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We present measurements of two-particle differential number correlation functions R2 and transverse momentum correlation functions P2, obtained from p-Pb collisions at 5.02 TeV and Pb-Pb collisions at 2.76 TeV. The results are obtained using charged particles in the pseudorapidity range |η|< 1.0, and transverse momentum range 0.2<pT<2.0 GeV/c as a function of pair separation in pseudorapidity, |Δη|, azimuthal angle, Δφ, and for several charged-particle multiplicity classes. Measurements are carried out for like-sign and unlike-sign charged-particle pairs separately and combined to obtain charge-independent and charge-dependent correlation functions. We study the evolution of the width of the near-side peak of these correlation functions with collision centrality. Additionally, we study Fourier decompositions of the correlators in Δφ as a function of the pair separation |Δη|. Significant differences in the dependence of their harmonic coefficients on multiplicity classes are found. These differences can be exploited, in theoretical models, to obtain further insight into charged-particle production and transport in heavy-ion collisions. Moreover, an upper limit of non-flow contributions to flow coefficients vn measured in Pb-Pb collisions based on the relative strength of Fourier coefficients measured in p-Pb interactions is estimated.
Inclusive Υ(1S) and Υ(2S) production have been measured in Pb-Pb collisions at the centre-of-mass energy per nucleon-nucleon pair sNN−−−√=5.02 TeV, using the ALICE detector at the CERN LHC. The Υ mesons are reconstructed in the centre-of-mass rapidity interval 2.5<y<4 and in the transverse-momentum range pT<15 GeV/c, via their decays to muon pairs. In this Letter, we present results on the inclusive Υ(1S) nuclear modification factor RAA as a function of collision centrality, transverse momentum and rapidity. The Υ(1S) and Υ(2S) RAA, integrated over the centrality range 0-90%, are 0.37±0.02(stat)±0.03(syst) and 0.10±0.04(stat)±0.02(syst), respectively, leading to a ratio RΥ(2S)AA/RΥ(1S)AA of 0.28±0.12(stat)±0.06(syst). The observed Υ(1S) suppression increases with the centrality of the collision and no significant variation is observed as a function of transverse momentum and rapidity.
Transverse momentum (pT) spectra of charged particles at mid-pseudorapidity in Xe-Xe collisions at sNN−−−√ = 5.44 TeV measured with the ALICE apparatus at the Large Hadron Collider are reported. The kinematic range 0.15<pT<50 GeV/c and |η|<0.8 is covered. Results are presented in nine classes of collision centrality in the 0-80% range. For comparison, a pp reference at the collision energy of s√ = 5.44 TeV is obtained by interpolating between existing \pp measurements at s√ = 5.02 and 7 TeV. The nuclear modification factors in central Xe-Xe collisions and Pb-Pb collisions at a similar center-of-mass energy of sNN−−−√ = 5.02 TeV, and in addition at 2.76 TeV, at analogous ranges of charged particle multiplicity density ⟨dNch/dη⟩ show a remarkable similarity at pT>10 GeV/c. The centrality dependence of the ratio of the average transverse momentum ⟨pT⟩ in Xe-Xe collisions over Pb-Pb collision at s√ = 5.02 TeV is compared to hydrodynamical model calculations.
Inclusive Υ(1S) and Υ(2S) production have been measured in Pb-Pb collisions at the centre-of-mass energy per nucleon-nucleon pair sNN−−−√=5.02 TeV, using the ALICE detector at the CERN LHC. The Υ mesons are reconstructed in the centre-of-mass rapidity interval 2.5<y<4 and in the transverse-momentum range pT<15 GeV/c, via their decays to muon pairs. In this Letter, we present results on the inclusive Υ(1S) nuclear modification factor RAA as a function of collision centrality, transverse momentum and rapidity. The Υ(1S) and Υ(2S) RAA, integrated over the centrality range 0-90%, are 0.37±0.02(stat)±0.03(syst) and 0.10±0.04(stat)±0.02(syst), respectively, leading to a ratio RΥ(2S)AA/RΥ(1S)AA of 0.28±0.12(stat)±0.06(syst). The observed Υ(1S) suppression increases with the centrality of the collision and no significant variation is observed as a function of transverse momentum and rapidity.
Charged-particle spectra at midrapidity are measured in Pb-Pb collisions at the centre-of-mass energy per nucleon-nucleon pair sNN−−−√ = 5.02 TeV and presented in centrality classes ranging from most central (0-5%) to most peripheral (95-100%) collisions. Possible medium effects are quantified using the nuclear modification factor (RAA) by comparing the measured spectra with those from proton-proton collisions, scaled by the number of independent nucleon-nucleon collisions obtained from a Glauber model. At large transverse momenta (8<pT<20 GeV/c), the average RAA is found to increase from about 0.15 in 0-5% central to a maximum value of about 0.8 in 75-85% peripheral collisions, beyond which it falls off strongly to below 0.2 for the most peripheral collisions. Furthermore, RAA initially exhibits a positive slope as a function of pT in the 8-20 GeV/c interval, while for collisions beyond the 80% class the slope is negative. To reduce uncertainties related to event selection and normalization, we also provide the ratio of RAA in adjacent centrality intervals. Our results in peripheral collisions are consistent with a PYTHIA-based model without nuclear modification, demonstrating that biases caused by the event selection and collision geometry can lead to the apparent suppression in peripheral collisions. This explains the unintuitive observation that RAA is below unity in peripheral Pb-Pb, but equal to unity in minimum-bias p-Pb collisions despite similar charged-particle multiplicities.
We present the first measurements of femtoscopic correlations between the K0 S and K± particles in pp collisions at √s = 7 TeV measured by the ALICE experiment. The observed femtoscopic correlations are consistent with final-state interactions proceeding solely via the a0(980) resonance. The extracted kaon source radius and correlation strength parameters for K0 SK− are found to be equal within the experimental uncertainties to those for K0 SK+. Results of the present study are compared with those from identical-kaon femtoscopic studies also performed with pp collisions at √s = 7 TeV by ALICE andwith a K0 SK± measurement in Pb–Pb collisions at √sNN = 2.76 TeV. Combined with the Pb–Pb results, our pp analysis is found to be compatible with th e interpretation of the a0(980) having a tetraquark structure instead of that of a diquark.
The first measurements of anisotropic flow coefficients vn for mid-rapidity charged particles in Xe–Xe collisions at √sNN = 5.44 TeV are presented. Comparing these measurements to those from Pb–Pb collisions at √sNN = 5.02 TeV, v2 is found to be suppressed for mid-central collisions at the same centrality, and enhanced for central collisions. The values of v3 are generally larger in Xe–Xe than in Pb–Pb at a given centrality. These observations are consistent with expectations from hydrodynamic predictions. When both v2 and v3 are divided by their corresponding eccentricities for a variety of initial state models, they generally scale with transverse density when comparing Xe–Xe and Pb–Pb, with some deviations observed in central Xe–Xe and Pb–Pb collisions. These results assist in placing strong constraints on both the initial state geometry and medium response for relativistic heavy-ion collisions.
Transverse momentum (pT ) spectra of charged particles at mid-pseudorapidity in Xe–Xe collisions at √sNN=5.44TeV measured with the ALICE apparatus at the Large Hadron Collider are reported. The kinematic range 0.15<pT<50GeV/c and |η|<0.8 is covered. Results are presented in nine classes of collision centrality in the 0–80% range. For comparison, a pp reference at the collision energy of √s=5.44 TeV is obtained by interpolating between existing pp measurements at √s=5.02 and 7 TeV. The nuclear modification factors in central Xe–Xe collisions and Pb–Pb collisions at a similar center-of-mass energy of √sNN=5.02 TeV, and in addition at 2.76 TeV, at analogous ranges of charged particle multiplicity density 〈dNch/dη〉 show a remarkable similarity at pT>10 GeV/c. The centrality dependence of the ratio of the average transverse momentum 〈pT〉 in Xe–Xe collisions over Pb–Pb collision at √s=5.02 TeV is compared to hydrodynamical model calculations.
Isolated complex I deficiency is a common biochemical phenotype observed in pediatric mitochondrial disease and often arises as a consequence of pathogenic variants affecting one of the ∼65 genes encoding the complex I structural subunits or assembly factors. Such genetic heterogeneity means that application of next-generation sequencing technologies to undiagnosed cohorts has been a catalyst for genetic diagnosis and gene-disease associations. We describe the clinical and molecular genetic investigations of four unrelated children who presented with neuroradiological findings and/or elevated lactate levels, highly suggestive of an underlying mitochondrial diagnosis. Next-generation sequencing identified bi-allelic variants in NDUFA6, encoding a 15 kDa LYR-motif-containing complex I subunit that forms part of the Q-module. Functional investigations using subjects’ fibroblast cell lines demonstrated complex I assembly defects, which were characterized in detail by mass-spectrometry-based complexome profiling. This confirmed a marked reduction in incorporated NDUFA6 and a concomitant reduction in other Q-module subunits, including NDUFAB1, NDUFA7, and NDUFA12. Lentiviral transduction of subjects’ fibroblasts showed normalization of complex I. These data also support supercomplex formation, whereby the ∼830 kDa complex I intermediate (consisting of the P- and Q-modules) is in complex with assembled complex III and IV holoenzymes despite lacking the N-module. Interestingly, RNA-sequencing data provided evidence that the consensus RefSeq accession number does not correspond to the predominant transcript in clinically relevant tissues, prompting revision of the NDUFA6 RefSeq transcript and highlighting not only the importance of thorough variant interpretation but also the assessment of appropriate transcripts for analysis.
Non-standard errors
(2021)
In statistics, samples are drawn from a population in a data-generating process (DGP). Standard errors measure the uncertainty in sample estimates of population parameters. In science, evidence is generated to test hypotheses in an evidence-generating process (EGP). We claim that EGP variation across researchers adds uncertainty: non-standard errors. To study them, we let 164 teams test six hypotheses on the same sample. We find that non-standard errors are sizeable, on par with standard errors. Their size (i) co-varies only weakly with team merits, reproducibility, or peer rating, (ii) declines significantly after peer-feedback, and (iii) is underestimated by participants.
The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points.
Biallelic mutations in TMEM126B cause severe complex i deficiency with a variable clinical phenotype
(2016)
Complex I deficiency is the most common biochemical phenotype observed in individuals with mitochondrial disease. With 44 structural subunits and over 10 assembly factors, it is unsurprising that complex I deficiency is associated with clinical and genetic heterogeneity. Massively parallel sequencing (MPS) technologies including custom, targeted gene panels or unbiased whole-exome sequencing (WES) are hugely powerful in identifying the underlying genetic defect in a clinical diagnostic setting, yet many individuals remain without a genetic diagnosis. These individuals might harbor mutations in poorly understood or uncharacterized genes, and their diagnosis relies upon characterization of these orphan genes. Complexome profiling recently identified TMEM126B as a component of the mitochondrial complex I assembly complex alongside proteins ACAD9, ECSIT, NDUFAF1, and TIMMDC1. Here, we describe the clinical, biochemical, and molecular findings in six cases of mitochondrial disease from four unrelated families affected by biallelic (c.635G>T [p.Gly212Val] and/or c.401delA [p.Asn134Ilefs∗2]) TMEM126B variants. We provide functional evidence to support the pathogenicity of these TMEM126B variants, including evidence of founder effects for both variants, and establish defects within this gene as a cause of complex I deficiency in association with either pure myopathy in adulthood or, in one individual, a severe multisystem presentation (chronic renal failure and cardiomyopathy) in infancy. Functional experimentation including viral rescue and complexome profiling of subject cell lines has confirmed TMEM126B as the tenth complex I assembly factor associated with human disease and validates the importance of both genome-wide sequencing and proteomic approaches in characterizing disease-associated genes whose physiological roles have been previously undetermined.
Compartmentalization of immune response and microbial translocation in decompensated cirrhosis
(2019)
Background: Acquired dysfunctional immunity in cirrhosis predisposes patients to frequent bacterial infections, especially spontaneous bacterial peritonitis (SBP), leading to systemic inflammation that is associated with poor outcome. But systemic inflammation can also be found in the absence of a confirmed infection. Detection of bacterial DNA has been investigated as a marker of SBP and as a predictor of prognosis. Data is, however, contradictory. Here we investigated whether levels of IL-6 and IL-8 putatively produced by myeloid cells in ascites are associated with systemic inflammation and whether inflammation depends on the presence of specific bacterial DNA.
Methods and Materials: We enrolled 33 patients with decompensated liver cirrhosis from whom we collected paired samples of blood and ascites. IL-6 and IL-8 were measured in serum samples of all patients using ELISA. In a subset of 10 representative patients, bacterial DNA was extracted from ascites and whole blood, followed by 16S rRNA gene amplicon sequencing.
Results: There were significantly higher levels of IL-6 in ascites fluid compared to blood samples in all patients. Interestingly, IL-6 levels in blood correlated tightly with disease severity and surrogates of systemic inflammation, while IL-6 levels in ascites did not. Moreover, patients with higher blood CRP levels showed greater SBP prevalence compared to patients with lower levels, despite similar positive culture results. Bacterial richness was also significantly higher in ascites compared to the corresponding patient blood. We identified differences in microbial composition and diversity between ascites and blood, but no tight relationship with surrogates of systemic inflammation could be observed.
Discussion: In decompensated cirrhosis, markers of systemic inflammation and microbiota composition seem to be dysregulated in ascites and blood. While a relationship between systemic inflammation and microbiota composition seems to exist in blood, this is not the case for ascites in our hands. These data may suggest compartmentalization of the immune response and interaction of the latter with the microbiota especially in the blood compartment.
Background: Shortening duration of peginterferon-based HCV treatment reduces associated burden for patients. Primary objectives of this study were to assess the efficacy against the minimally acceptable response rate 12 weeks post-treatment (SVR12) and safety of simeprevir plus PR in treatment-naïve HCV GT1 patients treated for 12 weeks. Additional objectives included the investigation of potential associations of rapid viral response and baseline factors with SVR12.
Methods: In this Phase III, open-label study in treatment-naïve HCV GT1 patients with F0–F2 fibrosis, patients with HCV-RNA <25 IU/mL (detectable/undetectable) at Week 2, and undetectable HCV-RNA at Weeks 4 and 8, stopped all treatment at Week 12. All other patients continued PR for a further 12 weeks. Baseline factors significantly associated with SVR12 were identified through logistic regression.
Results: Of 163 patients who participated in the study, 123 (75%) qualified for 12-week treatment; of these, 81 (66%) achieved SVR12. Baseline factors positively associated with SVR12 rates in patients receiving the 12-week regimen were: IL28B CC genotype: (94% SVR12); HCV RNA ≤800,000 IU/mL (82%); F0–F1 fibrosis (74%). Among all 163 patients, 94% experienced ≥1 adverse event (AE), 4% a serious AE, and 2.5% discontinued due to an AE. Reduced impairment in patient-reported outcomes was observed in the 12-week vs >12-week regimen.
Conclusions: Overall SVR12 rate (66%) was below the target of 80%, indicating that shortening of treatment with simeprevir plus PR to 12 weeks based on very early response is not effective. However, baseline factors associated with higher SVR12 rates were identified. Therefore, while Week 2 response alone is insufficient to predict efficacy, GT1 patients with favourable baseline factors may benefit from a shortened simeprevir plus PR regimen.
Trial Registration: ClinicalTrials.gov NCT01846832
73Ge(n, γ ) cross sections were measured at the neutron time-of-flight facility n_TOF at CERN up to neutron energies of 300 keV, providing for the first time experimental data above 8 keV. Results indicate that the stellar cross section at kT = 30 keV is 1.5 to 1.7 times higher than most theoretical predictions. The new cross sections result in a substantial decrease of 73Ge produced in stars, which would explain the low isotopic abundance of 73Ge in the solar system.
APPEAL‐1: A pan‐European survey of patient/caregiver perceptions of peanut allergy management
(2020)
Background: Peanut allergy (PA) is associated with marked quality‐of‐life (QoL) impairment. However, data are lacking on the experience and impact of living with PA from the perspectives of persons with PA (PwPA) and their caregivers. Allergy to Peanuts imPacting Emotions And Life study 1 (APPEAL‐1) was a pan‐European survey investigating these perspectives. This first of two articles reports clinical characteristics of PwPA and PA management practices.
Methods: APPEAL‐1 was a quantitative, online survey conducted in eight European countries, developed by eight representatives of patient advocacy groups and five healthcare professionals and researchers. Eligible participants included adults with PA and parents/caregivers of PwPA who responded by self‐report and provided proxy‐report for the PwPA under their care. Data were summarized using nonweighted descriptive statistics.
Results: Of 1846 completed/analysed questionnaires, 528 were from adults with PA (self‐report); 437 by proxy for children with PA (34 aged 0‐3 years, 287 aged 4‐12 years, 116 aged 13‐17 years) and 881 from parents/caregivers (self‐report). Of PwPA (N = 965), 95% reported diagnosis by healthcare professionals, mostly by clinical history and peanut‐specific allergy testing. Rates of allergic rhinitis, asthma and other food allergies in PwPA were 50%, 42% and 79%, respectively. Only 31% of PwPA received HCP advice/support following their worst allergic reaction, and 28% had not been prescribed an adrenaline auto‐injector. Results were similar by country but varied by age group.
Conclusions: The APPEAL‐1 findings contribute to greater understanding of PA impact on PwPA, caregivers and family members and the need for improved PA management across Europe.
Investigators in the cognitive neurosciences have turned to Big Data to address persistent replication and reliability issues by increasing sample sizes, statistical power, and representativeness of data. While there is tremendous potential to advance science through open data sharing, these efforts unveil a host of new questions about how to integrate data arising from distinct sources and instruments. We focus on the most frequently assessed area of cognition - memory testing - and demonstrate a process for reliable data harmonization across three common measures. We aggregated raw data from 53 studies from around the world which measured at least one of three distinct verbal learning tasks, totaling N = 10,505 healthy and brain-injured individuals. A mega analysis was conducted using empirical bayes harmonization to isolate and remove site effects, followed by linear models which adjusted for common covariates. After corrections, a continuous item response theory (IRT) model estimated each individual subject’s latent verbal learning ability while accounting for item difficulties. Harmonization significantly reduced inter-site variance by 37% while preserving covariate effects. The effects of age, sex, and education on scores were found to be highly consistent across memory tests. IRT methods for equating scores across AVLTs agreed with held-out data of dually-administered tests, and these tools are made available for free online. This work demonstrates that large-scale data sharing and harmonization initiatives can offer opportunities to address reproducibility and integration challenges across the behavioral sciences.
The accurate knowledge of the neutron-induced fission cross-sections of actinides and other isotopes involved in the nuclear fuel cycle is essential for the design of advanced nuclear systems, such as Generation-IV nuclear reactors. Such experimental data can also provide the necessary feedback for the adjustment of nuclear model parameters used in the evaluation process, resulting in the further development of nuclear fission models. In the present work, the 240Pu(n,f) cross-section was measured at CERN's n_TOF facility relative to the well-known 235U(n,f) cross section, over a wide range of neutron energies, from meV to almost MeV, using the time-of-flight technique and a set-up based on Micromegas detectors. This measurement was the first experiment to be performed at n_TOF's new experimental area (EAR-2), which offers a significantly higher neutron flux compared to the already existing experimental area (EAR-1). Preliminary results as well as the experimental procedure, including a description of the facility and the data handling and analysis, are presented.
Neutron-induced reaction cross sections are important for a wide variety of research fields ranging from the study of nuclear level densities, nucleosynthesis to applications of nuclear technology like design, and criticality and safety assessment of existing and future nuclear reactors, radiation dosimetry, medical applications, nuclear waste transmutation, accelerator-driven systems and fuel cycle investigations. Simulations and calculations of nuclear technology applications largely rely on evaluated nuclear data libraries. The evaluations in these libraries are based both on experimental data and theoretical models. CERN’s neutron time-of-flight facility n_TOF has produced a considerable amount of experimental data since it has become fully operational with the start of its scientific measurement programme in 2001. While for a long period a single measurement station (EAR1) located at 185 m from the neutron production target was available, the construction of a second beam line at 20 m (EAR2) in 2014 has substantially increased the measurement capabilities of the facility. An outline of the experimental nuclear data activities at n_TOF will be presented.