Temperature induced crossover between 0 and pi states in S/F/S junctions

Ferromagnetic Josephson junctions can show at equilibrium a pi phase difference between the superconducting electrodes. We explain this pi state in an original way by a modified spectrum of Andreev bound states shifted by the exchange energy. A simplified expression for the spectral supercurrent density is calculated and the non-monotonic temperature dependence of the critical current is discussed. This model accounts for the cancellation of the critical current with temperature observed in a small range of barrier thickness in our Nb/Cu52Ni48/Nb junctions. This cancellation corresponds to an inversion of the supercurrent and to a ground state crossover from a 0 state to a pi state. This transition is caused both by the thermal distribution of quasi-particles and by the temperature dependence of the exchange energy. The experimental curves are well reproduced by our theoretical expression except for the very small amplitude of the supercurrent attributed to a large spin-flip scattering

Motion of a solid particle in a shear flow along a porous slab

International audienceThe flow field around a solid particle moving in a shear flow along a porous slab is obtained by solving the coupled Stokes-Darcy problem with the Beavers and Joseph slip boundary condition on the slab interfaces. The solution involves the Green's function of this coupled problem, which is given here. It is shown that the classical boundary integral method using this Green's function is inappropriate because of supplementary contributions due to the slip on the slab interfaces. An 'indirect boundary integral method' is therefore proposed, in which the unknown density on the particle surface is not the actual stress, but yet allows calculation of the force and torque on the particle. Various results are provided for the normalized force and torque, namely friction factors, on the particle. The cases of a sphere and an ellipsoid are considered. It is shown that the relationships between friction coefficients (torque due to rotation and force due to translation) that are classical for a no-slip plane do not apply here. This difference is exhibited Finally, results for the velocity of a freely moving particle in a linear and a quadratic shear flow are presented, for both a sphere and an ellipsoid

Discrete real-time flight plan optimization

Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Aeronautics and Astronautics, 1999.Includes bibliographical references (leaves 117-118).Worldwide, the continuously growing air traffic induces a need for new ATM concepts to be defined. One possibility is using a more decentralized system predicated mainly around free routings (Free Flight), for a more flexible management of airspace. The present study first highlights the discrepancies and inefficiencies of the current best flightplan optimizing software that use the Cost Index concept before departure. It then investigates techniques to perform enhanced flight-plan optimizations en-route, with algorithms that are less complex than using the Cost Index. The long-haul flight leg that is considered through the simulations is London (UK) - Boston (MA, USA), flown on a constant flight level. This study shows that running another optimization at the Top of Climb point reduces the average delay at destination from 6.9 minutes to 5.0 minutes. Then, the more futuristic method of considering discrete flight-plan optimizations, while en-route using updated weather forecasts, provides results that are more interesting. If the weather forecasts and the optimizations are done simultaneously every 3-hour or 1.5-hour, the average delay respectively becomes 2.6 minutes or 2.0 minutes. The second part of this work investigates ways of performing a Linear Program to fly a route close to a 4D-trajectory. This study provides ways of determining the exact weight values for the different state variables used in the cost function to minimize.by Francois Le Sellier.S.M

Triplet repeat RNA structure and its role as pathogenic agent and therapeutic target

This review presents detailed information about the structure of triplet repeat RNA and addresses the simple sequence repeats of normal and expanded lengths in the context of the physiological and pathogenic roles played in human cells. First, we discuss the occurrence and frequency of various trinucleotide repeats in transcripts and classify them according to the propensity to form RNA structures of different architectures and stabilities. We show that repeats capable of forming hairpin structures are overrepresented in exons, which implies that they may have important functions. We further describe long triplet repeat RNA as a pathogenic agent by presenting human neurological diseases caused by triplet repeat expansions in which mutant RNA gains a toxic function. Prominent examples of these diseases include myotonic dystrophy type 1 and fragile X-associated tremor ataxia syndrome, which are triggered by mutant CUG and CGG repeats, respectively. In addition, we discuss RNA-mediated pathogenesis in polyglutamine disorders such as Huntington's disease and spinocerebellar ataxia type 3, in which expanded CAG repeats may act as an auxiliary toxic agent. Finally, triplet repeat RNA is presented as a therapeutic target. We describe various concepts and approaches aimed at the selective inhibition of mutant transcript activity in experimental therapies developed for repeat-associated diseases

BMJ Med

OBJECTIVE: To evaluate the efficacy of covid-19 convalescent plasma to treat patients admitted to hospital for moderate covid-19 disease with or without underlying immunodeficiency (CORIPLASM trial). DESIGN: Open label, randomised clinical trial. SETTING: CORIMUNO-19 cohort (publicly supported platform of open label, randomised controlled trials of immune modulatory drugs in patients admitted to hospital with moderate or severe covid-19 disease) based on 19 university and general hospitals across France, from 16 April 2020 to 21 April 2021. PARTICIPANTS: 120 adults (n=60 in the covid-19 convalescent plasma group, n=60 in the usual care group) admitted to hospital with a positive SARS-CoV2 test result, duration of symptoms 40. MAIN OUTCOME MEASURES: Primary outcomes were proportion of patients with a WHO Clinical Progression Scale score of ≥6 on the 10 point scale on day 4 (higher values indicate a worse outcome), and survival without assisted ventilation or additional immunomodulatory treatment by day 14. Secondary outcomes were changes in WHO Clinical Progression Scale scores, overall survival, time to discharge, and time to end of dependence on oxygen supply. Predefined subgroups analyses included immunosuppression status, duration of symptoms before randomisation, and use of steroids. RESULTS: 120 patients were recruited and assigned to covid-19 convalescent plasma (n=60) or usual care (n=60), including 22 (covid-19 convalescent plasma) and 27 (usual care) patients who were immunocompromised. 13 (22%) patients who received convalescent plasma had a WHO Clinical Progression Scale score of ≥6 at day 4 versus eight (13%) patients who received usual care (adjusted odds ratio 1.88, 95% credible interval 0.71 to 5.24). By day 14, 19 (31.6%) patients in the convalescent plasma group and 20 (33.3%) patients in the usual care group needed ventilation, additional immunomodulatory treatment, or had died. For cumulative incidence of death, three (5%) patients in the convalescent plasma group and eight (13%) in the usual care group died by day 14 (adjusted hazard ratio 0.40, 95% confidence interval 0.10 to 1.53), and seven (12%) patients in the convalescent plasma group and 12 (20%) in the usual care group by day 28 (adjusted hazard ratio 0.51, 0.20 to 1.32). In a subgroup analysis performed in patients who were immunocompromised, transfusion of covid-19 convalescent plasma was associated with mortality (hazard ratio 0.39, 95% confidence interval 0.14 to 1.10). CONCLUSIONS: In this study, covid-19 convalescent plasma did not improve early outcomes in patients with moderate covid-19 disease. The efficacy of convalescent plasma in patients who are immunocompromised should be investigated further. TRIAL REGISTRATION: ClinicalTrials.gov NCT04345991

Splicing misregulation of SCN5A contributes to cardiac-conduction delay and heart arrhythmia in myotonic dystrophy

Myotonic dystrophy (DM) is caused by the expression of mutant RNAs containing expanded CUG repeats that sequester muscleblind-like (MBNL) proteins, leading to alternative splicing changes. Cardiac alterations, characterized by conduction delays and arrhythmia, are the second most common cause of death in DM. Using RNA sequencing, here we identify novel splicing alterations in DM heart samples, including a switch from adult exon 6B towards fetal exon 6A in the cardiac sodium channel, SCN5A. We find that MBNL1 regulates alternative splicing of SCN5A mRNA and that the splicing variant of SCN5A produced in DM presents a reduced excitability compared with the control adult isoform. Importantly, reproducing splicing alteration of Scn5a in mice is sufficient to promote heart arrhythmia and cardiac-conduction delay, two predominant features of myotonic dystrophy. In conclusion, misregulation of the alternative splicing of SCN5A may contribute to a subset of the cardiac dysfunctions observed in myotonic dystrophy.Peer reviewe

Spectroscopic Survey of the Galaxy with Gaia II. The expected science yield from the Radial Velocity Spectrometer

The Gaia mission is designed as a Galaxy explorer, and will measure simultaneously, in a survey mode, the five or six phase space parameters of all stars brighter than 20th magnitude, as well as providing a description of their astrophysical characteristics. These measurements are obtained by combining an astrometric instrument with micro-arcsecond capabilities, a photometric system giving the magnitudes and colours in 15 bands and a medium resolution spectrograph named the Radial Velocity Spectrometer (RVS). The latter instrument will produce spectra in the 848 to 874 nm wavelength range, with a resolving power R = 11 500, from which radial velocities, rotational velocities, atmospheric parameters and abundances can be derived. A companion paper (Katz et al. 2004) presents the characteristics of the RVS and its performance. This paper details the outstanding scientific impact of this important part of the Gaia satellite on some key open questions in present day astrophysics. The unbiased and simultaneous acquisition of multi-epoch radial velocities and individual abundances of key elements in parallel with the astrometric parameters is essential for the determination of the dynamical state and formation history of our Galaxy. Moreover, for stars brighter than V=15, the resolving power of the RVS will give information about most of the effects which influence the position of a star in the Hertzsprung-Russell diagram, placing unprecedented constraints on the age, internal structure and evolution of stars of all types. Finally, the RVS multi-epoch observations are ideally suited to the identification, classification and characterisation of the many types of double, multiple and variable stars.Comment: 33 pages, 11 figures, in press at MNRAS. Figs 1, 3 and 9 included at reduced resolution; available in full resolution at http://www.blackwell-synergy.com/doi/pdf/10.1111/j.1365-2966.2005.09012.

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

Background: We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases. Methods: We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results: No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5–528.7, P = 1.1 × 10−4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3–8.2], P = 2.1 × 10−4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1–2635.4], P = 3.4 × 10−3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3–8.4], P = 7.7 × 10−8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10−5). Conclusions: Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old