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Less than 5% of prenatal thymoctes express HLA-DR before week 12 of gestation. However, the number of HLA-DR- positive cells increases during the late second and third trimesters of development. To determine the role of alpha-smooth muscle actin in fetal thymic HLA-DR signaling in different stages of development we examined and compared the immunohistochemical expression of alpha-smooth muscle actin in the myoid cells of the thymic medulla stroma in the 2 nd, and 3rd trimesters of gestation respectively, over the equivalent expression of the protein in the 1 st trimester, in relation with the appearance of HLA-DR-positive thymocytes. Our results demonstrated a quantitative difference in the second and third trimesters of development concerning the expression of alpha-smooth muscle actin in the stromal myoid cells of the thymic medulla over the equivalent expression of the protein in the first (P

BackgroundLNK/SH2B3 inhibits Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling by hematopoietic cytokine receptors. Genome-wide association studies have shown association of a common single nucleotide polymorphism in LNK (R262W, T allele) with neutrophilia, thrombocytosis, and coronary artery disease. We have shown that LNK(TT) reduces LNK function and that LNK-deficient mice display prominent platelet-neutrophil aggregates, accelerated atherosclerosis, and thrombosis. Platelet-neutrophil interactions can promote neutrophil extracellular trap (NET) formation. The goals of this study were to assess the role of NETs in atherosclerosis and thrombosis in mice with hematopoietic Lnk deficiency.MethodsWe bred mice with combined deficiency of Lnk and the NETosis-essential enzyme PAD4 (peptidyl arginine deiminase 4) and transplanted their bone marrow into Ldlr-/- mice. We evaluated the role of LNK in atherothrombosis in humans and mice bearing a gain of function variant in JAK2 (JAK2V617F).ResultsLnk-deficient mice displayed accelerated carotid artery thrombosis with prominent NETosis that was completely reversed by PAD4 deficiency. Thrombin-activated Lnk-/- platelets promoted increased NETosis when incubated with Lnk-/- neutrophils compared with wild-type platelets or wild-type neutrophils. This involved increased surface exposure and release of oxidized phospholipids (OxPL) from Lnk-/- platelets, as well as increased priming and response of Lnk-/- neutrophils to OxPL. To counteract the effects of OxPL, we introduced a transgene expressing the single-chain variable fragment of E06 (E06-scFv). E06-scFv reversed accelerated NETosis, atherosclerosis, and thrombosis in Lnk-/- mice. We also showed increased NETosis when human induced pluripotent stem cell-derived LNK(TT) neutrophils were incubated with LNK(TT) platelet/megakaryocytes, but not in isogenic LNK(CC) controls, confirming human relevance. Using data from the UK Biobank, we found that individuals with the JAK2VF mutation only showed increased risk of coronary artery disease when also carrying the LNK R262W allele. Mice with hematopoietic Lnk+/- and Jak2VF clonal hematopoiesis showed accelerated arterial thrombosis but not atherosclerosis compared with Jak2VFLnk+/+ controls.ConclusionsHematopoietic Lnk deficiency promotes NETosis and arterial thrombosis in an OxPL-dependent fashion. LNK(R262W) reduces LNK function in human platelets and neutrophils, promoting NETosis, and increases coronary artery disease risk in humans carrying Jak2VF mutations. Therapies targeting OxPL may be beneficial for coronary artery disease in genetically defined human populations.

Background: Work and home stress, productivity, and self-care of academic medicine faculty in Spring 2021 was contrasted to faculty's experience in the Spring of 2020, both of which were relatively compared with the prepandemic period. Methods: A 93-question survey was sent to academic medicine faculty at an urban public university medical center in March 2020 and again in March 2021. Demographic, family, and academic characteristics, work distribution and productivity before and during the pandemic, perceived stress related to work and home activities, and self-care data compared with the prepandemic period were collected. Differences were assessed using chi-square or Fisher exact tests. Student t-test was used for the difference in mean values, while logistic regression was used to determine predictors of work stress. Results: Two hundred thirty-one faculty completed the survey in Spring 2020 and 118 faculty responded in Spring 2021. The proportion of faculty reporting increased work and home stress decreased in Spring 2021 compared with Spring 2020. A higher proportion of women compared with men reported increased work stress in both surveys. In Spring 2021, work stress decreased significantly for men but not for women. Home stress decreased significantly for women in Spring 2021 but remained stable for the men faculty. Research productivity increased for both genders in Spring 2021, but a greater percentage of women reported disturbed sleep and diet. There were no differences in home stress levels between genders when caring for young children. Conclusions: Men faculty are more likely to adapt to the ?new normal? by lowering work stressors and increasing productivity, whereas women's continued high work stress and increased productivity may occur at the expense of decreased self-care. The challenges associated with having young children continue to affect the productivity and well-being of all faculty.

Remodelling of cell–cell junctions is crucial for proper tissue development and barrier function. The cadherin-based adherens junctions anchor via β-catenin and α-catenin to the actomyosin cytoskeleton, together forming a junctional mechanotransduction complex. Tension-induced conformational changes in the mechanosensitive α-catenin protein induce junctional vinculin recruitment. In endothelial cells, vinculin protects the remodelling of VE–cadherin junctions. In this study, we have addressed the role of vinculin in endothelial barrier function in the developing vasculature. In vitro experiments, using endothelial cells in which α-catenin was replaced by a vinculin-binding-deficient mutant, showed that junctional recruitment of vinculin promotes endothelial barrier function. To assess the role of vinculin within blood vessels in vivo, we next investigated barrier function in the vasculature of vcl knockout zebrafish. In the absence of vinculin, sprouting angiogenesis and vessel perfusion still occurred. Intriguingly, the absence of vinculin made the blood vessels more permeable for 10 kDa dextran molecules but not for larger tracers. Taken together, our findings demonstrate that vinculin strengthens the endothelial barrier and prevents vascular leakage in developing vessels.

Background: Out-of-hospital cardiac arrest (OHCA) survival varies widely across the United States. The impact of hospital OHCA volume and ST-elevation myocardial infarction (STEMI) Receiving Center (SRC) designation on survival is not fully understood. Methods: This was a retrospective analysis of adult OHCA who survived to hospital admission reported to the Chicago Cardiac Arrest Registry to Enhance Survival (CARES) database from May 1, 2013 to December 31, 2019. Hierarchical logistic regression models were generated and adjusted by hospital characteristics. Survival to hospital discharge (SHD) and cerebral performance category (CPC) 1–2 at each hospital were calculated after adjusting for arrest characteristics. Hospitals were assigned quartiles (Q1-Q4) based on total arrest volume to allow for comparison of SHD and CPC 1–2 between quartiles. Results: 4,020 patients met inclusion criteria. 21 of the 33 Chicago hospitals included in this study were designated SRCs. Adjusted SHD and CPC 1–2 rates ranged from 27.3% to 37.0% and from 8.9% to 25.1%, respectively, by hospital. SRC designation did not significantly affect SHD (OR 0.96; 95% CI, 0.71–1.30) nor CPC 1–2 (OR 1.17; 95% CI, 0.74–1.84). OHCA volume quartiles did not significantly affect SHD (Q2: OR 0.94; 95% CI, 0.54–1.60; Q3: OR 1.30; 95% CI, 0.78–2.16; Q4: OR 1.25; 95% CI, 0.74–2.10) nor CPC 1–2 (Q2: OR 0.75; 95% CI, 0.36–1.54; Q3: OR 0.94; 95% CI, 0.48–1.87; Q4: OR 0.97; 95% CI, 0.48–1.97). Conclusion: Interhospital variability in both SHD and CPC 1–2 cannot be explained by hospital arrest volume nor SRC status. Further research is warranted to explore reasons for interhospital variability.

Sex- and gender-based differences are emerging as clinically significant in the epidemiology and resuscitation of patients with out-of-hospital cardiac arrest (OHCA). Female patients tend to be older, experience arrest in private locations, and have fewer initial shockable rhythms (ventricular fibrillation/ventricular tachycardia). Despite standardized algorithms for the management of OHCA, women are less likely to receive evidence-based interventions, including advanced cardiac life support medications, percutaneous coronary intervention, and targeted temperature management. While some data suggest a protective mechanism of estrogen in the heart, brain, and kidney, its role is incompletely understood. Female patients experience higher mortality from OHCA, prompting the need for sex-specific research.

Abstract Despite the initial success of some drugs and vaccines targeting COVID-19, understanding the mechanism underlying SARS-CoV-2 disease pathogenesis remains crucial for the development of further approaches to treatment. Some patients with severe Covid-19 experience a cytokine storm and display evidence of inflammasome activation leading to increased levels of IL-1β and IL-18; however, other reports have suggested reduced inflammatory responses to Sars-Cov-2. In this study we have examined the effects of the Sars-Cov-2 envelope (E) protein, a virulence factor in coronaviruses, on inflammasome activation and pulmonary inflammation. In cultured macrophages the E protein suppressed inflammasome priming and NLRP3 inflammasome activation. Similarly, in mice transfected with E protein and treated with poly(I:C) to simulate the effects of viral RNA, the E protein, in an NLRP3-dependent fashion, reduced expression of pro-IL-1β, levels of IL-1β and IL-18 in broncho-alveolar lavage fluid, and macrophage infiltration in the lung. To simulate the effects of more advanced infection, macrophages were treated with both LPS and poly(I:C). In this setting the E protein increased NLRP3 inflammasome activation in both murine and human macrophages. Thus, the Sars-Cov-2 E protein may initially suppress the host NLRP3 inflammasome response to viral RNA while potentially increasing NLRP3 inflammasome responses in the later stages of infection. Targeting the Sars-Cov-2 E protein especially in the early stages of infection may represent a novel approach to Covid-19 therapy.

Implementation science (IS) is an approach focused on increasing the application of evidence‐based health interventions into practice, through purposive and thoughtful planning to maximize uptake, scalability, and sustainability. Many of these principles can be readily applied to medical education, to help augment traditional approaches to curriculum design. In this paper, we summarize key components of IS with an emphasis on application to the medical educator. [ABSTRACT FROM AUTHOR]

Angiogenesis requires dynamic endothelial rearrangements and relative position changes within the vascular tubes. Here the authors show that a PI3K/NUAK1/MYPT1/MLCP pathway regulates actomyosin contractility in endothelial cells and cellular rearrangement during vascular patterning.

Summary: Leukemia stem cells (LSCs) are believed to have more distinct vulnerabilities than the bulk acute myeloid leukemia (AML) cells, but their rarity and the lack of universal markers for their prospective isolation hamper their study. We report that genetically clonal induced pluripotent stem cells (iPSCs) derived from an AML patient and characterized by exceptionally high engraftment potential give rise, upon hematopoietic differentiation, to a phenotypic hierarchy. Through fate-tracking experiments, xenotransplantation, and single-cell transcriptomics, we identify a cell fraction (iLSC) that can be isolated prospectively by means of adherent in vitro growth that resides on the apex of this hierarchy and fulfills the hallmark features of LSCs. Through integrative genomic studies of the iLSC transcriptome and chromatin landscape, we derive an LSC gene signature that predicts patient survival and uncovers a dependency of LSCs, across AML genotypes, on the RUNX1 transcription factor. These findings can empower efforts to therapeutically target AML LSCs.

Connexins are components of gap junctions that link cells and allow intercellular communication. Here, the authors show that the Connexin 43 carboxy tail interacts with basic transcription factor-3, leading to nuclear translocation and direct regulation of N-cadherin expression and neural crest migration.

Purpose/aim: To examine with immunohistochemical assay MTA1 protein expression levels in pancreatic cancer tissues defining its prognostic value. Material and Methods: The specimens derived from 51 patients who underwent surgery. The levels of MTA1 protein were compared with the age of the patients, their survival, and prognosis. Also, we studied clinical and histopathological factors such as the degree of tumor differentiation and its stage in correlation with MTA1 protein levels. In parallel, there was correlation between the expression of the ΜΤΑ1 protein and the aforementioned factors regarding survival rate. Furthermore, we independently correlated the patient's survival in relation to whether they had undergone adjuvant chemotherapy or not. Results: It has been found to be low, moderate, or high expression of MTA1 levels in 48 out of 51 cancer tissues. Specifically, 49.0% of patients had low expression, 33.3% moderate, and 11.8% high expression of MTA1. Regarding the expression of MTA1 protein in correlation with various clinical and histopathological factors, a statistically significant correlation was observed with the degree of differentiation (p = 0.0068) and with the stage of the disease (p = 0.0173), but not with survival (p = 0.0740) or the age of them (p = 0.1547). Finally, it was found that overexpression of the MTA1protein is a prognostic factor for shorter survival in patients with pancreatic cancer (average 4.67 ± 0.95 months). Conclusions: MTA 1 protein may constitute an important prognostic marker in pancreatic cancer and could improve prognosis and treatment.