New method for measuring azimuthal distributions in nucleus-nucleus collisions

The methods currently used to measure azimuthal distributions of particles in heavy ion collisions assume that all azimuthal correlations between particles result from their correlation with the reaction plane. However, other correlations exist, and it is safe to neglect them only if azimuthal anisotropies are much larger than 1/sqrt(N), with N the total number of particles emitted in the collision. This condition is not satisfied at ultrarelativistic energies. We propose a new method, based on a cumulant expansion of multiparticle azimuthal correlations, which allows to measure much smaller values of azimuthal anisotropies, down to 1/N. It is simple to implement and can be used to measure both integrated and differential flow. Furthermore, this method automatically eliminates the major systematic errors, which are due to azimuthal asymmetries in the detector acceptance.Comment: final version (misprints corrected), to be published in Phys.Rev.

Impact of CYP2C:TG Haplotype on CYP2C19 substrates clearance in vivo, protein content, and in vitro activity

A novel haplotype composed of two non-coding variants, CYP2C18 NM_000772.3:c.*31T (rs2860840) and NM_000772.2:c.819+2182G (rs11188059), referred to as “CYP2C:TG,” was recently associated with ultrarapid metabolism of various CYP2C19 substrates. As the underlying mechanism and clinical relevance of this effect remain uncertain, we analyzed existing in vivo and in vitro data to determine the magnitude of the CYP2C:TG haplotype effect. We assessed variability in pharmacokinetics of CYP2C19 substrates, including citalopram, sertraline, voriconazole, omeprazole, pantoprazole, and rabeprazole in 222 healthy volunteers receiving one of these six drugs. We also determined its impact on CYP2C8, CYP2C9, CYP2C18, and CYP2C19 protein abundance in 135 human liver tissue samples, and on CYP2C18/CYP2C19 activity in vitro using N-desmethyl atomoxetine formation. No effects were observed according to CYP2C:TG haplotype or to CYP2C19*1+TG alleles (i.e., CYP2C19 alleles containing the CYP2C:TG haplotype). In contrast, CYP2C19 intermediate (e.g., CYP2C19*1/*2) and poor metabolizers (e.g., CYP2C19*2/*2) showed significantly higher exposure in vivo, lower CYP2C19 protein abundance in human liver microsomes, and lower activity in vitro compared with normal, rapid (i.e., CYP2C19*1/*17), and ultrarapid metabolizers (i.e., CYP2C19*17/*17). Moreover, a tendency toward lower exposure was observed in ultrarapid metabolizers compared with rapid metabolizers and normal metabolizers. Furthermore, when the CYP2C19*17 allele was present, CYP2C18 protein abundance was increased suggesting that genetic variation in CYP2C19 may be relevant to the overall metabolism of certain drugs by regulating not only its expression levels, but also those of CYP2C18. Considering all available data, we conclude that there is insufficient evidence supporting clinical CYP2C:TG testing to inform drug therapyP.S.-C. is financed by Universidad Autónoma de Madrid (FPIUAM, 2021). P.Z. is financed by Universidad Autónoma de Madrid, Margarita Salas contract, grants for the requalification of the Spanish university system. A.R.-L. and E.G.-I. contracts are financed by Programa Investigo (NextGenerationEU funds of the Recovery and Resilience Facility), fellowship numbers 2022-C23.I01.P03. S0020–0000031 and 09-PIN1-00015.6/2022. Human liver tissue samples were obtained through the Liver Tissue Cell Distribution System, Minneapolis, MN, and Pittsburgh, PA, which was funded by NIH Contract #HHSN276201200017C. The proteomics part of the work was supported by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH) Grant R01.HD08129

Is the analysis of flow at the CERN SPS reliable?

Several heavy ion experiments at SPS have measured azimuthal distributions of particles with respect to the reaction plane. These distributions are deduced from two-particle azimuthal correlations under the assumption that they result solely from correlations with the reaction plane. In this paper, we investigate other sources of azimuthal correlations: transverse momentum conservation, which produces back-to-back correlations, resonance decays, HBT correlations and final state interactions. These correlations increase with impact parameter: most of them vary with the multiplicity N like 1/N. When they are taken into account, the experimental results of the NA49 collaboration at SPS are significantly modified. These correlations might also explain an important fraction of the pion directed flow observed by WA98. Data should be reanalyzed taking into account carefully these non--flow correlations.Comment: Revised version (minor corrections), 13 pages, LaTeX, 6 Postscript figures included. Submitted to Physical Review

Flow analysis from multiparticle azimuthal correlations

We present a new method for analyzing directed and elliptic flow in heavy ion collisions. Unlike standard methods, it separates the contribution of flow to azimuthal correlations from contributions due to other effects. The separation relies on a cumulant expansion of multiparticle azimuthal correlations, and includes corrections for detector inefficiencies. This new method allows the measurement of the flow of identified particles in narrow phase-space regions, and can be used in every regime, from intermediate to ultrarelativistic energies.Comment: 31 pages, revtex. Published version (references added

The logic of the floral transition: reverse-engineering the switch controlling the identity of lateral organs

Much laboratory work has been carried out to determine the gene regulatory network (GRN) that results in plant cells becoming flowers instead of leaves. However, this also involves the spatial distribution of different cell types, and poses the question of whether alternative networks could produce the same set of observed results. This issue has been addressed here through a survey of the published intercellular distribution of expressed regulatory genes and techniques both developed and applied to Boolean network models. This has uncovered a large number of models which are compatible with the currently available data. An exhaustive exploration had some success but proved to be unfeasible due to the massive number of alternative models, so genetic programming algorithms have also been employed. This approach allows exploration on the basis of both data-fitting criteria and parsimony of the regulatory processes, ruling out biologically unrealistic mechanisms. One of the conclusions is that, despite the multiplicity of acceptable models, an overall structure dominates, with differences mostly in alternative fine-grained regulatory interactions. The overall structure confirms the known interactions, including some that were not present in the training set, showing that current data are sufficient to determine the overall structure of the GRN. The model stresses the importance of relative spatial location, through explicit references to this aspect. This approach also provides a quantitative indication of how likely some regulatory interactions might be, and can be applied to the study of other developmental transitions

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

Low HIV incidence in pregnant and postpartum women receiving a community-based combination HIV prevention intervention in a high HIV incidence setting in South Africa

BACKGROUND: Young Southern African women have the highest HIV incidence globally. Pregnancy doubles the risk of HIV acquisition further, and maternal HIV acquisition contributes significantly to the paediatric HIV burden. Little data on combination HIV prevention interventions during pregnancy and lactation are available. We measured HIV incidence amongst pregnant and postpartum women receiving a community-based combination HIV prevention intervention in a high HIV incidence setting in South Africa. METHODS: A cohort study that included HIV-uninfected pregnant women was performed. Lay community- based workers provided individualized HIV prevention counselling and performed three-monthly home and clinic-based individual and couples HIV testing. Male partners were referred for circumcision, sexually transmitted infections or HIV treatment as appropriate. Kaplan-Meier analyses and Cox's regression were used to estimate HIV incidence and factors associated with HIV acquisition. RESULTS The 1356 women included (median age 22.5 years) received 5289 HIV tests. Eleven new HIV infections were detected over 828.3 person-years (PY) of follow-up, with an HIV incidence rate of 1.33 infections/100 PY (95% CI: 0.74±2.40). Antenatally, the HIV incidence rate was 1.49 infections/100 PY (95% CI: 0.64±2.93) and postnatally the HIV incidence rate was 1.03 infections/100 PY (95% CI: 0.33±3.19). 53% of male partners received HIV testing and 66% of eligible partners received referral for circumcision. Women within known serodiscordant couples, and women with newly diagnosed HIV-infected partners, adjusted hazard ratio (aHR) = 32.7 (95% CI: 3.8±282.2) and aHR = 126.4 (95% CI: 33.8±472.2) had substantially increased HIV acquisition, respectively. Women with circumcised partners had a reduced risk of incident HIV infection, aHR = 0.22 (95% CI: 0.03±1.86). CONCLUSIONS: Maternal HIV incidence was substantially lower than previous regional studies. Community-based combination HIV prevention interventions may reduce high maternal HIV incidence in resource-poor settings. Expanded roll-out of home-based couples HIV testing and initiating pre-exposure prophylaxis for pregnant women within serodiscordant couples is needed in Southern Africa