The Parkinson's disease-linked Leucine-rich repeat kinase 2 (LRRK2) is required for insulin-stimulated translocation of GLUT4

Mutations within Leucine-rich repeat kinase 2 (LRRK2) are associated with late-onset Parkinson's disease. The physiological function of LRRK2 and molecular mechanism underlying the pathogenic role of LRRK2 mutations remain uncertain. Here, we investigated the role of LRRK2 in intracellular signal transduction. We find that deficiency of Lrrk2 in rodents affects insulin-dependent translocation of glucose transporter type 4 (GLUT4). This deficit is restored during aging by prolonged insulin-dependent activation of protein kinase B (PKB, Akt) and Akt substrate of 160 kDa (AS160), and is compensated by elevated basal expression of GLUT4 on the cell surface. Furthermore, we find a crucial role of Rab10 phosphorylation by LRRK2 for efficient insulin signal transduction. Translating our findings into human cell lines, we find comparable molecular alterations in fibroblasts from Parkinson's patients with the known pathogenic G2019S LRRK2 mutation. Our results highlight the role of LRRK2 in insulin-dependent signalling with potential therapeutic implications

ARSB IS REQUIRED FOR BONE REMODELING

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Ten lessons on the resilience of the EU common fisheries policy towards climate change and fuel efficiency - A call for adaptive, flexible and well-informed fisheries management

To effectively future-proof the management of the European Union fishing fleets we have explored a suite of case studies encompassing the northeast and tropical Atlantic, the Mediterranean, Baltic and Black Seas. This study shows that European Union (EU) fisheries are likely resilient to climate-driven short-term stresses, but may be negatively impacted by long-term trends in climate change. However, fisheries' long-term stock resilience can be improved (and therefore be more resilient to increasing changes in climate) by adopting robust and adaptive fisheries management, provided such measures are based on sound scientific advice which includes uncertainty. Such management requires regular updates of biological reference points. Such updates will delineate safe biological limits for exploitation, providing both high long-term yields with reduced risk of stock collapse when affected by short-term stresses, and enhanced compliance with advice to avoid higher than intended fishing mortality. However, high resilience of the exploited ecosystem does not necessarily lead to the resilience of the economy of EU fisheries from suffering shocks associated with reduced yields, neither to a reduced carbon footprint if fuel use increases from lower stock abundances. Fuel consumption is impacted by stock development, but also by changes in vessel and gear technologies, as well as fishing techniques. In this respect, energy-efficient fishing technologies already exist within the EU, though implementing them would require improving the uptake of innovations and demonstrating to stakeholders the potential for both reduced fuel costs and increased catch rates. A transition towards reducing fuel consumption and costs would need to be supported by the setup of EU regulatory instruments. Overall, to effectively manage EU fisheries within a changing climate, flexible, adaptive, well-informed and well-enforced management is needed, with incentives provided for innovations and ocean literacy to cope with the changing conditions, while also reducing the dependency of the capture fishing industry on fossil fuels. To support such management, we provide 10 lessons to characterize 'win-win' fishing strategies for the European Union, which develop leverages in which fishing effort deployed corresponds to Maximum Sustainable Yield targets and Common Fisheries Policy minimal effects objectives. In these strategies, higher catch is obtained in the long run, less fuel is spent to attain the catch, and the fisheries have a higher resistance and resilience to shock and long-term factors to face climate-induced stresses

In vivo imaging of pancreatic tumours and liver metastases using 7 Tesla MRI in a murine orthotopic pancreatic cancer model and a liver metastases model

<p>Abstract</p> <p>Background</p> <p>Pancreatic cancer is the fourth leading cause of tumour death in the western world. However, appropriate tumour models are scarce. Here we present a syngeneic murine pancreatic cancer model using 7 Tesla MRI and evaluate its clinical relevance and applicability.</p> <p>Methods</p> <p>6606PDA murine pancreatic cancer cells were orthotopically injected into the pancreatic head. Liver metastases were induced through splenic injection. Animals were analyzed by MRI three and five weeks following injection. Tumours were detected using T2-weighted high resolution sequences. Tumour volumes were determined by callipers and MRI. Liver metastases were analyzed using gadolinium-EOB-DTPA and T1-weighted 3D-Flash sequences. Tumour blood flow was measured using low molecular gadobutrol and high molecular gadolinium-DTPA.</p> <p>Results</p> <p>MRI handling and applicability was similar to human systems, resolution as low as 0.1 mm. After 5 weeks tumour volumes differed significantly (p < 0.01) when comparing calliper measurments (n = 5, mean 1065 mm³+/-243 mm³) with MRI (mean 918 mm³+/-193 mm³) with MRI being more precise. Histology (n = 5) confirmed MRI tumour measurements (mean size MRI 38.5 mm²+/-22.8 mm²versus 32.6 mm²+/-22.6 mm²(histology), p < 0,0004) with differences due to fixation and processing of specimens. After splenic injection all mice developed liver metastases with a mean of 8 metastases and a mean volume of 173.8 mm³+/-56.7 mm³after 5 weeks. Lymphnodes were also easily identified. Tumour accumulation of gadobutrol was significantly (p < 0.05) higher than gadolinium-DTPA. All imaging experiments could be done repeatedly to comply with the 3R-principle thus reducing the number of experimental animals.</p> <p>Conclusions</p> <p>This model permits monitoring of tumour growth and metastasis formation in longitudinal non-invasive high-resolution MR studies including using contrast agents comparable to human pancreatic cancer. This multidisciplinary environment enables radiologists, surgeons and physicians to further improve translational research and therapies of pancreatic cancer.</p

Integrative phylogenetic, phylogeographic and morphological characterisation of the Unio crassus species complex reveals cryptic diversity with important conservation implications

The global decline of freshwater mussels and their crucial ecological services highlight the need to understand their phylogeny, phylogeography and patterns of genetic diversity to guide conservation efforts. Such knowledge is urgently needed for Unio crassus, a highly imperilled species originally widespread throughout Europe and southwest Asia. Recent studies have resurrected several species from synonymy based on mitochondrial data, revealing U. crassus to be a complex of cryptic species. To address long-standing taxonomic uncertainties hindering effective conservation, we integrate morphometric, phylogenetic, and phylogeographic analyses to examine species diversity within the U. crassus complex across its entire range. Phylogenetic analyses were performed using cytochrome c oxidase subunit I (815 specimens from 182 populations) and, for selected specimens, whole mitogenome sequences and Anchored Hybrid Enrichment (AHE) data on ∼ 600 nuclear loci. Mito-nuclear discordance was detected, consistent with mitochondrial DNA gene flow between some species during the Pliocene and Pleistocene. Fossil-calibrated phylogenies based on AHE data support a Mediterranean origin for the U. crassus complex in the Early Miocene. The results of our integrative approach support 12 species in the group: the previously recognised Unio bruguierianus, Unio carneus, Unio crassus, Unio damascensis, Unio ionicus, Unio sesirmensis, and Unio tumidiformis, and the reinstatement of five nominal taxa: Unio desectus stat. rev., Unio gontierii stat. rev., Unio mardinensis stat. rev., Unio nanus stat. rev., and Unio vicarius stat. rev. Morphometric analyses of shell contours reveal important morphospace overlaps among these species, highlighting cryptic, but geographically structured, diversity. The distribution, taxonomy, phylogeography, and conservation of each species are succinctly described.We thank Ana-Maria Benedek, Monica Sîrbu and Jouni Leinikki for their assistance with the fieldwork, and to Jeroen Goud, Sankurie Pye, Fiona Ware, Emily Mitchell, and Aleksandra Skawina for their assistance with the taxonomic investigation. We would also like to thank the editor, Dr. Guillermo Ortí, and two anonymous reviewers for their time and effort in reviewing our manuscript and for their insightful comments and valuable improvements to our work. This publication is based upon work from COST Action CA18239: CONFREMU - Conservation of freshwater mussels: a pan-European approach, supported by COST (European Cooperation in Science and Technology), including STSMs, the interaction of the authors and the writing of the paper. This work was supported by the project ConBiomics: The Missing Approach for the Conservation of Freshwater Bivalves Project No. POCI-01-0145-FEDER-030286, co-financed by FEDER through POCI and by FCT - Fundaç˜ao para a Ciˆencia e a Tecnologia, through national funds. Strategic funding UIDB/04423/2020 and UIDP/04423/2020 was provided by FCT. FCT also supported DVG (2020.03848.CEECIND), EF (CEECINST/00027/ 2021/CP2789/CT0003) and MLL (2020.03608.CEECIND). INB, AVK and IVV were supported by the Russian Science Foundation under grants (19-14-00066-P), (21-17-00126) and (21-74-10130) respectively. BVB acknowledges the bioinformatics platform of UMR 8198 for the computing resources to perform time-calibrated phylogenetic analyses; this platform is in part funded by CPER research project CLIMIBIO through the French Minist`ere de l’Enseignement Sup´erieur et de la Recherche, the Agence Nationale de la Recherche, the European Fund for Regional Development (FEDER) and the region Hauts-de-France (HdF). Support to KD came from the Czech Science Foundation (19–05510S). TT and MT were supported by the National Science Fund of Bulgaria under the project ‘Conservation of freshwater mussels on the Balkan Peninsula’ (KP-06-COST-9/20.07.2022). Any use of trade, firm, or product names is for descriptive purposes only and does not imply endorsement by the United States Government.info:eu-repo/semantics/publishedVersio

Human and mouse essentiality screens as a resource for disease gene discovery

The identification of causal variants in sequencing studies remains a considerable challenge that can be partially addressed by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and essentiality screens carried out on human cell lines. We propose a cross-species gene classification across the Full Spectrum of Intolerance to Loss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing biological properties. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented among genes non-essential for cell survival but required for organism development. After screening developmental disorder cases from three independent disease sequencing consortia, we identify potentially pathogenic variants in genes not previously associated with rare diseases. We therefore propose FUSIL as an efficient approach for disease gene discovery. Discovery of causal variants for monogenic disorders has been facilitated by whole exome and genome sequencing, but does not provide a diagnosis for all patients. Here, the authors propose a Full Spectrum of Intolerance to Loss-of-Function (FUSIL) categorization that integrates gene essentiality information to aid disease gene discovery

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Combinations of single-top-quark production cross-section measurements and vertical bar f(LV)V(tb)vertical bar determinations at root s=7 and 8 TeV with the ATLAS and CMS experiments

This paper presents the combinations of single-top-quark production cross-section measurements by the ATLAS and CMS Collaborations, using data from LHC proton-proton collisions at = 7 and 8 TeV corresponding to integrated luminosities of 1.17 to 5.1 fb(-1) at = 7 TeV and 12.2 to 20.3 fb(-1) at = 8 TeV. These combinations are performed per centre-of-mass energy and for each production mode: t-channel, tW, and s-channel. The combined t-channel cross-sections are 67.5 +/- 5.7 pb and 87.7 +/- 5.8 pb at = 7 and 8 TeV respectively. The combined tW cross-sections are 16.3 +/- 4.1 pb and 23.1 +/- 3.6 pb at = 7 and 8 TeV respectively. For the s-channel cross-section, the combination yields 4.9 +/- 1.4 pb at = 8 TeV. The square of the magnitude of the CKM matrix element V-tb multiplied by a form factor f(LV) is determined for each production mode and centre-of-mass energy, using the ratio of the measured cross-section to its theoretical prediction. It is assumed that the top-quark-related CKM matrix elements obey the relation |V-td|, |V-ts| << |V-tb|. All the |f(LV)V(tb)|(2) determinations, extracted from individual ratios at = 7 and 8 TeV, are combined, resulting in |f(LV)V(tb)| = 1.02 +/- 0.04 (meas.) +/- 0.02 (theo.). All combined measurements are consistent with their corresponding Standard Model predictions.Peer reviewe

The National Early Warning Score and its subcomponents recorded within ±24 hours of emergency medical admission are poor predictors of hospital-acquired acute kidney injury

YesBackground: Hospital-acquired Acute Kidney Injury (H-AKI) is a common cause of avoidable morbidity and mortality. Aim: To determine if the patients’ vital signs data as defined by a National Early Warning Score (NEWS), can predict H-AKI following emergency admission to hospital. Methods: Analyses of emergency admissions to York hospital over 24-months with NEWS data. We report the area under the curve (AUC) for logistic regression models that used the index NEWS (model A0), plus age and sex (A1), plus subcomponents of NEWS (A2) and two-way interactions (A3). Likewise for maximum NEWS (models B0,B1,B2,B3). Results: 4.05% (1361/33608) of emergency admissions had H-AKI. Models using the index NEWS had the lower AUCs (0.59 to 0.68) than models using the maximum NEWS AUCs (0.75 to 0.77). The maximum NEWS model (B3) was more sensitivity than the index NEWS model (A0) (67.60% vs 19.84%) but identified twice as many cases as being at risk of H-AKI (9581 vs 4099) at a NEWS of 5. Conclusions: The index NEWS is a poor predictor of H-AKI. The maximum NEWS is a better predictor but seems unfeasible because it is only knowable in retrospect and is associated with a substantial increase in workload albeit with improved sensitivity.The Health Foundatio