Finding genetically-supported drug targets for Parkinson’s disease using Mendelian randomization of the druggable genome

Parkinson’s disease is a neurodegenerative movement disorder that currently has no disease-modifying treatment, partly owing to inefficiencies in drug target identification and validation. We use Mendelian randomization to investigate over 3,000 genes that encode druggable proteins and predict their efficacy as drug targets for Parkinson’s disease. We use expression and protein quantitative trait loci to mimic exposure to medications, and we examine the causal effect on Parkinson’s disease risk (in two large cohorts), age at onset and progression. We propose 23 drug-targeting mechanisms for Parkinson’s disease, including four possible drug repurposing opportunities and two drugs which may increase Parkinson’s disease risk. Of these, we put forward six drug targets with the strongest Mendelian randomization evidence. There is remarkably little overlap between our drug targets to reduce Parkinson’s disease risk versus progression, suggesting different molecular mechanisms. Drugs with genetic support are considerably more likely to succeed in clinical trials, and we provide compelling genetic evidence and an analysis pipeline to prioritise Parkinson’s disease drug development

Loricate Choanoflagellates from the South Atlantic coastal zone (~32 S) including the description of diplotheca tricyclica sp. nov.

The biodiversity of marine heterotrophic protists is poorly known in the South Atlantic coastal zone (~32 °S) especially regarding the nanoflagellates. The presence of loricate choanoflagellates was reported for the first time in the Patos Lagoon estuary and the adjacent coastal zone. Seventeen species of eleven genera of loricate choanoflagellates were observed between October 1998 and May 2000 in fixed water samples (lugol's solution + glutaraldehyde) in a JEM 100-SX transmission electron microscope. Most species were recorded in euhaline and mixopolyhaline waters during the spring and summer, none in autumn and a few (four) in winter. The absence of choanoflagellates at the more sheltered inshore stations is due freshwater influence, and at the beach station,probably due the strong wave action. The probably cosmopolitan species Pleurasiga minima, Cosmoeca norvegica, C. ventricosa and Parvicorbicula circularis were present in spring or summer in the estuary channel and coastal area while Stephanoeca diplocostata which apparently prefers lower temperature, was recorded in winter. Calotheca alata and Campyloacantha spinifera are mainly temperate species and were present in spring. The new species Diplotheca tricyclica was recorded at the estuary channel in the summer 1999, in high salinity water.A biodiversidade de protistas heterotróficos é pouco conhecida na zona costeira do Atlântico Sul (~32 °S), especialmente dos nanoflagelados. No presente estudo, foi registrada pela primeira vez a presença de coanoflagelados loricados no estuário da Lagoa dos Patos e na zona costeira adjacente. Dezessete espécies de onze gêneros de coanoflagelados loricados foram observadas em amostras de água fixadas (solução de lugol + glutaraldeido) coletadas entre outubro de 1998 e maio de 2000, e analisadas em microscópio de transmissão JEM 100-SX. A maior parte das espécies foi registrada em águas euhalinas e mixopolihalinas durante a primavera e o verão, nenhuma no outono e poucas (quatro) no inverno. A ausência de coanoflagelados nas estações mais protegidas deve-se a influência da água doce, e na estação da praia deve-se, provavelmente, a forte ação das ondas. As espécies, provavelmente cosmopolitas, Pleurasiga minima, Cosmoeca norvegica, C. ventricosa and Parvicorbicula circularis ocorreram na primavera ou no verão no canal principal do estuário e na área costeira, enquanto Stephanoeca diplocostata, que aparentemente prefere baixas temperaturas, foi registrada no inverno. Calotheca alata e Campyloacantha spinifera são principalmente de ambientes temperados e estiveram presentes na primavera. Uma espécie nova, Diplotheca tricyclica, foi registrada na área do canal principal do estuário, no verão de 1999, em águas de alta salinidade

Measurement of the total cross section and ρ -parameter from elastic scattering in pp collisions at s = 13 TeV with the ATLAS detector

Acknowledgements: We thank CERN for the very successful operation of the LHC, as well as the support staff from our institutions without whom ATLAS could not be operated efficiently. We are indebted to the beam optics development team, led by H. Burkhardt, for the design, commissioning and thorough operation of the high-β* optics in dedicated LHC fills. We acknowledge the support of ANPCyT, Argentina; YerPhI, Armenia; ARC, Australia; BMWFW and FWF, Austria; ANAS, Azerbaijan; CNPq and FAPESP, Brazil; NSERC, NRC and CFI, Canada; CERN; ANID, Chile; CAS, MOST and NSFC, China; Minciencias, Colombia; MEYS CR, Czech Republic; DNRF and DNSRC, Denmark; IN2P3-CNRS and CEA-DRF/IRFU, France; SRNSFG, Georgia; BMBF, HGF and MPG, Germany; GSRI, Greece; RGC and Hong Kong SAR, China; ISF and Benoziyo Center, Israel; INFN, Italy; MEXT and JSPS, Japan; CNRST, Morocco; NWO, Netherlands; RCN, Norway; MEiN, Poland; FCT, Portugal; MNE/IFA, Romania; MESTD, Serbia; MSSR, Slovakia; ARRS and MIZS, Slovenia; DSI/NRF, South Africa; MICINN, Spain; SRC and Wallenberg Foundation, Sweden; SERI, SNSF and Cantons of Bern and Geneva, Switzerland; MOST, Taiwan; TENMAK, Turkiye; STFC, United Kingdom; DOE and NSF, United States of America. In addition, individual groups and members have received support from BCKDF, CANARIE, Compute Canada and CRC, Canada; PRIMUS 21/SCI/017 and UNCE SCI/013, Czech Republic; COST, ERC, ERDF, Horizon 2020 and Marie Sklodowska-Curie Actions, European Union; Investissements d'Avenir Labex, Investissements d'Avenir Idex and ANR, France; DFG and AvH Foundation, Germany; Herakleitos, Thales and Aristeia programmes co-financed by EU-ESF and the Greek NSRF, Greece; BSF-NSF and MINERVA, Israel; Norwegian Financial Mechanism 2014-2021, Norway; NCN and NAWA, Poland; La Caixa Banking Foundation, CERCA Programme Generalitat de Catalunya and PROMETEO and GenT Programmes Generalitat Valenciana, Spain; Goran Gustafssons Stiftelse, Sweden; The Royal Society and Leverhulme Trust, United Kingdom. The crucial computing support from all WLCG partners is acknowledged gratefully, in particular from CERN, the ATLAS Tier-1 facilities at TRIUMF (Canada), NDGF (Denmark, Norway, Sweden), CC-IN2P3 (France), KIT/GridKA (Germany), INFN-CNAF (Italy), NL-T1 (Netherlands), PIC (Spain), ASGC (Taiwan), RAL (UK) and BNL (USA), the Tier-2 facilities worldwide and large non-WLCG resource providers. Major contributors of computing resources are listed in Ref. [61].In a special run of the LHC with β*=2.5 km, proton-proton elastic-scattering events were recorded at s=13 TeV with an integrated luminosity of 340μb-1 using the ALFA subdetector of ATLAS in 2016. The elastic cross section was measured differentially in the Mandelstam t variable in the range from -t=2.5 10-4 GeV2 to -t=0.46 GeV2 using 6.9 million elastic-scattering candidates. This paper presents measurements of the total cross section σtot, parameters of the nuclear slope, and the ρ-parameter defined as the ratio of the real part to the imaginary part of the elastic-scattering amplitude in the limit t->0. These parameters are determined from a fit to the differential elastic cross section using the optical theorem and different parameterizations of the t-dependence. The results for σtot and ρ are σtot(pp->X)=104.7±1.1mb, ρ=0.098±0.011.The uncertainty in σtot is dominated by the luminosity measurement, and in ρ by imperfect knowledge of the detector alignment and by modelling of the nuclear amplitude