Atmospheric lepton fluxes at ultrahigh energies

In order to estimate the possibility to observe exotic physics in a neutrino telescope, it is essential to first understand the flux of atmospheric neutrinos, muons and dimuons. We study the production of these leptons by high-energy cosmic rays. We identify three main sources of muons of energy E > 10^6 GeV: the weak decay of charm and bottom mesons and the electromagnetic decay of unflavored mesons. Contrary to the standard assumption, we find that eta mesons, not the prompt decay of charm hadrons, are the dominant source of atmospheric muons at these energies. We show that, as a consequence, the ratio between the neutrino and muon fluxes is significantly reduced. For dimuons, which may be a background for long-lived staus produced near a neutrino telescope, we find that pairs of E ~ 10^7 GeV forming an angle above 10^-6 rad are produced through D (80%) or B (10%) meson decay and through Drell-Yan proceses (10%). The frequency of all these processes has been evaluated using the jet code PYTHIA.Comment: 10 pages, 4 figures; published versio

Normal Proliferation and Tumorigenesis but Impaired Pancreatic Function in Mice Lacking the Cell Cycle Regulator Sei1

Sei1 is a positive regulator of proliferation that promotes the assembly of Cdk4-cyclin D complexes and enhances the transcriptional activity of E2f1. The potential oncogenic role of Sei1 is further suggested by its overexpression in various types of human cancers. To study the role of Sei1, we have generated a mouse line deficient for this gene. Sei1-null fibroblasts did not show abnormalities regarding proliferation or susceptibility to neoplastic transformation, nor did we observe defects on Cdk4 complexes or E2f activity. Sei1-null mice were viable, did not present overt pathologies, had a normal lifespan, and had a normal susceptibility to spontaneous and chemically-induced cancer. Pancreatic insulin-producing cells are known to be particularly sensitive to Cdk4-cyclin D and E2f activities, and we have observed that Sei1 is highly expressed in pancreatic islets compared to other tissues. Interestingly, Sei1-null mice present lower number of islets, decreased β-cell area, impaired insulin secretion, and glucose intolerance. These defects were associated to nuclear accumulation of the cell-cycle inhibitors p21Cip1 and p27Kip1 in islet cells. We conclude that Sei1 plays an important role in pancreatic β-cells, which supports a functional link between Sei1 and the core cell cycle regulators specifically in the context of the pancreas

Beam-ion transport dependence on Magnetic Perturbations spectrum and plasma helicity in the ASDEX Upgrade tokamak

EUROfusion Consortium 63305

Subthalamic stimulation modulates context-dependent effects of beta bursts during fine motor control.

Increasing evidence suggests a considerable role of pre-movement beta bursts for motor control and its impairment in Parkinson's disease. However, whether beta bursts occur during precise and prolonged movements and if they affect fine motor control remains unclear. To investigate the role of within-movement beta bursts for fine motor control, we here combine invasive electrophysiological recordings and clinical deep brain stimulation in the subthalamic nucleus in 19 patients with Parkinson's disease performing a context-varying task that comprised template-guided and free spiral drawing. We determined beta bursts in narrow frequency bands around patient-specific peaks and assessed burst amplitude, duration, and their immediate impact on drawing speed. We reveal that beta bursts occur during the execution of drawing movements with reduced duration and amplitude in comparison to rest. Exclusively when drawing freely, they parallel reductions in acceleration. Deep brain stimulation increases the acceleration around beta bursts in addition to a general increase in drawing velocity and improvements of clinical function. These results provide evidence for a diverse and task-specific role of subthalamic beta bursts for fine motor control in Parkinson's disease; suggesting that pathological beta bursts act in a context dependent manner, which can be targeted by clinical deep brain stimulation

Metoprolol blunts the time-dependent progression of infarct size.

Early metoprolol administration protects against myocardial ischemia-reperfusion injury, but its effect on infarct size progression (ischemic injury) is unknown. Eight groups of pigs (total n = 122) underwent coronary artery occlusion of varying duration (20, 25, 30, 35, 40, 45, 50, or 60 min) followed by reperfusion. In each group, pigs were randomized to i.v. metoprolol (0.75 mg/kg) or vehicle (saline) 20 min after ischemia onset. The primary outcome measure was infarct size (IS) on day7 cardiac magnetic resonance (CMR) normalized to area at risk (AAR, measured by perfusion computed tomography [CT] during ischemia). Metoprolol treatment reduced overall mortality (10% vs 26%, p = 0.03) and the incidence and number of primary ventricular fibrillations during infarct induction. In controls, IS after 20-min ischemia was ≈ 5% of the area AAR. Thereafter, IS progressed exponentially, occupying almost all the AAR after 35 min of ischemia. Metoprolol injection significantly reduced the slope of IS progression (p = 0.004 for final IS). Head-to-head comparison (metoprolol treated vs vehicle treated) showed statistically significant reductions in IS at 30, 35, 40, and 50-min reperfusion. At 60-min reperfusion, IS was 100% of AAR in both groups. Despite more prolonged ischemia, metoprolol-treated pigs reperfused at 50 min had smaller infarcts than control pigs undergoing ischemia for 40 or 45 min and similar-sized infarcts to those undergoing 35-min ischemia. Day-45 LVEF was higher in metoprolol-treated vs vehicle-treated pigs (41.6% vs 36.5%, p = 0.008). In summary, metoprolol administration early during ischemia attenuates IS progression and reduces the incidence of primary ventricular fibrillation. These data identify metoprolol as an intervention ideally suited to the treatment of STEMI patients identified early in the course of infarction and requiring long transport times before primary angioplasty.This study received funding from the Ministry of Science and Innovation (“RETOS 2019” Grant no. PID2019-107332RB-I00), from the Instituto de Salud Carlos III (ISCIII; PI16/02110) and the European Regional Development Fund (ERDF) “A way of making Europe” (# AC16/00021), and from the Spanish Society of Cardiology through a 2017 Translational Research grant. BI has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (ERC-Consolidator Grant agreement no. 819775). M.L received support from a 2015 Severo Ochoa CNIC intramural grant. X.R. received support from the SEC-CNIC CARDIOJOVEN fellowship program. R.F-J is a recipient of funding from the Carlos III Institute of Health-Fondo de Investigacion Sanitaria (PI19/01704) and has received funding from the European Union Horizon 2020 research and innovation programme under Marie Skłodowska-Curie grant agreement No 707642. EO is recipient of funds from Programa de Atracción de Talento (2017-T1/BMD-5185) of Comunidad de Madrid. The CNIC is supported by the ISCIII, the Ministerio de Ciencia e Innovación (MICINN) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505).S

In vitro antileishmanial activity and iron superoxide dismutase inhibition of arylamine Mannich base derivatives

Leishmaniasis is one of the world’s most neglected diseases, and it has a worldwide prevalence of 12 million. There are no effective human vaccines for its prevention, and treatment is hampered by outdated drugs. Therefore, research aiming at the development of new therapeutic tools to fight Leishmaniasis remains a crucial goal today. With this purpose in mind, we present twenty arylaminoketone derivatives with a very interesting in vitro and in vivo efficacy against Trypanosoma cruzi that have now been studied against promastigote and amastigote forms of L. infantum, L. donovani and L. braziliensis strains. Six out of the twenty Mannich base-type derivatives showed Selectivity Index between 39 and 2337 times higher in the amastigote form than the reference drug glucantime. These six derivatives affected the parasite infectivity rates; the result was lower parasite infectivity rates than glucantime tested at a IC25 dose. In addition, these derivatives were substantially more active against the three Leishmania species tested than glucantime. The mechanism of action of these compounds has been studied, showing a greater alteration in glucose catabolism and leading to greater levels of Fe-SOD (iron superoxide dismutase) inhibition. These molecules could be potential candidates for Leishmaniasis chemotherapy

Newborn screening for presymptomatic diagnosis of complement and phagocyte deficiencies

The clinical outcomes of primary immunodeficiencies (PIDs) are greatly improved by accurate diagnosis early in life. However, it is not common to consider PIDs before the manifestation of severe clinical symptoms. Including PIDs in the nation-wide newborn screening programs will potentially improve survival and provide better disease management and preventive care in PID patients. This calls for the detection of disease biomarkers in blood and the use of dried blood spot samples, which is a part of routine newborn screening programs worldwide. Here, we developed a newborn screening method based on multiplex protein profiling for parallel diagnosis of 22 innate immunodeficiencies affecting the complement system and respiratory burst function in phagocytosis. The proposed method uses a small fraction of eluted blood from dried blood spots and is applicable for population-scale performance. The diagnosis method is validated through a retrospective screening of immunodeficient patient samples. This diagnostic approach can pave the way for an earlier, more comprehensive and accurate diagnosis of complement and phagocytic disorders, which ultimately lead to a healthy and active life for the PID patientsThis work was supported by the Swedish Research Council (VR) and grants provided by the Stockholm County Council (ALF)

Beam modulation and bump-on-tail effects on Alfvén eigenmode stability in DIII-D

Beam modulation effects on Alfvén eigenmode stability have been investigated in a recent DIII-D experiment and show that variations in neutral beam modulation period can have an impact on the beam driven Alfvén eigenmode spectrum and resultant fast ion transport despite similar time-averaged input power. The experiment was carried out during the current ramp phase of L-mode discharges heated with sub-Alfvénic 50–80 kV deuterium neutral beams that drive a variety of Alfvén eigenmodes unstable. The modulation period of two interleaved beams with different tangency radii was varied from shot to shot in order to modify the relative time dependent mix of the beam pitch angle distribution as well as the persistence of a bump-on-tail feature near the injection energy (a feature confirmed by imaging neutral particle analyzer measurements). As the beam modulation period is varied from 7 ms to 30 ms on/off (typical full energy slowing down time of τslow ≈ 50 ms at mid-radius), toroidicity-induced Alfvén eigenmodes (TAEs) located in the outer periphery of the plasma become intermittent and coincident with the more tangential beam. Core mode activity changes from reversed shear Alfvén eigenmodes (RSAEs) to a mix of RSAE and beta-induced Alfvén eigenmodes. Discharges with 30 ms on/off period do not have a persistent bump-on-tail feature, have the lowest average mode amplitude and least fast ion transport. Detailed analysis of an individual TAE using TRANSP kick modeling (Monte Carlo evolution of the distribution function with probabilistic \u27kicks\u27 by the AEs) and the resistive MHD code with kinetic fast ions, MEGA, find no strong role of energy gradient drive due to bump-on-tail features. Instead, the observed TAE modulation with interleaved beams is likely a pitch angle dependent result combined with slowing down of the tangential beam between pulses. For the conditions investigated, bump-on-tail contributions to TAE drive were found to be 5% or less of the total drive at any given time

Comprehensive analysis and insights gained from long-term experience of the Spanish DILI Registry

Background & aims: Prospective drug-induced liver injury (DILI) registries are important sources of information on idiosyncratic DILI. We aimed to present a comprehensive analysis of 843 patients with DILI enrolled into the Spanish DILI Registry over a 20-year time period. Methods: Cases were identified, diagnosed and followed prospectively. Clinical features, drug information and outcome data were collected. Results: A total of 843 patients, with a mean age of 54 years (48% females), were enrolled up to 2018. Hepatocellular injury was associated with younger age (adjusted odds ratio [aOR] per year 0.983; 95% CI 0.974-0.991) and lower platelet count (aOR per unit 0.996; 95% CI 0.994-0.998). Anti-infectives were the most common causative drug class (40%). Liver-related mortality was more frequent in patients with hepatocellular damage aged ≥65 years (p = 0.0083) and in patients with underlying liver disease (p = 0.0221). Independent predictors of liver-related death/transplantation included nR-based hepatocellular injury, female sex, higher onset aspartate aminotransferase (AST) and bilirubin values. nR-based hepatocellular injury was not associated with 6-month overall mortality, for which comorbidity burden played a more important role. The prognostic capacity of Hy's law varied between causative agents. Empirical therapy (corticosteroids, ursodeoxycholic acid and MARS) was prescribed to 20% of patients. Drug-induced autoimmune hepatitis patients (26 cases) were mainly females (62%) with hepatocellular damage (92%), who more frequently received immunosuppressive therapy (58%).The present study has been supported by grants of Instituto de Salud Carlos III cofounded by Fondo Europeo de Desarrollo Regional – FEDER (contract numbers: PI19/00883, PI16/01748, PI18/00901, PI18/01804, PI-0285-2016, PI-0274-2016, PI-0310- 2018, PT17/0017/0020) and Agencia Española del Medicamento. CIBERehd and Plataforma ISCIII Ensayos Clinicos are funded by Instituto de Salud Carlos III. MRD holds a Joan Rodes (JR16/ 00015)/Acción B clinicos investigadores (B-0002-2019) and JSC a Rio Hortega (CM17/00243) research contract from ISCIII and Consejería de Salud de Andalucía. The funding sources had no involvement in the study design; in the collection, analysis, and interpretation of data; in the writing of the report or in the de- cision to submit the manuscript for publication