Perturbed autophagy and DNA repair converge to promote neurodegeneration in amyotrophic lateral sclerosis and dementia

Maintaining genomic stability constitutes a major challenge facing cells. DNA breaks can arise from direct oxidative damage to the DNA backbone, the inappropriate activities of endogenous enzymes such as DNA topoisomerases, or due to transcriptionallyderived RNA/DNA hybrids (R-loops). The progressive accumulation of DNA breaks has been linked to several neurological disorders. Recently, however, several independent studies have implicated nuclear and mitochondrial genomic instability, perturbed co-transcriptional processing, and impaired cellular clearance pathways as causal and intertwined mechanisms underpinning neurodegeneration. Here, we discuss this emerging paradigm in the context of amyotrophic lateral sclerosis and frontotemporal dementia, and outline how this knowledge paves the way to novel therapeutic interventions

Factors Associated with Revision Surgery after Internal Fixation of Hip Fractures

Background: Femoral neck fractures are associated with high rates of revision surgery after management with internal fixation. Using data from the Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trial evaluating methods of internal fixation in patients with femoral neck fractures, we investigated associations between baseline and surgical factors and the need for revision surgery to promote healing, relieve pain, treat infection or improve function over 24 months postsurgery. Additionally, we investigated factors associated with (1) hardware removal and (2) implant exchange from cancellous screws (CS) or sliding hip screw (SHS) to total hip arthroplasty, hemiarthroplasty, or another internal fixation device. Methods: We identified 15 potential factors a priori that may be associated with revision surgery, 7 with hardware removal, and 14 with implant exchange. We used multivariable Cox proportional hazards analyses in our investigation. Results: Factors associated with increased risk of revision surgery included: female sex, [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.25-2.50; P = 0.001], higher body mass index (fo

Motor cortical and corticospinal function differ during an isometric squat compared to isometric knee extension

It has been suggested that task-specific changes in neurophysiological function (neuroplasticity), should be assessed using testing modalities that replicate the characteristics of the intervention. The squat is a commonly prescribed resistance exercise that has been shown to elicit changes in central nervous system (CNS) function. However, previous studies have assessed squat-induced neuroplasticity using isometric knee extension, potentially confounding the results. The present study aimed to assess the agreement between corticospinal and intracortical activity relating to the knee extensors during isometric knee extension compared to an isometric squat task. Eleven males completed a neurophysiological assessment in an isometric squat (IS), and knee extension (KE) task matched for joint-angles (hip, knee, and ankle). Single- and paired-pulse transcranial magnetic stimulation (TMS) were delivered during isometric contractions at a range of intensities to assess short-interval cortical inhibition (SICI) and corticospinal excitability. Group mean values for SICI (70 ± 14% vs. 63 ± 12% of unconditioned MEP during IS and KE, respectively) and corticospinal excitability (mean differences 2-5% of Mmax at 25, 50, 75 and 100% MVC between the IS and KE) were not different between the two tasks (P > 0.05) in the vastus lateralis (VL). However, limits of agreement were wide, with poor-to-moderate average ICCs (SICI: ICC3,1 = 0.15, corticospinal excitability: average ICC3,1 range = 0.0-0.63), indicating disparate corticospinal and intracortical activity between the IS and KE. These data highlight the importance of task-specificity when assessing the modulation of corticospinal excitability and SICI in response to interventions resulting in neuroplastic changes

Motor cortical and corticospinal function differ during an isometric squat compared with isometric knee extension

It has been suggested that task‐specific changes in neurophysiological function (neuroplasticity) should be assessed using testing modalities that replicate the characteristics of the intervention. The squat is a commonly prescribed resistance exercise that has been shown to elicit changes in CNS function. However, previous studies have assessed squat‐induced neuroplasticity using isometric knee extension, potentially confounding the results. The aim of the present study was to assess the agreement between corticospinal and intracortical activity relating to the knee extensors during isometric knee extension compared with an isometric squat task. Eleven males completed a neurophysiological assessment in an isometric squat (IS) and knee‐extension (KE) task matched for joint angles (hip, knee and ankle). Single‐ and paired‐pulse transcranial magnetic stimulation was delivered during isometric contractions at a range of intensities to assess short‐interval cortical inhibition (SICI) and corticospinal excitability. Group mean values for SICI (70 ± 14 versus 63 ± 12% of unconditioned motor evoked potential during IS and KE, respectively) and corticospinal excitability (mean differences 2–5% of the maximal compound muscle action potential at 25, 50, 75 and 100% maximal voluntary contraction between the IS and KE) were not different between the two tasks (P > 0.05) in the vastus lateralis. However, limits of agreement were wide, with poor‐to‐moderate average intraclass correlation coefficients (ICCs) (SICI, ICC3,1 = 0.15; corticospinal excitability, average ICC3,1 range = 0.0–0.63), indicating disparate corticospinal and intracortical activity between the IS and KE. These data highlight the importance of task specificity when assessing the modulation of corticospinal excitability and SICI in response to interventions resulting in neuroplastic change

Direct Mass Measurements of Neutron-Rich Zinc and Gallium Isotopes : An Investigation of the Formation of the First -Process Peak

The prediction of isotopic abundances resulting from the rapid neutron capture process ( process) requires high-precision mass measurements. Using TITAN’s on-line time-of-flight spectrometer, first time mass measurements are performed for 83Zn and 86Ga. These measurements reduced uncertainties, and are used to calculate isotopic abundances near the first -process abundance peak using astrophysical conditions present during a binary neutron star (BNS) merger. Good agreement in abundance across a range of trajectories is found when comparing to several metal-poor stars while also strongly deviating from the solar -process pattern. These findings point to a high degree of sensitivity to the electron fraction of a BNS merger on the final elemental abundance pattern for certain elements near the first -process peak while others display universality. We find that small changes in electron fraction can produce distinct abundance patterns that match those of metal-poor stars with different classifications.peerReviewe

The DUNE Far Detector Vertical Drift Technology, Technical Design Report

International audienceDUNE is an international experiment dedicated to addressing some of the questions at the forefront of particle physics and astrophysics, including the mystifying preponderance of matter over antimatter in the early universe. The dual-site experiment will employ an intense neutrino beam focused on a near and a far detector as it aims to determine the neutrino mass hierarchy and to make high-precision measurements of the PMNS matrix parameters, including the CP-violating phase. It will also stand ready to observe supernova neutrino bursts, and seeks to observe nucleon decay as a signature of a grand unified theory underlying the standard model. The DUNE far detector implements liquid argon time-projection chamber (LArTPC) technology, and combines the many tens-of-kiloton fiducial mass necessary for rare event searches with the sub-centimeter spatial resolution required to image those events with high precision. The addition of a photon detection system enhances physics capabilities for all DUNE physics drivers and opens prospects for further physics explorations. Given its size, the far detector will be implemented as a set of modules, with LArTPC designs that differ from one another as newer technologies arise. In the vertical drift LArTPC design, a horizontal cathode bisects the detector, creating two stacked drift volumes in which ionization charges drift towards anodes at either the top or bottom. The anodes are composed of perforated PCB layers with conductive strips, enabling reconstruction in 3D. Light-trap-style photon detection modules are placed both on the cryostat's side walls and on the central cathode where they are optically powered. This Technical Design Report describes in detail the technical implementations of each subsystem of this LArTPC that, together with the other far detector modules and the near detector, will enable DUNE to achieve its physics goals