surface and acid cells and collagen fibers in the body, all of which contained substantial polysaccharides, may play a key protective role during freezing. Our results indicate that the resistance of leeches to ultra-low temperatures can be explained by cryoprotective dehydration/vitrification strategies. This article has an associated First Person interview with the first author of the paper.Most patients with acute promyelocytic leukemia (APL) can be cured with combined All Trans Retinoic Acid (ATRA) and Arsenic Trioxide therapy, which induce the destruction of PML-RARA, the initiating fusion protein for this disease1. However, the underlying mechanisms by which PML-RARA initiates and maintains APL cells are still not clear. We therefore identified genes that are dysregulated by PML-RARA in mouse and human APL cells, and prioritized GATA2 for functional studies because 1) it is highly expressed in pre-leukemic cells expressing PML-RARA, 2) its high expression persists in transformed APL cells, and 3) spontaneous somatic mutations of GATA2 occur during APL progression in both mice and humans. These and other findings suggested that GATA2 may be upregulated to thwart the proliferative signal generated by PML-RARA, and that its inactivation by mutation (and/or epigenetic silencing) may accelerate disease progression in APL and other forms of AML. Indeed, biallelic knockout of Gata2 with CRISPR/Cas9-mediated gene editing increased the serial replating efficiency of PML-RARA-expressing myeloid progenitors (and also progenitors expressing RUNX1-RUNX1T1, or deficient for Cebpa), increased mouse APL penetrance, and decreased latency.
Homepage: https://www.selleckchem.com/products/Myricetin(Cannabiscetin).html
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