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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.
Neurons of the mammalian neocortex are produced by proliferating cells located in the ventricular zone (VZ) lining the lateral ventricles. This is a complex and sequential process, requiring precise control of cell cycle progression, fate commitment and differentiation. We have analyzed publicly available databases from mouse and human to identify candidate genes that are potentially involved in regulating early neocortical development and neurogenesis. We used a mouse in situ hybridization dataset (The Allen Institute for Brain Science) to identify 13 genes (Cdon, Celsr1, Dbi, E2f5, Eomes, Hmgn2, Neurog2, Notch1, Pcnt, Sox3, Ssrp1, Tead2, Tgif2) with high correlation of expression in the proliferating cells of the VZ of the neocortex at early stages of development (E15.5). We generated a similar human brain network using microarray and RNA-seq data (BrainSpan Atlas) and identified 407 genes with high expression in the developing human VZ and subventricular zone (SVZ) at 8–9 post-conception weeks. Seven of the human genes were also present in the mouse VZ network. The human and mouse networks were extended using available genetic and proteomic datasets through GeneMANIA. A gene ontology search of the mouse and human networks indicated that many of the genes are involved in the cell cycle, DNA replication, mitosis and transcriptional regulation. The reported involvement of Cdon, Celsr1, Dbi, Eomes, Neurog2, Notch1, Pcnt, Sox3, Tead2, and Tgif2 in neural development or diseases resulting from the disruption of neurogenesis validates these candidate genes. Taken together, our knowledge-based discovery method has validated the involvement of many genes already known to be involved in neocortical development and extended the potential number of genes by 100's, many of which are involved in functions related to cell proliferation but others of which are potential candidates for involvement in the regulation of neocortical development.
Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.
Comprehensive results on the production of unidentified charged particles, π±, K±, K0S, K*(892)0, p, p¯¯¯, ϕ(1020), Λ, Λ¯¯¯¯, Ξ−, Ξ¯¯¯¯+, Ω− and Ω¯¯¯¯+ hadrons in proton-proton (pp) collisions at s√ = 7 TeV at midrapidity (|y|<0.5) as a function of charged-particle multiplicity density are presented. In order to avoid auto-correlation biases, the actual transverse momentum (pT) spectra of the particles under study and the event activity are measured in different rapidity windows. In the highest multiplicity class, the charged-particle density reaches about 3.5 times the value measured in inelastic collisions. While the yield of protons normalized to pions remains approximately constant as a function of multiplicity, the corresponding ratios of strange hadrons to pions show a significant enhancement that increases with increasing strangeness content. Furthermore, all identified particle to pion ratios are shown to depend solely on charged-particle multiplicity density, regardless of system type and collision energy. The evolution of the spectral shapes with multiplicity and hadron mass shows patterns that are similar to those observed in p-Pb and Pb-Pb collisions at LHC energies. The obtained pT distributions and yields are compared to expectations from QCD-based pp event generators as well as to predictions from thermal and hydrodynamic models. These comparisons indicate that traces of a collective, equilibrated system are already present in high-multiplicity pp collisions.
Comprehensive results on the production of unidentified charged particles, π±, K±, K0S, K*(892)0, p, p¯¯¯, ϕ(1020), Λ, Λ¯¯¯¯, Ξ−, Ξ¯¯¯¯+, Ω− and Ω¯¯¯¯+ hadrons in proton-proton (pp) collisions at s√ = 7 TeV at midrapidity (|y|<0.5) as a function of charged-particle multiplicity density are presented. In order to avoid auto-correlation biases, the actual transverse momentum (pT) spectra of the particles under study and the event activity are measured in different rapidity windows. In the highest multiplicity class, the charged-particle density reaches about 3.5 times the value measured in inelastic collisions. While the yield of protons normalized to pions remains approximately constant as a function of multiplicity, the corresponding ratios of strange hadrons to pions show a significant enhancement that increases with increasing strangeness content. Furthermore, all identified particle to pion ratios are shown to depend solely on charged-particle multiplicity density, regardless of system type and collision energy. The evolution of the spectral shapes with multiplicity and hadron mass shows patterns that are similar to those observed in p-Pb and Pb-Pb collisions at LHC energies. The obtained pT distributions and yields are compared to expectations from QCD-based pp event generators as well as to predictions from thermal and hydrodynamic models. These comparisons indicate that traces of a collective, equilibrated system are already present in high-multiplicity pp collisions.
Comprehensive results on the production of unidentified charged particles, π±, K±, K0S, K*(892)0, p, p¯¯¯, ϕ(1020), Λ, Λ¯¯¯¯, Ξ−, Ξ¯¯¯¯+, Ω− and Ω¯¯¯¯+ hadrons in proton-proton (pp) collisions at s√ = 7 TeV at midrapidity (|y|<0.5) as a function of charged-particle multiplicity density are presented. In order to avoid auto-correlation biases, the actual transverse momentum (pT) spectra of the particles under study and the event activity are measured in different rapidity windows. In the highest multiplicity class, the charged-particle density reaches about 3.5 times the value measured in inelastic collisions. While the yield of protons normalized to pions remains approximately constant as a function of multiplicity, the corresponding ratios of strange hadrons to pions show a significant enhancement that increases with increasing strangeness content. Furthermore, all identified particle to pion ratios are shown to depend solely on charged-particle multiplicity density, regardless of system type and collision energy. The evolution of the spectral shapes with multiplicity and hadron mass shows patterns that are similar to those observed in p-Pb and Pb-Pb collisions at LHC energies. The obtained pT distributions and yields are compared to expectations from QCD-based pp event generators as well as to predictions from thermal and hydrodynamic models. These comparisons indicate that traces of a collective, equilibrated system are already present in high-multiplicity pp collisions.
We present the first measurements of femtoscopic correlations between the K0S 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 K0SK− are found to be equal within the experimental uncertainties to those for K0SK+. 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 and with a K0SK± 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 the interpretation of the a0(980) having a tetraquark structure instead of that of a diquark.
We present the first measurements of femtoscopic correlations between the K0S 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 K0SK− are found to be equal within the experimental uncertainties to those for K0SK+. 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 and with a K0SK± 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 the interpretation of the a0(980) having a tetraquark structure instead of that of a diquark.
The second (v2) and third (v3) flow harmonic coefficients of J/ψ mesons are measured at forward rapidity (2.5 < y < 4.0) in Pb-Pb collisions at sNN−−−√ = 5.02 TeV with the ALICE detector at the LHC. Results are obtained with the scalar product method and reported as a function of transverse momentum, pT, for various collision centralities. A positive value of J/ψ v3 is observed with 3.7σ significance. The measurements, compared to those of prompt D0 mesons and charged particles at mid-rapidity, indicate an ordering with vn(J/ψ) <vn(D0) <vn(h±) (n = 2, 3) at low and intermediate pT up to 6 GeV/c and a convergence with v2(J/ψ) ≈v2(D0) ≈v2(h±) at high pT above 6-8 GeV/c. In semi-central collisions (5-40% and 10-50% centrality intervals) at intermediate pT between 2 and 6 GeV/c, the ratio v3/v2 of J/ψ mesons is found to be significantly lower (4.6σ) with respect to that of charged particles. In addition, the comparison to the prompt D0-meson ratio in the same pT interval suggests an ordering similar to that of the v2 and v3 coefficients. The J/ψ v2 coefficient is further studied using the Event Shape Engineering technique. The obtained results are found to be compatible with the expected variations of the eccentricity of the initial-state geometry.
The second (v2) and third (v3) flow harmonic coefficients of J/ψ mesons are measured at forward rapidity (2.5 < y < 4.0) in Pb-Pb collisions at sNN−−−√ = 5.02 TeV with the ALICE detector at the LHC. Results are obtained with the scalar product method and reported as a function of transverse momentum, pT, for various collision centralities. A positive value of J/ψ v3 is observed with 3.7σ significance. The measurements, compared to those of prompt D0 mesons and charged particles at mid-rapidity, indicate an ordering with vn(J/ψ) <vn(D0) <vn(h±) (n = 2, 3) at low and intermediate pT up to 6 GeV/c and a convergence with v2(J/ψ) ≈v2(D0) ≈v2(h±) at high pT above 6-8 GeV/c. In semi-central collisions (5-40% and 10-50% centrality intervals) at intermediate pT between 2 and 6 GeV/c, the ratio v3/v2 of J/ψ mesons is found to be significantly lower (4.6σ) with respect to that of charged particles. In addition, the comparison to the prompt D0-meson ratio in the same pT interval suggests an ordering similar to that of the v2 and v3 coefficients. The J/ψ v2 coefficient is further studied using the Event Shape Engineering technique. The obtained results are found to be compatible with the expected variations of the eccentricity of the initial-state geometry.
The ALICE Collaboration has measured the energy dependence of exclusive photoproduction of J/ψ vector mesons off proton targets in ultra-peripheral p-Pb collisions at a centre-of-mass energy per nucleon pair sNN−−−√=5.02 TeV. The e+e− and μ+μ− decay channels are used to measure the cross section as a function of the rapidity of the J/ψ in the range −2.5<y<2.7, corresponding to an energy in the γp centre-of-mass in the interval 40<Wγp<550 GeV. The measurements, which are consistent with a power law dependence of the exclusive J/ψ photoproduction cross section, are compared to previous results from HERA and the LHC and to several theoretical models. They are found to be compatible with previous measurements.
The ALICE Collaboration has measured the energy dependence of exclusive photoproduction of J/ψ vector mesons off proton targets in ultra-peripheral p-Pb collisions at a centre-of-mass energy per nucleon pair sNN−−−√=5.02 TeV. The e+e− and μ+μ− decay channels are used to measure the cross section as a function of the rapidity of the J/ψ in the range −2.5<y<2.7, corresponding to an energy in the γp centre-of-mass in the interval 40<Wγp<550 GeV. The measurements, which are consistent with a power law dependence of the exclusive J/ψ photoproduction cross section, are compared to previous results from HERA and the LHC and to several theoretical models. They are found to be compatible with previous measurements.
We present a new type of flow analysis, based on a particle-pair correlation function, in which there is no need for an event-by-event determination of the reaction plane. Consequently, the need to correct for dispersion in an estimated reaction plane does not arise. Our method also offers the option to avoid any influence from particle misidentification. Using this method, streamer chamber data for collisions of Ar+KCl and Ar+BaI2 at 1.2 GeV/nucleon are compared with predictions of a nuclear transport model.
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.
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.
Background: Misconceptions about ADHD stigmatize affected people, reduce credibility of providers, and prevent/delay treatment. To challenge misconceptions, we curated findings with strong evidence base. Methods: We reviewed studies with more than 2000 participants or meta-analyses from five or more studies or 2000 or more participants. We excluded meta-analyses that did not assess publication bias, except for meta-analyses of prevalence. For network meta-analyses we required comparison adjusted funnel plots. We excluded treatment studies with waiting-list or treatment as usual controls. From this literature, we extracted evidence-based assertions about the disorder. Results: We generated 208 empirically supported statements about ADHD. The status of the included statements as empirically supported is approved by 80 authors from 27 countries and 6 continents. The contents of the manuscript are endorsed by 366 people who have read this document and agree with its contents. Conclusions: Many findings in ADHD are supported by meta-analysis. These allow for firm statements about the nature, course, outcome causes, and treatments for disorders that are useful for reducing misconceptions and stigma.
Streamer chamber data for collisions of Ar + KCl and Ar + BaI2 at 1.2 GeV/nucleon are compared with microscopic model predictions based on the Vlasov-Uehling-Uhlenbeck equation, for various density-dependent nuclear equations of state. Multiplicity distributions and inclusive rapidity and transverse momentum spectra are in good agreement. Rapidity spectra show evidence of being useful in determining whether the model uses the correct cross sections for binary collisions in the nuclear medium, and whether momentum-dependent interactions are correctly incorporated. Sideward flow results do not favor the same nuclear stiffness parameter at all multiplicities.
In the past two decades, pions created in the high density regions of heavy ion collisions have been predicted to be sensitive at high densities to the symmetry energy term in the nuclear equation of state, a property that is key to our understanding of neutron stars. In a new experiment designed to study the symmetry energy, the multiplicities of negatively and positively charged pions have been measured with high accuracy for central 132Sn+124Sn, 112Sn+124Sn, and 108Sn+112Sn collisions at E/A = 270 MeV with the SπRIT Time Projection Chamber. While individual pion multiplicities are measured to 4% accuracy, those of the charged pion multiplicity ratios are measured to 2% accuracy. We compare these data to predictions from seven major transport models. The calculations reproduce qualitatively the dependence of the multiplicities and their ratios on the total neutron and proton number in the colliding systems. However, the predictions of the transport models from different codes differ too much to allow extraction of reliable constraints on the symmetry energy from the data. This finding may explain previous contradictory conclusions on symmetry energy constraints obtained from pion data in Au+Au system. These new results call for still better understanding of the differences among transport codes, and new observables that are more sensitive to the density dependence of the symmetry energy.
Background: Denosumab treatment for up to 8 years in the FREEDOM study and Extension was associated with low fracture incidence. It was not clear whether subjects who discontinued during the study conduct had a higher risk of fracture than those who remained enrolled, thereby underestimating the true fracture risk for the entire trial cohort. Thus, we explored the influence of early withdrawals on nonvertebral fracture incidence during the Extension study.
Methods: To understand the potential effect of depletion of susceptible subjects on fracture incidence, we first evaluated subject characteristics in patients who were enrolled in the Extension vs those who were not. We subsequently employed a Kaplan-Meier multiple imputation (KMMI) approach to consider subjects who discontinued as if they remained enrolled with a 0%, 20%, 50%, and 100% increase in fracture risk compared with participants remaining on study.
Results: Extension enrollees were generally similar to nonparticipants in median age (71.9 and 73.1 years, respectively), mean total hip bone mineral density T-score (–1.9 and –2.0, respectively), and probability of fracture risk by Fracture Risk Assessment Tool (FRAX®) at FREEDOM baseline (16.9% and 17.7% for major osteoporotic fracture and 6.7% and 7.4% for hip fracture, respectively). When we assumed a doubled fracture risk (100% increase) after discontinuation in KMMI analyses, nonvertebral fracture rate estimates were only marginally higher than the observed rates for both the crossover group (10.32% vs 9.16%, respectively) and the long-term group (7.63% vs 6.63%, respectively).
Conclusion: The observation of continued denosumab efficacy over 8 years of treatment was robust and does not seem to be explained by depletion of susceptible subjects.
Trial registration: ClincalTrials.gov registration number NCT00523341; registered August 30, 2007
New technologies and therapies designed to facilitate development of personalized treatments are rapidly emerging in the field of biomedicine. Strikingly, the goal of personalized medicine refined the concept of therapy by developing cell-based therapies, the so-called “living drugs”. Breakthrough advancements were achieved in this regard in the fields of gene therapy, cell therapy, tissue-engineered products and advanced therapeutic techniques. The Advanced Therapies in Healthcare symposium, organized by the Clinical Research Center Department of Sidra Medicine, in Doha, Qatar (October 2017), brought together world-renowned experts from the fields of oncology, hematology, immunology, inflammation, autoimmune disorders, and stem cells to offer a comprehensive picture of the status of worldwide advanced therapies in both pre-clinical and clinical development, providing insights to the research phase, clinical data and regulatory aspects of these therapies. Highlights of the meeting are provided in this meeting report.