Regulation of sertoli-germ cell adherens junction dynamics via changes in protein-protein interactions of the N-cadherin-β-catenin protein complex which are possibly mediated by c-Src and myotubularin-related protein 2: An in vivo study using an androgen suppression model

Using a well characterized model of cell-cell actin-based adherens junction (AJ) disruption by suppressing the intratesticular testosterone level in adult rats with testosterone-estradiol implants, we have confirmed earlier findings that Sertoli-germ cell AJ dynamics are regulated by the activation of kinases via putative signaling pathways but with some unexpected findings as follows. First, the loss of germ cells from the seminiferous epithelium during androgen suppression was associated with a surge in myotubularin-related protein 2 (MTMR2, a lipid phosphatase, in which adult MTMH2-/- mice were recently shown to be azoospermic because of the loss of cell adhesion function between germ and Sertoli cells); kinases: phosphatidylinositol 3-kinase, c-Src, and C-terminal Src kinase; adaptors: α-actinin, vinculin, afadin, and p130 Crk-associated protein; and AJ-integral membrane proteins at the ectoplasmic specialization (ES, a testis-specific cell-cell actin-based AJ type) site: N-cadherin, β-catenin, integrin β1, and nectin 3. Second, MTMR2, instead of structurally interacting with phosphatidylinositol 3-kinase, a protein and lipid kinase, was shown to associate only with c-Src, a nonreceptor protein tyrosine kinase, as demonstrated by both coimmunoprecipitation and fluorescent microscopy at the site of apical ES, but none of the kinases, adaptors, and AJ-infegral proteins that were examined. Collectively, these results suggest that the MTMR2/c-Src is an important phosphatase/kinase protein pair in AJ dynamics in the testis. Because c-Src is known to associate with the cadherin/catenin protein complex at the ES in the testis, we next sought to investigate any changes in the protein-protein interactions of this protein complex during androgen suppression-induced germ cell loss. Indeed, there was a loss of N-cadherin and β-catenin association, accompanied by a surge in Tyr phosphorylation of β-catenin, during germ cell loss from the epithelium. Third, and perhaps the most important of all, during natural recovery of the epithelium after removal of testosterene-estradiol implants when spermatids were reattaching to Sertoli cells, an increase in N-cadherin and β-catenin association was detected with a concomitant loss in the increased Tyr phosphorylation in β-catenin. In summary, these results illustrate that the cadherin/catenin is a crucial cell adhesion complex that regulates AJ dynamics in the testis, and its functionality is likely modulated by the MTMR2/c-Src protein complex.postprin

Territory-Wide Chinese Cohort of Long QT Syndrome: Random Survival Forest and Cox Analyses

Introduction: Congenital long QT syndrome (LQTS) is a cardiac ion channelopathy that predisposes affected individuals to spontaneous ventricular tachycardia/fibrillation (VT/VF) and sudden cardiac death (SCD). The main aims of the study were to: (1) provide a description of the local epidemiology of LQTS, (2) identify significant risk factors of ventricular arrhythmias in this cohort, and (3) compare the performance of traditional Cox regression with that of random survival forests. / Methods: This was a territory-wide retrospective cohort study of patients diagnosed with congenital LQTS between 1997 and 2019. The primary outcome was spontaneous VT/VF. / Results: This study included 121 patients [median age of initial presentation: 20 (interquartile range: 8–44) years, 62% female] with a median follow-up of 88 (51–143) months. Genetic analysis identified novel mutations in KCNQ1, KCNH2, SCN5A, ANK2, CACNA1C, CAV3, and AKAP9. During follow-up, 23 patients developed VT/VF. Univariate Cox regression analysis revealed that age [hazard ratio (HR): 1.02 (1.01–1.04), P = 0.007; optimum cut-off: 19 years], presentation with syncope [HR: 3.86 (1.43–10.42), P = 0.008] or VT/VF [HR: 3.68 (1.62–8.37), P = 0.002] and the presence of PVCs [HR: 2.89 (1.22–6.83), P = 0.015] were significant predictors of spontaneous VT/VF. Only initial presentation with syncope remained significant after multivariate adjustment [HR: 3.58 (1.32–9.71), P = 0.011]. Random survival forest (RSF) model provided significant improvement in prediction performance over Cox regression (precision: 0.80 vs. 0.69; recall: 0.79 vs. 0.68; AUC: 0.77 vs. 0.68; c-statistic: 0.79 vs. 0.67). Decision rules were generated by RSF model to predict VT/VF post-diagnosis. / Conclusions: Effective risk stratification in congenital LQTS can be achieved by clinical history, electrocardiographic indices, and different investigation results, irrespective of underlying genetic defects. A machine learning approach using RSF can improve risk prediction over traditional Cox regression models

Sarcopenia and mortality in different clinical conditions: A meta-analysis

Objectives: Sarcopenia is recognized to be a health problem which is as serious as obesity, but its relevance to mortality is unclear. We conducted a meta-analysis of cohort studies on lean mass and mortality in populations with different health conditions. / Methods: In this study, a systematic search of PubMed, Cochrane Library and Embase was performed for cohort studies published before Dec 20, 2017 which examined the relationship between lean mass and mortality. We included studies reporting lean mass measurement by dual-energy X-ray absorptiometry, bioimpedance analysis or computed tomography, as continuous (per standard deviation [SD] decrease) or binary variables (using sarcopenia cutoffs). We excluded studies which used muscle mass surrogates, anthropometric measurement of muscle, rate of change in muscle mass, and sarcopenia defined by composite criteria. The primary study outcome was all-cause mortality. Pooled hazard ratio estimates were calculated using a random effects model. / Results: A total of 9602 articles were identified from the systematic search, and 188 studies with 98 468 participants from 34 countries were included in the meta-analysis. Of the 68 studies included in the present meta-analysis, the pooled HR was 1.36 and 1.74 for every SD decrease in lean mass and in people with low lean mass (cutoffs), respectively. Significant associations were also observed in elderly and all disease subgroups, irrespective of the measurement modalities. / Conclusions: Lower lean mass is robustly associated with increased mortality, regardless of health conditions and lean mass measurement modalities. This meta-analysis highlighted low lean mass as a key public health issue

Multivariate biophysical markers predictive of mesenchymal stromal cell multipotency

The capacity to produce therapeutically relevant quantities of multipotent mesenchymal stromal cells (MSCs) via in vitro culture is a common prerequisite for stem cell-based therapies. Although culture expanded MSCs are widely studied and considered for therapeutic applications, it has remained challenging to identify a unique set of characteristics that enables robust identification and isolation of the multipotent stem cells. New means to describe and separate this rare cell type and its downstream progenitor cells within heterogeneous cell populations will contribute significantly to basic biological understanding and can potentially improve efficacy of stem and progenitor cell-based therapies. Here, we use multivariate biophysical analysis of culture-expanded, bone marrow-derived MSCs, correlating these quantitative measures with biomolecular markers and in vitro and in vivo functionality. We find that, although no single biophysical property robustly predicts stem cell multipotency, there exists a unique and minimal set of three biophysical markers that together are predictive of multipotent subpopulations, in vitro and in vivo. Subpopulations of culture-expanded stromal cells from both adult and fetal bone marrow that exhibit sufficiently small cell diameter, low cell stiffness, and high nuclear membrane fluctuations are highly clonogenic and also exhibit gene, protein, and functional signatures of multipotency. Further, we show that high-throughput inertial microfluidics enables efficient sorting of committed osteoprogenitor cells, as distinct from these mesenchymal stem cells, in adult bone marrow. Together, these results demonstrate novel methods and markers of stemness that facilitate physical isolation, study, and therapeutic use of culture-expanded, stromal cell subpopulations.National University of Singapore (Graduate School for Integrative Sciences and Engineering Program)Singapore-MIT Alliance (Singapore-MIT Alliance-3 graduate fellowship program)Singapore. National Research FoundationSingapore-MIT Alliance for Research and Technology (BioSystems and Micromechanics Interdisciplinary Research Group)Singapore. National Medical Research Council (NMRC/Clinician Scientist Award/012/2009

Different definition of sarcopenia and mortality in cancer: A meta-analysis

Objectives: Sarcopenia has been an emerging theme in clinical oncology. Various definitions of sarcopenia have been proposed, but their prognostic performance have yet to be evaluated and compared. The aim of this meta-analysis is to comprehensively evaluate the performance of different cutoff definitions of sarcopenia in cancer mortality prognostication. / Methods: This is a meta-analysis. Cohort studies on lean mass and mortality published before December 20, 2017 were obtained by systematic search on PubMed, Cochrane Library, and Embase. Inclusion criteria were cohort studies reporting binary lean mass categorized according to clearly defined cutoffs, and with all-cause mortality as study outcome. Studies were stratified according to the cutoff(s) used in defining low lean mass. The cutoff-specific hazard ratios (HRs) and 95% confidence intervals (CIs) of low lean mass on cancer mortality were pooled with a random-effects model and compared. / Results: Altogether 81 studies that studied binary lean mass were included. The pooled HRs on cancer mortality using the 3 most used definitions were: 1.74 (95% CI, 1.46–2.07) using the definition proposed by International Consensus of Cancer Cachexia, 1.45 (95% CI, 1.21–1.75) using that by Martin, and 1.58 (95% CI, 1.35–1.84) using that by Prado. The associations between sarcopenia and cancer mortality using other definitions were all statistically significant, despite different estimates were observed. / Conclusions: The association of low lean mass with increased mortality was consistent across different definitions; this provides further evidence on the poorer survival in cancer patients with sarcopenia. However, further studies evaluating the performance of each definition are warranted

Identifying the Service Gaps in the Management of Severe Systemic Allergic Reaction/Anaphylaxis by Paediatrics Departments of the Hospital Authority

Abstract Background: Anaphylaxis and severe systemic allergic reaction are potentially life-threatening conditions. There is a paucity of data on the management of such condition amongst Hong Kong children. Objective: This review was designed to assist health professionals to evaluate the current process of care for children admitted with anaphylaxis or severe systemic allergic reaction, to identify service gaps so that patients are appropriately investigated, treated and taught how to recognise and manage severe allergic reactions. Methods: The anaphylaxis and severe allergic reaction/angioedema for children under age of 18 were identified using ICD-9 codes 995.0, 995.1, 995.6. We performed a retrospective chart review of on

Detectors for the James Webb Space Telescope Near-Infrared Spectrograph I: Readout Mode, Noise Model, and Calibration Considerations

We describe how the James Webb Space Telescope (JWST) Near-Infrared Spectrograph's (NIRSpec's) detectors will be read out, and present a model of how noise scales with the number of multiple non-destructive reads sampling-up-the-ramp. We believe that this noise model, which is validated using real and simulated test data, is applicable to most astronomical near-infrared instruments. We describe some non-ideal behaviors that have been observed in engineering grade NIRSpec detectors, and demonstrate that they are unlikely to affect NIRSpec sensitivity, operations, or calibration. These include a HAWAII-2RG reset anomaly and random telegraph noise (RTN). Using real test data, we show that the reset anomaly is: (1) very nearly noiseless and (2) can be easily calibrated out. Likewise, we show that large-amplitude RTN affects only a small and fixed population of pixels. It can therefore be tracked using standard pixel operability maps.Comment: 55 pages, 10 figure

New measurement of θ13\theta_{13} via neutron capture on hydrogen at Daya Bay

This article reports an improved independent measurement of neutrino mixing angle $\theta_{13}$ at the Daya Bay Reactor Neutrino Experiment. Electron antineutrinos were identified by inverse $\beta$-decays with the emitted neutron captured by hydrogen, yielding a data-set with principally distinct uncertainties from that with neutrons captured by gadolinium. With the final two of eight antineutrino detectors installed, this study used 621 days of data including the previously reported 217-day data set with six detectors. The dominant statistical uncertainty was reduced by 49%. Intensive studies of the cosmogenic muon-induced $^9$Li and fast neutron backgrounds and the neutron-capture energy selection efficiency, resulted in a reduction of the systematic uncertainty by 26%. The deficit in the detected number of antineutrinos at the far detectors relative to the expected number based on the near detectors yielded $\sin^22\theta_{13} = 0.071 \pm 0.011$ in the three-neutrino-oscillation framework. The combination of this result with the gadolinium-capture result is also reported.Comment: 26 pages, 23 figure