Miracle-dz/UniFAR-FTUs huggingface dataset:
Coxsackievirus B3 Infection Triggers Autophagy through 3 Pathways of Endoplasmic Reticulum Stress

Abstract Objective Autophagy is a highly conserved intracellular degradation pathway. Many picornaviruses induce autophagy to benefit viral replication, but an understanding of how autophagy occurs remains incomplete. In this study, we explored whether coxsackievirus B3 (CVB3) infection induced autophagy through endoplasmic reticulum (ER) stress. Methods In CVB3-infected HeLa cells, the specific molecules of ER stress and autophagy were detected using Western blotting, reverse transcription polymerase chain reaction (RT-PCR), and confocal microscopy. Then PKR-like ER protein kinase (PERK) inhibitor, inositol-requiring protein-1 (IRE1) inhibitor, or activating transcription factor-6 (ATF6) inhibitor worked on CVB3-infected cells, their effect on autophagy was assessed by Western blotting for detecting microtubule-associated protein light chain 3 (LC3). Results CVB3 infection induced ER stress, and ER stress sensors PERK/eIF2α, IRE1/XBP1, and ATF6 were activated. CVB3 infection increased the accumulation of green fluorescent protein (GFP)-LC3 punctuation and induced the conversion from LC3-I to phosphatidylethanolamine-conjugated LC3-1 (LC3-II). CVB3 infection still decreased the expression of mammalian target of rapamycin (mTOR) and p-mTOR. Inhibition of PERK, IRE1, or ATF6 significantly decreased the ratio of LC3-II to LC3-I in CVB3-infected HeLa cells. Conclusion CVB3 infection induced autophagy through ER stress in HeLa cells, and PERK, IRE1, and ATF6a pathways participated in the regulation of autophagy. Our data suggested that ER stress may inhibit mTOR signaling pathway to induce autophagy during CVB3 infection.
Legalization of Medical Cannabis and Potential Implications for Healthcare Delivery in the United States

Cannabis legalization is currently a topic of significant interest within the American healthcare system. Existing research has demonstrated the effects of medical cannabis in alleviating manifestations of several common health conditions which affect many Americans, including cancer and chronic pain. Additionally, research has demonstrated that medical cannabis programs have positive implications for the objectives of government health initiatives such as the Institute for Healthcare Improvement (IHI) Triple Aim. Economic benefits from cannabis taxation have also been documented in states with active medical cannabis programs. While federal restrictions inhibit extensive cannabis research, the legalization of medical cannabis has significant implications for the American healthcare system in terms of cost, access, and quality. This paper is a review of current literature and research regarding medical cannabis legalization in the United States.
Combined targeted DNA and RNA sequencing of advanced NSCLC in routine molecular diagnostics: Analysis of the first 3,000 Heidelberg cases

Tyrosine kinase inhibitors currently confer the greatest survival gain for nonsmall cell lung cancer (NSCLC) patients with actionable genetic alterations. Simultaneously, the increasing number of targets and compounds poses the challenge of reliable, broad and timely molecular assays for the identification of patients likely to benefit from novel treatments. Here, we demonstrate the feasibility and clinical utility of comprehensive, NGS‐based genetic profiling for routine workup of advanced NSCLC based on the first 3,000 patients analyzed in our department. Following automated extraction of DNA and RNA from formalin‐fixed, paraffin‐embedded tissue samples, parallel sequencing of DNA and RNA for detection of mutations and gene fusions, respectively, was performed using PCR‐based enrichment with an ion semiconductor sequencing platform. Overall, 807 patients (27%) were eligible for currently approved, EGFR‐/BRAF‐/ALK‐ and ROS1‐directed therapies, while 218 additional cases (7%) with MET, ERBB2 (HER2) and RET alterations could potentially benefit from experimental targeted compounds. In addition, routine capturing of comutations, e.g. TP53 (55%), KEAP1 (11%) and STK11 (11%), as well as the precise typing of fusion partners and involved exons in case of actionable translocations including ALK and ROS1, are prognostic and predictive tools currently gaining importance for further refinement of therapeutic and surveillance strategies. The reliability, low dropout rates (<5%), minimal tissue requirements, fast turnaround times (6 days on average) and lower costs of the diagnostic approach presented here compared to sequential single‐gene testing, highlight its practicability in order to support individualized decisions in routine patient care, enrollment in molecularly stratified clinical trials, as well as translational research.
Monoclonal antibody 197 (anti‐FcγRI) infusion in a patient with immune thrombocytopenia purpura (ITP) results in down‐modulation of FcγRI on circulating monocytes

A 44‐year‐old woman with refractory immune thrombocytopenia purpura was treated with the murine monoclonal antibody 197 in a phase I trial. In vitro studies have demonstrated that the monoclonal antibody 197 (subclass IgG2a) binds to two distinct epitopes of FcγRI, with the constant domain binding to the Fc‐binding portion of the FcγRI and the variable domain binding to a different epitope, resulting in crosslinking and modulation of this receptor. The monoclonal antibody 197 was administered on days 1, 3 and 5 at doses of 0.25 mg/kg, 0.35 mg/kg and 0.45 mg/kg, respectively. The infusions were well tolerated with transient facial flushing, and wheal‐and‐flare rash during the first infusion, which resolved with a slower infusion rate and the administration of diphenhydramine and acetaminophen. Although a marked clinical improvement did occur with resolution of oral ecchymoses and epistaxis after the first mAb infusion, the initial platelet count of 6×109 l did not change appreciably over the 5 d course of monoclonal antibody treatment. Binding of fluorescein‐labelled monoclonal antibody 197 to peripheral monocytes showed a rapid and persistently decreased mean fluorescence intensity, indicating binding of administered 197 to the monocytes in vivo. Indirect staining for FcγRI using fluorescein‐labelled goat anti‐mouse immunoglobulin was also decreased, suggesting modulation of the receptor. The patient experienced monocytopenia which persisted throughout the 5 d of monoclonal antibody 197 therapy, but reversed following institution of intravenous IgG. These data indicate that intravenous monoclonal antibody 197 induces specific down‐modulation of FcγRI expression on monocytes.
Effect of Penalty Minute Rule Change on Injuries and Game Disqualification Penalties in High School Ice Hockey

Background: Recent efforts have focused on eliminating dangerous hits in ice hockey. Fair play rule changes have successfully reduced injury risk but have not been widely implemented. Purpose: To determine the effect of a penalty infraction minutes (PIM) rule change in high school boys’ ice hockey on injuries and game disqualification penalties. Study Design: Cohort study; Level of evidence, 3. Methods: Injury data were collected from 2 Rhode Island hospital systems and game/penalty data through the Rhode Island Hockey Coaches Association website. Participants included high school boys’ hockey varsity players aged 13 to 19 years presenting to 5 emergency departments for hockey injuries during 6 seasons (December 2012–April 2018). Rule change for the 2015-2016 season implemented varying suspensions for players accumulating ≥50 PIM and ≥70 PIM during regular season and playoffs. Injuries were classified as body checking or non–body checking related, and injury rates pre– versus post–rule change were compared via the Cochran-Mantel-Haenszel chi-square test with the odds ratio (OR) to measure risk reduction. Results: During the study period, 1762 boys’ high school varsity hockey games were played. Of 134 game-related injuries, 82 (61.2%) were attributable to body checking. The PIM rule change was associated with a significant reduction in all injuries (OR, 0.55; 95% CI, 0.35-0.86; P = .008), concussion/closed head injury (OR, 0.44; 95% CI, 0.23-0.85; P = .012), and combined subgroups of concussion/closed head injury and upper body injury (OR, 0.50; 95% CI, 0.31-0.80; P = .003). Game disqualification penalties per season were not significantly reduced following the rule change, occurring in 5.2% of games before the rule change and 4.4% of games after (OR, 0.84; 95% CI, 0.54-1.31; P = .440). Conclusion: Implementation of a statewide PIM restriction rule change effectively reduced the mean number of game-related injuries per season among high school boys’ hockey varsity players.
Nonlinear Processing of Shape Information in Rat Lateral Extrastriate Cortex

In rodents, the progression of extrastriate areas located laterally to primary visual cortex (V1) has been assigned to a putative object-processing pathway (homologous to the primate ventral stream), based on anatomical considerations. Recently, we found functional support for such attribution (Tafazoli et al., 2017), by showing that this cortical progression is specialized for coding object identity despite view changes, the hallmark property of a ventral-like pathway. Here, we sought to clarify what computations are at the base of such specialization. To this aim, we performed multielectrode recordings from V1 and laterolateral area LL (at the apex of the putative ventral-like hierarchy) of male adult rats, during the presentation of drifting gratings and noise movies. We found that the extent to which neuronal responses were entrained to the phase of the gratings sharply dropped from V1 to LL, along with the quality of the receptive fields inferred through reverse correlation. Concomitantly, the tendency of neurons to respond to different oriented gratings increased, whereas the sharpness of orientation tuning declined. Critically, these trends are consistent with the nonlinear summation of visual inputs that is expected to take place along the ventral stream, according to the predictions of hierarchical models of ventral computations and a meta-analysis of the monkey literature. This suggests an intriguing homology between the mechanisms responsible for building up shape selectivity and transformation tolerance in the visual cortex of primates and rodents, reasserting the potential of the latter as models to investigate ventral stream functions at the circuitry level. SIGNIFICANCE STATEMENT Despite the growing popularity of rodents as models of visual functions, it remains unclear whether their visual cortex contains specialized modules for processing shape information. To addresses this question, we compared how neuronal tuning evolves from rat primary visual cortex (V1) to a downstream visual cortical region (area LL) that previous work has implicated in shape processing. In our experiments, LL neurons displayed a stronger tendency to respond to drifting gratings with different orientations while maintaining a sustained response across the whole duration of the drift cycle. These trends match the increased complexity of pattern selectivity and the augmented tolerance to stimulus translation found in monkey visual temporal cortex, thus revealing a homology between shape processing in rodents and primates.
Higher serum VGF protein levels discriminate bipolar depression from major depressive disorder

Misdiagnosis between major depressive disorder (MDD) and bipolar depression (BD) is quite common. Our previous study found significantly lower serum VGF (non‐acronymic) in MDD patients. However, it is unclear whether same changes occur in BD patients. Therefore, we aimed to investigate the relationship between serum VGF levels in BD and MDD patients. General information, scores of 17‐item Hamilton Depression Rating Scale (HDRS), and fasting blood samples of all participants including 30 MDD patients, 20 BD patients, and 30 healthy controls (HC) were collected. Serum VGF levels were measured by Enzyme‐linked immunosorbent assay kits. Pearson correlation analysis was used to analyze correlations between serum VGF levels and clinical information. Receiver operating characteristic (ROC) curve and likelihood ratios (LRs) were used to analyze the differential potential of serum VGF. Serum VGF levels were significantly lower in MDD patients but higher in BD patients compared with HC (both PTukey < 0.01). No correlation was found between serum VGF levels and any data of subjects. The optimal cutoff for serum VGF in discriminating BD patients from MDD patients was ≥1093.85 pg/ml (AUC = 0.990, sensitivity of 95%, specificity of 100% and accuracy of 95%). LRs further confirmed the differential efficiency of serum VGF in distinguishing BD and MDD patients with +LR of infinity and –LR of 0. The results suggest that serum VGF level changed significantly in MDD and BD patients and serum VGF may be an indicator for differentiating BD patients from MDD patients.
Chest Compressions in the Delivery Room

Annually, an estimated 13–26 million newborns need respiratory support and 2–3 million newborns need extensive resuscitation, defined as chest compression and 100% oxygen with or without epinephrine in the delivery room. Despite such care, there is a high incidence of mortality and neurologic morbidity. The poor prognosis associated with receiving chest compression alone or with medications in the delivery room raises questions as to whether improved cardiopulmonary resuscitation methods specifically tailored to the newborn could improve outcomes. This review discusses the current recommendations, mode of action, different compression to ventilation ratios, continuous chest compression with asynchronous ventilations, chest compression and sustained inflation optimal depth, and oxygen concentration during cardiopulmonary resuscitation.
Genetic regulation of the placental transcriptome underlies birth weight and risk of childhood obesity

GWAS identified variants associated with birth weight (BW), childhood obesity (CO) and childhood BMI (CBMI), and placenta is a critical organ for fetal development and postnatal health. We examined the role of placental transcriptome and eQTLs in mediating the genetic causes for BW, CO and CBMI, and applied integrative analysis (Colocalization and MetaXcan). GWAS loci associated with BW, CO, and CBMI were substantially enriched for placenta eQTLs (6.76, 4.83 and 2.26 folds, respectively). Importantly, compared to eQTLs of adult tissues, only placental eQTLs contribute significantly to both anthropometry outcomes at birth (BW) and childhood phenotypes (CO/CBMI). Eight, six and one transcripts colocalized with BW, CO and CBMI risk loci, respectively. Our study reveals that placental transcription in utero likely plays a key role in determining postnatal body size, and as such may hold new possibilities for therapeutic interventions to prevent childhood obesity.
South African women's perspectives on self-sampling for cervical cancer screening: A mixed-methods study.

BACKGROUND Self-sampling as a method of screening for cervical cancer and its precursors is an attractive option for low-resource settings. However, to allow successful integration of self-sampling into national screening programmes, it is necessary to understand women's perceptions and beliefs surrounding this method of sampling the cervix. OBJECTIVES To explore women's attitudes to self-collection of samples for cervical screening in a low-resource setting in South Africa (SA). METHODS Mixed methods were used to meet the study objectives. We recruited women aged 30 - 65 years into a study in Cape Town, SA, to participate in a cross-sectional survey. All women collected a vaginal self-sample, and underwent visual inspection with acetic acid, colposcopy, and collection of cervical samples and appropriate histology specimens by a doctor. Women had a quantitative questionnaire-based exit interview. A subset of these women participated in focus group discussions (FGDs). RESULTS A total of 822 women answered the exit survey questionnaire and 41 women participated in the FGDs. Most women from the survey had a positive perception of self-sampling, with 93.6% of the women reporting not feeling embarrassed and 89.4% reporting experiencing no discomfort at all when taking a self-sample. This was corroborated by the FGD participants, who found self-sampling easier, more comfortable and less embarrassing than clinician sampling. However, many women (64.7%) felt more confident when the sample was taken by a clinician, despite having a positive attitude towards self-sampling. In most cases this was because they thought that the clinician would take a better sample, as explained by the FGD participants. Although 93.9% of the women were willing to collect a self-sample, the women in the FGDs expressed a preference for doing so at the health facility rather than at home. There were many reasons for this, including the cost of returning to the clinic with the sample. CONCLUSIONS Attitudes regarding self-sample collection were positive in this study population. Participants were willing to perform self-sampling, but expressed concerns regarding the quality of the specimen and the financial implications of returning to the clinic with it. Pilot implementation studies will be useful before this method of sampling is adopted and integrated into screening programmes.
Distinct timescales of RNA regulators enable the construction of a genetic pulse generator

To build complex genetic networks with predictable behaviours, synthetic biologists use libraries of modular parts that can be characterized in isolation and assembled together to create programmable higher-order functions. Characterization experiments and computational models for gene regulatory parts operating in isolation are routinely employed to predict the dynamics of interconnected parts and guide the construction of new synthetic devices. Here, we individually characterize two modes of RNA-based transcriptional regulation, using small transcription activating RNAs (STARs) and CRISPR interference (CRISPRi), and show how their distinct regulatory timescales can be used to engineer a composed feedforward loop that creates a pulse of gene expression. We use a cell-free transcription-translation system (TXTL) to rapidly characterize the system, and we apply Bayesian inference to extract kinetic parameters for an ODE-based mechanistic model. We then demonstrate in simulation and verify with TXTL experiments that the simultaneous regulation of a single gene target with STARs and CRISPRi leads to a pulse of gene expression. Our results suggest the modularity of the two regulators in an integrated genetic circuit, and we anticipate that construction and modeling frameworks that can leverage this modularity will become increasingly important as synthetic circuits increase in complexity.
Luspatercept improves hemoglobin levels and blood transfusion requirements in a study of patients with β-thalassemia.

β-thalassemia is a hereditary disorder with limited approved treatment options; patients experience anemia and its complications, including iron overload. The study aim was to determine whether luspatercept could improve anemia and disease complications in patients with β-thalassemia. This open-label, nonrandomized, uncontrolled study consisted of a 24-week dose-finding and expansion stage (initial stage) and a 5-year extension stage, currently ongoing. Sixty-four patients were enrolled; 33 were non-transfusion dependent (mean hemoglobin, <10.0 g/dL; <4 red blood cell [RBC] units transfused per 8 weeks), and 31 were transfusion dependent (≥4 RBC units per 8 weeks). Patients received 0.2 to 1.25 mg/kg luspatercept subcutaneously every 21 days for ≥5 cycles (dose-finding stage) and 0.8 to 1.25 mg/kg (expansion cohort and 5-year extension). The primary end point was erythroid response, defined as hemoglobin increase of ≥1.5 g/dL from baseline for ≥14 consecutive days (without RBC transfusions) for non-transfusion-dependent patients or RBC transfusion burden reduction ≥20% over a 12-week period vs the 12 weeks before treatment for transfusion-dependent patients. Eighteen non-transfusion-dependent patients (58%) receiving higher dose levels of luspatercept (0.6-1.25 mg/kg) achieved mean hemoglobin increase ≥1.5 g/dL over ≥14 days vs baseline. Twenty-six (81%) transfusion-dependent patients achieved ≥20% reduction in RBC transfusion burden. The most common grade 1 to 2 adverse events were bone pain, headache, and myalgia. As of the cutoff, 33 patients remain on study. In this study, a high percentage of β-thalassemia patients receiving luspatercept had hemoglobin or transfusion burden improvements. These findings support a randomized clinical trial to assess efficacy and safety. This study was registered at www.clinicaltrials. gov as #NCT01749540 and #NCT02268409.
Vaccination and Host Marek's Disease-Resistance Genotype Significantly Reduce Oncogenic Gallid alphaherpesvirus 2 Telomere Integration in Host Birds

Marek's disease (MD) is an infectious disease characterized by lymphomas and high mortality in susceptible chickens. The causative and ubiquitous alpha-herpesvirus known as MD virus (MDV) integrates into host telomeres during early infection through latency, known to be an important phase for oncogenic transformation. Herein, we sought to determine the influence of vaccination and host genetics on the temporal dynamics of MDV-host genome interactions. We studied integration profiles using 2 MD vaccines that vary in protective efficacy in 2 genetic lines that differ in MD resistance/susceptibility. Virus integration of both oncogenic MDV and vaccine strains was observed in both MD susceptible and resistant birds, however, the lines differed in their dynamic telomere-integration profiles. Notably, the resistant host genotype exhibited a smaller percentage of replicating cells with the virus telomere-integrated only phenotype as compared to the susceptible genotype. Vaccination with Rispens, the most protective MD vaccine, also reduced the establishment of the virus telomere-integrated only phenotype, suggesting a significant role of the phenotype in MD lymphoma development. The effect of Rispens vaccination was most dramatic in the susceptible genotype. These results suggest important connections between vaccinal immunity, MDV telomere integration, virus-induced oncogenesis, and virus-host genome interactions in the context of host genetics and disease susceptibility.