Gustafssonblack7153

V(D)J recombination assembles and diversifies Ig and T cell receptor genes in developing B and T lymphocytes. The reaction is initiated by the RAG1-RAG2 protein complex which binds and cleaves at discrete gene segments in the antigen receptor loci. To identify mechanisms that regulate V(D)J recombination, we used proximity-dependent biotin identification to analyze the interactomes of full-length and truncated forms of RAG1 in pre-B cells. This revealed an association of RAG1 with numerous nucleolar proteins in a manner dependent on amino acids 216 to 383 and allowed identification of a motif required for nucleolar localization. Experiments in transformed pre-B cell lines and cultured primary pre-B cells reveal a strong correlation between disruption of nucleoli, reduced association of RAG1 with a nucleolar marker, and increased V(D)J recombination activity. Mutation of the RAG1 nucleolar localization motif boosts recombination while removal of the first 215 amino acids of RAG1, required for efficient egress from nucleoli, reduces recombination activity. Our findings indicate that nucleolar sequestration of RAG1 is a negative regulatory mechanism in V(D)J recombination and identify regions of the RAG1 N-terminal region that control nucleolar association and egress.Mammalian cells present a fingerprint of their proteome to the adaptive immune system through the display of endogenous peptides on MHC-I complexes. MHC-I-bound peptides originate from protein degradation by the proteasome, suggesting that stably folded, long-lived proteins could evade monitoring. Here, we investigate the role in antigen presentation of the ribosome-associated quality control (RQC) pathway for the degradation of nascent polypeptides that are encoded by defective messenger RNAs and undergo stalling at the ribosome during translation. We find that degradation of model proteins by RQC results in efficient MHC-I presentation, independent of their intrinsic folding properties. Quantitative profiling of MHC-I peptides in wild-type and RQC-deficient cells by mass spectrometry showed that RQC substantially contributes to the composition of the immunopeptidome. Our results also identify endogenous substrates of the RQC pathway in human cells and provide insight into common principles causing ribosome stalling under physiological conditions. Copyright © 2020 the Author(s). Published by PNAS.BACKGROUND The original bubble continuous positive airway pressure (bCPAP) design has wide-bore tubing and a low-resistance interface. This creates a stable airway pressure that is reflected by the submersion depth of the expiratory tubing. Several systems with alterations to the original bCPAP design are now available. Most of these are aimed for use in low-income and middle-income countries and have not been compared with the original design. OBJECTIVE We identified three major alterations to the original bCPAP design (1) resistance of nasal interface, (2) volume of dead space and (3) diameter of expiratory tubing. Our aim was to study the effect of these alterations on CPAP delivery and work of breathing in a mechanical lung model. Dead space should always be avoided and was not further tested. METHODS The effect of nasal interface resistance and expiratory tubing diameter was evaluated with simulated breathing in a mechanical lung model without interface leakage. The main outcome was delivered CPAP and imposed work of breathing. RESULTS High-resistance interfaces and narrow expiratory tubing increased the work of breathing. Additionally, narrow expiratory tubing resulted in higher CPAP levels than indicated by the submersion depth. CONCLUSION Our study shows the significant effect on CPAP delivery and imposed work of breathing when using high-resistance interfaces and narrow expiratory tubing in bCPAP systems. read more New systems should include low-resistance interfaces and wide-bore tubing and be compared with the original bCPAP. Referring to all systems that bubble as bCPAP is misleading and potentially hazardous. © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.OBJECTIVES To describe and compare patient and event characteristics and outcomes in pediatric massive pulmonary embolism (MPE) and submassive pulmonary embolism (SMPE). METHODS A retrospective cohort study at a quaternary-care pediatric hospital was conducted. Patients age less then 19 years with MPE (acute pulmonary embolism [PE] with cardiac arrest, hypotension, or compensated shock due to PE) or SMPE (right ventricular strain due to acute PE) between January 1997 and June 2019 were included. RESULTS Thirty-three patients were identified, including 9 (27%) patients with MPE and 24 (73%) patients with SMPE. The most commonly identified risk factor was use of oral contraceptive pills in 16 (49%) patients. Six (18%) patients died, 3 (9%) of which were PE-related deaths. Before PE, patients with MPE were more likely to be hospitalized (89% vs 13%, P less then .001), have major comorbidities (89% vs 25%, P = .002), central venous catheters (67% vs 17%, P = .01), critical illness (56% vs 8%, P = .009), immobility (67% vs 13%, P = .005), and be postoperative (44% vs 4%, P = .01). MPE patients were also more likely to die before discharge (56% vs 4%, P = .003). Both groups were equally likely to have primary reperfusion attempts (78% of MPE versus 67% of SMPE, P = .69). CONCLUSIONS Pediatric MPE and SMPE differed in presentation, comorbidities, and risk factors, many of which were associated with hospitalization status. Pediatric-specific studies are warranted to determine risk assessment and management strategies, which may differ from adult guidelines. Copyright © 2020 by the American Academy of Pediatrics.Although endometrial cancer (EC) is often diagnosed at an early curable stage, the incidence and mortality from EC is rising and minority women are particularly at risk. We hypothesize that delays in clinical presentation contribute to racial disparities in EC mortality and treatment related morbidity. Improved methods for EC risk assessment and distinguishing abnormal uterine bleeding and postmenopausal bleeding from physiological variation are needed. Accordingly, we propose a multi-pronged strategy that combines innovative patient education with novel early detection strategies to reduce health impacts of EC and its precursors, especially among Black women. Futuristic approaches using gamification, smartphone apps, artificial intelligence, and health promotion outside of the physical clinic hold promise in preventing EC and reducing morbidity and mortality related to the disease, but they also raise a number of questions that will need to be addressed by future research. Copyright ©2020, American Association for Cancer Research.