GAR22β regulates cell migration, sperm motility, and axoneme structure

© 2016 Gamper et al. Spatiotemporal cytoskeleton remodeling is pivotal for cell adhesion and migration. Here we investigated the function of Gas2-related protein on chromosome 22 (GAR22β), a poorly characterized protein that interacts with actin and microtubules. Primary and immortalized GAR22β-/- Sertoli cells moved faster than wild-type cells. In addition, GAR22β-/- cells showed a more prominent focal adhesion turnover. GAR22β overexpression or its reexpression in GAR22β-/- cells reduced cell motility and focal adhesion turnover. GAR22β-actin interaction was stronger than GAR22β-microtubule interaction, resulting in GAR22β localization and dynamics that mirrored those of the actin cytoskeleton. Mechanistically, GAR22β interacted with the regulator of microtubule dynamics end-binding protein 1 (EB1) via a novel noncanonical amino acid sequence, and this GAR22β-EB1 interaction was required for the ability of GAR22β to modulate cell motility. We found that GAR22β is highly expressed in mouse testes, and its absence resulted in reduced spermatozoa generation, lower actin levels in testes, and impaired motility and ultrastructural disorganization of spermatozoa. Collectively our findings identify GAR22β as a novel regulator of cell adhesion and migration and provide a foundation for understanding the molecular basis of diverse cytoskeleton-dependent processes

SH3TC2, a protein mutant in Charcot-Marie-Tooth neuropathy, links peripheral nerve myelination to endosomal recycling

Patients with Charcot-Marie-Tooth neuropathy and gene targeting in mice revealed an essential role for the SH3TC2 gene in peripheral nerve myelination. SH3TC2 expression is restricted to Schwann cells in the peripheral nervous system, and the gene product, SH3TC2, localizes to the perinuclear recycling compartment. Here, we show that SH3TC2 interacts with the small guanosine triphosphatase Rab11, which is known to regulate the recycling of internalized membranes and receptors back to the cell surface. Results of protein binding studies and transferrin receptor trafficking are in line with a role of SH3TC2 as a Rab11 effector molecule. Consistent with a function of Rab11 in Schwann cell myelination, SH3TC2 mutations that cause neuropathy disrupt the SH3TC2/Rab11 interaction, and forced expression of dominant negative Rab11 strongly impairs myelin formation in vitro. Our data indicate that the SH3TC2/Rab11 interaction is relevant for peripheral nerve pathophysiology and place endosomal recycling on the list of cellular mechanisms involved in Schwann cell myelinatio

Real-world safety and effectiveness of ombitasvir/paritaprevir/ritonavir +/- dasabuvir +/- ribavirin in hepatitis C virus genotype 1-and 4-infected patients with diverse comorbidities and comedications: A pooled analysis of post-marketing observational studies from 13 countries

International audienceOmbitasvir/paritaprevir/ritonavir ± dasabuvir ± ribavirin (OBV/PTV/r ± DSV ± RBV) regimens show high efficacy and good tolerability in clinical trials for chronic hepatitis C virus (HCV) genotypes (GT) 1 or 4. To evaluate whether these results translate to clinical practice, data were pooled from observational studies across 13 countries. Treatment‐naïve or ‐experienced patients, with or without cirrhosis, received OBV/PTV/r ± DSV ± RBV according to approved local labels and clinical practice. Sustained virologic response at post‐treatment Week 12 (SVR12), adverse events (AEs) and comedication management were assessed for patients initiating treatment before 1 June 2017. The safety population included 3850 patients who received ≥1 dose of study drug. The core population (N = 3808) further excluded patients with unknown GT or cirrhosis status, or who received off‐label treatment. Patients had HCV GT1a (n = 732; 19%), GT1b (n = 2619; 69%) or GT4 (n = 457; 12%). In 3546 patients with sufficient follow‐up data at post‐treatment Week 12, the SVR12 rate was 96% (n/N = 3401/3546 [95% CI 95.2‐96.5]). In patients with or without cirrhosis, SVR12 was comparable (96%). In patients with HCV GT1a, GT1b or GT4, SVR12 rates were 93%, 97% and 94%. In GT1b‐infected patients with planned treatment for 8 weeks, SVR12 was 96%. In patients with ≥1 comorbidity (67%), SVR12 was 95%. 58% of patients received ≥1 comedication, and there was minimal impact on SVR12 rates using comedications for peptic ulcers and gastro‐esophageal reflux disease, statins, antipsychotics or antiepileptics. Most comedications were maintained during treatment although 58% of patients changed their statin medication. AEs and serious AEs occurred in 26% and 3% of patients. Post‐baseline Grade 3‐4 laboratory abnormalities were rare (<3%), and discontinuation rates were low (<4%). Real‐world evidence confirms the effectiveness of OBV/PTV/r ± DSV ± RBV in patients with HCV GT1 or GT4, regardless of common comorbidities or comedications, and is consistent with clinical trial results. Adverse safety outcomes may be limited by underreporting in the real‐world setting

LFB-Labs-digital: Schülerlabore als Ort der Lehrkräftefortbildung in der digitalen Welt: Ein Bericht zur Konzeption eines Verbundprojektes

Schülerlabore haben unter anderem zum Ziel, die Motivation, insbesondere das Interesse – i.S. einer gegenstandsbezogenen Motivation – von Schüler*innen an MINT-Themen und -Arbeitsweisen zu fördern. Darüber hinaus konnten sie sich schneller und produktiver als die formalen Bildungsorte den Herausforderungen der digitalen Transformation stellen. Das Potenzial, Schülerlabore auch als innovative Orte der Lehrkräftefortbildung (LFB) zu nutzen und digitalisierungsbezogene Kompetenzen bei Lehrkräften aufzubauen, wurde bisher nicht ausgeschöpft. Im Verbundprojekt mit insgesamt acht Standorten werden Schülerlabore zu LFB-Labs-digital ausgebaut und die Frage nach Implementierungsvoraussetzungen gelingender Fortbildungen in der digitalen Welt im MINT-Bereich bearbeitet. In diesem Artikel werden die theoretische Fundierung, Ziele und anvisierten Forschungsarbeiten des Verbunds LFB-Labs-digital dargelegt. Zur Unterstützung der mit der forschungsbasierten Qualitätsentwicklung der MINT-bezogenen Aus-, Fort- und Weiterbildung von Lehrkräften betrauten Einrichtungen in den Ländern sollen in Kooperation mit dem Kompetenzzentrum MINT des Bundes die Lernorte „Schülerlabore“ für die digitale LFB erschlossen werden, um vermittelt hierüber die Motivation von Schüler*innen für die MINT-Fächer zu fördern. Die in den Schülerlaboren evaluierten und vom fächerübergreifenden adaptiven Qualitätsmanagement für die LFB wissenschaftlich begleiteten Good-Practice-Beispiele werden zur Grundlage für den „Referenzrahmen LFB-Labs-digital“. Dieser wird – vor dem Hintergrund einer Ergebnistriangulation aus der Begleitforschung sowie den damit parallelisierten Studien zur Evidenzbasierung der Lehrkräftequalifizierung in der digitalen Welt und dem Musterqualitätshandbuch LFB – entwickelt und von einem Implementierungsbeirat mit ausgewiesenen Expert*innen in diesem Bereich auf Transferoptionen hin geprüft. Die digitale Infrastruktur für die LFB-Labs-digital-Veranstaltungsformate wird hierzu prozessbegleitend ausgebaut