Parkin interacts with Ambra1 to induce mitophagy

Mutations in the gene encoding Parkin are a major cause of recessive Parkinson's disease. Recent work has shown that Parkin translocates from the cytosol to depolarized mitochondria and induces their autophagic removal (mitophagy). However, the molecular mechanisms underlying Parkin-mediated mitophagy are poorly understood. Here, we investigated whether Parkin interacts with autophagy-regulating proteins. We purified Parkin and associated proteins from HEK293 cells using tandem affinity purification and identified the Parkin interactors using mass spectrometry. We identified the autophagy-promoting protein Ambra1 (activating molecule in Beclin1-regulated autophagy) as a Parkin interactor. Ambra1 activates autophagy in the CNS by stimulating the activity of the class III phosphatidylinositol 3-kinase (PI3K) complex that is essential for the formation of new phagophores. We found Ambra1, like Parkin, to be widely expressed in adult mouse brain, including midbrain dopaminergic neurons. Endogenous Parkin and Ambra1 coimmunoprecipitated from HEK293 cells, SH-SY5Y cells, and adult mouse brain. We found no evidence for ubiquitination of Ambra1 by Parkin. The interaction of endogenous Parkin and Ambra1 strongly increased during prolonged mitochondrial depolarization. Ambra1 was not required for Parkin translocation to depolarized mitochondria but was critically important for subsequent mitochondrial clearance. In particular, Ambra1 was recruited to perinuclear clusters of depolarized mitochondria and activated class III PI3K in their immediate vicinity. These data identify interaction of Parkin with Ambra1 as a key mechanism for induction of the final clearance step of Parkin-mediated mitophagy

Wintersterfte van bijenvolken 2018-2019 : Resultaten enquête wintersterfte bijenvolken in Nederland in de winter van 2018-2019

Sinds 2003 wordt in Nederland jaarlijks de wintersterfte van bijenvolken gemonitord. Dit geeft een indicatie van de gezondheidstoestand van de gehouden populatie honingbijen in Nederland. Aan de wintersterfte-enquête van 2018-2019 deden 2032 bijenhouders mee. Dit is ongeveer 20% van alle bijenhouders in Nederland in 2018. De enquête bestond uit 3 gedeeltes, het eerste gedeelte ging over de gegevens van de bijenhouder, het tweede gedeelte over de bepaling van de wintersterfte en het laatste gedeelte was de COLOSS-enquête met een aantal toegevoegde vragen die relevant zijn voor de Nederlandse bijenhouderij. De wintersterfte van bijenvolken in Nederland in de winter van 2018-2019 was 9,2%. Dit is lager dan de twee voorgaande winters (14,3% en 15,7%). Van de respondenten gaf 69% te kennen geen wintersterfte van bijenvolken te hebben gehad in 2018-2019. Van diegene met sterfte van volken in de winter, gaf 68% te kennen koninginnenproblemen als oorzaak van de sterfte te zien. Verder werd berekend dat bijenhouders in Nederland gemiddeld genomen 8 bijenvolken hadden in 2018 en dat de totaalpopulatie gehouden bijenvolken ongeveer 75.000 bijenvolken bedroeg (najaar 2018). Per volk werd gemiddeld 13 kg honing geoogst. Per respondent was de gemiddelde honingopbrengst 101kg in 2018. Een gemiddelde prijs van €7,71 werd gevraagd voor een kilo honing en de respondenten hadden gemiddeld €448,- aan productiekosten. Het overgrote deel van de respondenten (88%) gaf te kennen varroa te bestrijden en de meerderheid (60%) monitort de varroabesmetting op enigerlei wijze. De resultaten van de COLOSS-enquête worden in internationaal verband geanalyseerd en vergeleken met de resultaten uit andere landen. In totaal doen zo’n 35 landen mee aan de COLOSS-enquête. De resultaten worden in de loop van 2020 ter publicatie aan een wetenschappelijk tijdschrift aangeboden

Multiscale fatigue modelling of additively manufactured metallic components

Additively manufactured metallic components have been used in medical and aerospace applications. In these components, surface roughness and porosity are integral features that might significantly reduce their fatigue lives, especially in the high cycle fatigue regime. Thus, to precisely estimate the fatigue life of an additively manufactured component, these defective features are incorporated into our proposed fatigue model. To capture the local plasticity caused by the defects, a nonlinear isotropic-kinematic hardening elasto-plasticity model is employed in our finite element (FE) models. Additionally, the gas-entrapped pores are modeled as circles whilst the surface topography, which was measured using stylus-based profilometer, is explicitly mo deled in the FE models. The finite element results are post-processed by our in-house software to extract the Smith-Watson-Topper (SWT) fatigue indicator parameter. This parameter is calculated at each element centroid of the FE mesh, i.e., the local indicator. Afterward, an average value of the SWT parameter over a so-called critical area whose center is located at the considered centroid is also calculated, i.e., the nonlocal indicator. The results show that the local SWT indicator is too conservative in predicting the fatigue life of the componentwhile the nonlocal SWT one can provide good results

A genetic predisposition score for muscular endophenotypes predicts the increase in aerobic power after training: the CAREGENE study

<p>Abstract</p> <p>Background</p> <p>It is widely accepted that genetic variability might explain a large part of the observed heterogeneity in aerobic capacity and its response to training. Significant associations between polymorphisms of different genes with muscular strength, anaerobic phenotypes and body composition have been reported. Muscular endophenotypes are positively correlated with aerobic capacity, therefore, we tested the association of polymorphisms in twelve muscular related genes on aerobic capacity and its response to endurance training.</p> <p>Methods</p> <p>935 Coronary artery disease patients (CAD) who performed an incremental exercise test until exhaustion at baseline and after three months of training were included. Polymorphisms of the genes were detected using the invader assay. Genotype-phenotype association analyses were performed using ANCOVA. Different models for a genetic predisposition score (GPS) were constructed based on literature and own data and were related to baseline and response VO₂scores.</p> <p>Results</p> <p>Carriers of the minor allele in the R23K polymorphism of the glucocorticoid receptor gene (<it>GR</it>) and the ciliary neurotrophic factor gene (<it>CNTF</it>) had a significantly higher increase in peakVO₂after training (p < 0.05). Carriers of the minor allele (C34T) in the adenosine monophosphate deaminase (<it>AMPD1</it>) gene had a significantly lower relative increase (p < 0.05) in peakVO₂. GPS of data driven models were significantly associated with the increase in peakVO₂after training.</p> <p>Conclusions</p> <p>In CAD patients, suggestive associations were found in the <it>GR, CNTF </it>and the <it>AMPD1 </it>gene with an improved change in aerobic capacity after three months of training. Additionally data driven models with a genetic predisposition score (GPS) showed a significant predictive value for the increase in peakVO₂.</p

Mapping QTL influencing gastrointestinal nematode burden in Dutch Holstein-Friesian dairy cattle

BACKGROUND: Parasitic gastroenteritis caused by nematodes is only second to mastitis in terms of health costs to dairy farmers in developed countries. Sustainable control strategies complementing anthelmintics are desired, including selective breeding for enhanced resistance. RESULTS AND CONCLUSION: To quantify and characterize the genetic contribution to variation in resistance to gastro-intestinal parasites, we measured the heritability of faecal egg and larval counts in the Dutch Holstein-Friesian dairy cattle population. The heritability of faecal egg counts ranged from 7 to 21% and was generally higher than for larval counts. We performed a whole genome scan in 12 paternal half-daughter groups for a total of 768 cows, corresponding to the approximately 10% most and least infected daughters within each family (selective genotyping). Two genome-wide significant QTL were identified in an across-family analysis, respectively on chromosomes 9 and 19, coinciding with previous findings in orthologous chromosomal regions in sheep. We identified six more suggestive QTL by within-family analysis. An additional 73 informative SNPs were genotyped on chromosome 19 and the ensuing high density map used in a variance component approach to simultaneously exploit linkage and linkage disequilibrium in an initial inconclusive attempt to refine the QTL map position

Yap1-Driven Intestinal Repair Is Controlled by Group 3 Innate Lymphoid Cells

Intestinal repair is driven by epithelial stem cells, but how these stem cells are instructed to initiate repair was unknown. Here, Romera-Hernández et al. report that epithelial proliferation after damage is independent of the stem cell-protective signal IL-22 but requires ILC3-dependent amplification of regenerative YAP1 signaling in stem cells.Tissue repair requires temporal control of progenitor cell proliferation and differentiation to replenish damaged cells. In response to acute insult, group 3 innate lymphoid cells (ILC3s) regulate intestinal stem cell maintenance and subsequent tissue repair. ILC3-derived IL-22 is important for stem cell protection, but the mechanisms of ILC3-driven tissue regeneration remain incompletely defined. Here we report that ILC3-driven epithelial proliferation and tissue regeneration are independent of IL-22. In contrast, ILC3s amplify the magnitude of Hippo-Yap1 signaling in intestinal crypt cells, ensuring adequate initiation of tissue repair and preventing excessive pathology. Mechanistically, ILC3-driven tissue repair is Stat3 indepe

Metaphor in organizational research: Context, modalities and implications for research introduction

We provide a general overview of previous work which has explored the use of metaphors in organizational research. Differences in focus and form of research on metaphors are noted. Work in organization theory (OT) and organizational communication (OC) generally features prescriptive metaphors that aid the practice of theorizing and research; research in organizational development (OD) tends to use metaphors for intervention in individual and group decision-making; while studies of organizational behaviour (OB) emphasize the metaphors-in-use within individuals' sensemaking accounts of critical events within their organization. Alongside these differences in focus, the form of metaphor analysis also differs across these contexts, ranging from text- and discourse-based analysis to the analysis of non-linguistic modalities such as pictorial signs, gestures and artefacts. Based on our overview of previous work, we call for greater attention to methodological issues around metaphor identification and analysis and outline a number of directions for further research

Biological efficacy of low versus medium dose aspirin after coronary surgery: results from a randomized trial [NCT00262275]

BACKGROUND: The beneficial effect of aspirin after coronary surgery is established; however, a recent study reported the inability of low doses (100 mg) to inhibit postoperative platelet function. We conducted a double-blind randomised trial to establish the efficacy of low dose aspirin and to compare it against medium dose aspirin. METHODS: Patients undergoing coronary surgery were invited to participate and consenting patients were randomised to 100 mg or 325 mg of aspirin daily for 5 days. Our primary outcome was the difference in platelet aggregation (day 5 – baseline) using 1 μg/ml of collagen. Secondary outcomes were differences in EC50 of collagen, ADP and epinephrine (assessed using the technique of Born). RESULTS: From September 2002 to April 2004, 72 patients were randomised; 3 patients discontinued, leaving 35 and 34 in the low and medium dose aspirin arms respectively. The mean aggregation (using 1.1 μg/ml of collagen) was reduced in both the medium and low dose aspirin arms by 37% and 36% respectively. The baseline adjusted difference (low – medium) was 6% (95% CI -3 to 14; p = 0.19). The directions of the results for the differences in EC50 (low – medium) were consistent for collagen, ADP and epinephrine at -0.07 (-0.53 to 0.40), -0.08 (-0.28 to 0.11) and -4.41 (-10.56 to 1.72) respectively, but none were statistically significant. CONCLUSION: Contrary to recent findings, low dose aspirin is effective and medium dose aspirin did not prove superior for inhibiting platelet aggregation after coronary surgery

Landowners’ Сolonization of Bashkiria

The “closed city” practice, exercised in Ufa province before 1735, together with the unfavourable political situation led to the bad crisis of estate landownership of the Ufa district. The population polls of the mid-XVII — beginning of XVIII cc. justify the fact that Ufa noblemen had to succumb to the fate of socially deprived Siberian nobility, practically devoid of serf peasants. The beginning of the largest-scale Bashkir insurrection of 1735–1736 made the administration review its attitude to the former ban on Bashkir estate lands sale. In the history of Bashkir landowners’ colonization the edict dated February 11th, 1736, allowing the local officers and officials to buy lands from Bashkir communities, was of principal importance. This procedure was exercised simultaneously with the establishment of the Russian government military control over the south-eastern border, separating Bashkir estate lands from Kazakh migratory tribes. From this moment on there is a stop in diplomatic contacts of the Bashkir elite with the governors of the Middle Asia, Kazakhstan and Turkey that meant the complete loss of political subjection by the Bashkirs. Bashkir communities become active participants of economic relations with Russian landowners, plant owners and the state institutions. Russian government preserved estate dynastic rights with the Bashkirs and refused from large-scale operations on the expropriation of Bashkir lands, transferring the mission of colonization to private persons, who had to arrange the issue with the local communities by themselves. The permission to sell estate lands forced landowners to active participation in the system of Russian legal relations, to contact the Russian government and customers