Leu27IGF2 plays an opposite role to IGF1 to induce H9c2 cardiomyoblast cell apoptosis via G alpha q signaling

[[abstract]]This study examines the role of IGF2/mannose 6-phosphate receptor (IGF2R) signaling in the signaling transduction regulation and cell apoptosis in H9c2 cardiomyoblast cells. However, it is difficult to recognize the distinct activation of IGF2 signaling without interfacing with IGF1 receptor (IGF1R) after exposure to IGF2. Leu27IGF2, an analog of IGF2 that interacts selectively with the IGF2R, was used to specifically activate IGF2R signaling in this study. DNA fragmentation and TUNEL assay revealed that in contrast to IGF1 treatment preventing angiotensin 11 and AG1024-induced cell apoptosis, Leu27IGF2 appears to synergistically increase apoptosis in those cells. We further found cell apoptosis induction and an increase in the active form of caspase 3 in the treatment of cells with Leu27IGF2, but not IGF1. To detect the interaction between IGF2R and G alpha q using the immunoprecipitation assay, we found that IGF2R could directly interact with G alpha q and after treatment with Leu27IGF2 the binding ability of G alpha q to IGF2R had increased. This sequentially resulted in the phosphorylation of phospholipase C-beta, a key downstream modulator of G alpha q, on serine 537. Moreover, disruption of the G alpha q protein by small interferon RNA reduced the cell apoptosis induced by Leu27IGF2. Our findings demonstrate that IGF2R activation appears to induce cell apoptosis via G alpha q-deriving signaling cascades and its effect is completely different from IGF1R survival signaling

Enhancement of beta-catenin in cardiomyocytes suppresses survival protein expression but promotes apoptosis and fibrosis

Background: Beta-catenin has been implicated in cell-cell communication in a wide variety of developmental and physiological processes. Defective Wnt signaling could result in various cardiac and vascular abnormalities. Little is known regarding Wnt/frizzled pathway in cardiomyocyte apoptosis. Methods: In this study, the role of b-catenin in apoptosis was investigated in H9c2 cardiomyocytes and primary cardiomyocytes isolated in diabetic Wistar rats. The cardiomyocytes were transfected with porcine cytomegalovirus (pCMV)-b-catenin plasmid in order to overexpress b-catenin. Results: The transcription factor displayed a significant nuclear localization in Wistar rats with cardiac hypertension. Transfection of b-catenin plasmid induced apoptosis and reduced expression of survival pathway markers in cardiomyocytes in a dose-dependent manner. Furthermore, expression of fibrosis protein markers was upregulated by the overexpression. Conclusions: Taken together, these results revealed that altered Wnt/b-catenin signaling might provoke heart failure. (Cardiol J 2017; 24, 2: 195–205

Evaluation of individual and ensemble probabilistic forecasts of COVID-19 mortality in the United States

Short-term probabilistic forecasts of the trajectory of the COVID-19 pandemic in the United States have served as a visible and important communication channel between the scientific modeling community and both the general public and decision-makers. Forecasting models provide specific, quantitative, and evaluable predictions that inform short-term decisions such as healthcare staffing needs, school closures, and allocation of medical supplies. Starting in April 2020, the US COVID-19 Forecast Hub (https://covid19forecasthub.org/) collected, disseminated, and synthesized tens of millions of specific predictions from more than 90 different academic, industry, and independent research groups. A multimodel ensemble forecast that combined predictions from dozens of groups every week provided the most consistently accurate probabilistic forecasts of incident deaths due to COVID-19 at the state and national level from April 2020 through October 2021. The performance of 27 individual models that submitted complete forecasts of COVID-19 deaths consistently throughout this year showed high variability in forecast skill across time, geospatial units, and forecast horizons. Two-thirds of the models evaluated showed better accuracy than a naïve baseline model. Forecast accuracy degraded as models made predictions further into the future, with probabilistic error at a 20-wk horizon three to five times larger than when predicting at a 1-wk horizon. This project underscores the role that collaboration and active coordination between governmental public-health agencies, academic modeling teams, and industry partners can play in developing modern modeling capabilities to support local, state, and federal response to outbreaks

The United States COVID-19 Forecast Hub dataset

Academic researchers, government agencies, industry groups, and individuals have produced forecasts at an unprecedented scale during the COVID-19 pandemic. To leverage these forecasts, the United States Centers for Disease Control and Prevention (CDC) partnered with an academic research lab at the University of Massachusetts Amherst to create the US COVID-19 Forecast Hub. Launched in April 2020, the Forecast Hub is a dataset with point and probabilistic forecasts of incident cases, incident hospitalizations, incident deaths, and cumulative deaths due to COVID-19 at county, state, and national, levels in the United States. Included forecasts represent a variety of modeling approaches, data sources, and assumptions regarding the spread of COVID-19. The goal of this dataset is to establish a standardized and comparable set of short-term forecasts from modeling teams. These data can be used to develop ensemble models, communicate forecasts to the public, create visualizations, compare models, and inform policies regarding COVID-19 mitigation. These open-source data are available via download from GitHub, through an online API, and through R packages

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defi ned as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium ) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the fi eld understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation it is imperative to delete or knock down more than one autophagy-related gene. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways so not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field

Open data from the third observing run of LIGO, Virgo, KAGRA and GEO

The global network of gravitational-wave observatories now includes five detectors, namely LIGO Hanford, LIGO Livingston, Virgo, KAGRA, and GEO 600. These detectors collected data during their third observing run, O3, composed of three phases: O3a starting in April of 2019 and lasting six months, O3b starting in November of 2019 and lasting five months, and O3GK starting in April of 2020 and lasting 2 weeks. In this paper we describe these data and various other science products that can be freely accessed through the Gravitational Wave Open Science Center at https://gwosc.org. The main dataset, consisting of the gravitational-wave strain time series that contains the astrophysical signals, is released together with supporting data useful for their analysis and documentation, tutorials, as well as analysis software packages.Comment: 27 pages, 3 figure

Mortality Factors in Major Trauma Patients: Nation-wide Population-based Research in Taiwan

Background: Major trauma remains a significant medical concern, leading to about 10,000 deaths annually in Taiwan. Trauma system implementation has been shown to improve the outcomes in different countries. Using the National Health Insurance data, our study examined the influence of age and other factors on the outcomes of trauma patients. Materials and methods: We collected the original claim data of 1 million beneficiaries who enrolled in the National Health Insurance program from 2006 to 2008. ICDMAP-90 was used for calculating the Injury Severity Score (ISS), which was required for assessing the disease severity and implementing appropriate control measures. Other variables included age, sex, triage classifications, pre-existing comorbidities, and hospital levels. The Charlson Comorbidity Index for the year of admission was used for adjusting comorbid conditions. Results: A total of 2497 major trauma patients (ISS >15) were identified in our database. After controlling all the variables in a logistic regression model, for all the major trauma patients, a significant difference was observed between different hospital levels. Compared with the trauma centers, the risk of mortality in nontrauma centers was 1.58 times that in trauma centers (p = 0.004). In the younger groups (aged <40 and 41–60 years), hospital levels had no significant effect on mortality (p = 0.40, 0.41). However, the risk of mortality was 1.89 times in nontrauma centers, compared to that in trauma centers, in the oldest group (p = 0.005). Conclusion: Our study suggests that all major trauma patients should be sent to trauma centers, especially the older patients

Topical diltiazem ointment in post-hemorrhoidectomy pain relief: A meta-analysis of randomized controlled trials

Summary: Background: Hemorrhoidectomy is commonly associated with postoperative pain. Calcium channel blockers are known to cause relaxation of gastrointestinal smooth muscle and oral diltiazem has also been shown to reduce the resting anal pressure. Objective: We attempted to analyze efficacy and side effects of topical diltiazem oint. in post-operative pain control. Methods: This is a meta-analysis of patients who underwent hemorrhoidectomy using topical diltiazem oint. versus placebo (Vaseline) for pain control. Patients with third or fourth degree hemorrhoids undergoing traditional hemorrhoidectomy were included. Procedures took place in the colorectal division of a hospital in 5 countries. Five randomized control trials (RCTs) published between 2005 and 2016 including 227 patients were included our meta-analysis (Diltiazem (calcium channel block) group = 137; Placebo (Vaseline) group = 90). Pain assessment was performed using a standardized Visual Analogue Scale. Any side effects of surgery or medication use, which were noted by the patient or the surgeon, also were recorded. Results: A total of 227 patients were included in the meta-analysis. The results revealed that Diltiazem ointment was statistically significant in reducing pain within 48 h, at 72 h, and more than 96 h after operation compared to the placebo group. Regarding overall complications (including headache), there was no statistical significance between diltiazem and placebo group. Conclusions: Topical application of diltiazem effectively relieves pain after hemorrhoidectomy with minimal side effects. Further large studies are needed to substantiate its value in clinical practice. Keywords: Hemorrhoidectomy, Post-hemorrhoidectomy, Diltiazem ointment, Calcium channel blocker, Meta-analysi

Risk factors for 14-day rehospitalization following trauma with new traumatic spinal cord injury diagnosis: A 10-year nationwide study in Taiwan.

Fourteen-day rehospitalization with new traumatic spinal cord injury (tSCI) diagnosis is used as an indicator for the diagnostic quality of the first hospitalization. In this nationwide population-based cohort study, we identified risk factors for this indicator.We conducted a nested case-control study by using the data of patients who received a first hospitalization for trauma between 2001 and 2011. The data were retrieved from Taiwan's National Health Insurance Research Database. Variables including demographic and trauma characteristics were compared between patients diagnosed with tSCI at the first hospitalization and those receiving a 14-day rehospitalization with new tSCI diagnosis.Of the 23 617 tSCI patients, 997 had 14-day rehospitalization with new tSCI diagnosis (incidence rate, 4.22%). The risk of 14-day rehospitalization with new tSCI diagnosis was significantly lower in patients with severe (injury severity score [ISS] = 16-24; odds ratio [OR], 0.17; 95% confidence interval [CI], 0.13-0.21) and profound (ISS > 24; OR, 0.11; 95% CI, 0.07-0.18) injuries. Interhospital transfer (OR, 8.20; 95% CI, 6.48-10.38) was a significant risk factor, along with injuries at the thoracic (OR, 1.62; 95% CI, 1.21-2.18), lumbar (OR, 1.30; 95% CI, 1.02-1.65), and multiple (OR, 3.23; 95% CI, 1.86-5.61) levels. Brain (OR, 2.82), chest (OR, 2.99), and abdominal (OR, 2.74) injuries were also identified as risk factors. In addition, the risk was higher in patients treated at the orthopedic department (OR, 2.26; 95% CI, 1.78-2.87) and those of other surgical disciplines (OR, 1.89; 95% CI, 1.57-2.28) than in those treated at the neurosurgery department.Delayed tSCI diagnoses are not uncommon, particularly among trauma patients with ISSs < 16 or those who are transferred from lower-level hospitals. Further validation and implementation of evidence-based decision rules is essential for improving the diagnostic quality of traumatic thoracolumbar SCI