Knocking down metabotropic glutamate receptor 1 improves survival and disease progression in the SOD1G93A mouse model of amyotrophic lateral sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) is a late-onset fatal neurodegenerative disease reflecting degeneration of upper and lower motoneurons (MNs). The cause of ALS and the mechanisms of neuronal death are still largely obscure, thus impairing the establishment of efficacious therapies. Glutamate (Glu)-mediated excitotoxicity plays a major role in MN degeneration in ALS. We recently demonstrated that the activation of Group I metabotropic Glu autoreceptors, belonging to both type 1 and type 5 receptors (mGluR1 and mGluR5), at glutamatergic spinal cord nerve terminals, produces excessive Glu release in mice over-expressing human superoxide-dismutase carrying the G93A point mutation (SOD1G93A), a widely used animal model of human ALS. To establish whether these receptors are implicated in ALS, we generated mice expressing half dosage of mGluR1 in the SOD1G93A background (SOD1G93AGrm1crv4/+), by crossing the SOD1G93A mutant mouse with the Grm1crv4/+ mouse, lacking mGluR1 because of a spontaneous recessive mutation. SOD1G93AGrm1crv4/+ mice showed prolonged survival probability, delayed pathology onset, slower disease progression and improved motor performances compared to SOD1G93A mice. These effects were associated to reduction of mGluR5 expression, enhanced number of MNs, decreased astrocyte and microglia activation, normalization of metallothionein and catalase mRNA expression, reduced mitochondrial damage, and decrease of abnormal Glu release in spinal cord of SOD1G93AGrm1crv4/+compared to SOD1G93A mice. These results demonstrate that a lower constitutive level of mGluR1 has a significant positive impact on mice with experimental ALS, thus providing the rationale for future pharmacological approaches to ALS by selectively blocking Group I metabotropic Glu receptors

Improving the Characterization of Radiologically Isolated Syndrome Suggestive of Multiple Sclerosis

OBJECTIVE: To improve the characterization of asymptomatic subjects with brain magnetic resonance imaging (MRI) abnormalities highly suggestive of multiple sclerosis (MS), a condition named as "radiologically isolated syndrome" (RIS). METHODS: Quantitative MRI metrics such as brain volumes and magnetization transfer (MT) were assessed in 19 subjects previously classified as RIS, 20 demographically-matched relapsing-remitting MS (RRMS) patients and 20 healthy controls (HC). Specific measures were: white matter (WM) lesion volumes (LV), total and regional brain volumes, and MT ratio (MTr) in lesions, normal-appearing WM (NAWM) and cortex. RESULTS: LV was similar in RIS and RRMS, without differences in distribution and frequency at lesion mapping. Brain volumes were similarly lower in RRMS and RIS than in HC (p<0.001). Lesional-MTr was lower in RRMS than in RIS (p = 0.048); NAWM-MTr and cortical-MTr were similar in RIS and HC and lower (p<0.01) in RRMS. These values were particularly lower in RRMS than in RIS in the sensorimotor and memory networks. A multivariate logistic regression analysis showed that 13/19 RIS had ≥70% probability of being classified as RRMS on the basis of their brain volume and lesional-MTr values. CONCLUSIONS: Macroscopic brain damage was similar in RIS and RRMS. However, the subtle tissue damage detected by MTr was milder in RIS than in RRMS in clinically relevant brain regions, suggesting an explanation for the lack of clinical manifestations of subjects with RIS. This new approach could be useful for narrowing down the RIS individuals with a high risk of progression to MS

Data monitoring roadmap. The experience of the Italian Multiple Sclerosis and Related Disorders Register

Introduction Over the years, disease registers have been increasingly considered a source of reliable and valuable population studies. However, the validity and reliability of data from registers may be limited by missing data, selection bias or data quality not adequately evaluated or checked.This study reports the analysis of the consistency and completeness of the data in the Italian Multiple Sclerosis and Related Disorders Register.MethodsThe Register collects, through a standardized Web-based Application, unique patients.Data are exported bimonthly and evaluated to assess the updating and completeness, and to check the quality and consistency. Eight clinical indicators are evaluated.ResultsThe Register counts 77,628 patients registered by 126 centres. The number of centres has increased over time, as their capacity to collect patients.The percentages of updated patients (with at least one visit in the last 24 months) have increased from 33% (enrolment period 2000-2015) to 60% (enrolment period 2016-2022). In the cohort of patients registered after 2016, there were &gt;= 75% updated patients in 30% of the small centres (33), in 9% of the medium centres (11), and in all the large centres (2).Clinical indicators show significant improvement for the active patients, expanded disability status scale every 6 months or once every 12 months, visits every 6 months, first visit within 1 year and MRI every 12 months.ConclusionsData from disease registers provide guidance for evidence-based health policies and research, so methods and strategies ensuring their quality and reliability are crucial and have several potential applications

Searches for transverse momentum dependent flow vector fluctuations in Pb-Pb and p-Pb collisions at the LHC

CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFINANCIADORA DE ESTUDOS E PROJETOS - FINEPFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPThe measurement of azimuthal correlations of charged particles is presented for Pb-Pb collisions at root S-NN 2.76 TeV and p-Pb collisions at root S-NN 5.02 TeV with the ALICE detector at the CERN Large Hadron Collider. These correlations are measured for the second, third and fourth order flow vector in the pseudorapidity region vertical bar eta vertical bar 0.8 as a function of centrality and transverse momentum pT using two observables, to search for evidence of PT-dependent flow vector fluctuations. For Ph-Ph collisions at 2.76 TeV, the measurements indicate that PT-dependent fluctuations are only present for the second order flow vector. Similar results have been found for p-Pb collisions at 5.02 TeV. These measurements are compared to hydrodynamic model calculations with event-by-event geometry fluctuations in the initial state to constrain the initial conditions and transport properties of the matter created in Ph-Ph and p-Pb collisions.9133CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFINANCIADORA DE ESTUDOS E PROJETOS - FINEPFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPCONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFINANCIADORA DE ESTUDOS E PROJETOS - FINEPFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPSem informaçãoSem informaçãoSem informaçãoThe ALICE collaboration would like to thank all its engineers and technicians for their invaluable contributions to the construction of the experiment and the CERN accelerator teams for the outstanding performance of the LHC complex. The ALICE collaboration gratefully acknowledges the resources and support provided by all Grid centres and the Worldwide LHC Computing Grid (WLCG) collaboration. The ALICE collaboration acknowledges the following funding agencies for their support in building and running the ALICE detector: A.I. Alikhanyan National Science Laboratory (Yerevan Physics Institute) Foundation (ANSL), State Committee of Science and World Federation of Scientists (WFS), Armenia; Austrian Academy of Sciences and Nationalstiftung fur Forschung, Technologie und Entwicklung, Austria; Ministry of Communications and High Technologies, National Nuclear Research Center, Azerbaijan; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), Universidade Federal do Rio Grande do Sul (UFRGS), Financiadora de Estudos e Projetos (Finep) and Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP), Brazil; Ministry of Science & Technology of China (MSTC), National Natural Science Foundation of China (NSFC) and Ministry of Education of China (MOEC), China; Ministry of Science, Education and Sport and Croatian Science Foundation, Croatia; Ministry of Education, Youth and Sports of the Czech Republic, Czech Republic; The Danish Council for Independent Research Natural Sciences, the Carlsberg Foundation and Danish National Research Foundation (DNRF), Denmark; Helsinki Institute of Physics (HIP), Finland; Commissariat a l'Energie Atomique (CEA) and Institut National de Physique Nucleaire et de Physique des Particules (IN2P3) and Centre National de la Recherche Scientifique (CNRS), France; Bundesministerium fur Bildung, Wissenschaft, Forschung und Technologie (BMBF) and GSI Helmholtzzentrum fur Schwerionenforschung GmbH, Germany; General Secretariat for Research and Technology, Ministry of Education, Research and Religions, Greece; National Research, Development and Innovation Office, Hungary; Department of Atomic Energy Government of India (DAE) and Council of Scientific and Industrial Research (CSIR), New Delhi, India; Indonesian Institute of Science, Indonesia; Centro Fermi Museo Storico della Fisica e Centro Studi e Ricerche Enrico Fermi and Istituto Nazionale di Fisica Nucleare (INFN), Italy; Institute for Innovative Science and Technology, Nagasaki Institute of Applied Science (IIST), Japan Society for the Promotion of Science (JSPS) KAKENHI and Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan; Consejo Nacional de Ciencia (CONACYT) y Tecnologia, through Fondo de Cooperacion Internacional en Ciencia y Tecnologia (FONCICYT) and Direccion General de Asuntos del Personal Academico (DGAPA), Mexico; Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO), Netherlands; The Research Council of Norway, Norway; Commission on Science and Technology for Sustainable Development in the South (COMSATS), Pakistan; Pontificia Universidad Catolica del Peril, Peru; Ministry of Science and Higher Education and National Science Centre, Poland; Korea Institute of Science and Technology Information and National Research Foundation of Korea (NRF), Republic of Korea; Ministry of Education and Scientific Research, Institute of Atomic Physics and Romanian National Agency for Science, Technology and Innovation, Romania; Joint Institute for Nuclear Research (JINR), Ministry of Education and Science of the Russian Federation and National Research Centre Kurchatov Institute, Russia; Ministry of Education, Science, Research and Sport of the Slovak Republic, Slovakia; National Research Foundation of South Africa, South Africa; Centro de Aplicaciones Tecnologicas y Desarrollo Nuclear (CEADEN), Cubaenergia, Cuba, Ministerio de Ciencia e Innovacion and Centro de Investigaciones Energeticas, Medioambientales y Tecnologicas (CIEMAT), Spain; Swedish Research Council (VR) and Knut & Alice Wallenberg Foundation (KAW), Sweden; European Organization for Nuclear Research, Switzerland; National Science and Technology Development Agency (NSDTA), Suranaree University of Technology (SUT) and Office of the Higher Education Commission under NRU project of Thailand, Thailand; Turkish Atomic Energy Agency (TAEK), Turkey; National Academy of Sciences of Ukraine, Ukraine; Science and Technology Facilities Council (STFC), United Kingdom; National Science Foundation of the United States of America (NSF) and United States Department of Energy, Office of Nuclear Physics (DOE NP), United States of America

Low exposure long-baseline neutrino oscillation sensitivity of the DUNE experiment

The Deep Underground Neutrino Experiment (DUNE) will produce world-leading neutrino oscillation measurements over the lifetime of the experiment. In this work, we explore DUNE's sensitivity to observe charge-parity violation (CPV) in the neutrino sector, and to resolve the mass ordering, for exposures of up to 100 kiloton-megawatt-years (kt-MW-yr). The analysis includes detailed uncertainties on the flux prediction, the neutrino interaction model, and detector effects. We demonstrate that DUNE will be able to unambiguously resolve the neutrino mass ordering at a 3$\sigma$ (5$\sigma$) level, with a 66 (100) kt-MW-yr far detector exposure, and has the ability to make strong statements at significantly shorter exposures depending on the true value of other oscillation parameters. We also show that DUNE has the potential to make a robust measurement of CPV at a 3$\sigma$ level with a 100 kt-MW-yr exposure for the maximally CP-violating values \delta_{\rm CP}} = \pm\pi/2. Additionally, the dependence of DUNE's sensitivity on the exposure taken in neutrino-enhanced and antineutrino-enhanced running is discussed. An equal fraction of exposure taken in each beam mode is found to be close to optimal when considered over the entire space of interest

Snowmass Neutrino Frontier: DUNE Physics Summary

The Deep Underground Neutrino Experiment (DUNE) is a next-generation long-baseline neutrino oscillation experiment with a primary physics goal of observing neutrino and antineutrino oscillation patterns to precisely measure the parameters governing long-baseline neutrino oscillation in a single experiment, and to test the three-flavor paradigm. DUNE's design has been developed by a large, international collaboration of scientists and engineers to have unique capability to measure neutrino oscillation as a function of energy in a broadband beam, to resolve degeneracy among oscillation parameters, and to control systematic uncertainty using the exquisite imaging capability of massive LArTPC far detector modules and an argon-based near detector. DUNE's neutrino oscillation measurements will unambiguously resolve the neutrino mass ordering and provide the sensitivity to discover CP violation in neutrinos for a wide range of possible values of δCP. DUNE is also uniquely sensitive to electron neutrinos from a galactic supernova burst, and to a broad range of physics beyond the Standard Model (BSM), including nucleon decays. DUNE is anticipated to begin collecting physics data with Phase I, an initial experiment configuration consisting of two far detector modules and a minimal suite of near detector components, with a 1.2 MW proton beam. To realize its extensive, world-leading physics potential requires the full scope of DUNE be completed in Phase II. The three Phase II upgrades are all necessary to achieve DUNE's physics goals: (1) addition of far detector modules three and four for a total FD fiducial mass of at least 40 kt, (2) upgrade of the proton beam power from 1.2 MW to 2.4 MW, and (3) replacement of the near detector's temporary muon spectrometer with a magnetized, high-pressure gaseous argon TPC and calorimeter

Snowmass Neutrino Frontier: DUNE Physics Summary

The Deep Underground Neutrino Experiment (DUNE) is a next-generation long-baseline neutrino oscillation experiment with a primary physics goal of observing neutrino and antineutrino oscillation patterns to precisely measure the parameters governing long-baseline neutrino oscillation in a single experiment, and to test the three-flavor paradigm. DUNE's design has been developed by a large, international collaboration of scientists and engineers to have unique capability to measure neutrino oscillation as a function of energy in a broadband beam, to resolve degeneracy among oscillation parameters, and to control systematic uncertainty using the exquisite imaging capability of massive LArTPC far detector modules and an argon-based near detector. DUNE's neutrino oscillation measurements will unambiguously resolve the neutrino mass ordering and provide the sensitivity to discover CP violation in neutrinos for a wide range of possible values of $\delta_{CP}$. DUNE is also uniquely sensitive to electron neutrinos from a galactic supernova burst, and to a broad range of physics beyond the Standard Model (BSM), including nucleon decays. DUNE is anticipated to begin collecting physics data with Phase I, an initial experiment configuration consisting of two far detector modules and a minimal suite of near detector components, with a 1.2 MW proton beam. To realize its extensive, world-leading physics potential requires the full scope of DUNE be completed in Phase II. The three Phase II upgrades are all necessary to achieve DUNE's physics goals: (1) addition of far detector modules three and four for a total FD fiducial mass of at least 40 kt, (2) upgrade of the proton beam power from 1.2 MW to 2.4 MW, and (3) replacement of the near detector's temporary muon spectrometer with a magnetized, high-pressure gaseous argon TPC and calorimeter.Comment: Contribution to Snowmass 202

Identification and reconstruction of low-energy electrons in the ProtoDUNE-SP detector

Measurements of electrons from $\nu_e$ interactions are crucial for the Deep Underground Neutrino Experiment (DUNE) neutrino oscillation program, as well as searches for physics beyond the standard model, supernova neutrino detection, and solar neutrino measurements. This article describes the selection and reconstruction of low-energy (Michel) electrons in the ProtoDUNE-SP detector. ProtoDUNE-SP is one of the prototypes for the DUNE far detector, built and operated at CERN as a charged particle test beam experiment. A sample of low-energy electrons produced by the decay of cosmic muons is selected with a purity of 95%. This sample is used to calibrate the low-energy electron energy scale with two techniques. An electron energy calibration based on a cosmic ray muon sample uses calibration constants derived from measured and simulated cosmic ray muon events. Another calibration technique makes use of the theoretically well-understood Michel electron energy spectrum to convert reconstructed charge to electron energy. In addition, the effects of detector response to low-energy electron energy scale and its resolution including readout electronics threshold effects are quantified. Finally, the relation between the theoretical and reconstructed low-energy electron energy spectrum is derived and the energy resolution is characterized. The low-energy electron selection presented here accounts for about 75% of the total electron deposited energy. After the addition of lost energy using a Monte Carlo simulation, the energy resolution improves from about 40% to 25% at 50~MeV. These results are used to validate the expected capabilities of the DUNE far detector to reconstruct low-energy electrons.Comment: 19 pages, 10 figure

A Gaseous Argon-Based Near Detector to Enhance the Physics Capabilities of DUNE

This document presents the concept and physics case for a magnetized gaseous argon-based detector system (ND-GAr) for the Deep Underground Neutrino Experiment (DUNE) Near Detector. This detector system is required in order for DUNE to reach its full physics potential in the measurement of CP violation and in delivering precision measurements of oscillation parameters. In addition to its critical role in the long-baseline oscillation program, ND-GAr will extend the overall physics program of DUNE. The LBNF high-intensity proton beam will provide a large flux of neutrinos that is sampled by ND-GAr, enabling DUNE to discover new particles and search for new interactions and symmetries beyond those predicted in the Standard Model