Ca 2+-CaM Dependent Inactivation of RyR2 Underlies Ca 2+ Alternans in Intact Heart

Rationale: Ca2+ alternans plays an essential role in cardiac alternans that can lead to ventricular fibrillation, but the mechanism underlying Ca2+ alternans remains undefined. Increasing evidence suggests that Ca2+ alternans results from alternations in the inactivation of cardiac RyR2 (ryanodine receptor 2). However, what inactivates RyR2 and how RyR2 inactivation leads to Ca2+ alternans are unknown. Objective: To determine the role of CaM (calmodulin) on Ca2+ alternans in intact working mouse hearts. Methods and results: We used an in vivo local gene delivery approach to alter CaM function by directly injecting adenoviruses expressing CaM-wild type, a loss-of-function CaM mutation, CaM (1-4), and a gain-of-function mutation, CaM-M37Q, into the anterior wall of the left ventricle of RyR2 wild type or mutant mouse hearts. We monitored Ca2+ transients in ventricular myocytes near the adenovirus-injection sites in Langendorff-perfused intact working hearts using confocal Ca2+ imaging. We found that CaM-wild type and CaM-M37Q promoted Ca2+ alternans and prolonged Ca2+ transient recovery in intact RyR2 wild type and mutant hearts, whereas CaM (1-4) exerted opposite effects. Altered CaM function also affected the recovery from inactivation of the L-type Ca2+ current but had no significant impact on sarcoplasmic reticulum Ca2+ content. Furthermore, we developed a novel numerical myocyte model of Ca2+ alternans that incorporates Ca2+-CaM-dependent regulation of RyR2 and the L-type Ca2+ channel. Remarkably, the new model recapitulates the impact on Ca2+ alternans of altered CaM and RyR2 functions under 9 different experimental conditions. Our simulations reveal that diastolic cytosolic Ca2+ elevation as a result of rapid pacing triggers Ca2+-CaM dependent inactivation of RyR2. The resultant RyR2 inactivation diminishes sarcoplasmic reticulum Ca2+ release, which, in turn, reduces diastolic cytosolic Ca2+, leading to alternations in diastolic cytosolic Ca2+, RyR2 inactivation, and sarcoplasmic reticulum Ca2+ release (ie, Ca2+ alternans). Conclusions: Our results demonstrate that inactivation of RyR2 by Ca2+-CaM is a major determinant of Ca2+ alternans, making Ca2+-CaM dependent regulation of RyR2 an important therapeutic target for cardiac alternans.This work was supported by research grants from the Heart and Stroke Foundation of Canada (G-19-0026444), the Heart and Stroke Foundation Chair in Cardiovascular Research (END611955), the Canadian Institutes of Health Research to S.R.W. Chen (PJT-155940), the Spanish Ministry of Science Innovation and Universities SAF2017-88019-C3-1R, 2R, and 3R (to L. Hove-Madsen, R. Benitez, and B. Echebarria), Marato-TV3 20152030 (to L. Hove-Madsen) and 20151110 (to B. Echebarria), and Generalitat de Catalunya SGR2017-1769 (to L. Hove-Madsen).Peer reviewe

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Primary central nervous system CD20-negative diffuse large B-cell lymphoma: a case report

Abstract Background CD20-negative diffuse large B-cell lymphoma is a very rare and heterogeneous invasive cancer characterized by chemical resistance and poor prognosis. Primary CD20-negative diffuse large B-cell lymphoma of the central nervous system is even rarer, presenting great challenges in pathological diagnosis and clinical treatment. Case presentation We report a case of primary CD20-negative diffuse large B-cell lymphoma of the CNS in a 54-year-old woman admitted to the hospital with a headache lasting more than 10 days. CT and MRI scans showed right temporal lobe lymphoma. Microscopically, large infiltrating lymphoid cells that induced brain tissue damage were observed. Immunohistochemistry showed that the tumor cells were CD79a+, PAX-5+, MUM1+, and CD20-. The patient was diagnosed with lymphoma and transferred to an oncology hospital for chemotherapy. However, because the disease progressed rapidly, the patient died only after two rounds of chemotherapy. Conclusions To the best of our knowledge, this is one of the first reported cases of unclassifiable CD20-negative diffuse large B-cell lymphoma located in the CNS. This case report aims to deepen the understanding of clinicopathological features of this type of lymphoma and expand the scope of this disease

Method of Feature Reduction in Short Text Classification Based on Feature Clustering

One decisive problem of short text classification is the serious dimensional disaster when utilizing a statistics-based approach to construct vector spaces. Here, a feature reduction method is proposed that is based on two-stage feature clustering (TSFC), which is applied to short text classification. Features are semi-loosely clustered by combining spectral clustering with a graph traversal algorithm. Next, intra-cluster feature screening rules are designed to remove outlier feature words, which improves the effect of similar feature clusters. We classify short texts with corresponding similar feature clusters instead of original feature words. Similar feature clusters replace feature words, and the dimension of vector space is significantly reduced. Several classifiers are utilized to evaluate the effectiveness of this method. The results show that the method largely resolves the dimensional disaster and it can significantly improve the accuracy of short text classification

Next-Generation Sequencing Analysis of 3 Uterine Adenosarcomas with Heterogeneously Differentiated Genomic Mutations

Uterine adenosarcoma (UA) is an uncommon mixed tumor containing a benign to at most mildly atypical epithelial component and a sarcoma-like stroma, usually a low-grade, stromal component, with rare heterogeneous elements. Currently, tumor etiology is largely unknown. To better understand the gene mutations in UA, next-generation sequencing (NGS) technology analysis was performed. This study showed that two low-grade UAs with heterologous components had ATRX gene frameshift mutation, and one patient had a MED12 missense mutation. Copy number amplification genes were mainly observed on chromosome 12q13–15. In this study, PIK3/AKT/PTEN pathway mutations were found to be common in adenosarcoma. In addition, a rare BCORL1-PRR14L fusion mutation was also identified. These findings provide a basis for future research into these molecular changes in tumorigenesis and targeted therapy

Feature Fusion Information Statistics for feature matching in cluttered scenes

Object recognizing in cluttered scenes remains a largely unsolved problem, especially when applying feature matching to cluttered scenes there are many feature mismatches between the scenes and models. We propose our Feature Fusion Information Statistics (FFIS) as the calculation framework for extracting salient information from a Local Surface Patch (LSP) by a Local Reference Frame (LRF). Our LRF is defined on each LSP by projecting the scatter matrix’s eigenvectors to a plane which is perpendicular to the normal of the LSP. Based on this, our FFIS descriptor of each LSP is calculated, for which we use the combined distribution of mesh and point information in a local domain. Finally, we evaluate the speed, robustness and descriptiveness of our FFIS with the state-of-the-art methods on several public benchmarks. Our experiments show that our FFIS is fast and obtains a more reliable matching rate than other approaches in cluttered situations

Whole-Genome Comparative and Pathogenicity Analysis of Salmonella enterica subsp. enterica Serovar Rissen

Salmonella are a type of bacteria known to cause food-borne illness. Their host range varies widely, and their susceptibility to the host determines its pathogenicity. Salmonella enterica serovar Rissen (S. Rissen) is a widely distributed serotype; however, its virulence and pathogenicity are poorly understood. In this study, the pathogenicity and antibiotic resistance of a representative S. Rissen isolate were investigated. The cell model results showed that S. Rissen preferred to replicate in human macrophage cells U937 compared to murine macrophage cells RAW264.7, suggesting that it has a level of host adaptability. Genome sequencing and comparison analysis revealed that the distribution and nonsynonymous single nucleotide polymorphisms of virulence factors in S. Rissen were similar to those in S. Typhi rather than to those in S. Typhimurium. Taken together, our results suggest that although S. Rissen is a common serotype distributed in swine herds, pork and chicken products, it has strong ability to infect humans