Ablation of elongation factor 2 kinase enhances heat-shock protein 90 chaperone expression and protects cells under proteotoxic stress

Eukaryotic elongation factor 2 kinase (eEF2K) negatively regulates the elongation stage of mRNA translation and is activated under different stress conditions to slow down protein synthesis. One effect of eEF2K is to alter the repertoire of expressed proteins, perhaps to aid survival of stressed cells. Here, we applied pulsed stable isotope labeling with amino acids in cell culture (SILAC) to study changes in the synthesis of specific proteins in human lung adenocarcinoma (A549) cells in which eEF2K had been depleted by an inducible shRNA. We discovered that levels of heat-shock protein 90 (HSP90) are increased in eEF2K-depleted human cells as well as in eEF2K-knockout (eEF2K-/-) mouse embryonic fibroblasts (MEFs). This rise in HSP90 coincided with an increase in the fraction of HSP90 mRNAs associated with translationally active polysomes, irrespective of unchanged total HSP90 levels. These results indicate that blocking eEF2K function can enhance expression of HSP90 chaperones. In eEF2K-/- mouse embryonic fibroblasts (MEFs), inhibition of HSP90 by its specific inhibitor AUY922 promoted the accumulation of ubiquitinated proteins. Notably, HSP90 inhibition promoted apoptosis of eEF2K-/- MEFs under proteostatic stress induced by the proteasome inhibitor MG132. Up-regulation of HSP90 likely protects cells from protein folding stress, arising, for example, from faster rates of polypeptide synthesis due to the lack of eEF2K. Our findings indicate that eEF2K and HSPs closely cooperate to maintain proper proteostasis and suggest that concomitant inhibition of HSP90 and eEF2K could be a strategy to decrease cancer cell survival

Challenges and priorities for river cetacean conservation

River cetaceans are particularly vulnerable to anthropogenic impacts due to their constrained ranges in freshwater systems of China, South Asia, and South America. We undertook an exhaustive review of 280 peer-reviewed papers and grey literature reports (1998-2020) to examine the current status of knowledge regarding these cetaceans and their conservation. We aimed to better understand the scale of threats they face, and to identify and propose priority future efforts to better conserve these species. We found that the species have been studied with varying frequency and that most of the research on threats has focused on habitat degradation and fragmentation (43%, mainly driven by dams and extractive activities such as sand mining and deforestation), and fishery interactions (39%, in the form of bycatch and direct take). These threats occur across all species, but more information is needed, primarily on quantifying the population impacts as a basis for designing mitigation measures. Other threats identified include pollution, vessel collisions, traditional use, and poorly managed tourism. Emerging methods such as environmental DNA and unmanned aerial vehicles are described for studying these species. Promising conservation interventions include cetacean-specific protected areas, natural ex situ protection, community-led conservation, and education programmes. However, transnational political will is required for a step change towards broad-scale protection in freshwater environments. In addition, we propose increasing capacity building, developing management plans, working closely with fishing communities, enhancing public awareness, expanding regional collaborations, and diversifying funding

2017 Research & Innovation Day Program

A one day showcase of applied research, social innovation, scholarship projects and activities.https://first.fanshawec.ca/cri_cripublications/1004/thumbnail.jp

Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

A. Palotie on työryhmän Schizophrenia Working Grp Psychiat jäsen.We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05-21.6; P = 1 x 10(-4)) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P = 8.4 x 10(-7)). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08-1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies.Peer reviewe

Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension

OBJECTIVE: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension. METHODS: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study. RESULTS: A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected. CONCLUSION: Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population. CLINICALTRIALSGOV IDENTIFIER: REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo

Minimal Symptom Expression' in Patients With Acetylcholine Receptor Antibody-Positive Refractory Generalized Myasthenia Gravis Treated With Eculizumab

The efficacy and tolerability of eculizumab were assessed in REGAIN, a 26-week, phase 3, randomized, double-blind, placebo-controlled study in anti-acetylcholine receptor antibody-positive (AChR+) refractory generalized myasthenia gravis (gMG), and its open-label extension

Editorial

During the IX Congress of Wildlife Management, in May 2010, in Bolivia, a meeting with attending giant otter researchers was called to discuss the progress of research and conservation of Pteronura brasiliensis, which resulted in this issue

Projet CHOUCAS : Intégration de données hétérogènes et raisonnement spatial pour l'aide à la localisation des victimes en montagne

National audienceL'objectif de l'article est de présenter le projet ANR CHOUCAS qui ambitionne de proposer des méthodes et des outils pour constituer, enrichir, interroger et visualiser des données spatiales issues de sources hétérogènes, et mener sur ces données un raisonnement spatial flou, avec comme contexte applicatif l'aide à la localisation de victimes en montagne

Challenges of a Hidden Epidemic: HIV Prevention Among Women in the United States

HIV/AIDS trends in the United States depict a concentrated epidemic with hot spots that vary by location, poverty, race/ethnicity, and transmission mode. HIV/AIDS is a leading cause of death among US women of color; two thirds of new infections among women occur in black women, despite the fact that black women account for just 14% of the US female population. The gravity of the HIV epidemic among US women is often not appreciated by those at risk as well as by the broader scientific community. We summarize the current epidemiology of HIV/AIDS among US women and discuss clinical, research, and public health intervention components that must be brought together in a cohesive plan to reduce new HIV infections in US women. Only by accelerating research and programmatic efforts will the hidden epidemic of HIV among US women emerge into the light and come under control