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- Berry, Joe Scott, et al.
(author)
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Examining the biological pathways underlying clinical heterogeneity in Sjogren's syndrome : proteomic and network analysis
- 2024
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In: Annals of the Rheumatic Diseases. - : BMJ Publishing Group Ltd. - 0003-4967 .- 1468-2060. ; 83:1, s. 88-95
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Journal article (peer-reviewed)abstract
- Objectives: Stratification approaches are vital to address clinical heterogeneity in Sjogren's syndrome (SS). We previously described that the Newcastle Sjogren's Stratification Tool (NSST) identified four distinct clinical subtypes of SS. We performed proteomic and network analysis to analyse the underlying pathobiology and highlight potential therapeutic targets for different SS subtypes.Method: We profiled serum proteins using O-link technology of 180 SS subjects. We used 5 O-link proteomics panels which included a total of 454 unique proteins. Network reconstruction was performed using the ARACNE algorithm, with differential expression estimates overlaid on these networks to reveal the key subnetworks of differential expression. Furthermore, data from a phase III trial of tocilizumab in SS were reanalysed by stratifying patients at baseline using NSST.Results: Our analysis highlights differential expression of chemokines, cytokines and the major autoantigen TRIM21 between the SS subtypes. Furthermore, we observe differential expression of several transcription factors associated with energy metabolism and redox balance namely APE1/Ref-1, FOXO1, TIGAR and BACH1. The differentially expressed proteins were inter-related in our network analysis, supporting the concept that distinct molecular networks underlie the clinical subtypes of SS. Stratification of patients at baseline using NSST revealed improvement of fatigue score only in the subtype expressing the highest levels of serum IL-6.Conclusions: Our data provide clues to the pathways contributing to the glandular and non-glandular manifestations of SS and to potential therapeutic targets for different SS subtypes. In addition, our analysis highlights the need for further exploration of altered metabolism and mitochondrial dysfunction in the context of SS subtypes.
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- Fresard, Laure, et al.
(author)
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Identification of rare-disease genes using blood transcriptome sequencing and large control cohorts
- 2019
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In: Nature Medicine. - : NATURE PUBLISHING GROUP. - 1078-8956 .- 1546-170X. ; 25:6, s. 911-919
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Journal article (peer-reviewed)abstract
- It is estimated that 350 million individuals worldwide suffer from rare diseases, which are predominantly caused by mutation in a single gene(1). The current molecular diagnostic rate is estimated at 50%, with whole-exome sequencing (WES) among the most successful approaches(2-5). For patients in whom WES is uninformative, RNA sequencing (RNA-seq) has shown diagnostic utility in specific tissues and diseases(6-8). This includes muscle biopsies from patients with undiagnosed rare muscle disorders(6,9), and cultured fibroblasts from patients with mitochondrial disorders(7). However, for many individuals, biopsies are not performed for clinical care, and tissues are difficult to access. We sought to assess the utility of RNA-seq from blood as a diagnostic tool for rare diseases of different pathophysiologies. We generated whole-blood RNA-seq from 94 individuals with undiagnosed rare diseases spanning 16 diverse disease categories. We developed a robust approach to compare data from these individuals with large sets of RNA-seq data for controls (n = 1,594 unrelated controls and n = 49 family members) and demonstrated the impacts of expression, splicing, gene and variant filtering strategies on disease gene identification. Across our cohort, we observed that RNA-seq yields a 7.5% diagnostic rate, and an additional 16.7% with improved candidate gene resolution.
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- Hudson, Lawrence N, et al.
(author)
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The database of the PREDICTS (Projecting Responses of Ecological Diversity In Changing Terrestrial Systems) project
- 2017
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In: Ecology and Evolution. - : John Wiley & Sons. - 2045-7758. ; 7:1, s. 145-188
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Journal article (peer-reviewed)abstract
- The PREDICTS project-Projecting Responses of Ecological Diversity In Changing Terrestrial Systems (www.predicts.org.uk)-has collated from published studies a large, reasonably representative database of comparable samples of biodiversity from multiple sites that differ in the nature or intensity of human impacts relating to land use. We have used this evidence base to develop global and regional statistical models of how local biodiversity responds to these measures. We describe and make freely available this 2016 release of the database, containing more than 3.2 million records sampled at over 26,000 locations and representing over 47,000 species. We outline how the database can help in answering a range of questions in ecology and conservation biology. To our knowledge, this is the largest and most geographically and taxonomically representative database of spatial comparisons of biodiversity that has been collated to date; it will be useful to researchers and international efforts wishing to model and understand the global status of biodiversity.
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- Murari, A., et al.
(author)
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A control oriented strategy of disruption prediction to avoid the configuration collapse of tokamak reactors
- 2024
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In: Nature Communications. - 2041-1723 .- 2041-1723. ; 15:1
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Journal article (peer-reviewed)abstract
- The objective of thermonuclear fusion consists of producing electricity from the coalescence of light nuclei in high temperature plasmas. The most promising route to fusion envisages the confinement of such plasmas with magnetic fields, whose most studied configuration is the tokamak. Disruptions are catastrophic collapses affecting all tokamak devices and one of the main potential showstoppers on the route to a commercial reactor. In this work we report how, deploying innovative analysis methods on thousands of JET experiments covering the isotopic compositions from hydrogen to full tritium and including the major D-T campaign, the nature of the various forms of collapse is investigated in all phases of the discharges. An original approach to proximity detection has been developed, which allows determining both the probability of and the time interval remaining before an incoming disruption, with adaptive, from scratch, real time compatible techniques. The results indicate that physics based prediction and control tools can be developed, to deploy realistic strategies of disruption avoidance and prevention, meeting the requirements of the next generation of devices.
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- Swanson, Chad J., et al.
(author)
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A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer's disease with lecanemab, an anti-A beta protofibril antibody
- 2021
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In: Alzheimer's Research & Therapy. - : BioMed Central (BMC). - 1758-9193. ; 13
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Journal article (peer-reviewed)abstract
- Background: Lecanemab (BAN2401), an IgG1 monoclonal antibody, preferentially targets soluble aggregated amyloid beta (A beta), with activity across oligomers, protofibrils, and insoluble fibrils. BAN2401-G000-201, a randomized double-blind clinical trial, utilized a Bayesian design with response-adaptive randomization to assess 3 doses across 2 regimens of lecanemab versus placebo in early Alzheimer's disease, mild cognitive impairment due to Alzheimer's disease (AD) and mild AD dementia.Methods: BAN2401-G000-201 aimed to establish the effective dose 90% (ED90), defined as the simplest dose that achieves >= 90% of the maximum treatment effect. The primary endpoint was Bayesian analysis of 12-month clinical change on the Alzheimer's Disease Composite Score (ADCOMS) for the ED90 dose, which required an 80% probability of >= 25% clinical reduction in decline versus placebo. Key secondary endpoints included 18-month Bayesian and frequentist analyses of brain amyloid reduction using positron emission tomography; clinical decline on ADCOMS, Clinical Dementia Rating-Sum-of-Boxes (CDR-SB), and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14); changes in CSF core biomarkers; and total hippocampal volume (HV) using volumetric magnetic resonance imaging.Results: A total of 854 randomized subjects were treated (lecanemab, 609; placebo, 245). At 12 months, the 10-mg/kg biweekly ED90 dose showed a 64% probability to be better than placebo by 25% on ADCOMS, which missed the 80% threshold for the primary outcome. At 18 months, 10-mg/kg biweekly lecanemab reduced brain amyloid (-0.306 SUVr units) while showing a drug-placebo difference in favor of active treatment by 27% and 30% on ADCOMS, 56% and 47% on ADAS-Cog14, and 33% and 26% on CDR-SB versus placebo according to Bayesian and frequentist analyses, respectively. CSF biomarkers were supportive of a treatment effect. Lecanemab was well-tolerated with 9.9% incidence of amyloid-related imaging abnormalities-edema/effusion at 10 mg/kg biweekly.Conclusions: BAN2401-G000-201 did not meet the 12-month primary endpoint. However, prespecified 18-month Bayesian and frequentist analyses demonstrated reduction in brain amyloid accompanied by a consistent reduction of clinical decline across several clinical and biomarker endpoints. A phase 3 study (Clarity AD) in early Alzheimer's disease is underway.
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- Wang, Z., et al.
(author)
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Genome-wide association analyses of physical activity and sedentary behavior provide insights into underlying mechanisms and roles in disease prevention
- 2022
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 54:9, s. 1332-1344
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Journal article (peer-reviewed)abstract
- Although physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Combining data for up to 703,901 individuals from 51 studies in a multi-ancestry meta-analysis of genome-wide association studies yields 99 loci that associate with self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA), leisure screen time (LST) and/or sedentary behavior at work. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. A missense variant in ACTN3 makes the alpha-actinin-3 filaments more flexible, resulting in lower maximal force in isolated type IIA muscle fibers, and possibly protection from exercise-induced muscle damage. Finally, Mendelian randomization analyses show that beneficial effects of lower LST and higher MVPA on several risk factors and diseases are mediated or confounded by body mass index (BMI). Our results provide insights into physical activity mechanisms and its role in disease prevention. Multi-ancestry meta-analyses of genome-wide association studies for self-reported physical activity during leisure time, leisure screen time, sedentary commuting and sedentary behavior at work identify 99 loci associated with at least one of these traits.
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- 2017
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In: Physical Review D. - 2470-0010 .- 2470-0029. ; 96:2
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Journal article (peer-reviewed)
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- Glasbey, JC, et al.
(author)
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- 2021
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swepub:Mat__t
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- Bravo, L, et al.
(author)
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- 2021
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swepub:Mat__t
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- Tabiri, S, et al.
(author)
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- 2021
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swepub:Mat__t
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- Aad, G., et al.
(author)
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Commissioning of the ATLAS Muon Spectrometer with cosmic rays
- 2010
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In: European Physical Journal C. Particles and Fields. - : Springer Science and Business Media LLC. - 1434-6044 .- 1434-6052. ; 70:3, s. 875-916
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Journal article (peer-reviewed)abstract
- The ATLAS detector at the Large Hadron Collider has collected several hundred million cosmic ray events during 2008 and 2009. These data were used to commission the Muon Spectrometer and to study the performance of the trigger and tracking chambers, their alignment, the detector control system, the data acquisition and the analysis programs. We present the performance in the relevant parameters that determine the quality of the muon measurement. We discuss the single element efficiency, resolution and noise rates, the calibration method of the detector response and of the alignment system, the track reconstruction efficiency and the momentum measurement. The results show that the detector is close to the design performance and that the Muon Spectrometer is ready to detect muons produced in high energy proton-proton collisions.
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- Aad, G., et al.
(author)
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Readiness of the ATLAS Tile Calorimeter for LHC collisions
- 2010
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In: European Physical Journal C. Particles and Fields. - : Springer Science and Business Media LLC. - 1434-6044 .- 1434-6052. ; 70:4, s. 1193-1236
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Journal article (peer-reviewed)abstract
- The Tile hadronic calorimeter of the ATLAS detector has undergone extensive testing in the experimental hall since its installation in late 2005. The readout, control and calibration systems have been fully operational since 2007 and the detector has successfully collected data from the LHC single beams in 2008 and first collisions in 2009. This paper gives an overview of the Tile Calorimeter performance as measured using random triggers, calibration data, data from cosmic ray muons and single beam data. The detector operation status, noise characteristics and performance of the calibration systems are presented, as well as the validation of the timing and energy calibration carried out with minimum ionising cosmic ray muons data. The calibration systems' precision is well below the design value of 1%. The determination of the global energy scale was performed with an uncertainty of 4%.
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- Aad, G, et al.
(author)
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Search for Higgs Boson Pair Production in the γγbb[over ¯] Final State Using pp Collision Data at sqrt[s]=8 TeV from the ATLAS Detector.
- 2015
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In: Physical Review Letters. - 1079-7114. ; 114:8
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Journal article (peer-reviewed)abstract
- Searches are performed for resonant and nonresonant Higgs boson pair production in the γγbb[over ¯] final state using 20 fb^{-1} of proton-proton collisions at a center-of-mass energy of 8 TeV recorded with the ATLAS detector at the CERN Large Hadron Collider. A 95% confidence level upper limit on the cross section times branching ratio of nonresonant production is set at 2.2 pb, while the expected limit is 1.0 pb. The difference derives from a modest excess of events, corresponding to 2.4 standard deviations from the background-only hypothesis. The limit observed in the search for a narrow X→hh resonance ranges between 0.7 and 3.5 pb as a function of the resonance mass.
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