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The ALICE Collaboration reports the first fully-corrected measurements of the N-subjettiness observable for track-based jets in heavy-ion collisions. This study is performed using data recorded in pp and Pb-Pb collisions at centre-of-mass energies of s√ = 7 TeV and sNN−−−√ = 2.76 TeV, respectively. In particular the ratio of 2-subjettiness to 1-subjettiness, τ2/τ1, which is sensitive to the rate of two-pronged jet substructure, is presented. Energy loss of jets traversing the strongly interacting medium in heavy-ion collisions is expected to change the rate of two-pronged substructure relative to vacuum. The results are presented for jets with a resolution parameter of R = 0.4 and charged jet transverse momentum of 40 ≤ pT,jet ≤ 60 GeV/c, which constitute a larger jet resolution and lower jet transverse momentum interval than previous measurements in heavy-ion collisions. This has been achieved by utilising a semi-inclusive hadron-jet coincidence technique to suppress the larger jet combinatorial background in this kinematic region. No significant modification of the τ2/τ1 observable for track-based jets in Pb-Pb collisions is observed relative to vacuum PYTHIA6 and PYTHIA8 references at the same collision energy. The measurements of τ2/τ1, together with the splitting aperture angle ∆R, are also performed in pp collisions at s√ = 7 TeV for inclusive jets. These results are compared with PYTHIA calculations at s√ = 7 TeV, in order to validate the model as a vacuum reference for the Pb-Pb centre-of-mass energy. The PYTHIA references for τ2/τ1 are shifted to larger values compared to the measurement in pp collisions. This hints at a reduction in the rate of two-pronged jets in Pb-Pb collisions compared to pp collisions.
Activation of TRPC6 channels is essential for lung ischaemia–reperfusion induced oedema in mice
(2012)
Lung ischaemia–reperfusion-induced oedema (LIRE) is a life-threatening condition that causes pulmonary oedema induced by endothelial dysfunction. Here we show that lungs from mice lacking nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox2y/−) or the classical transient receptor potential channel 6 (TRPC6−/−) are protected from LIR-induced oedema (LIRE). Generation of chimeric mice by bone marrow cell transplantation and endothelial-specific Nox2 deletion showed that endothelial Nox2, but not leukocytic Nox2 or TRPC6, are responsible for LIRE. Lung endothelial cells from Nox2- or TRPC6-deficient mice showed attenuated ischaemia-induced Ca2+ influx, cellular shape changes and impaired barrier function. Production of reactive oxygen species was completely abolished in Nox2y/− cells. A novel mechanistic model comprising endothelial Nox2-derived production of superoxide, activation of phospholipase C-γ, inhibition of diacylglycerol (DAG) kinase, DAG-mediated activation of TRPC6 and ensuing LIRE is supported by pharmacological and molecular evidence. This mechanism highlights novel pharmacological targets for the treatment of LIRE.
Dendrite morphology, a neuron's anatomical fingerprint, is a neuroscientist's asset in unveiling organizational principles in the brain. However, the genetic program encoding the morphological identity of a single dendrite remains a mystery. In order to obtain a formal understanding of dendritic branching, we studied distributions of morphological parameters in a group of four individually identifiable neurons of the fly visual system. We found that parameters relating to the branching topology were similar throughout all cells. Only parameters relating to the area covered by the dendrite were cell type specific. With these areas, artificial dendrites were grown based on optimization principles minimizing the amount of wiring and maximizing synaptic democracy. Although the same branching rule was used for all cells, this yielded dendritic structures virtually indistinguishable from their real counterparts. From these principles we derived a fully-automated model-based neuron reconstruction procedure validating the artificial branching rule. In conclusion, we suggest that the genetic program implementing neuronal branching could be constant in all cells whereas the one responsible for the dendrite spanning field should be cell specific.
Measurements of event-by-event fluctuations of charged-particle multiplicities in Pb–Pb collisions at sNN−−−√ = 2.76 TeV using the ALICE detector at the CERN Large Hadron Collider (LHC) are presented in the pseudorapidity range |η|<0.8 and transverse momentum 0.2<pT<2.0 GeV/c. The amplitude of the fluctuations is expressed in terms of the variance normalized by the mean of the multiplicity distribution. The η and pT dependences of the fluctuations and their evolution with respect to collision centrality are investigated. The multiplicity fluctuations tend to decrease from peripheral to central collisions. The results are compared to those obtained from HIJING and AMPT Monte Carlo event generators as well as to experimental data at lower collision energies. Additionally, the measured multiplicity fluctuations are discussed in the context of the isothermal compressibility of the high-density strongly-interacting system formed in central Pb–Pb collisions.
The pT-differential production cross sections of prompt and non-prompt (produced in beauty-hadron decays) D mesons were measured by the ALICE experiment at midrapidity (|y| < 0.5) in proton-proton collisions at s√ = 5.02 TeV. The data sample used in the analysis corresponds to an integrated luminosity of (19.3 ± 0.4) nb−1. D mesons were reconstructed from their decays D0 → K−π+, D+ → K−π+π+, and D+s→φπ+→K−K+π+ and their charge conjugates. Compared to previous measurements in the same rapidity region, the cross sections of prompt D+ and D+s mesons have an extended pT coverage and total uncertainties reduced by a factor ranging from 1.05 to 1.6, depending on pT, allowing for a more precise determination of their pT-integrated cross sections. The results are well described by perturbative QCD calculations. The fragmentation fraction of heavy quarks to strange mesons divided by the one to non-strange mesons, fs/(fu + fd), is compatible for charm and beauty quarks and with previous measurements at different centre-of-mass energies and collision systems. The bb¯¯¯ production cross section per rapidity unit at midrapidity, estimated from non-prompt D-meson measurements, is dσbb¯¯¯/dy∣∣|y|<0.5=34.5±2.4(stat)+4.7−2.9(tot.syst) μb. It is compatible with previous measurements at the same centre-of-mass energy and with the cross section pre- dicted by perturbative QCD calculations.
Simple Summary: Acute myeloid leukemia (AML) is a genetically heterogeneous disease. Clinical phenotypes of frequent mutations and their impact on patient outcome are well established. However, the role of rare mutations often remains elusive. We retrospectively analyzed 1529 newly diagnosed and intensively treated AML patients for mutations of BCOR and BCORL1. We report a distinct co-mutational pattern that suggests a role in disease progression rather than initiation, especially affecting mechanisms of DNA-methylation. Further, we found loss-of-function mutations of BCOR to be independent markers of poor outcomes in multivariable analysis. Therefore, loss-of-function mutations of BCOR need to be considered for AML management, as they may influence risk stratification and subsequent treatment allocation.
Abstract: Acute myeloid leukemia (AML) is characterized by recurrent genetic events. The BCL6 corepressor (BCOR) and its homolog, the BCL6 corepressor-like 1 (BCORL1), have been reported to be rare but recurrent mutations in AML. Previously, smaller studies have reported conflicting results regarding impacts on outcomes. Here, we retrospectively analyzed a large cohort of 1529 patients with newly diagnosed and intensively treated AML. BCOR and BCORL1 mutations were found in 71 (4.6%) and 53 patients (3.5%), respectively. Frequently co-mutated genes were DNTM3A, TET2 and RUNX1. Mutated BCORL1 and loss-of-function mutations of BCOR were significantly more common in the ELN2017 intermediate-risk group. Patients harboring loss-of-function mutations of BCOR had a significantly reduced median event-free survival (HR = 1.464 (95%-Confidence Interval (CI): 1.005–2.134), p = 0.047), relapse-free survival (HR = 1.904 (95%-CI: 1.163–3.117), p = 0.01), and trend for reduced overall survival (HR = 1.495 (95%-CI: 0.990–2.258), p = 0.056) in multivariable analysis. Our study establishes a novel role for loss-of-function mutations of BCOR regarding risk stratification in AML, which may influence treatment allocation.
A complex aberrant karyotype consisting of multiple unrelated cytogenetic abnormalities is associated with poor prognosis in patients with acute myeloid leukemia (AML). The European Leukemia Net classification and the UK Medical Research Council recommendation provide prognostic categories that differ in the definition of unbalanced aberrations as well as the number of single aberrations. The aim of this study on 3526 AML patients was to redefine and validate a cutoff for karyotype complexity in AML with regard to adverse prognosis. Our study demonstrated that (1) patients with a pure hyperdiploid karyotype have an adverse risk irrespective of the number of chromosomal gains, (2) patients with translocation t(9;11)(p21~22;q23) have an intermediate risk independent of the number of additional aberrations, (3) patients with greater than or equal to4 abnormalities have an adverse risk per se and (4) patients with three aberrations in the absence of abnormalities of strong influence (hyperdiploid karyotype, t(9;11)(p21~22;q23), CBF-AML, unique adverse-risk aberrations) have borderline intermediate/adverse risk with a reduced overall survival compared with patients with a normal karyotype.
In our Galaxy, light antinuclei composed of antiprotons and antineutrons can be produced through high-energy cosmic-ray collisions with the interstellar medium or could also originate from the annihilation of dark-matter particles that have not yet been discovered. On Earth, the only way to produce and study antinuclei with high precision is to create them at high-energy particle accelerators. Although the properties of elementary antiparticles have been studied in detail, the knowledge of the interaction of light antinuclei with matter is limited. We determine the disappearance probability of 3He¯¯¯¯¯¯ when it encounters matter particles and annihilates or disintegrates within the ALICE detector at the Large Hadron Collider. We extract the inelastic interaction cross section, which is then used as input to calculations of the transparency of our Galaxy to the propagation of 3He¯¯¯¯¯¯ stemming from dark-matter annihilation and cosmic-ray interactions within the interstellar medium. For a specific dark-matter profile, we estimate a transparency of about 50%, whereas it varies with increasing 3He¯¯¯¯¯¯ momentum from 25% to 90% for cosmic-ray sources. The results indicate that 3He¯¯¯¯¯¯ nuclei can travel long distances in the Galaxy, and can be used to study cosmic-ray interactions and dark-matter annihilation.
Antimatter particles such as positrons and antiprotons abound in the cosmos. Much less common are light antinuclei, composed of antiprotons and antineutrons, which can be produced in our galaxy via high-energy cosmic-ray collisions with the interstellar medium or could also originate from the annihilation of the still undiscovered dark-matter particles. On Earth, the only way to produce and study antinuclei with high precision is to create them at high-energy particle accelerators like the Large Hadron Collider (LHC). Though the properties of elementary antiparticles have been studied in detail, knowledge of the interaction of light antinuclei with matter is rather limited. This work focuses on the determination of the disappearance probability of \ahe\ when it encounters matter particles and annihilates or disintegrates. The material of the ALICE detector at the LHC serves as a target to extract the inelastic cross section for \ahe\ in the momentum range of 1.17≤p<10 GeV/c. This inelastic cross section is measured for the first time and is used as an essential input to calculations of the transparency of our galaxy to the propagation of 3He¯¯¯¯¯¯ stemming from dark-matter decays and cosmic-ray interactions within the interstellar medium. A transparency of about 50% is estimated using the GALPROP program for a specific dark-matter profile and a standard set of propagation parameters. For cosmic-ray sources, the obtained transparency with the same propagation scheme varies with increasing 3He¯¯¯¯¯¯ momentum from 25% to 90%. The absolute uncertainties associated to the 3He¯¯¯¯¯¯ inelastic cross section measurements are of the order of 10%−15%. The reported results indicate that 3He¯¯¯¯¯¯ nuclei can travel long distances in the galaxy, and can be used to study cosmic-ray interactions and dark-matter decays.
Background: The clinical presentation of gastroesophageal reflux disease (GERD) shows a large symptom variation also in different intensities among patients. As several studies have shown, there is a large overlap in the symptomatic spectrum between proven GERD and other disorders such as dyspepsia, functional heartburn and/or somatoform disorders.
Aim: To prospectively evaluate the GERD patients with and without somatoform disorders before and after laparoscopic antireflux surgery.
Methods: In a tertiary referral center for foregut surgery over a period of 3 years patients with GERD, qualifying for the indication of laparoscopic antireflux surgery, were investigated prospectively regarding their symptomatic spectrum in order to identify GERD and associated somatoform disorders. Assessment of symptoms was performed by an instrument for the evaluation of somatoform disorders [Somatoform Symptom Index (SSI) > 17]. Quality of life was evaluated by Gastrointestinal Quality of Life Index (GIQLI).
Results: In 123 patients an indication for laparoscopic antireflux surgery was established and in 43 patients further medical therapy was suggested. The portion of somatoform tendencies in the total patient population was 20.48% (34 patients). Patients with a positive SSI had a preoperative GIQLI of 77 (32-111). Patients with a normal SSI had a GIQLI of 105 (29-140) (P < 0.0001). In patients with GERD the quality of life could be normalized from preoperative reduced values of GIQLI 102 (47-140) to postoperative values of 117 (44-144). In patients with GERD and somatoform disorders, the GIQLI was improved from preoperative GIQLI 75 (47-111) to postoperative 95 (44-122) (P < 0.0043).
Conclusion: Patients with GERD and associated somatoform disorders have significantly worse levels of quality of life. The latter patients can also benefit from laparoscopic fundoplication, however they will not reach a normal level.
Pathogenic variants in PRRT2, encoding the proline-rich transmembrane protein 2, have been associated with an evolving spectrum of paroxysmal neurologic disorders. Based on a cohort of children with PRRT2-related infantile epilepsy, this study aimed at delineating the broad clinical spectrum of PRRT2-associated phenotypes in these children and their relatives. Only a few recent larger cohort studies are on record and findings from single reports were not confirmed so far. We collected detailed genetic and phenotypic data of 40 previously unreported patients from 36 families. All patients had benign infantile epilepsy and harbored pathogenic variants in PRRT2 (core cohort). Clinical data of 62 family members were included, comprising a cohort of 102 individuals (extended cohort) with PRRT2-associated neurological disease. Additional phenotypes in the cohort of patients with benign sporadic and familial infantile epilepsy consist of movement disorders with paroxysmal kinesigenic dyskinesia in six patients, infantile-onset movement disorders in 2 of 40 individuals, and episodic ataxia after mild head trauma in one girl with bi-allelic variants in PRRT2. The same girl displayed a focal cortical dysplasia upon brain imaging. Familial hemiplegic migraine and migraine with aura were reported in nine families. A single individual developed epilepsy with continuous spikes and waves during sleep. In addition to known variants, we report the novel variant c.843G>T, p.(Trp281Cys) that co-segregated with benign infantile epilepsy and migraine in one family. Our study highlights the variability of clinical presentations of patients harboring pathogenic PRRT2 variants and expands the associated phenotypic spectrum.