52 research outputs found

    The prion-like RNA-processing protein HNRPDL forms inherently toxic amyloid-like inclusion bodies in bacteria

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    BACKGROUND: The formation of protein inclusions is connected to the onset of many human diseases. Human RNA binding proteins containing intrinsically disordered regions with an amino acid composition resembling those of yeast prion domains, like TDP-43 or FUS, are being found to aggregate in different neurodegenerative disorders. The structure of the intracellular inclusions formed by these proteins is still unclear and whether these deposits have an amyloid nature or not is a matter of debate. Recently, the aggregation of TDP-43 has been modelled in bacteria, showing that TDP-43 inclusion bodies (IBs) are amorphous but intrinsically neurotoxic. This observation raises the question of whether it is indeed the lack of an ordered structure in these human prion-like protein aggregates the underlying cause of their toxicity in different pathological states. RESULTS: Here we characterize the IBs formed by the human prion-like RNA-processing protein HNRPDL. HNRPDL is linked to the development of limb-girdle muscular dystrophy 1G and shares domain architecture with TDP-43. We show that HNRPDL IBs display characteristic amyloid hallmarks, since these aggregates bind to amyloid dyes in vitro and inside the cell, they are enriched in intermolecular β-sheet conformation and contain inner amyloid-like fibrillar structure. In addition, despite their ordered structure, HNRPDL IBs are highly neurotoxic. CONCLUSIONS: Our results suggest that at least some of the disorders caused by the aggregation of human prion-like proteins would rely on the formation of classical amyloid assemblies rather than being caused by amorphous aggregates. They also illustrate the power of microbial cell factories to model amyloid aggregation. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12934-015-0284-7) contains supplementary material, which is available to authorized users

    Further studies on the physics potential of an experiment using LHC neutrinos

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    We discuss an experiment to investigate neutrino physics at the LHC, with emphasis on tau flavour. As described in our previous paper Beni et al (2019 J. Phys. G: Nucl. Part. Phys. 46 115008), the detector can be installed in the decommissioned TI18 tunnel, ≈ 480 m downstream the ATLAS cavern, after the first bending dipoles of the LHC arc. The detector intercepts the intense neutrino flux, generated by the LHC beams colliding in IP1, at large pseudorapidity η, where neutrino energies can exceed a TeV. This paper focuses on exploring the neutrino pseudorapity versus energy phase space available in TI18 in order to optimize the detector location and acceptance for neutrinos originating at the pp interaction point, in contrast to neutrinos from pion and kaon decays. The studies are based on the comparison of simulated pp collisions at √s = 13 TeV: PYTHIA events of heavy quark (c and b) production, compared to DPMJET minimum bias events (including charm) with produced particles traced through realistic LHC optics with FLUKA. Our studies favour a configuration where the detector is positioned off the beam axis, slightly above the ideal prolongation of the LHC beam from the straight section, covering 7.4 < η < 9.2. In this configuration, the flux at high energies (0.5-1.5 TeV and beyond) is found to be dominated by neutrinos originating directly from IP1, mostly from charm decays, of which ∼50% are electron neutrinos and ∼5% are tau neutrinos. The contribution of pion and kaon decays to the muon neutrino flux is found small at those high energies. With 150 f b-1 of delivered LHC luminosity in Run 3 the experiment can record a few thousand very high energy neutrino charged current (CC) interactions and over 50 tau neutrino CC events. These events provide useful information in view of a high statistics experiment at HL-LHC. The electron and muon neutrino samples can extend the knowledge of the charm PDF to a new region of x, which is dominated by theory uncertainties. The tau neutrino sample can provide first experience on reconstruction of tau neutrino events in a very boosted regime

    First results of the140ce(N,Ò¯)141ce cross-section measurement at n_tof

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    An accurate measurement of the140Ce(n,Ò¯) energy-dependent cross-section was performed at the n_TOF facility at CERN. This cross-section is of great importance because it represents a bottleneck for the s-process nucleosynthesis and determines to a large extent the cerium abundance in stars. The measurement was motivated by the significant difference between the cerium abundance measured in globular clusters and the value predicted by theoretical stellar models. This discrepancy can be ascribed to an overestimation of the140Ce capture cross-section due to a lack of accurate nuclear data. For this measurement, we used a sample of cerium oxide enriched in140Ce to 99.4%. The experimental apparatus consisted of four deuterated benzene liquid scintillator detectors, which allowed us to overcome the difficulties present in the previous measurements, thanks to their very low neutron sensitivity. The accurate analysis of the p-wave resonances and the calculation of their average parameters are fundamental to improve the evaluation of the140Ce Maxwellian-averaged cross-section

    SND@LHC: The Scattering and Neutrino Detector at the LHC

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    SND@LHC is a compact and stand-alone experiment designed to perform measurements with neutrinos produced at the LHC in the pseudo-rapidity region of 7.2<η<8.4{7.2 < \eta < 8.4}. The experiment is located 480 m downstream of the ATLAS interaction point, in the TI18 tunnel. The detector is composed of a hybrid system based on an 830 kg target made of tungsten plates, interleaved with emulsion and electronic trackers, also acting as an electromagnetic calorimeter, and followed by a hadronic calorimeter and a muon identification system. The detector is able to distinguish interactions of all three neutrino flavours, which allows probing the physics of heavy flavour production at the LHC in the very forward region. This region is of particular interest for future circular colliders and for very high energy astrophysical neutrino experiments. The detector is also able to search for the scattering of Feebly Interacting Particles. In its first phase, the detector will operate throughout LHC Run 3 and collect a total of 250 fb−1\text{fb}^{-1}

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

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    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&nbsp;years old

    Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

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    Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

    Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

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    Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

    Direct and indirect impacts of climate and socio-economic change in Europe: a sensitivity analysis for key land- and water-based sectors

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    Integrated cross-sectoral impact assessments facilitate a comprehensive understanding of interdependencies and potential synergies, conflicts, and trade-offs between sectors under changing conditions. This paper presents a sensitivity analysis of a European integrated assessment model, the CLIMSAVE integrated assessment platform (IAP). The IAP incorporates important cross-sectoral linkages between six key European land- and water-based sectors: agriculture, biodiversity, flooding, forests, urban, and water. Using the IAP, we investigate the direct and indirect implications of a wide range of climatic and socio-economic drivers to identify: (1) those sectors and regions most sensitive to future changes, (2) the mechanisms and directions of sensitivity (direct/indirect and positive/negative), (3) the form and magnitudes of sensitivity (linear/non-linear and strong/weak/insignificant), and (4) the relative importance of the key drivers across sectors and regions. The results are complex. Most sectors are either directly or indirectly sensitive to a large number of drivers (more than 18 out of 24 drivers considered). Over twelve of these drivers have indirect impacts on biodiversity, forests, land use diversity, and water, while only four drivers have indirect effects on flooding. In contrast, for the urban sector all the drivers are direct. Moreover, most of the driver–indicator relationships are non-linear, and hence there is the potential for ‘surprises’. This highlights the importance of considering cross-sectoral interactions in future impact assessments. Such systematic analysis provides improved information for decision-makers to formulate appropriate adaptation policies to maximise benefits and minimise unintended consequence

    Mechanical and thermal design of the target neutral beam absorber for the High-Luminosity LHC upgrade

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    The High-Luminosity target neutral beam absorber (TAXN) is the radiation absorber of the neutral particle debris generated at the beam collisions carried out in the ATLAS and CMS detectors at the Large Hadron Collider (LHC). The new absorber will protect the superconducting magnets from this radiation to prevent their quenching at a design luminosity of 7.5×1034  cm−2 s−1. This article describes the mechanical design of the TAXN assembly and the recombination chamber together with the thermal computations performed for the water-cooling and bakeout system prepared for the engineering design review held in January, 2021. It takes into account the internal integration of the zero degree calorimeter and beam rate of neutrals luminosity detector as well as their physics case overview. In addition, it provides the beam aperture breakdown and the heat deposition expected in the absorber
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