Miracle-dz/UniFAR-FTUs huggingface dataset:
The store-operated Ca2+ entry complex comprises a small cluster of STIM1 associated with one Orai1 channel

Significance Store-operated Ca2+ entry (SOCE) links Ca2+ release from endoplasmic reticulum (ER) to Ca2+ entry across the plasma membrane (PM). SOCE is unusual in requiring interaction between proteins in different membranes. STIM1, when it senses loss of ER Ca2+, unfurls domains that interact with Orai1 PM Ca2+ channels. The stoichiometry of the SOCE complex is contentious, but it determines the regulation and functional consequences of SOCE. We show that native complexes are likely to comprise a single Orai1 channel and a few STIM1 dimers, too few to cluster Orai1 channels. We suggest that SOCE may be digitally regulated by local ER depletion, and that local SOCE-evoked Ca2+ fluxes are small enough to allow substantial intracellular redistribution of Ca2+ through ER tunnels. Increases in cytosolic Ca2+ concentration regulate diverse cellular activities and are usually evoked by opening of Ca2+ channels in intracellular Ca2+ stores and the plasma membrane (PM). For the many signals that evoke formation of inositol 1,4,5-trisphosphate (IP3), IP3 receptors coordinate the contributions of these two Ca2+ sources by mediating Ca2+ release from the endoplasmic reticulum (ER). Loss of Ca2+ from the ER then activates store-operated Ca2+ entry (SOCE) by causing dimers of STIM1 to cluster and unfurl cytosolic domains that interact with the PM Ca2+ channel, Orai1, causing its pore to open. The relative concentrations of STIM1 and Orai1 are important, but most analyses of their interactions use overexpressed proteins that perturb the stoichiometry. We tagged endogenous STIM1 with EGFP using CRISPR/Cas9. SOCE evoked by loss of ER Ca2+ was unaffected by the tag. Step-photobleaching analysis of cells with empty Ca2+ stores revealed an average of 14.5 STIM1 molecules within each sub-PM punctum. The fluorescence intensity distributions of immunostained Orai1 puncta were minimally affected by store depletion, and similar for Orai1 colocalized with STIM1 puncta or remote from them. We conclude that each native SOCE complex is likely to include only a few STIM1 dimers associated with a single Orai1 channel. Our results, demonstrating that STIM1 does not assemble clusters of interacting Orai channels, suggest mechanisms for digital regulation of SOCE by local depletion of the ER.
Human–Computer Agreement of Electrocardiogram Interpretation for Patients Referred to and Declined for Primary Percutaneous Coronary Intervention: Retrospective Data Analysis Study

Background When a patient is suspected of having an acute myocardial infarction, they are accepted or declined for primary percutaneous coronary intervention partly based on clinical assessment of their 12-lead electrocardiogram (ECG) and ST-elevation myocardial infarction criteria. Objective We retrospectively determined the agreement rate between human (specialists called activator nurses) and computer interpretations of ECGs of patients who were declined for primary percutaneous coronary intervention. Methods Various features of patients who were referred for primary percutaneous coronary intervention were analyzed. Both the human and computer ECG interpretations were simplified to either “suggesting” or “not suggesting” acute myocardial infarction to avoid analysis of complex heterogeneous and synonymous diagnostic terms. Analyses, to measure agreement, and logistic regression, to determine if these ECG interpretations (and other variables such as patient age, chest pain) could predict patient mortality, were carried out. Results Of a total of 1464 patients referred to and declined for primary percutaneous coronary intervention, 722 (49.3%) computer diagnoses suggested acute myocardial infarction, whereas 634 (43.3%) of the human interpretations suggested acute myocardial infarction (P<.001). The human and computer agreed that there was a possible acute myocardial infarction for 342 out of 1464 (23.3%) patients. However, there was a higher rate of human–computer agreement for patients not having acute myocardial infarctions (450/1464, 30.7%). The overall agreement rate was 54.1% (792/1464). Cohen κ showed poor agreement (κ=0.08, P=.001). Only the age (odds ratio [OR] 1.07, 95% CI 1.05-1.09) and chest pain (OR 0.59, 95% CI 0.39-0.89) independent variables were statistically significant (P=.008) in predicting mortality after 30 days and 1 year. The odds for mortality within 1 year of referral were lower in patients with chest pain compared to those patients without chest pain. A referral being out of hours was a trending variable (OR 1.41, 95% CI 0.95-2.11, P=.09) for predicting the odds of 1-year mortality. Conclusions Mortality in patients who were declined for primary percutaneous coronary intervention was higher than the reported mortality for ST-elevation myocardial infarction patients at 1 year. Agreement between computerized and human ECG interpretation is poor, perhaps leading to a high rate of inappropriate referrals. Work is needed to improve computer and human decision making when reading ECGs to ensure that patients are referred to the correct treatment facility for time-critical therapy.
Cyberbullying victimization and depression: self-esteem as a mediator and approach coping strategies as moderators

Abstract Objective: The percentage of victims of cyberbullying among college students seems to increase. However, research on the mechanisms by which cyberbullying victimization (CV) suffer from depression is scarce. This study has purpose to figure out the mediating role of self-esteem (SE) as well as the moderating role of approach coping strategies in the association between CV and depression among Vietnamese college students. Methods: A total of 606 Vietnamese university students completed the Self-Esteem Scale, The Self-Report Coping Scale, The cyberbullying victimization scale, DASS 21. Results: The results indicated that SE partially mediated the relation between CV and depression among Vietnamese college students as well as approach coping strategies moderated the involvement between CV and depression among Vietnamese college students. Conclusions: Our findings can help psychological service providers identify the methods by which cyberbullying sufferers related to depression and provide interventions to reduce depression for cyberbullying victims.
Estimation of change in pleural pressure in assisted and unassisted spontaneous breathing pediatric patients using fluctuation of central venous pressure: A preliminary study

Background It is important to evaluate the size of respiratory effort to prevent patient self-inflicted lung injury and ventilator-induced diaphragmatic dysfunction. Esophageal pressure (Pes) measurement is the gold standard for estimating respiratory effort, but it is complicated by technical issues. We previously reported that a change in pleural pressure (ΔPpl) could be estimated without measuring Pes using change in CVP (ΔCVP) that has been adjusted with a simple correction among mechanically ventilated, paralyzed pediatric patients. This study aimed to determine whether our method can be used to estimate ΔPpl in assisted and unassisted spontaneous breathing patients during mechanical ventilation. Methods The study included hemodynamically stable children (aged <18 years) who were mechanically ventilated, had spontaneous breathing, and had a central venous catheter and esophageal balloon catheter in place. We measured the change in Pes (ΔPes), ΔCVP, and ΔPpl that was calculated using a corrected ΔCVP (cΔCVP-derived ΔPpl) under three pressure support levels (10, 5, and 0 cmH2O). The cΔCVP-derived ΔPpl value was calculated as follows: cΔCVP-derived ΔPpl = k × ΔCVP, where k was the ratio of the change in airway pressure (ΔPaw) to the ΔCVP during airway occlusion test. Results Of the 14 patients enrolled in the study, 6 were excluded because correct positioning of the esophageal balloon could not be confirmed, leaving eight patients for analysis (mean age, 4.8 months). Three variables that reflected ΔPpl (ΔPes, ΔCVP, and cΔCVP-derived ΔPpl) were measured and yielded the following results: -6.7 ± 4.8, − -2.6 ± 1.4, and − -7.3 ± 4.5 cmH2O, respectively. The repeated measures correlation between cΔCVP-derived ΔPpl and ΔPes showed that cΔCVP-derived ΔPpl had good correlation with ΔPes (r = 0.84, p< 0.0001). Conclusions ΔPpl can be estimated reasonably accurately by ΔCVP using our method in assisted and unassisted spontaneous breathing children during mechanical ventilation.
Tetrandrine attenuates ischemia/reperfusion-induced neuronal damage in the subacute phase

Ischemic stroke, the third leading cause of disability globally, imposes a notable economic burden. Tetrandrine (Tet), which has been widely used clinically, exhibits potential protective effects against stroke. However, there has been little pre-clinical research to evaluate the therapeutic effects of Tet on stroke. The present study investigated the beneficial effect of Tet on ischemia-reperfusion (I/R) injury and its underlying mechanism in rats. Rats were subjected to occlusion of the middle cerebral artery, then treated with Tet (30 mg/kg/day, intraperitoneal) in the subacute phase for 7 days. In order to detect the effects of Tet on the behavior of rats, modified neurological severity score and longa behavior, grasping capability and inclined plane tests were conducted on days 1, 3 and 7 following cerebral ischemia. In addition, neuronal apoptosis in the cortex and hippocampus following ischemia was assessed by Nissl staining and TUNEL assay. Finally, oxidative stress was evaluated by measurement of free radicals and immunofluorescence staining of LC3 was used to assess autophagy. Tet improved neurological function and decreased infarct volume in I/R injury rats. Tet also prevented neuronal apoptosis in the cortex and hippocampus region. In addition, Tet protected against oxidative damage following ischemia, which was reflected by decreased levels of nitric oxide and malondialdehyde and increased levels of glutathione (GSH) and GSH peroxidase. In addition, the expression levels of the autophagy marker LC3 decreased in the Tet treatment group. In conclusion, Tet attenuated I/R-induced neuronal damage in the subacute phase by decreasing oxidative stress, apoptosis and autophagy.
Population pharmacokinetic analysis of apomorphine sublingual film or subcutaneous apomorphine in healthy subjects and patients with Parkinson’s disease

Apomorphine is an on‐demand treatment of “OFF” episodes in patients with Parkinson’s disease (PD). A joint parent‐metabolite population pharmacokinetic (PK) model characterized apomorphine and apomorphine‐sulfate following administration of apomorphine sublingual film (APL) and two formulations of subcutaneous apomorphine. Overall, 2485 samples from 87 healthy subjects and 71 patients with PD and “OFF” episodes were analyzed using nonlinear mixed‐effects modeling. Apomorphine PK was adequately described by a two‐compartment model with first‐order transit absorption via both routes of administration and first‐order metabolism to apomorphine‐sulfate with one‐compartment disposition and first‐order elimination. Bioavailability of apomorphine sublingual film was ~ 18% relative to subcutaneous apomorphine. Among covariates tested, only body weight had a large effect on apomorphine exposure (maximum plasma concentration and area under the concentration–time curve [AUC0–∞]), with greater weight resulting in lower exposure. Model‐predicted apomorphine exposure was similar between apomorphine sublingual film 30 mg and subcutaneous apomorphine 5 mg (median AUC0–24, 66.7 ng•h/mL, geometric mean ratio of 0.99; 90% confidence interval [CI], 0.96−1.03) and was comparable between apomorphine sublingual film 35 mg and subcutaneous apomorphine 6 mg (median AUC0–24, 75.4 and 80.0 ng•h/mL, respectively; geometric mean ratio of 0.94; 90% CI, 0.90−0.97) administered every 2 h for a maximum of 5 doses per day. In a typical patient with PD, predicted apomorphine exposure increased with increasing doses of apomorphine sublingual film; however, the increase was less than dose proportional. Similar apomorphine exposure was predicted in patients with mild renal impairment versus normal renal function. PK properties of apomorphine sublingual film support its administration for a wide range of patients with PD and “OFF” episodes, regardless of demographic and clinical characteristics.
Accuracy and comparison of two rapid multiplex PCR tests for gastroenteritis pathogens: a systematic review and meta-analysis

Objectives The primary aim is to provide a summary of evidence for the diagnostic accuracies of multiplex PCR gastrointestinal (GI) panels—BioFire FilmArray and Luminex xTAG on the detection of gastroenteritis pathogens. The secondary aim is to compare the performance of these GI panels head to head. Methods A comprehensive search up to 1 December 2019 was conducted on PubMed, Embase, Ovid Medline and Web of Science for studies that used FilmArray or Luminex xTAG Gastrointestinal Pathogen Panel (GPP) for diagnosis of acute gastroenteritis. A summary of diagnostic accuracies for the 16 pathogens were calculated by comparing the GI panels to the current gold standards (conventional standard microbiology techniques such as culture or PCR for bacteria, PCR or enzyme immunoassay (EIA) for viruses, microscopy or EIA for parasite). Hierarchical summary receiver operating characteristic (HSROC) curve analysis, pretest and post-test probabilities were used for estimating the pathogen detection performance. Results A total of 11 studies with 7085 stool samples were eligible for analysis. Multiplex PCRs demonstrated high diagnostic accuracy, with specificity ≧0.98 and area under the ROC curve (AUROC) ≧0.97 for all the pathogens except for Yersinia enterocolitica (AUROC 0.91). The FilmArray panel demonstrated a higher sensitivity than xTAG GPP for most of the pathogens with the exception of Rotavirus A (xTAG GPP and FilmArray were both 0.93). Conclusions This is the first meta-analysis that is a head-to-head comparison examining the performance of the novel multiplex PCR-based tests Luminex xTAG GPP and FilmArray GI panel in detecting each pathogen. Point estimates calculated from eligible studies showed that both GI panels are highly accurate and may provide important diagnostic information for early identification of gastroenteritis. In addition, although FilmArray has higher sensitivity and post-test probability than xTAG GPP for most of the pathogens, how this will translate to a clinical setting remains unclear.
Experimentally-manipulated perceptions of good sleep predict greater reactivity to and poorer recovery from a social stressor in university students

Abstract Objective The present study was conducted to examine the impact of experimentally-manipulated perceptions of sleep on self-reported affective reactivity and recovery from a social stressor in undergraduate students. Design The study design is experimental, as the participants were randomly assigned to either good or poor perceived sleep quality conditions. Main outcome measures The impact of condition on self-reported affective responses to and recovery from the social stressor were assessed as well as whether the observed effects were moderated by stress, rumination, and depression. Results Participants in the good sleep condition reported increased negative affect (NA) after the social stressor and after a six-minute recovery period relative to participants in the poor sleep condition; participants in the former condition also reported heightened NA post-recovery relative to baseline (a comparison that was non-significant for participants in the poor sleep condition). The effect of condition on NA post-stressor and post-recovery was moderated by depression and rumination, with important implications for participants in the good sleep condition in particular. Conclusions These findings may have resulted from participant expectations about the impacts of sleep on their behaviour, although additional research remains to be conducted to identify the mechanism responsible for the obtained pattern of results.
“Here Comes the Junkies,” Opioid Replacement Therapy in Rural Australia

Abstract Background Opioid replacement therapy (ORT) offers a harm minimization approach and is the mainstay treatment option for opioid dependence in Australia. Recovery is known to be complicated because of service access, cost, workforce availability, privacy, stigma, and discrimination. Rural living is considered to magnify each complication of recovery, yet little is understood about how opioid dependence recovery is experienced in rural Australia. This study aimed to explore the lived experience of people receiving ORT in rural Australia and describe impediments to recovery. Methods In this qualitative study design, all outpatients enrolled in ORT at two rural Australian sites were invited to participate. Six volunteers from each site participated in a semistructured interview (eight men, four women; mean age = 44.8 years). Results The participants had completed 3 years of secondary school education on average. Four major themes emerged: reinvention, restriction, employment, and reconnection. Small communities increased the likelihood of ORT participants knowing people both directly and indirectly, affecting their ability to reconstruct an identity. Lived distance from prescribers and dosing points dictated daily activity, including opportunities to seek and maintain employment. Rural ORT treatment seekers indicated that geographical displacement and separation from family, the people they needed to reconnect with, were challenging. Conclusion Rural people engaged in ORT require positive reinforcement from service providers, enabling identity reinvention and disconnection from the drug-seeking world. Acknowledging underlying trauma and supporting reconnection with loved ones may foster positive social connectedness.
Symbiotic bracovirus of a parasite manipulates host lipid metabolism via tachykinin signaling

Parasites alter host energy homeostasis for their own development, but the mechanisms underlying this phenomenon remain largely unknown. Here, we show that Cotesia vestalis, an endoparasitic wasp of Plutella xylostella larvae, stimulates a reduction of host lipid levels. This process requires excess secretion of P. xylostella tachykinin (PxTK) peptides from enteroendocrine cells (EEs) in the midgut of the parasitized host larvae. We found that parasitization upregulates PxTK signaling to suppress lipogenesis in midgut enterocytes (ECs) in a non-cell-autonomous manner, and the reduced host lipid level benefits the development of wasp offspring and their subsequent parasitic ability. We further found that a C. vestalis bracovirus (CvBV) gene, CvBV 9–2, is responsible for PxTK induction, which in turn reduces the systemic lipid level of the host. Taken together, these findings illustrate a novel mechanism for parasite manipulation of host energy homeostasis by a symbiotic bracovirus gene to promote the development and increase the parasitic efficiency of an agriculturally important wasp species.
The impact of public coverage of newer hepatitis C medications on utilization, adherence, and costs in British Columbia

Background Sofosbuvir and ledipasvir-sofosbuvir are both newer direct-acting antiviral agents for the treatment of hepatitis C. The high list prices for both drugs have led to concern about the budget impact for public drug coverage programs. Therefore, we studied the impact of public prescription drug coverage for both drugs on utilization, adherence, and public and private expenditure in British Columbia, Canada. Methods We used provincial administrative claims data from January 2014 to June 2017 for all individuals historically tested for either hepatitis C and/or human immunodeficiency virus. Using interrupted time series analysis, we examined the impact of public insurance coverage on treatment uptake, adherence (proportion of days covered), and public and private expenditures. Results Over our study period, 4,462 treatment initiations were eligible for analysis (1,131 sofosbuvir and 3,331 ledipasvir-sofosbuvir, which include 19 patients initiated on both treatments). We found the start of public coverage for sofosbuvir and ledipasvir-sofosbuvir increased treatment uptake by 154%. Adherence rates were consistently high and did not change with public coverage. Finally, public expenditure increased after the policy change, and crowded out some private expenditure. Conclusion Public coverage for high-cost drugs for hepatitis C dramatically increased use of these drugs, but did not reduce adherence. From a health policy perspective, public payers should be prepared for increased treatment uptake following the availability of public coverage. However, they should not be concerned that populations without private insurance coverage will be less adherent and not finish their treatment course.
Structural basis for IFN antagonism by human respiratory syncytial virus nonstructural protein 2

Significance The human respiratory syncytial virus (RSV) is a significant cause of lower respiratory tract infections in the young and the elderly and a substantial burden to global human health. Currently, there are no specific and effective treatments for RSV infections. Here we report the first X-ray crystal structure of RSV nonstructural protein 2 (NS2), which revealed a unique fold. The combined biochemical and structural analyses of the NS2 structure identified a region that binds to and inhibits ubiquitination of an inactive form of RIG-I and MDA5, preventing downstream signaling and type I interferon production. Our study provides structural insight into the mechanism of how NS2 antagonizes IFN response to RSV infection and defines a target for antiviral development. Human respiratory syncytial virus (RSV) nonstructural protein 2 (NS2) inhibits host interferon (IFN) responses stimulated by RSV infection by targeting early steps in the IFN-signaling pathway. But the molecular mechanisms related to how NS2 regulates these processes remain incompletely understood. To address this gap, here we solved the X-ray crystal structure of NS2. This structure revealed a unique fold that is distinct from other known viral IFN antagonists, including RSV NS1. We also show that NS2 directly interacts with an inactive conformation of the RIG-I–like receptors (RLRs) RIG-I and MDA5. NS2 binding prevents RLR ubiquitination, a process critical for prolonged activation of downstream signaling. Structural analysis, including by hydrogen-deuterium exchange coupled to mass spectrometry, revealed that the N terminus of NS2 is essential for binding to the RIG-I caspase activation and recruitment domains. N-terminal mutations significantly diminish RIG-I interactions and result in increased IFNβ messenger RNA levels. Collectively, our studies uncover a previously unappreciated regulatory mechanism by which NS2 further modulates host responses and define an approach for targeting host responses.