Transcriptome Pathway Analysis of Pathological and Physiological Aldosterone-Producing Human Tissues.

Primary aldosteronism is present in ≈10% of hypertensives. We previously performed a microarray assay on aldosterone-producing adenomas and their paired zona glomerulosa and fasciculata. Confirmation of top genes validated the study design and functional experiments of zona glomerulosa selective genes established the role of the encoded proteins in aldosterone regulation. In this study, we further analyzed our microarray data using AmiGO 2 for gene ontology enrichment and Ingenuity Pathway Analysis to identify potential biological processes and canonical pathways involved in pathological and physiological aldosterone regulation. Genes differentially regulated in aldosterone-producing adenoma and zona glomerulosa were associated with steroid metabolic processes gene ontology terms. Terms related to the Wnt signaling pathway were enriched in zona glomerulosa only. Ingenuity Pathway Analysis showed "NRF2-mediated oxidative stress response pathway" and "LPS (lipopolysaccharide)/IL-1 (interleukin-1)-mediated inhibition of RXR (retinoid X receptor) function" were affected in both aldosterone-producing adenoma and zona glomerulosa with associated genes having up to 21- and 8-fold differences, respectively. Comparing KCNJ5-mutant aldosterone-producing adenoma, zona glomerulosa, and zona fasciculata samples with wild-type samples, 138, 56, and 59 genes were differentially expressed, respectively (fold-change >2; P<0.05). ACSS3, encoding the enzyme that synthesizes acetyl-CoA, was the top gene upregulated in KCNJ5-mutant aldosterone-producing adenoma compared with wild-type. NEFM, a gene highly upregulated in zona glomerulosa, was upregulated in KCNJ5 wild-type aldosterone-producing adenomas. NR4A2, the transcription factor for aldosterone synthase, was highly expressed in zona fasciculata adjacent to a KCNJ5-mutant aldosterone-producing adenoma. Further interrogation of these genes and pathways could potentially provide further insights into the pathology of primary aldosteronism

DACH1, a zona glomerulosa selective gene in the human adrenal, activates transforming growth factor-β signaling and suppresses aldosterone secretion.

Common somatic mutations in CACNAID and ATP1A1 may define a subgroup of smaller, zona glomerulosa (ZG)-like aldosterone-producing adenomas. We have therefore sought signature ZG genes, which may provide insight into the frequency and pathogenesis of ZG-like aldosterone-producing adenomas. Twenty-one pairs of zona fasciculata and ZG and 14 paired aldosterone-producing adenomas from 14 patients with Conn's syndrome and 7 patients with pheochromocytoma were assayed by the Affymetrix Human Genome U133 Plus 2.0 Array. Validation by quantitative real-time polymerase chain reaction was performed on genes >10-fold upregulated in ZG (compared with zona fasciculata) and >10-fold upregulated in aldosterone-producing adenomas (compared with ZG). DACH1, a gene associated with tumor progression, was further analyzed. The role of DACH1 on steroidogenesis, transforming growth factor-β, and Wnt signaling activity was assessed in the human adrenocortical cell line, H295R. Immunohistochemistry confirmed selective expression of DACH1 in human ZG. Silencing of DACH1 in H295R cells increased CYP11B2 mRNA levels and aldosterone production, whereas overexpression of DACH1 decreased aldosterone production. Overexpression of DACH1 in H295R cells activated the transforming growth factor-β and canonical Wnt signaling pathways but inhibited the noncanonical Wnt signaling pathway. Stimulation of primary human adrenal cells with angiotensin II decreased DACH1 mRNA expression. Interestingly, there was little overlap between our top ZG genes and those in rodent ZG. In conclusion, (1) the transcriptome profile of human ZG differs from rodent ZG, (2) DACH1 inhibits aldosterone secretion in human adrenals, and (3) transforming growth factor-β signaling pathway is activated in DACH1 overexpressed cells and may mediate inhibition of aldosterone secretion in human adrenals.The work was funded by a National Institute for Health Research (NIHR) Senior Investigator Award (NF-SI-0512-10052) to M.J. Brown, the Wellcome Trust (085687/Z/08/A), and the NIHR Cambridge Biomedical Research Centre (Cardiovascular). J. Zhou and E.A.B. Azizan were supported by The Cambridge Commonwealth, European & International Trust. J. Zhou was also supported by the Sun Hung Kai Properties–Kwoks’ Foundation.This is the final version of the article. It first appeared from the American Heart Association via http://dx.doi.org/10.1161/HYP.000000000000002

A Genome-Wide Metabolic QTL Analysis in Europeans Implicates Two Loci Shaped by Recent Positive Selection

We have performed a metabolite quantitative trait locus (mQTL) study of the 1H nuclear magnetic resonance spectroscopy (1H NMR) metabolome in humans, building on recent targeted knowledge of genetic drivers of metabolic regulation. Urine and plasma samples were collected from two cohorts of individuals of European descent, with one cohort comprised of female twins donating samples longitudinally. Sample metabolite concentrations were quantified by 1H NMR and tested for association with genome-wide single-nucleotide polymorphisms (SNPs). Four metabolites' concentrations exhibited significant, replicable association with SNP variation (8.6×10−11<p<2.8×10−23). Three of these—trimethylamine, 3-amino-isobutyrate, and an N-acetylated compound—were measured in urine. The other—dimethylamine—was measured in plasma. Trimethylamine and dimethylamine mapped to a single genetic region (hence we report a total of three implicated genomic regions). Two of the three hit regions lie within haplotype blocks (at 2p13.1 and 10q24.2) that carry the genetic signature of strong, recent, positive selection in European populations. Genes NAT8 and PYROXD2, both with relatively uncharacterized functional roles, are good candidates for mediating the corresponding mQTL associations. The study's longitudinal twin design allowed detailed variance-components analysis of the sources of population variation in metabolite levels. The mQTLs explained 40%–64% of biological population variation in the corresponding metabolites' concentrations. These effect sizes are stronger than those reported in a recent, targeted mQTL study of metabolites in serum using the targeted-metabolomics Biocrates platform. By re-analysing our plasma samples using the Biocrates platform, we replicated the mQTL findings of the previous study and discovered a previously uncharacterized yet substantial familial component of variation in metabolite levels in addition to the heritability contribution from the corresponding mQTL effects

A Genome-Wide Metabolic QTL Analysis in Europeans Implicates Two Loci Shaped by Recent Positive Selection

We have performed a metabolite quantitative trait locus (mQTL) study of the 1H nuclear magnetic resonance spectroscopy (1H NMR) metabolome in humans, building on recent targeted knowledge of genetic drivers of metabolic regulation. Urine and plasma samples were collected from two cohorts of individuals of European descent, with one cohort comprised of female twins donating samples longitudinally. Sample metabolite concentrations were quantified by 1H NMR and tested for association with genome-wide single-nucleotide polymorphisms (SNPs). Four metabolites' concentrations exhibited significant, replicable association with SNP variation (8.6×10−11<p<2.8×10−23). Three of these—trimethylamine, 3-amino-isobutyrate, and an N-acetylated compound—were measured in urine. The other—dimethylamine—was measured in plasma. Trimethylamine and dimethylamine mapped to a single genetic region (hence we report a total of three implicated genomic regions). Two of the three hit regions lie within haplotype blocks (at 2p13.1 and 10q24.2) that carry the genetic signature of strong, recent, positive selection in European populations. Genes NAT8 and PYROXD2, both with relatively uncharacterized functional roles, are good candidates for mediating the corresponding mQTL associations. The study's longitudinal twin design allowed detailed variance-components analysis of the sources of population variation in metabolite levels. The mQTLs explained 40%–64% of biological population variation in the corresponding metabolites' concentrations. These effect sizes are stronger than those reported in a recent, targeted mQTL study of metabolites in serum using the targeted-metabolomics Biocrates platform. By re-analysing our plasma samples using the Biocrates platform, we replicated the mQTL findings of the previous study and discovered a previously uncharacterized yet substantial familial component of variation in metabolite levels in addition to the heritability contribution from the corresponding mQTL effects

Two-particle Bose-Einstein correlations and their Lévy parameters in PbPb collisions at sNN\sqrt{s_\mathrm{NN}} = 5.02 TeV

Two-particle Bose-Einstein momentum correlation functions are studied for charged-hadron pairs in lead-lead collisions at a center-of-mass energy per nucleon pair of $\sqrt{s_\mathrm{NN}}$ = 5.02 TeV. The data sample, containing 4.27$\times10^{9}$ minimum bias events corresponding to an integrated luminosity of 0.607 nb$^{-1}$, was collected by the CMS experiment in 2018. The experimental results are discussed in terms of a L\'evy-type source distribution. The parameters of this distribution are extracted as functions of particle pair average transverse mass and collision centrality. These parameters include the L\'evy index or shape parameter ($\alpha$), the L\'evy scale parameter ($R$), and the correlation strength parameter ($\lambda$). The source shape, characterized by $\alpha$, is found to be neither Cauchy nor Gaussian, implying the need for a full L\'evy analysis. Similarly to what was previously found for systems characterized by Gaussian source radii, a hydrodynamical scaling is observed for the L\'evy $R$ parameter. The $\lambda$ parameter is studied in terms of the core-halo model.Comment: Submitted to Physical Review C. All figures and tables can be found at http://cms-results.web.cern.ch/cms-results/public-results/publications/HIN-21-011 (CMS Public Pages

Search for top squark pair production in a final state with at least one hadronically decaying tau lepton in proton-proton collisions at s \sqrt{s} = 13 TeV

A search for pair production of the supersymmetric partner of the top quark, the top squark, in proton-proton collisions at $\sqrt{s}$ = 13 TeV is presented in final states containing at least one hadronically decaying tau lepton and large missing transverse momentum. This final state is highly sensitive to scenarios of supersymmetry in which the decay of the top squark to tau leptons is enhanced. The search uses a data sample corresponding to an integrated luminosity of 138 fb$^{−1}$, which was recorded with the CMS detector during 2016–2018. No significant excess is observed with respect to the standard model predictions. Exclusion limits at 95% confidence level on the masses of the top squark and the lightest neutralino are presented under the assumptions of simplified models. The results probe top squark masses up to 1150 GeV for a nearly massless neutralino. This search covers a relatively less explored parameter space in the context of supersymmetry, and the exclusion limit is the most stringent to date for the model considered here.[graphic not available: see fulltext

Measurement of the cross section of top quark-antiquark pair production in association with a W boson in proton-proton collisions at s \sqrt{s} = 13 TeV

The production of a top quark-antiquark pair in association with a W boson ($\textrm{t}\overline{\textrm{t}}\textrm{W}$) is measured in proton-proton collisions at a center-of-mass energy of 13 TeV. The analyzed data was recorded by the CMS experiment at the CERN LHC and corresponds to an integrated luminosity of 138 fb$^{−1}$. Events with two or three leptons (electrons and muons) and additional jets are selected. In events with two leptons, a multiclass neural network is used to distinguish between the signal and background processes. Events with three leptons are categorized based on the number of jets and of jets originating from b quark hadronization, and the lepton charges. The inclusive $\textrm{t}\overline{\textrm{t}}\textrm{W}$ production cross section in the full phase space is measured to be 868 ± 40(stat) ± 51(syst) fb. The $\textrm{t}\overline{\textrm{t}}\textrm{W} ^{+}$ and $\textrm{t}\overline{\textrm{t}}\textrm{W} ^{−}$ cross sections are also measured as 553 ± 30(stat) ± 30(syst) and 343 ± 26(stat) ± 25(syst) fb, respectively, and the corresponding ratio of the two cross sections is found to be $1.61\pm 0.15{\left(\textrm{stat}\right)}_{-0.05}^{+0.07}\left(\textrm{syst}\right)$. The measured cross sections are larger than but consistent with the standard model predictions within two standard deviations, and represent the most precise measurement of these cross sections to date.[graphic not available: see fulltext

Search for a new resonance decaying into two spin-0 bosons in a final state with two photons and two bottom quarks in proton-proton collisions at s\sqrt{s} = 13 TeV

International audienceA search for a new boson X is presented using CERN LHC proton-proton collision data collected by the CMS experiment at $\sqrt{s}$ = 13 TeV in 2016-2018, and corresponding to an integrated luminosity of 138 fb$^{-1}$. The resonance X decays into either a pair of Higgs bosons HH of mass 125 GeV or an H and a new spin-0 boson Y. One H subsequently decays to a pair of photons, and the second H or Y, to a pair of bottom quarks. The explored mass ranges of X are 260-1000 GeV and 300-1000 GeV, for decays to HH and to HY, respectively, with the Y mass range being 90-800 GeV. For a spin-0 X hypothesis, the 95% confidence level upper limit on the product of its production cross section and decay branching fraction is observed to be within 0.90-0.04 fb, depending on the masses of X and Y. The largest deviation from the background-only hypothesis with a local (global) significance of 3.8 (2.8) standard deviations is observed for X and Y masses of 650 and 90 GeV, respectively. The limits are interpreted using several models of new physics

Search for central exclusive production of top quark pairs in proton-proton collisions at s\sqrt{s} = 13 TeV with tagged protons

International audienceA search for the central exclusive production of top quark-antiquark pairs ($\mathrm{t\bar{t}}$) is performed for the first time using proton-tagged events in proton-proton collisions at the LHC at a centre-of-mass energy of 13 TeV. The data correspond to an integrated luminosity of 29.4 fb$^{-1}$. The $\mathrm{t\bar{t}}$ decay products are reconstructed using the central CMS detector, while forward protons are measured in the CMS-TOTEM precision proton spectrometer. An observed (expected) upper bound on the production cross section of 0.59 (1.14) pb is set at 95% confidence level, for collisions of protons with fractional momentum losses between 2 and 20%

Measurement of the primary Lund jet plane density in proton-proton collisions at s\sqrt{s} = 13 TeV

International audienceA measurement is presented of the primary Lund jet plane (LJP) density in inclusive jet production in proton-proton collisions. The analysis uses 138 fb$^{-1}$ of data collected by the CMS experiment at $\sqrt{s}$ = 13 TeV. The LJP, a representation of the phase space of emissions inside jets, is constructed using iterative jet declustering. The transverse momentum $k_\mathrm{T}$ and the splitting angle $\Delta R$ of an emission relative to its emitter are measured at each step of the jet declustering process. The average density of emissions as function of $\ln(k_\mathrm{T}$/GeV) and $\ln(R/\Delta R)$ is measured for jets with distance parameters $R$ = 0.4 or 0.8, transverse momentum $p_\mathrm{T} \gt$ 700 GeV, and rapidity $\vert y\vert \lt$ 1.7. The jet substructure is measured using the charged-particle tracks of the jet. The measured distributions, unfolded to the level of stable particles, are compared with theoretical predictions from simulations and with perturbative quantum chromodynamics calculations. Due to the ability of the LJP to factorize physical effects, these measurements can be used to improve different aspects of the physics modeling in event generators