Mind bomb 1 in the lymphopoietic niches is essential for T and marginal zone B cell development

Notch signaling regulates lineage decisions at multiple stages of lymphocyte development, and Notch activation requires the endocytosis of Notch ligands in the signal-sending cells. Four E3 ubiquitin ligases, Mind bomb (Mib) 1, Mib2, Neuralized (Neur) 1, and Neur2, regulate the Notch ligands to activate Notch signaling, but their roles in lymphocyte development have not been defined. We show that Mib1 regulates T and marginal zone B (MZB) cell development in the lymphopoietic niches. Inactivation of the Mib1 gene, but not the other E3 ligases, Mib2, Neur1, and Neur2, abrogated T and MZB cell development. Reciprocal bone marrow (BM) transplantation experiments revealed that Mib1 in the thymic and splenic niches is essential for T and MZB cell development. Interestingly, when BM cells from transgenic Notch reporter mice were transplanted into Mib1-null mice, the Notch signaling was abolished in the double-negative thymocytes. In addition, the endocytosis of Dll1 was impaired in the Mib1-null microenvironment. Moreover, the block in T cell development and the failure of Dll1 endocytosis were also observed in coculture system by Mib1 knockdown. Our study reveals that Mib1 is the essential E3 ligase in T and MZB cell development, through the regulation of Notch ligands in the thymic and splenic microenvironments

Clinical Factors Associated with Obstructive Coronary Artery Disease in Patients with Out-of-Hospital Cardiac Arrest: Data from the Korean Cardiac Arrest Research Consortium (KoCARC) Registry

Background: Although coronary artery disease (CAD) is a major cause of out-of-hospital cardiac arrest (OHCA), there has been no convinced data on the necessity of routine invasive coronary angiography (ICA) in OHCA. We investigated clinical factors associated with obstructive CAD in OHCA. Methods: Data from 516 OHCA patients (mean age 58 years, 83% men) who underwent ICA after resuscitation was obtained from a nation-wide OHCA registry. Obstructive CAD was defined as the lesions with diameter stenosis >= 50% on ICA. Independent clinical predictors for obstructive CAD were evaluated using multiple logistic regression analysis, and their prediction performance was compared using area under the receiver operating characteristic curve with 10,000 repeated random permutations. Results: Among study patients, 254 (49%) had obstructive CAD. Those with obstructive CAD were older (61 vs. 55 years, P < 0.001) and had higher prevalence of hypertension (54% vs. 36%, P < 0.001), diabetes mellitus (29% vs. 21%, P = 0.032), positive cardiac enzyme (84% vs. 74%, P = 0.010) and initial shockable rhythm (70% vs. 61%, P = 0.033). In multiple logistic regression analysis, old age (>= 60 years) (odds ratio [On 2.01; 95% confidence interval [CI], 1.36-3.00; P = 0.001), hypertension (OR, 1.74; 95% CI, 1.18-2.57; P = 0.005), positive cardiac enzyme (OR, 1.72; 95% CI, 1.09-2.70; P = 0.019), and initial shockable rhythm (OR, 1.71; 95% CI, 1.16-2.54; P = 0.007) were associated with obstructive CAD. Prediction ability for obstructive CAD increased proportionally when these 4 factors were sequentially combined (P < 0.001). Conclusion: In patients with OHCA, those with old age, hypertension, positive cardiac enzyme and initial shockable rhythm were associated with obstructive CAD. Early ICA should be considered in these patients.Y