Knockdown of the C. elegans kinome identifies kinases required for normal protein homeostasis, mitochondrial network structure, and sarcomere structure in muscle

Kinases are important signalling molecules for modulating cellular processes and major targets of drug discovery programs. However, functional information for roughly half the human kinome is lacking. We conducted three kinome wide, >90%, RNAi screens and epistasis testing of some identified kinases against known intramuscular signalling systems to increase the functional annotation of the C. elegans kinome and expand our understanding of kinome influence upon muscle protein degradation

Enhancing folic acid metabolism suppresses defects associated with loss of Drosophila mitofusin.

Mutations in the mitochondrial GTPase mitofusin 2 (MFN2) cause Charcot-Marie-Tooth disease type 2 (CMT2A), a form of peripheral neuropathy that compromises axonal function. Mitofusins promote mitochondrial fusion and regulate mitochondrial dynamics. They are also reported to be involved in forming contacts between mitochondria and the endoplasmic reticulum. The fruit fly, Drosophila melanogaster, is a powerful tool to model human neurodegenerative diseases, including CMT2A. Here, we have downregulated the expression of the Drosophila mitofusin (dMfn RNAi) in adult flies and showed that this activates mitochondrial retrograde signalling and is associated with an upregulation of genes involved in folic acid (FA) metabolism. Additionally, we demonstrated that pharmacological and genetic interventions designed to increase the FA metabolism pathway suppresses the phenotype of the dMfn RNAi flies. We conclude that strategies to increase FA metabolism may ameliorate diseases, such as peripheral neuropathies, that are associated with loss of mitochondrial function. A video abstract for this article is available at  https://youtu.be/fs1G-QRo6xI .Medical Research Counci

German general practitioners' self-reported management of patients with chronic depression

Background: Patients with chronic depression (persisting symptoms for >= 2 years) are a clinically relevant group with extensive (co) morbidity, high functional impairment and associated costs in primary care. The General Practitioner (GP) is the main health professional attending to these patients. The aim of this study was to examine the GPs' perception on managing patients with chronic depression. Methods: We performed an explorative cross-sectional study with a systematic sample of GPs in central Germany. Source of data was a written questionnaire (46 items). Descriptive analysis was carried out. Results: Two hundred twenty (out of 1000;22%) GPs participated. 93% of the GPs distinguish between care for patients with chronic depression and acute depressive episode. 92% would recommend psychotherapeutic co-treatment to the chronically depressed patient. 52% of GPs would favour a general restraint on antidepressants (ADs) in older chronically depressed patients (>= 75 years) whereas 40% suggest long-term pharmacotherapy. If severe physical comorbidity is present GPs would be restrictive in prescribing ADs (65%) or would urgently refer to specialist psychiatric services (40%). In case of a comorbid anxiety disorder 66% of the GPs would suggest a combined psycho- und pharmacotherapy. If a substance use disorder coexists 84% would prefer urgent referrals to specialist services. Conclusions: Participating GPs report awareness towards chronic depression in their patients. Physical and mental comorbidity seem to play an important role in GPs' treatment decisions

dATF4 regulation of mitochondrial folate-mediated one-carbon metabolism is neuroprotective.

Neurons rely on mitochondria as their preferred source of energy. Mutations in PINK1 and PARKIN cause neuronal death in early-onset Parkinson's disease (PD), thought to be due to mitochondrial dysfunction. In Drosophila pink1 and parkin mutants, mitochondrial defects lead to the compensatory upregulation of the mitochondrial one-carbon cycle metabolism genes by an unknown mechanism. Here we uncover that this branch is triggered by the activating transcription factor 4 (ATF4). We show that ATF4 regulates the expression of one-carbon metabolism genes SHMT2 and NMDMC as a protective response to mitochondrial toxicity. Suppressing Shmt2 or Nmdmc caused motor impairment and mitochondrial defects in flies. Epistatic analyses showed that suppressing the upregulation of Shmt2 or Nmdmc deteriorates the phenotype of pink1 or parkin mutants. Conversely, the genetic enhancement of these one-carbon metabolism genes in pink1 or parkin mutants was neuroprotective. We conclude that mitochondrial dysfunction caused by mutations in the Pink1/Parkin pathway engages ATF4-dependent activation of one-carbon metabolism as a protective response. Our findings show a central contribution of ATF4 signalling to PD that may represent a new therapeutic strategy. A video abstract for this article is available at https://youtu.be/cFJJm2YZKKM

Quantitative Detection and Biological Propagation of Scrapie Seeding Activity In Vitro Facilitate Use of Prions as Model Pathogens for Disinfection

Prions are pathogens with an unusually high tolerance to inactivation and constitute a complex challenge to the re-processing of surgical instruments. On the other hand, however, they provide an informative paradigm which has been exploited successfully for the development of novel broad-range disinfectants simultaneously active also against bacteria, viruses and fungi. Here we report on the development of a methodological platform that further facilitates the use of scrapie prions as model pathogens for disinfection. We used specifically adapted serial protein misfolding cyclic amplification (PMCA) for the quantitative detection, on steel wires providing model carriers for decontamination, of 263K scrapie seeding activity converting normal protease-sensitive into abnormal protease-resistant prion protein. Reference steel wires carrying defined amounts of scrapie infectivity were used for assay calibration, while scrapie-contaminated test steel wires were subjected to fifteen different procedures for disinfection that yielded scrapie titre reductions of ≤101- to ≥105.5-fold. As confirmed by titration in hamsters the residual scrapie infectivity on test wires could be reliably deduced for all examined disinfection procedures, from our quantitative seeding activity assay. Furthermore, we found that scrapie seeding activity present in 263K hamster brain homogenate or multiplied by PMCA of scrapie-contaminated steel wires both triggered accumulation of protease-resistant prion protein and was further propagated in a novel cell assay for 263K scrapie prions, i.e., cerebral glial cell cultures from hamsters. The findings from our PMCA- and glial cell culture assays revealed scrapie seeding activity as a biochemically and biologically replicative principle in vitro, with the former being quantitatively linked to prion infectivity detected on steel wires in vivo. When combined, our in vitro assays provide an alternative to titrations of biological scrapie infectivity in animals that substantially facilitates the use of prions as potentially highly indicative test agents in the search for novel broad-range disinfectants

Der Geologische Dienst in Sachsen: Festband zum Jubiläum 150 Jahre Landesgeologie

Der Geologische Dienst von Sachsen feiert im Jahr 2022 sein 150-jähriges Jubiläum – am 6. April 1872 wurde die Geologische Landesuntersuchung im Königreich Sachsen gegründet. Auf 153 Seiten der Reihe „Geoprofil“ werden Einblicke in die Arbeit des Geologischen Dienstes im LfULG, seinen Aufgaben und die Dienste als zuständige Fachbehörde gegeben. Die elf Einzelbeiträge zeigen die aktuellen Herausforderungen und Chancen, die sich aus den Themenbereichen Umwelt, Naturschutz und Geologie für Sachsen stellen. Im Einzelnen geht es in den Beiträgen um die sächsische Rohstoffstrategie, die Suche nach einem Endlagerstandort für radioaktive Abfälle, Erdwärme, Hydrogeologie, die Eisenbahn Neubaustrecke Dresden – Prag, Naturgefahren, das geowissenschaftliche Archiv, Träger öffentlicher Belange (TöB), Geoparks und einen Blick in die 150 jährige Geschichte. Redaktionsschluss: 30.11.202

Calpains Mediate Integrin Attachment Complex Maintenance of Adult Muscle in Caenorhabditis elegans

Two components of integrin containing attachment complexes, UNC-97/PINCH and UNC-112/MIG-2/Kindlin-2, were recently identified as negative regulators of muscle protein degradation and as having decreased mRNA levels in response to spaceflight. Integrin complexes transmit force between the inside and outside of muscle cells and signal changes in muscle size in response to force and, perhaps, disuse. We therefore investigated the effects of acute decreases in expression of the genes encoding these multi-protein complexes. We find that in fully developed adult Caenorhabditis elegans muscle, RNAi against genes encoding core, and peripheral, members of these complexes induces protein degradation, myofibrillar and mitochondrial dystrophies, and a movement defect. Genetic disruption of Z-line– or M-line–specific complex members is sufficient to induce these defects. We confirmed that defects occur in temperature-sensitive mutants for two of the genes: unc-52, which encodes the extra-cellular ligand Perlecan, and unc-112, which encodes the intracellular component Kindlin-2. These results demonstrate that integrin containing attachment complexes, as a whole, are required for proper maintenance of adult muscle. These defects, and collapse of arrayed attachment complexes into ball like structures, are blocked when DIM-1 levels are reduced. Degradation is also blocked by RNAi or drugs targeting calpains, implying that disruption of integrin containing complexes results in calpain activation. In wild-type animals, either during development or in adults, RNAi against calpain genes results in integrin muscle attachment disruptions and consequent sub-cellular defects. These results demonstrate that calpains are required for proper assembly and maintenance of integrin attachment complexes. Taken together our data provide in vivo evidence that a calpain-based molecular repair mechanism exists for dealing with attachment complex disruption in adult muscle. Since C. elegans lacks satellite cells, this mechanism is intrinsic to the muscles and raises the question if such a mechanism also exists in higher metazoans

ARTEFACTS: How do we want to deal with the future of our one and only planet?

The European Commission’s Science and Knowledge Service, the Joint Research Centre (JRC), decided to try working hand-in-hand with leading European science centres and museums. Behind this decision was the idea that the JRC could better support EU Institutions in engaging with the European public. The fact that European Union policies are firmly based on scientific evidence is a strong message which the JRC is uniquely able to illustrate. Such a collaboration would not only provide a platform to explain the benefits of EU policies to our daily lives but also provide an opportunity for European citizens to engage by taking a more active part in the EU policy making process for the future. A PILOT PROGRAMME To test the idea, the JRC launched an experimental programme to work with science museums: a perfect partner for three compelling reasons. Firstly, they attract a large and growing number of visitors. Leading science museums in Europe have typically 500 000 visitors per year. Furthermore, they are based in large European cities and attract local visitors as well as tourists from across Europe and beyond. The second reason for working with museums is that they have mastered the art of how to communicate key elements of sophisticated arguments across to the public and making complex topics of public interest readily accessible. That is a high-value added skill and a crucial part of the valorisation of public-funded research, never to be underestimated. Finally museums are, at present, undergoing something of a renaissance. Museums today are vibrant environments offering new techniques and technologies to both inform and entertain, and attract visitors of all demographics.JRC.H.2-Knowledge Management Methodologies, Communities and Disseminatio

Besondere Anforderungen an die Last Mile Supply Chain im Onlinehandel mit Lebensmitteln -am Beispiel der Otto Gourmet GmbH für die Warengruppe Fleisch-

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Identification and functional analysis of kinases and phosphatases contributing to muscle homeostasis in Caenorhabditis elegans

Loss of muscle homeostasis can lead to muscle atrophy, the severe wasting of muscle mass associated with clinical conditions such as cancer, diabetes and heart failure and which occurs progressively in the elderly increasing morbidity and mortality. Several extracellular signals are known to be associated with muscle atrophy in humans; however the regulatory intramuscular signalling mechanisms are incompletely understood. To identify new regulators of muscle homeostasis and to gain insight into the global regulation of a single tissue in vivo, the effect of knockdown of 401 kinase-encoding genes (kinome) and 193 phosphatase-encoding genes (phosphatome) by RNAi was examined. A strain containing a muscle lacZ reporter established to read out on cytosolic muscle protein degradation and two GFP strains established to identify dystrophies of myofibres, mitochondria and nuclei were employed. This screen identified 161 kinases and 98 phosphatases which appear to negatively regulate cytosolic protein degradation, mitochondrial dynamics or sarcomere assembly. Functional clustering of genes identified to induce cytosolic protein degradation upon RNAi knockdown into known proteolytic signalling mechanisms demonstrated that half appear to contribute to autophagy-mediated degradation and two thirds signal through MPK-1. Construction of predicted interaction networks between the genes identified illustrated testable models of regulation. In summary, this study quantified the complexity of the regulation of muscle homeostasis and specific subcellular processes by the kinome and phospatome and provides a platform for further study of individual kinases and phosphatases within a single tissue in vivo. As 70% of the genes identified have human orthologues or homologues of which 60% are known to be expressed in human skeletal muscle, knowledge about these genes may be transferred to humans for further study of muscle atrophy. Identification of potential signalling mechanisms and coordinate regulation of different subcellular processes may provide opportunities for the application of specific inhibitory drugs for use in clinical practice.EThOS - Electronic Theses Online ServiceGBUnited Kingdo