A Yeast Model of FUS/TLS-Dependent Cytotoxicity

FUS/TLS is a nucleic acid binding protein that, when mutated, can cause a subset of familial amyotrophic lateral sclerosis (fALS). Although FUS/TLS is normally located predominantly in the nucleus, the pathogenic mutant forms of FUS/TLS traffic to, and form inclusions in, the cytoplasm of affected spinal motor neurons or glia. Here we report a yeast model of human FUS/TLS expression that recapitulates multiple salient features of the pathology of the disease-causing mutant proteins, including nuclear to cytoplasmic translocation, inclusion formation, and cytotoxicity. Protein domain analysis indicates that the carboxyl-terminus of FUS/TLS, where most of the ALS-associated mutations are clustered, is required but not sufficient for the toxicity of the protein. A genome-wide genetic screen using a yeast over-expression library identified five yeast DNA/RNA binding proteins, encoded by the yeast genes ECM32, NAM8, SBP1, SKO1, and VHR1, that rescue the toxicity of human FUS/TLS without changing its expression level, cytoplasmic translocation, or inclusion formation. Furthermore, hUPF1, a human homologue of ECM32, also rescues the toxicity of FUS/TLS in this model, validating the yeast model and implicating a possible insufficiency in RNA processing or the RNA quality control machinery in the mechanism of FUS/TLS mediated toxicity. Examination of the effect of FUS/TLS expression on the decay of selected mRNAs in yeast indicates that the nonsense-mediated decay pathway is probably not the major determinant of either toxicity or suppression.Fidelity Biosciences (Firm)Fidelity Biosciences (Firm) (Research Inititative)ALS Therapy AllianceNational Institutes of Health (U.S.) (NIH 1RC1NS06839)National Institutes of Health (U.S.) (NIH U01NS05225-03)National Institutes of Health (U.S.) (NIH R01NS050557-05)National Institutes of Health (U.S.) (NIH 1RC2NS070342-01)Pierre L. de Bourgknecht ALS Research FoundationNational Science Foundation (U.S.) (NS614192

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

An open-label pilot study to explore usefulness of Homoeopathic treatment in nonerosive gastroesophageal reflux disease

Background and Aim: Nonerosive gastroesophageal reflux disease or nonerosive reflux disease (NERD) is characterized by troublesome reflux-related symptoms in the absence of esophageal erosions/breaks at conventional endoscopy. There are a number of medicines cited in homoeopathic literature which can be used for treatment of symptoms such as heartburn and regurgitation. A pilot study was undertaken to explore usefulness of homoeopathic medicines in treatment of NERD. Methodology: In this study, 78 patients were screened and 34 were enrolled, having symptoms of heartburn and/or regurgitation at least twice a week, having a gastroesophageal reflux disease (GERD) symptom score of more than 4. Homoeopathic medicine was prescribed on the basis of presenting symptoms. Response to treatment was assessed on GERD symptom score, visual analog scale (VAS) for heartburn, and World Health Organization quality of life-BREF (WHO-QOL) questionnaire evaluated at baseline and at end of 8 weeks of treatment . Results: Significant difference was found in pre- and post-treatment GERD symptom score (8.79 ± 2.7 vs. 0.76 ± 1.8; P = 0.001) and VAS for heartburn (47.47 ± 19.6 vs. 5.06 ± 11.8; P = 0.001). Statistically significant improvement was seen in three domains of WHO-QOL score, i.e. psychological health, social relationship, and environmental domain. Conclusion: The findings are encouraging to open avenues for further studies on reflux disease

Aggravation of seizures and/or EEG features in children treated with oxcarbazepine monotherapy.

PURPOSE: Exacerbation of epilepsy may occur following initiation of therapy with antiepileptic drugs (AEDs). The aim of this study is to analyze the clinical and EEG characteristics of a group of pediatric patients with worsening of seizures and/or EEG deterioration while on oxcarbazepine (OXC). METHODS: A retrospective analysis of a clinical database was performed to identify patients with epilepsy treated with OXC over the past 3 years. History, neurological examination, and EEG findings were reviewed to identify any who had developed exacerbation of seizures or new abnormalities on EEG. RESULTS: Of 290 patients on OXC, we identified 12 patients with new onset seizures, all with initial normal neurological exam and normal EEG, who developed either worsening of preexisting seizures, new seizure types, and/or EEG deterioration following introduction of OXC monotherapy. EEG changes were primarily characterized by new onset of generalized epileptiform activity not reported on the initial baseline EEG. Following substitution of OXC with a broad spectrum AED, significant improvement of seizure control and improvement in the EEG was observed. CONCLUSIONS: These findings suggest that OXC can aggravate seizures and/or worsen EEG features in children. Following initiation of therapy with OXC, monitoring of patients with follow-up EEGs may be important, especially in patients who do not show adequate response to therapy