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Neutral pion (π0) and η meson production cross sections were measured up to unprecedentedly high transverse momenta (pT) in p–Pb collisions at √sNN = 8.16 TeV. The mesons were reconstructed via their two-photon decay channel in the rapidity interval −1.3 < y < 0.3 in the ranges of 0.4 < pT < 200 GeV/c and 1.0 < pT < 50 GeV/c, respectively. The respective nuclear modification factor (RpPb) is presented for pT up to of 200 and 30 GeV/c, where the former was achieved by extending the π0 measurement in pp collisions at √s = 8 TeV using the merged cluster technique. The values of RpPb are below unity for pT < 10 GeV/c, while they are consistent with unity for pT > 10 GeV/c, leaving essentially no room for final state energy loss. The new data provide strong constraints for nuclear parton distribution and fragmentation functions over a broad kinematic range and are compared to model predictions as well as previous results at √sNN = 5.02 TeV.
The interaction of Λ and Σ hyperons (Y) with nucleons (N) is strongly influenced by the coupled-channel dynamics. Due to the small mass difference of the NΛ and NΣ systems, the sizable coupling strength of the NΣ ↔ NΛ processes constitutes a crucial element in the determination of the NΛ interaction. In this letter we present the most precise measurements on the interaction of p pairs, from zero relative momentum up to the opening of the NΣ channel. The correlation function in the relative momentum space for p ⊕ p pairs measured in high-multiplicity triggered pp collisions at √s = 13 TeV at the LHC is reported. The opening of the inelastic NΣ channels is visible in the extracted correlation function as a cusp-like structure occurring at relative momentum k∗ = 289 MeV/c. This represents the first direct experimental observation of the NΣ ↔ NΛ coupled channel in the p system. The correlation function is compared with recent chiral effective field theory calculations, based on different strengths of the NΣ ↔ NΛ transition potential. A weaker coupling, as possibly supported by the present measurement, would require a more repulsive three-body NNΛ interaction for a proper description of the in-medium properties, which has implications on the nuclear equation of state and for the presence of hyperons inside neutron stars.
The production of baryons and K0 S mesons (V0 particles) was measured in p–Pb collisions at √sNN = 5.02 TeV and pp collisions at √s = 7 TeV with ALICE at the LHC. The production of these strange particles is studied separately for particles associated with hard scatterings and the underlying event to shed light on the baryon-to-meson ratio enhancement observed at intermediate transverse momentum (pT) in high multiplicity pp and p–Pb collisions. Hard scatterings are selected on an eventby-event basis with jets reconstructed with the anti-kT algorithm using charged particles. The production of strange particles associated with jets pch T, jet > 10 and pch T, jet > 20 GeV/c in p–Pb collisions, and with jet pch T, jet > 10 GeV/c in pp collisions is reported as a function of pT. Its dependence on angular distance from the jet axis, R(V0, jet), for jets with pch T, jet > 10 GeV/c in p–Pb collisions is reported as well. The pT-differential production spectra of strange particles associated with jets are found to be harder compared to that in the underlying event and both differ from the inclusive measurements. In events containing a jet, the density of the V0 particles in the underlying event is found to be larger than the density in the minimum bias events. The /K0 S ratio associated with jets in p–Pb collisions is consistent with the ratio in pp collisions and follows the expectation of jets fragmenting in vacuum. On the other hand, this ratio within jets is consistently lower than the one obtained in the underlying event and it does not show the characteristic enhancement of baryons at intermediate pT often referred to as “baryon anomaly” in the inclusive measurements.
HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders
(2021)
Bipolar affective disorder (BD) is a severe psychiatric illness, for which lithium (Li) is the gold standard for acute and maintenance therapies. The therapeutic response to Li in BD is heterogeneous and reliable biomarkers allowing patients stratification are still needed. A GWAS performed by the International Consortium on Lithium Genetics (ConLiGen) has recently identified genetic markers associated with treatment responses to Li in the human leukocyte antigens (HLA) region. To better understand the molecular mechanisms underlying this association, we have genetically imputed the classical alleles of the HLA region in the European patients of the ConLiGen cohort. We found our best signal for amino-acid variants belonging to the HLA-DRB1*11:01 classical allele, associated with a better response to Li (p < 1 × 10−3; FDR < 0.09 in the recessive model). Alanine or Leucine at position 74 of the HLA-DRB1 heavy chain was associated with a good response while Arginine or Glutamic acid with a poor response. As these variants have been implicated in common inflammatory/autoimmune processes, our findings strongly suggest that HLA-mediated low inflammatory background may contribute to the efficient response to Li in BD patients, while an inflammatory status overriding Li anti-inflammatory properties would favor a weak response.
Mapping cortical brain asymmetry in 17,141 healthy individuals worldwide via the ENIGMA Consortium
(2017)
Background: Berotralstat (BCX7353) is an oral, once-daily inhibitor of plasma kallikrein in development for the prophylaxis of hereditary angioedema (HAE) attacks.
Objective: Our aim was to determine the efficacy, safety, and tolerability of berotralstat in patients with HAE over a 24-week treatment period (the phase 3 APeX-2 trial).
Methods: APeX-2 was a double-blind, parallel-group study that randomized patients at 40 sites in 11 countries 1:1:1 to receive once-daily berotralstat in a dose of 110 mg or 150 mg or placebo (Clinicaltrials.gov identifier NCT03485911). Patients aged 12 years or older with HAE due to C1 inhibitor deficiency and at least 2 investigator-confirmed HAE attacks in the first 56 days of a prospective run-in period were eligible. The primary efficacy end point was the rate of investigator-confirmed HAE attacks during the 24-week treatment period.
Results: A total of 121 patients were randomized; 120 of them received at least 1 dose of the study drug (n = 41, 40, and 39 in the 110-mg dose of berotralstat, 150-mg of dose berotralstat, and placebo groups, respectively). Berotralstat demonstrated a significant reduction in attack rate at both 110 mg (1.65 attacks per month; P = .024) and 150 mg (1.31 attacks per month; P < .001) relative to placebo (2.35 attacks per month). The most frequent treatment-emergent adverse events that occurred more with berotralstat than with placebo were abdominal pain, vomiting, diarrhea, and back pain. No drug-related serious treatment-emergent adverse events occurred.
Conclusion: Both the 110-mg and 150-mg doses of berotralstat reduced HAE attack rates compared with placebo and were safe and generally well tolerated. The most favorable benefit-to-risk profile was observed at a dose of 150 mg per day.
A wide variety of enzymatic pathways that produce specialized metabolites in bacteria, fungi and plants are known to be encoded in biosynthetic gene clusters. Information about these clusters, pathways and metabolites is currently dispersed throughout the literature, making it difficult to exploit. To facilitate consistent and systematic deposition and retrieval of data on biosynthetic gene clusters, we propose the Minimum Information about a Biosynthetic Gene cluster (MIBiG) data standard.
The Transition Radiation Detector (TRD) was designed and built to enhance the capabilities of the ALICE detector at the Large Hadron Collider (LHC). While aimed at providing electron identification and triggering, the TRD also contributes significantly to the track reconstruction and calibration in the central barrel of ALICE. In this paper the design, construction, operation, and performance of this detector are discussed. A pion rejection factor of up to 410 is achieved at a momentum of 1 GeV/c in p-Pb collisions and the resolution at high transverse momentum improves by about 40% when including the TRD information in track reconstruction. The triggering capability is demonstrated both for jet, light nuclei, and electron selection.
The Transition Radiation Detector (TRD) was designed and built to enhance the capabilities of the ALICE detector at the Large Hadron Collider (LHC). While aimed at providing electron identification and triggering, the TRD also contributes significantly to the track reconstruction and calibration in the central barrel of ALICE. In this paper the design, construction, operation, and performance of this detector are discussed. A pion rejection factor of up to 410 is achieved at a momentum of 1 GeV/c in p-Pb collisions and the resolution at high transverse momentum improves by about 40% when including the TRD information in track reconstruction. The triggering capability is demonstrated both for jet, light nuclei, and electron selection.
The Transition Radiation Detector (TRD) was designed and built to enhance the capabilities of the ALICE detector at the Large Hadron Collider (LHC). While aimed at providing electron identification and triggering, the TRD also contributes significantly to the track reconstruction and calibration in the central barrel of ALICE. In this paper the design, construction, operation, and performance of this detector are discussed. A pion rejection factor of up to 410 is achieved at a momentum of 1 GeV/c in p–Pb collisions and the resolution at high transverse momentum improves by about 40% when including the TRD information in track reconstruction. The triggering capability is demonstrated both for jet, light nuclei, and electron selection.
Objective: The glucose stimulation of insulin secretion (GSIS) by pancreatic β-cells critically depends on increased production of metabolic coupling factors, including NADPH. Nicotinamide nucleotide transhydrogenase (NNT) typically produces NADPH at the expense of NADH and ΔpH in energized mitochondria. Its spontaneous inactivation in C57BL/6J mice was previously shown to alter ATP production, Ca2+ influx, and GSIS, thereby leading to glucose intolerance. Here, we tested the role of NNT in the glucose regulation of mitochondrial NADPH and glutathione redox state and reinvestigated its role in GSIS coupling events in mouse pancreatic islets.
Methods: Islets were isolated from female C57BL/6J mice (J-islets), which lack functional NNT, and genetically close C57BL/6N mice (N-islets). Wild-type mouse NNT was expressed in J-islets by adenoviral infection. Mitochondrial and cytosolic glutathione oxidation was measured with glutaredoxin 1-fused roGFP2 probes targeted or not to the mitochondrial matrix. NADPH and NADH redox state was measured biochemically. Insulin secretion and upstream coupling events were measured under dynamic or static conditions by standard procedures.
Results: NNT is largely responsible for the acute glucose-induced rise in islet NADPH/NADP+ ratio and decrease in mitochondrial glutathione oxidation, with a small impact on cytosolic glutathione. However, contrary to current views on NNT in β-cells, these effects resulted from a glucose-dependent reduction in NADPH consumption by NNT reverse mode of operation, rather than from a stimulation of its forward mode of operation. Accordingly, the lack of NNT in J-islets decreased their sensitivity to exogenous H2O2 at non-stimulating glucose. Surprisingly, the lack of NNT did not alter the glucose-stimulation of Ca2+ influx and upstream mitochondrial events, but it markedly reduced both phases of GSIS by altering Ca2+-induced exocytosis and its metabolic amplification.
Conclusion: These results drastically modify current views on NNT operation and mitochondrial function in pancreatic β-cells.
We provide the first comprehensive taxonomic revision of the poorly known South American butterfly genus Zischkaia Forster, 1964, hitherto regarded as including three described species. A phylogenetic analysis based on DNA sequence data shows that Zischkaia is monophyletic and consists of two morphologically diagnosable clades. Morphological characters and DNA 'barcodes' support the recognition of twelve species in the genus, a significant increase even for the relatively poorly studied subtribe Euptychiina. Consequently, nine new species are described and named herein, including Z. arctoa Nakahara, sp. nov., Z. chullachaki Nakahara & Zacca, sp. nov., Z. baku Zacca, Dolibaina & Dias, sp. nov., Z. arenisca Nakahara, Willmott & Hall, sp. nov., Z. argyrosflecha Nakahara, L. Miller & Huertas, sp. nov., Z. abanico Nakahara & Petit, sp. nov., Z. josti Nakahara & Kleckner, sp. nov., Z. mielkeorum Dolibaina, Dias & Zacca, sp. nov. and Z. warreni Dias, Zacca & Dolibaina, sp. nov. In addition, a neotype is designated for Satyrus pacarus Godart, [1824], and lectotypes are designated for Euptychia amalda Weymer, 1911, Euptychia fumata Butler, 1867 and Euptychia saundersii Butler, 1867.
Targeting self-renewal and tumorigenicity has been proposed as a potential strategy against cancer stem cells (CSCs). Epigenetic proteins are key modulators of gene expression and cancer development contributing to regulation and maintenance of self-renewal and tumorigenicity. Here, we have screened a small-molecule epigenetic inhibitor library using 3D in vitro models in order to determine potential epigenetic targets associated with self-renewal and tumorigenicity in Canine Mammary Cancer (CMC) cells. We identified inhibition of BET proteins as a promising strategy to inhibit CMC colonies and tumorspheres formation. Low doses of (+)-JQ1 were able to downregulate important genes associated to self-renewal pathways such as WNT, NOTCH, Hedgehog, PI3K/AKT/mTOR, EGF receptor and FGF receptor in CMC tumorspheres. In addition, we observed downregulation of ZEB2, a transcription factor important for the maintenance of self-renewal in canine mammary cancer cells. Furthermore, low doses of (+)-JQ1 were not cytotoxic in CMC cells cultured in 2D in vitro models but induced G2/M cell cycle arrest accompanied by upregulation of G2/M checkpoint-associated genes including BTG2 and CCNG2. Our work indicates the BET inhibition as a new strategy for canine mammary cancers by modulating the self-renewal phenotype in tumorigenic cells such as CSCs.
A measurement of the production of prompt +c baryons in Pb–Pb collisions at √sNN = 5.02 TeV with the ALICE detector at the LHC is reported. The +c and − c were reconstructed at midrapidity (|y| < 0.5) via the hadronic decay channel +c → pK0 S (and charge conjugate) in the transverse momentum and centrality intervals 6 < pT < 12 GeV/c and 0–80%. The +c /D0 ratio, which is sensitive to the charm quark hadronisation mechanisms in the medium, is measured and found to be larger than the ratio measured in minimum-bias pp collisions at √s = 7 TeV and in p–Pb collisions at √sNN = 5.02 TeV. In particular, the values in p–Pb and Pb–Pb collisions differ by about two standard deviations of the combined statistical and systematic uncertainties in the common pT interval covered by the measurements in the two collision systems. The + c /D0 ratio is also compared with model calculations including different implementations of charm quark hadronisation. The measured ratio is reproduced by models implementing a pure coalescence scenario, while adding a fragmentation contribution leads to an underestimation. The + c nuclear modification factor, RAA, is also presented. The measured values of the RAA of + c , D+ s and non-strange D mesons are compatible within the combined statistical and systematic uncertainties. They show, however, a hint of a hierarchy (RD0 AA < RD+ s AA < R+ c AA ), conceivable with a contribution from coalescence mechanisms to charm hadron formation in the medium.
The jet radial structure and particle transverse momentum (pT) composition within jets are presented in centrality-selected Pb–Pb collisions at √sNN = 2.76 TeV. Track-based jets, which are also called charged jets, were reconstructed with a resolution parameter of R = 0.3 at midrapidity |ηch jet| < 0.6 for transverse momenta pT, ch jet = 30–120 GeV/c. Jet–hadron correlations in relative azimuth and pseudorapidity space (Δϕ, Δη) are measured to study the distribution of the associated particles around the jet axis for different pT,assoc-ranges between 1 and 20 GeV/c. The data in Pb–Pb collisions are compared to reference distributions for pp collisions, obtained using embedded PYTHIA simulations. The number of high-pT associate particles (4 < pT,assoc < 20 GeV/c) in Pb–Pb collisions is found to be suppressed compared to the reference by 30 to 10% depending on centrality. The radial particle distribution relative to the jet axis shows a moderate modification in Pb–Pb collisions with respect to PYTHIA. High-pT associate particles are slightly more collimated in Pb–Pb collisions compared to the reference, while low-pT associate particles tend to be broadened. The results, which are presented for the first time down to pT, ch jet = 30 GeV/c in Pb–Pb collisions, are compatible with both previous jet–hadron-related measurements from the CMS Collaboration and jet shape measurements from the ALICE Collaboration at higher pT, and add further support for the established picture of in-medium parton energy loss.
Study of the Λ–Λ interaction with femtoscopy correlations in pp and p–Pb collisions at the LHC
(2019)
This work presents new constraints on the existence and the binding energy of a possible – bound state, the H-dibaryon, derived from – femtoscopic measurements by the ALICE collaboration. The results are obtained from a new measurement using the femtoscopy technique in pp collisions at √s = 13 TeV and p–Pb collisions at √sNN = 5.02 TeV, combined with previously published results from pp collisions at √s = 7 TeV. The – scattering parameter space, spanned by the inverse scattering length f −1 0 and the effective range d0, is constrained by comparing the measured – correlation function with calculations obtained within the Lednický model. The data are compatible with hypernuclei results and lattice computations, both predicting a shallow attractive interaction, and permit to test different theoretical approaches describing the – interaction. The region in the (f −1 0 ,d0) plane which would accommodate a – bound state is substantially restricted compared to previous studies. The binding energy of the possible – bound state is estimated within an effective-range expansion approach and is found to be B = 3.2+1.6 −2.4(stat)+1.8 −1.0(syst) MeV.
Loss of the tumor suppressor Pdcd4 was reported for various tumor entities and proposed as a prognostic marker in tumorigenesis. We previously characterized decreased Pdcd4 protein stability in response to mitogenic stimuli, which resulted from p70S6K1-dependent protein phosphorylation, β-TrCP1-mediated ubiquitination, and proteasomal destruction. Following high-throughput screening of natural product extract libraries using a luciferase-based reporter assay to monitor phosphorylation-dependent proteasomal degradation of the tumor suppressor Pdcd4, we succeeded in showing that a crude extract from Eriophyllum lanatum stabilized Pdcd4 from TPA-induced degradation. Erioflorin was identified as the active component and inhibited not only degradation of the Pdcd4-luciferase-based reporter but also of endogenous Pdcd4 at low micromolar concentrations. Mechanistically, erioflorin interfered with the interaction between the E3-ubiquitin ligase β-TrCP1 and Pdcd4 in cell culture and in in vitro binding assays, consequently decreasing ubiquitination and degradation of Pdcd4. Interestingly, while erioflorin stabilized additional β-TrCP-targets (such as IκBα and β-catenin), it did not prevent the degradation of targets of other E3-ubiquitin ligases such as p21 (a Skp2-target) and HIF-1α (a pVHL-target), implying selectivity for β-TrCP. Moreover, erioflorin inhibited the tumor-associated activity of known Pdcd4- and IκBα-regulated αtranscription factors, that is, AP-1 and NF-κB, altered cell cycle progression and suppressed proliferation of various cancer cell lines. Our studies succeeded in identifying erioflorin as a novel Pdcd4 stabilizer that inhibits the interaction of Pdcd4 with the E3-ubiquitin ligase β-TrCP1. Inhibition of E3-ligase/target-protein interactions may offer the possibility to target degradation of specific proteins only as compared to general proteasome inhibition.
In this letter, the production of deuterons and anti-deuterons in pp collisions at √s = 7 TeV is studied as a function of the charged-particle multiplicity density at mid-rapidity with the ALICE detector at the LHC. Production yields are measured at mid-rapidity in five multiplicity classes and as a function of the deuteron transverse momentum (pT). The measurements are discussed in the context of hadron–coalescence models. The coalescence parameter B2, extracted from the measured spectra of (anti-)deuterons and primary (anti-)protons, exhibits no significant pT-dependence for pT < 3 GeV/c, in agreement with the expectations of a simple coalescence picture. At fixed transverse momentum per nucleon, the B2 parameter is found to decrease smoothly from low multiplicity pp to Pb–Pb collisions, in qualitative agreement with more elaborate coalescence models. The measured mean transverse momentum of (anti-)deuterons in pp is not reproduced by the Blast-Wave model calculations that simultaneously describe pion, kaon and proton spectra, in contrast to central Pb–Pb collisions. The ratio between the pT-integrated yield of deuterons to protons, d/p, is found to increase with the chargedparticle multiplicity, as observed in inelastic pp collisions at different centre-of-mass energies. The d/p ratios are reported in a wide range, from the lowest to the highest multiplicity values measured in pp collisions at the LHC.
Matsucoccus krystalae Ahmed and Miller, new species, (Hemiptera:Coccomorpha: Matsucoccidae) is described based on morphological characters of adult females and third-instar males. We designate the lectotype of Matsucoccus alabamae Morrison. Matsucoccus alabamae Morrison and M. gallicolus Morrison are redescribed, also based on adult females and third-instar males. Detailed illustrations and descriptions are presented for each species and an identification key for the five species occurring in the eastern U.S. is provided. Analysis of 18S, 28S D2/D3, and 28S D10 loci were performed to support morphological determination. Barcodes using 5′ COI of M. alabamae and M. krystalae were generated, the first such data from authoritatively identified Matsucoccus species. Of particular interest is that most of the specimens in the study were taken in Lindgren funnel traps.
Fire is an integral component of many ecosystems worldwide. Many plant species require fire-related cues, primarily heat and smoke, to trigger germination. Despite the importance of this process, the responses of many Australian species to these cues are unknown. Without this knowledge fire management strategies may be developed that are inappropriate for individual species and vegetation communities. In this study we examined the responses of a dry sclerophyll forest seed bank to heat and smoke germination cues. Analysis was possible for 48 taxa within the soil seedbank with 34 of these showing a response to one or both of the germination cues. 10 species responded to the heat treatment, 11 species responded to the smoke treatment and 13 species responded to both the heat and smoke treatments. Germination cues acted independently for all species considered. Results in this study were consistent with published reports for most species, although some differences were seen at the species and genus level. The study highlights the importance of fire-related cues in enhancing germination of a large proportion of the species occurring in dry sclerophyll forests.
Teleconnections of the Quasi-Biennial Oscillation in a multi-model ensemble of QBO-resolving models
(2021)
The Quasi-biennial Oscillation (QBO) dominates the interannual variability of the tropical stratosphere and influences other regions of the atmosphere. The high predictability of the QBO implies that its teleconnections could lead to increased skill of seasonal and decadal forecasts provided the relevant mechanisms are accurately represented in models. Here modelling and sampling uncertainties of QBO teleconnections are examined using a multi-model ensemble of QBO-resolving atmospheric general circulation models that have carried out a set of coordinated experiments as part of the Stratosphere-troposphere Processes And their Role in Climate (SPARC) QBO initiative (QBOi). During Northern Hemisphere winter, the stratospheric polar vortex in most of these models strengthens when the QBO near 50 hPa is westerly and weakens when it is easterly, consistent with, but weaker than, the observed response. These weak responses are likely due to model errors, such as systematically weak QBO amplitudes near 50 hPa, affecting the teleconnection. The teleconnection to the North Atlantic Oscillation is less well captured overall, but of similar strength to the observed signal in the few models that do show it. The models do not show clear evidence of a QBO teleconnection to the Northern Hemisphere Pacific-sector subtropical jet.
The ALICE collaboration performed the first rapidity-differential measurement of coherent J/ψ photoproduction in ultra-peripheral Pb–Pb collisions at a center-of-mass energy √sNN = 5.02 TeV. The J/ψ is detected via its dimuon decay in the forward rapidity region (−4.0 < y < −2.5) for events where the hadronic activity is required to be minimal. The analysis is based on an event sample corresponding to an integrated luminosity of about 750 μb−1. The cross section for coherent J/ψ production is presented in six rapidity bins. The results are compared with theoretical models for coherent J/ψ photoproduction. These comparisons indicate that gluon shadowing effects play a role in the photoproduction process. The ratio of ψ to J/ψ coherent photoproduction cross sections was measured and found to be consistent with that measured for photoproduction off protons.
Multiplicity dependence of light (anti-)nuclei production in p–Pb collisions at √sNN =5.02 TeV
(2020)
The measurement of the deuteron and anti-deuteron production in the rapidity range −1 < y < 0 as a function of transverse momentum and event multiplicity in p–Pb collisions at √sNN = 5.02 TeV is presented. (Anti-)deuterons are identified via their specific energy loss dE/dx and via their time-offlight. Their production in p–Pb collisions is compared to pp and Pb–Pb collisions and is discussed within the context of thermal and coalescence models. The ratio of integrated yields of deuterons to protons (d/p) shows a significant increase as a function of the charged-particle multiplicity of the event starting from values similar to those observed in pp collisions at low multiplicities and approaching those observed in Pb–Pb collisions at high multiplicities. The mean transverse particle momenta are extracted from the deuteron spectra and the values are similar to those obtained for p and particles. Thus, deuteron spectra do not follow mass ordering. This behaviour is in contrast to the trend observed for non-composite particles in p–Pb collisions. In addition, the production of the rare 3He and 3He nuclei has been studied. The spectrum corresponding to all non-single diffractive p-Pb collisions is obtained in the rapidity window −1 < y < 0 and the pT-integrated yield dN/dy is extracted. It is found that the yields of protons, deuterons, and 3He, normalised by the spin degeneracy factor, follow an exponential decrease with mass number.
The ALICE collaboration at the CERN LHC reports novel measurements of jet substructure in pp collisions at √s = 7 TeV and central Pb–Pb collisions at √sNN = 2.76 TeV. Jet substructure of track-based jets is explored via iterative declustering and grooming techniques. We present the measurement of the momentum sharing of two-prong substructure exposed via grooming, the zg, and its dependence on the opening angle, in both pp and Pb–Pb collisions. We also present the measurement of the distribution of the number of branches obtained in the iterative declustering of the jet, which is interpreted as the number of its hard splittings. In Pb–Pb collisions, we observe a suppression of symmetric splittings at large opening angles and an enhancement of splittings at small opening angles relative to pp collisions, with no significant modification of the number of splittings. The results are compared to predictions from various Monte Carlo event generators to test the role of important concepts in the evolution of the jet in the medium such as colour coherence.
Aims: Carotid intima media thickness (CIMT) predicts cardiovascular (CVD) events, but the predictive value of CIMT change is debated. We assessed the relation between CIMT change and events in individuals at high cardiovascular risk.
Methods and results: From 31 cohorts with two CIMT scans (total n = 89070) on average 3.6 years apart and clinical follow-up, subcohorts were drawn: (A) individuals with at least 3 cardiovascular risk factors without previous CVD events, (B) individuals with carotid plaques without previous CVD events, and (C) individuals with previous CVD events. Cox regression models were fit to estimate the hazard ratio (HR) of the combined endpoint (myocardial infarction, stroke or vascular death) per standard deviation (SD) of CIMT change, adjusted for CVD risk factors. These HRs were pooled across studies.
In groups A, B and C we observed 3483, 2845 and 1165 endpoint events, respectively. Average common CIMT was 0.79mm (SD 0.16mm), and annual common CIMT change was 0.01mm (SD 0.07mm), both in group A. The pooled HR per SD of annual common CIMT change (0.02 to 0.43mm) was 0.99 (95% confidence interval: 0.95–1.02) in group A, 0.98 (0.93–1.04) in group B, and 0.95 (0.89–1.04) in group C. The HR per SD of common CIMT (average of the first and the second CIMT scan, 0.09 to 0.75mm) was 1.15 (1.07–1.23) in group A, 1.13 (1.05–1.22) in group B, and 1.12 (1.05–1.20) in group C.
Conclusions: We confirm that common CIMT is associated with future CVD events in individuals at high risk. CIMT change does not relate to future event risk in high-risk individuals.
Two-particle correlation functions were measured for pp, p, p, and pairs in Pb–Pb collisions at √sNN = 2.76 TeV and √sNN = 5.02 TeV recorded by the ALICE detector. From a simultaneous fit to all obtained correlation functions, real and imaginary components of the scattering lengths, as well as the effective ranges, were extracted for combined p and p pairs and, for the first time, for pairs. Effective averaged scattering parameters for heavier baryon–antibaryon pairs, not measured directly, are also provided. The results reveal similarly strong interaction between measured baryon–antibaryon pairs, suggesting that they all annihilate in the same manner at the same pair relative momentum k∗. Moreover, the reported significant non-zero imaginary part and negative real part of the scattering length provide motivation for future baryon–antibaryon bound state searches.
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.
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 Kinase Chemogenomic Set (KCGS): an open science resource for kinase vulnerability identification
(2021)
We describe the assembly and annotation of a chemogenomic set of protein kinase inhibitors as an open science resource for studying kinase biology. The set only includes inhibitors that show potent kinase inhibition and a narrow spectrum of activity when screened across a large panel of kinase biochemical assays. Currently, the set contains 187 inhibitors that cover 215 human kinases. The kinase chemogenomic set (KCGS), current Version 1.0, is the most highly annotated set of selective kinase inhibitors available to researchers for use in cell-based screens.
The Kinase Chemogenomic Set (KCGS): An open science resource for kinase vulnerability identification
(2019)
We describe the assembly and annotation of a chemogenomic set of protein kinase inhibitors as an open science resource for studying kinase biology. The set only includes inhibitors that show potent kinase inhibition and a narrow spectrum of activity when screened across a large panel of kinase biochemical assays. Currently, the set contains 187 inhibitors that cover 215 human kinases. The kinase chemogenomic set (KCGS) is the most highly annotated set of selective kinase inhibitors available to researchers for use in cell-based screens.
Back-angle enhancements of elastic alpha -scattering cross sections have been observed for nuclei at the ends of the 1p, 2s-1d, and f7 / 2 shells. Strong reduction of this enhancement occurs if excess neutrons enter the next open major shell. The results are discussed in terms of intermediate alpha structure.
Unequivocal international guidelines regarding the diagnosis and management of patients with acute appendicitis are lacking. The aim of the consensus meeting 2015 of the EAES was to generate a European guideline based on best available evidence and expert opinions of a panel of EAES members. After a systematic review of the literature by an international group of surgical research fellows, an expert panel with extensive clinical experience in the management of appendicitis discussed statements and recommendations. Statements and recommendations with more than 70 % agreement by the experts were selected for a web survey and the consensus meeting of the EAES in Bucharest in June 2015. EAES members and attendees at the EAES meeting in Bucharest could vote on these statements and recommendations. In the case of more than 70 % agreement, the statement or recommendation was defined as supported by the scientific community. Results from both the web survey and the consensus meeting in Bucharest are presented as percentages. In total, 46 statements and recommendations were selected for the web survey and consensus meeting. More than 232 members and attendees voted on them. In 41 of 46 statements and recommendations, more than 70 % agreement was reached. All 46 statements and recommendations are presented in this paper. They comprise topics regarding the diagnostic work-up, treatment indications, procedural aspects and post-operative care. The consensus meeting produced 46 statements and recommendations on the diagnostic work-up and management of appendicitis. The majority of the EAES members supported these statements. These consensus proceedings provide additional guidance to surgeons and surgical residents providing care to patients with appendicitis.
Background: Bipolar disorder is associated with circadian disruption and a high risk of suicidal behavior. In a previous exploratory study of patients with bipolar I disorder, we found that a history of suicide attempts was associated with differences between winter and summer levels of solar insolation. The purpose of this study was to confirm this finding using international data from 42% more collection sites and 25% more countries. Methods: Data analyzed were from 71 prior and new collection sites in 40 countries at a wide range of latitudes. The analysis included 4876 patients with bipolar I disorder, 45% more data than previously analyzed. Of the patients, 1496 (30.7%) had a history of suicide attempt. Solar insolation data, the amount of the sun’s electromagnetic energy striking the surface of the earth, was obtained for each onset location (479 locations in 64 countries). Results: This analysis confirmed the results of the exploratory study with the same best model and slightly better statistical significance. There was a significant inverse association between a history of suicide attempts and the ratio of mean winter insolation to mean summer insolation (mean winter insolation/mean summer insolation). This ratio is largest near the equator which has little change in solar insolation over the year, and smallest near the poles where the winter insolation is very small compared to the summer insolation. Other variables in the model associated with an increased risk of suicide attempts were a history of alcohol or substance abuse, female gender, and younger birth cohort. The winter/summer insolation ratio was also replaced with the ratio of minimum mean monthly insolation to the maximum mean monthly insolation to accommodate insolation patterns in the tropics, and nearly identical results were found. All estimated coefficients were significant at p < 0.01. Conclusion: A large change in solar insolation, both between winter and summer and between the minimum and maximum monthly values, may increase the risk of suicide attempts in bipolar I disorder. With frequent circadian rhythm dysfunction and suicidal behavior in bipolar disorder, greater understanding of the optimal roles of daylight and electric lighting in circadian entrainment is needed.
First results on the longitudinal asymmetry and its effect on the pseudorapidity distributions in Pb–Pb collisions at √sNN = 2.76 TeV at the Large Hadron Collider are obtained with the ALICE detector. The longitudinal asymmetry arises because of an unequal number of participating nucleons from the two colliding nuclei, and is estimated for each event by measuring the energy in the forward neutron-ZeroDegree-Calorimeters (ZNs). The effect of the longitudinal asymmetry is measured on the pseudorapidity distributions of charged particles in the regions |η| < 0.9, 2.8 < η < 5.1 and −3.7 < η < −1.7 by taking the ratio of the pseudorapidity distributions from events corresponding to different regions of asymmetry. The coefficients of a polynomial fit to the ratio characterise the effect of the asymmetry. A Monte Carlo simulation using a Glauber model for the colliding nuclei is tuned to reproduce the spectrum in the ZNs and provides a relation between the measurable longitudinal asymmetry and the shift in the rapidity (y0) of the participant zone formed by the unequal number of participating nucleons. The dependence of the coefficient of the linear term in the polynomial expansion, c1, on the mean value of y0 is investigated.
The production of the charm-strange baryon Ξc0 is measured for the first time at the LHC via its semileptonic decay into eΞ−+νe in pp collisions at s=7 TeV with the ALICE detector. The transverse momentum (pT) differential cross section multiplied by the branching ratio is presented in the interval 1<pT<8 GeV/c at mid-rapidity, |y|<0.5. The transverse momentum dependence of the Ξc0 baryon production relative to the D0 meson production is compared to predictions of event generators with various tunes of the hadronisation mechanism, which are found to underestimate the measured cross-section ratio.
Azimuthally-differential femtoscopic measurements, being sensitive to spatio-temporal characteristics of the source as well as to the collective velocity fields at freeze out, provide very important information on the nature and dynamics of the system evolution. While the HBT radii oscillations relative to the second harmonic event plane measured recently reflect mostly the spatial geometry of the source, model studies have shown that the HBT radii oscillations relative to the third harmonic event plane are predominantly defined by the velocity fields. In this Letter, we present the first results on azimuthally-differential pion femtoscopy relative to the third harmonic event plane as a function of the pion pair transverse momentum kT for different collision centralities in Pb–Pb collisions at √sNN = 2.76 TeV. We find that the Rside and Rout radii, which characterize the pion source size in the directions perpendicular and parallel to the pion transverse momentum, oscillate in phase relative to the third harmonic event plane, similar to the results from 3+1D hydrodynamical calculations. The observed radii oscillations unambiguously signal a collective expansion and anisotropy in the velocity fields. A comparison of the measured radii scillations with the Blast-Wave model calculations indicate that the initial state triangularity is washedout at freeze out.
We present a measurement of azimuthal correlations between inclusive J/ψ and charged hadrons in p–Pb collisions recorded with the ALICE detector at the CERN LHC. The J/ψ are reconstructed at forward (p-going, 2.03<y<3.53) and backward (Pb-going, −4.46<y<−2.96) rapidity via their μ+μ− decay channel, while the charged hadrons are reconstructed at mid-rapidity (|η|<1.8). The correlations are expressed in terms of associated charged-hadron yields per J/ψ trigger. A rapidity gap of at least 1.5 units is required between the trigger J/ψ and the associated charged hadrons. Possible correlations due to collective effects are assessed by subtracting the associated per-trigger yields in the low-multiplicity collisions from those in the high-multiplicity collisions. After the subtraction, we observe a strong indication of remaining symmetric structures at Δφ≈0 and Δφ≈π, similar to those previously found in two-particle correlations at middle and forward rapidity. The corresponding second-order Fourier coefficient (v2) in the transverse momentum interval between 3 and 6 GeV/c is found to be positive with a significance of about 5σ. The obtained results are similar to the J/ψ v2 coefficients measured in Pb–Pb collisions at sNN=5.02 TeV, suggesting a common mechanism at the origin of the J/ψ v2.
The release of RNA-containing extracellular vesicles (EV) into the extracellular milieu has been demonstrated in a multitude of different in vitro cell systems and in a variety of body fluids. RNA-containing EV are in the limelight for their capacity to communicate genetically encoded messages to other cells, their suitability as candidate biomarkers for diseases, and their use as therapeutic agents. Although EV-RNA has attracted enormous interest from basic researchers, clinicians, and industry, we currently have limited knowledge on which mechanisms drive and regulate RNA incorporation into EV and on how RNA-encoded messages affect signalling processes in EV-targeted cells. Moreover, EV-RNA research faces various technical challenges, such as standardisation of EV isolation methods, optimisation of methodologies to isolate and characterise minute quantities of RNA found in EV, and development of approaches to demonstrate functional transfer of EV-RNA in vivo. These topics were discussed at the 2015 EV-RNA workshop of the International Society for Extracellular Vesicles. This position paper was written by the participants of the workshop not only to give an overview of the current state of knowledge in the field, but also to clarify that our incomplete knowledge – of the nature of EV(-RNA)s and of how to effectively and reliably study them – currently prohibits the implementation of gold standards in EV-RNA research. In addition, this paper creates awareness of possibilities and limitations of currently used strategies to investigate EV-RNA and calls for caution in interpretation of the obtained data.
The Birds of the Highlands of South-West Saudi Arabia and adjacent parts of the Tihama: July 2010
(2010)
The objective of the survey was to compare habitats and bird life in the Asir region, particularly Jebal Souda and the Raydah escarpment protected area of the Saudi Wildlife Commission, and adjacent regions of the tihama, with those observed in July 1987 (Jennings, et al., 1988). The two surveys were approximately the same length and equal amounts of time were spent in the highlands and on the tihama. A number of walked censuses were carried out during 2010 on Jebal Souda, using the same methodology as walked censuses in 1987, and the results are compared. Broadly speaking the comparison of censuses revealed that in 2010 there were less birds and reduced diversity on the Jebal Souda plateau, compared to 1987. However in the Raydah reserve the estimates of breeding bird populations compiled in the mid 1990s was little changed as far as could be assessed in 2010. The highland region of south-west Saudi Arabia, especially Jebal Souda, has been much developed since the 1987 survey and is now an important internal recreation and resort area. This has lead to a reduction in the region’s importance for terraced agriculture. These changes may be a contributing factor to changes in bird numbers on the plateau. Subsidiary tasks that arose during the 2010 survey were to help locate satellite tagged Bald Ibises Geronticus eremita from Syria which were transiting Saudi Arabia at the time. Secondly to search for the Asir subspecies of the Eurasian Magpie Pica pica asirensis, which is endemic to the south-west Saudi Arabia highlands, and is reported to be in decline. A separate team searching for the Bald Ibis located some individuals and one was found dead. Few Magpies were located and it seems clear that this very scarce bird has declined further in numbers in recent years. A number of interesting records of birds were obtained, especially on the tihama, where two new birds for Saudi Arabia were observed, Black-headed Heron Ardea melanocephala and Painted Snipe Rostratula benghalensis and one species, Glossy Ibis Plegadis falcinellus was found breeding for the first time in the Arabian Peninsula. Some recommendations for the protection and management of the Raydah reserve are presented. A systematic list of all birds seen is provided.
The genus Squamidium, a group of mosses with a tropical to subtropical American-African distribution, consists of two sections and seven species (prior to this study 27 species were recognized): sect. Squamidium (S. leucotrichum, S. livens, S. isocladum, S. nigricans, S. brasiliense) and sect. Macrosquamidium (S. macrocarpum and S. diversicoma). Twenty-four names are treated as syn. nov., three are provisionally excluded pending an examination of their types, and one new combination is made: Orthostichopsis pilotrichelloides (Sehnem) Allen & Crosby. Section Squamidium ist characterized by immersed capsules, stolon leaves with entire margins, and a relatively high basal membrane. Section Macrosquamidium is characterized by exserted capsules, stolon leaves with sharply recurved marginal teeth, and a relatively low basal membrane. The genus is retained in the Meteoriaceae. Within the Meteoriaceae Squamidium, is most closely related to Zelotmeteorium from which it differs only by its lack of squarrose-recurved leaves and its more well-developed alar cells. Squamidium, which in the absence of sporophytes has been confused consistently with Orthostichopsis, is separated from that genus on the basis of its lack of pseudoparaphyllia, weaker costae, lack of a distinct region of reddish cells across the leaf base, and strongly decurrent alar cells.
Background: Pythium ultimum (P. ultimum) is a ubiquitous oomycete plant pathogen responsible for a variety of diseases on a broad range of crop and ornamental species. Results: The P. ultimum genome (42.8 Mb) encodes 15,290 genes and has extensive sequence similarity and synteny with related Phytophthora species, including the potato blight pathogen Phytophthora infestans. Whole transcriptome sequencing revealed expression of 86% of genes, with detectable differential expression of suites of genes under abiotic stress and in the presence of a host. The predicted proteome includes a large repertoire of proteins involved in plant pathogen interactions although surprisingly, the P. ultimum genome does not encode any classical RXLR effectors and relatively few Crinkler genes in comparison to related phytopathogenic oomycetes. A lower number of enzymes involved in carbohydrate metabolism were present compared to Phytophthora species, with the notable absence of cutinases, suggesting a significant difference in virulence mechanisms between P. ultimum and more host specific oomycete species. Although we observed a high degree of orthology with Phytophthora genomes, there were novel features of the P. ultimum proteome including an expansion of genes involved in proteolysis and genes unique to Pythium. We identified a small gene family of cadherins, proteins involved in cell adhesion, the first report in a genome outside the metazoans. Conclusions: Access to the P. ultimum genome has revealed not only core pathogenic mechanisms within the oomycetes but also lineage specific genes associated with the alternative virulence and lifestyles found within the pythiaceous lineages compared to the Peronosporaceae.
The purpose of this study of early social-cognitive development was to assess the very young child's behaviorally expressed knowledge of people's visual-attentional acts and abilities. Boys and girls (N = 60) 1, 1 1/2, 2, 2 1/2, and 3 years of age were tested in their homes with their mothers' help. Three sorts of tasks were used: 1. Percept production. The child's task was to produce a visual percept in the other. Examples include pointing to objects ("productive pointing") and a wide variety of object-showing problems. 2. Percept deprivation. The opposite, exemplified by a variety of object-hiding problems. 3. Percept diagnosis. The child's task was to determine what the other was already visually attending to, either by looking where his or her finger was pointed ("receptive pointing") or where his eyes were directed. It was found that the majority of l-year-olds produced and comprehended pointing, and would sometimes hold out a toy to show it, but did little else. The 3-year-olds were at ceiling on virtually all tasks. At 1 1/2 years, children usually showed a picture by holding it flat so that both they and the other could see it. From 2 on, they usually turned it toward the other in the adult fashion. Very few children of any age showed egocentrically - i.e., orienting the picture so only they could see it. By age 2, the children solved what were presumably novel showing problems for them: e.g., successfully showing to another a picture pasted on the inside bottom of a hollow cube. Hiding ability emerged later than showing ability but seemed well established by age 3. The role of the other's eyes in seeing appeared to be quite well understood at least by age 2-2 1/2. As examples, children of this age took the other's hands away from her or his eyes before trying to show her something, and could usually tell where she was looking from her eye orientation alone. These age trends presumably reflect important developments in the area of social interaction and communication, as well as with respect to cognition about percepts.
Hatching asynchrony and the onset of incubation in birds revisited : when is the critical period?
(1995)
1. Birds are unique among animals in being able to influence the birthing intervals of their young through the timing of the onset incubation. However, many species hatch their young asynchronously, frequently resulting in reduced survivorship for later-hatched young. This is the Paradox of Hatching Asynchrony. 2. The Brood Reduction Hypothesis provided a resolution to the paradox by suggesting an adaptive function to the offspring mortality that results from asynchrony. Experimental tests have provided little support, and 16 alternative hypotheses have been proposed, but few have been tested. Most experimental tests have not measured important parameters such as parental effort and postfledging survival. Many have lacked adequate controls or sufficient statistical power. 3. We divide the hypotheses for hatching asynchrony into four categories based on the effects of intrinsic or extrinsic factors during a critical period of the nesting cycle which constrains reproductive success. Hatching asynchrony could be simply the consequence of the early onset of incubation during egg-laying, either as a result of physiological constraints on incubation or because parents derive fitness benefits from the protective function of early incubation. During the nestling period, hatching asynchrony could be adaptive if it allowed parents to eliminate one or more nestlings selectively, or increased parental efficiency. Alternatively, parents could manipulate the duration of the different periods of the nesting cycle to maximize benefits. 4. Because the onset of incubation generally determines hatching patterns, we encourage refocusing attention from the search for adaptive hatching patterns during the nestling period to the events surrounding the onset of incubation during egg-laying. Many factors can affect when incubation is begun, including physiology, and interactions with the environment, predators, competitors, and mates. 5. Patterns of the onset of incubation are difficult to determine and to quantify, in part because many birds begin incubating gradually, or at night. In some species, the onset of incubation varies with clutch size, but not in others. 6. The onset of incubation is the principle proximate control of hatching patterns, but other factors, such as egg size, embryonic vocalizations, and time of year may also affect hatching patterns. 7. Synchronous hatching is the primitive condition in birds, and is widespread in the lower, primarily precocial taxa. Most altricial species hatch their eggs asynchronously, although some exhibit synchrony as a secondarily derived trait. Hatching patterns show wide variation within some orders and families. 8. Patterns of the onset of incubation and hatching in a species may reflect the influence of multiplefactors. The relative importance of those factors may depend on the trade-offs associated with the potential benefits of early incubation to the survival of eggs and the potential costs to the survivor of later-hatching young associatedwith nestling size hierarchies. 9. The relative effects of multiple factors can be examined by integrating the results of empirical tests of single factors through modeling. 10. We demonstrated the use of a stochastic model by using empirical data from the House Sparrow. Results revealed the trade-offs inherent in the onset of incubation from differences in egg viability and nestling survivorship. An intermediate onset of incubation produced the greatest fledging success. 11. Other factors may be integrated into such models if they can be measured in terms of their effects on fledging success. Different factors, represented by different hypotheses, vary in how readily they may be modeled.
The ( J, T ) = (1, 1) parity doublet in 20Ne at 11.26 MeV is a good candidate to study parity violation in nuclei. However, its energy splitting is known with insufficient accuracy for quantitative estimates of parity violating effects. To improve on this unsatisfactory situation, nuclear resonance fluorescence experiments using linearly and circularly polarized γ -ray beams were used to determine the energy difference of the parity doublet E = E(1−) − E(1+) = −3.2(±0.7)stat( +0.6 −1.2)sys keV and the ratio of their integrated cross sections I (+) s,0 /I (−) s,0 = 29(±3)stat( +14 −7 )sys. Shell-model calculations predict a parityviolating matrix element having a value in the range 0.46–0.83 eV for the parity doublet. The small energy difference of the parity doublet makes 20Ne an excellent candidate to study parity violation in nuclear excitations.
Background: There is no international consensus up to which age women with a diagnosis of triple-negative breast cancer (TNBC) and no family history of breast or ovarian cancer should be offered genetic testing for germline BRCA1 and BRCA2 (gBRCA) mutations. Here, we explored the association of age at TNBC diagnosis with the prevalence of pathogenic gBRCA mutations in this patient group.
Methods: The study comprised 802 women (median age 40 years, range 19–76) with oestrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2 negative breast cancers, who had no relatives with breast or ovarian cancer. All women were tested for pathogenic gBRCA mutations. Logistic regression analysis was used to explore the association between age at TNBC diagnosis and the presence of a pathogenic gBRCA mutation.
Results: A total of 127 women with TNBC (15.8%) were gBRCA mutation carriers (BRCA1: n = 118, 14.7%; BRCA2: n = 9, 1.1%). The mutation prevalence was 32.9% in the age group 20–29 years compared to 6.9% in the age group 60–69 years. Logistic regression analysis revealed a significant increase of mutation frequency with decreasing age at diagnosis (odds ratio 1.87 per 10 year decrease, 95%CI 1.50–2.32, p < 0.001). gBRCA mutation risk was predicted to be > 10% for women diagnosed below approximately 50 years.
Conclusions: Based on the general understanding that a heterozygous mutation probability of 10% or greater justifies gBRCA mutation screening, women with TNBC diagnosed before the age of 50 years and no familial history of breast and ovarian cancer should be tested for gBRCA mutations. In Germany, this would concern approximately 880 women with newly diagnosed TNBC per year, of whom approximately 150 are expected to be identified as carriers of a pathogenic gBRCA mutation.