HSD3B1 genotype identifies glucocorticoid responsiveness in severe asthma

Asthma resistance to glucocorticoid treatment is a major health problem with unclear etiology. Glucocorticoids inhibit adrenal androgen production. However, androgens have potential benefits in asthma. HSD3B1 encodes for 3β-hydroxysteroid dehydrogenase-1 (3β-HSD1), which catalyzes peripheral conversion from adrenal dehydroepiandrosterone (DHEA) to potent androgens and has a germline missense-encoding polymorphism. The adrenal restrictive HSD3B1(1245A) allele limits conversion, whereas the adrenal permissive HSD3B1(1245C) allele increases DHEA metabolism to potent androgens. In the Severe Asthma Research Program (SARP) III cohort, we determined the association between DHEA-sulfate and percentage predicted forced expiratory volume in 1 s (FEV1PP). HSD3B1(1245) genotypes were assessed, and association between adrenal restrictive and adrenal permissive alleles and FEV1PP in patients with (GC) and without (noGC) daily oral glucocorticoid treatment was determined (n = 318). Validation was performed in a second cohort (SARP I&II; n = 184). DHEA-sulfate is associated with FEV1PP and is suppressed with GC treatment. GC patients homozygous for the adrenal restrictive genotype have lower FEV1PP compared with noGC patients (54.3% vs. 75.1%; P < 0.001). In patients with the homozygous adrenal permissive genotype, there was no FEV1PP difference in GC vs. noGC patients (73.4% vs. 78.9%; P = 0.39). Results were independently confirmed: FEV1PP for homozygous adrenal restrictive genotype in GC vs. noGC is 49.8 vs. 63.4 (P < 0.001), and for homozygous adrenal permissive genotype, it is 66.7 vs. 67.7 (P = 0.92). The adrenal restrictive HSD3B1(1245) genotype is associated with GC resistance. This effect appears to be driven by GC suppression of 3β-HSD1 substrate. Our results suggest opportunities for prediction of GC resistance and pharmacologic intervention

A Common Variant in MIR182 Is Associated With Primary Open-Angle Glaucoma in the NEIGHBORHOOD Consortium

PURPOSE. Noncoding microRNAs (miRNAs) have been implicated in the pathogenesis of glaucoma. We aimed to identify common variants in miRNA coding genes (MIR) associated with primary open-angle glaucoma (POAG). METHODS. Using the NEIGHBORHOOD data set (3853 cases/33,480 controls with European ancestry), we first assessed the relation between 85 variants in 76 MIR genes and overall POAG. Subtype-specific analyses were performed in high-tension glaucoma (HTG) and normal-tension glaucoma subsets. Second, we examined the expression of miR-182, which was associated with POAG, in postmortem human ocular tissues (ciliary body, cornea, retina, and trabecular meshwork [TM]), using miRNA sequencing (miRNA-Seq) and droplet digital PCR (ddPCR). Third, miR-182 expression was also examined in human aqueous humor (AH) by using miRNA-Seq. Fourth, exosomes secreted from primary human TM cells were examined for miR-182 expression by using miRNA-Seq. Fifth, using ddPCR we compared miR182 expression in AH between five HTG cases and five controls. RESULTS. Only rs76481776 in MIR182 gene was associated with POAG after adjustment for multiple comparisons (odds ratio [OR] ¼ 1.23, 95% confidence interval [CI]: 1.11–1.42, P ¼ 0.0002). Subtype analysis indicated that the association was primarily in the HTG subset (OR ¼ 1.26, 95% CI: 1.08–1.47, P ¼ 0.004). The risk allele T has been associated with elevated miR-182 expression in vitro. Data from ddPCR and miRNA-Seq confirmed miR-182 expression in all examined ocular tissues and TM-derived exosomes. Interestingly, miR-182 expression in AH was 2-fold higher in HTG patients than nonglaucoma controls (P ¼ 0.03) without controlling for medication treatment. CONCLUSIONS. Our integrative study is the first to associate rs76481776 with POAG via elevated miR-182 expression

A Common Variant in MIR182 Is Associated With Primary Open-Angle Glaucoma in the NEIGHBORHOOD Consortium

PURPOSE. Noncoding microRNAs (miRNAs) have been implicated in the pathogenesis of glaucoma. We aimed to identify common variants in miRNA coding genes (MIR) associated with primary open-angle glaucoma (POAG). METHODS. Using the NEIGHBORHOOD data set (3853 cases/33,480 controls with European ancestry), we first assessed the relation between 85 variants in 76 MIR genes and overall POAG. Subtype-specific analyses were performed in high-tension glaucoma (HTG) and normal-tension glaucoma subsets. Second, we examined the expression of miR-182, which was associated with POAG, in postmortem human ocular tissues (ciliary body, cornea, retina, and trabecular meshwork [TM]), using miRNA sequencing (miRNA-Seq) and droplet digital PCR (ddPCR). Third, miR-182 expression was also examined in human aqueous humor (AH) by using miRNA-Seq. Fourth, exosomes secreted from primary human TM cells were examined for miR-182 expression by using miRNA-Seq. Fifth, using ddPCR we compared miR182 expression in AH between five HTG cases and five controls. RESULTS. Only rs76481776 in MIR182 gene was associated with POAG after adjustment for multiple comparisons (odds ratio [OR] ¼ 1.23, 95% confidence interval [CI]: 1.11–1.42, P ¼ 0.0002). Subtype analysis indicated that the association was primarily in the HTG subset (OR ¼ 1.26, 95% CI: 1.08–1.47, P ¼ 0.004). The risk allele T has been associated with elevated miR-182 expression in vitro. Data from ddPCR and miRNA-Seq confirmed miR-182 expression in all examined ocular tissues and TM-derived exosomes. Interestingly, miR-182 expression in AH was 2-fold higher in HTG patients than nonglaucoma controls (P ¼ 0.03) without controlling for medication treatment. CONCLUSIONS. Our integrative study is the first to associate rs76481776 with POAG via elevated miR-182 expression

Observation of charge-dependent azimuthal correlations and possible local strong parity violation in heavy ion collisions

Parity-odd domains, corresponding to non-trivial topological solutions of the QCD vacuum, might be created during relativistic heavy-ion collisions. These domains are predicted to lead to charge separation of quarks along the orbital momentum of the system created in non-central collisions. To study this effect, we investigate a three particle mixed harmonics azimuthal correlator which is a \P-even observable, but directly sensitive to the charge separation effect. We report measurements of this observable using the STAR detector in Au+Au and Cu+Cu collisions at $\sqrt{s_{NN}}$=200 and 62~GeV. The results are presented as a function of collision centrality, particle separation in rapidity, and particle transverse momentum. A signal consistent with several of the theoretical expectations is detected in all four data sets. We compare our results to the predictions of existing event generators, and discuss in detail possible contributions from other effects that are not related to parity violation.Comment: 17 pages, 14 figures, as accepted for publication in Physical Review C

Charged and strange hadron elliptic flow in Cu+Cu collisions at sNN\sqrt{s_{NN}} = 62.4 and 200 GeV

We present the results of an elliptic flow analysis of Cu+Cu collisions recorded with the STAR detector at 62.4 and 200GeV. Elliptic flow as a function of transverse momentum is reported for different collision centralities for charged hadrons and strangeness containing hadrons $K_{S}^{0}$, $\Lambda$, $\Xi$, $\phi$ in the midrapidity region $|eta|<1.0$. Significant reduction in systematic uncertainty of the measurement due to non-flow effects has been achieved by correlating particles at midrapidity, $|\eta|<1.0$, with those at forward rapidity, $2.5<|\eta|<4.0$. We also present azimuthal correlations in p+p collisions at 200 GeV to help estimating non-flow effects. To study the system-size dependence of elliptic flow, we present a detailed comparison with previously published results from Au+Au collisions at 200 GeV. We observe that $v_{2}$($p_{T}$) of strange hadrons has similar scaling properties as were first observed in Au+Au collisions, i.e.: (i) at low transverse momenta, $p_T<2GeV/c$, $v_{2}$ scales with transverse kinetic energy, $m_{T}-m$, and (ii) at intermediate $p_T$, $2<p_T<4GeV/c$, it scales with the number of constituent quarks, $n_q$. We have found that ideal hydrodynamic calculations fail to reproduce the centrality dependence of $v_{2}$($p_{T}$) for $K_{S}^{0}$ and $\Lambda$. Eccentricity scaled $v_2$ values, $v_{2}/\epsilon$, are larger in more central collisions, suggesting stronger collective flow develops in more central collisions. The comparison with Au+Au collisions which go further in density shows $v_{2}/\epsilon$ depend on the system size, number of participants $N_{part}$. This indicates that the ideal hydrodynamic limit is not reached in Cu+Cu collisions, presumably because the assumption of thermalization is not attained.Comment: 18 pages, 14 figure

Studying Parton Energy Loss in Heavy-Ion Collisions via Direct-Photon and Charged-Particle Azimuthal Correlations

Charged-particle spectra associated with direct photon ($\gamma_{dir}$) and $\pi^0$ are measured in $p$+$p$ and Au+Au collisions at center-of-mass energy $\sqrt{s_{_{NN}}}=200$ GeV with the STAR detector at RHIC. A hower-shape analysis is used to partially discriminate between $\gamma_{dir}$ and $\pi^0$. Assuming no associated charged particles in the $\gamma_{dir}$ direction (near side) and small contribution from fragmentation photons ($\gamma_{frag}$), the associated charged-particle yields opposite to $\gamma_{dir}$ (away side) are extracted. At mid-rapidity ($|\eta|<0.9$) in central Au+Au collisions, charged-particle yields associated with $\gamma_{dir}$ and $\pi^0$ at high transverse momentum ($8< p_{T}^{trig}<16$ GeV/$c$) are suppressed by a factor of 3-5 compared with $p$ + $p$ collisions. The observed suppression of the associated charged particles, in the kinematic range $|\eta|<1$ and $3< p_{T}^{assoc} < 16$ GeV/$c$, is similar for $\gamma_{dir}$ and $\pi^0$, and independent of the $\gamma_{dir}$ energy within uncertainties. These measurements indicate that the parton energy loss, in the covered kinematic range, is insensitive to the parton path length.Comment: submitted to Phys. Rev. Lett, 6 pages, 4 figure

Identified high-pTp_{T} spectra in Cu+Cu collisions at sNN\sqrt{s_{NN}}=200 GeV

We report new results on identified (anti)proton and charged pion spectra at large transverse momenta (3<$p_{T}$<10 GeV/c) from Cu+Cu collisions at $\sqrt{s_{NN}}$=200 GeV using the STAR detector at the Relativistic Heavy Ion Collider (RHIC). This study explores the system size dependence of two novel features observed at RHIC with heavy ions: the hadron suppression at high-$p_{T}$ and the anomalous baryon to meson enhancement at intermediate transverse momenta. Both phenomena could be attributed to the creation of a new form of QCD matter. The results presented here bridge the system size gap between the available pp and Au+Au data, and allow the detailed exploration for the on-set of the novel features. Comparative analysis of all available 200 GeV data indicates that the system size is a major factor determining both the magnitude of the hadron spectra suppression at large transverse momenta and the relative baryon to meson enhancement.Comment: Submitted to Phys. Rev. C, 9 pages, 5 figure

Measurements of ϕ\phi meson production in relativistic heavy-ion collisions at RHIC

We present results for the measurement of $\phi$ meson production via its charged kaon decay channel $\phi \to K^+K^-$ in Au+Au collisions at $\sqrt{s_{_{NN}}}=62.4$, 130, and 200 GeV, and in $p+p$ and $d$+Au collisions at $\sqrt{s_{_{NN}}}=200$ GeV from the STAR experiment at the BNL Relativistic Heavy Ion Collider (RHIC). The midrapidity ($|y|<0.5$) $\phi$ meson transverse momentum ($p_{T}$) spectra in central Au+Au collisions are found to be well described by a single exponential distribution. On the other hand, the $p_{T}$ spectra from $p+p$, $d$+Au and peripheral Au+Au collisions show power-law tails at intermediate and high $p_{T}$ and are described better by Levy distributions. The constant $\phi/K^-$ yield ratio vs beam species, collision centrality and colliding energy is in contradiction with expectations from models having kaon coalescence as the dominant mechanism for $\phi$ production at RHIC. The $\Omega/\phi$ yield ratio as a function of $p_{T}$ is consistent with a model based on the recombination of thermal $s$ quarks up to $p_{T}\sim 4$ GeV/$c$, but disagrees at higher transverse momenta. The measured nuclear modification factor, $R_{dAu}$, for the $\phi$ meson increases above unity at intermediate $p_{T}$, similar to that for pions and protons, while $R_{AA}$ is suppressed due to the energy loss effect in central Au+Au collisions. Number of constituent quark scaling of both $R_{cp}$ and $v_{2}$ for the $\phi$ meson with respect to other hadrons in Au+Au collisions at $\sqrt{s_{_{NN}}}$=200 GeV at intermediate $p_{T}$ is observed. These observations support quark coalescence as being the dominant mechanism of hadronization in the intermediate $p_{T}$ region at RHIC.Comment: 22 pages, 21 figures, 4 table

Hadronic resonance production in dd+Au collisions at sNN\sqrt{s_{_{NN}}} = 200 GeV at RHIC

We present the first measurements of the $\rho(770)^0$, $K^*$(892), $\Delta$(1232)$^{++}$, $\Sigma$(1385), and $\Lambda$(1520) resonances in $d$+Au collisions at $\sqrt{s_{_{NN}}}$ = 200 GeV, reconstructed via their hadronic decay channels using the STAR detector at RHIC. The masses and widths of these resonances are studied as a function of transverse momentum ($p_T$). We observe that the resonance spectra follow a generalized scaling law with the transverse mass ($m_T$). The $$of resonances in minimum bias collisions is compared to the$$ of $\pi$, $K$, and $\bar{p}$. The $\rho^0/\pi^-$, $K^*/K^-$, $\Delta^{++}/p$, $\Sigma(1385)/\Lambda$, and $\Lambda(1520)/\Lambda$ ratios in $d$+Au collisions are compared to the measurements in minimum bias $p+p$ interactions, where we observe that both measurements are comparable. The nuclear modification factors ($R_{dAu}$) of the $\rho^0$, $K^*$, and $\Sigma^*$ scale with the number of binary collisions ($N_{bin}$) for $p_T >$ 1.2 GeV/$c$.Comment: STAR Collaboration. Submitted to PR

Enhanced strange baryon production in Au+Au collisions compared to p+p at sqrts = 200 GeV

We report on the observed differences in production rates of strange and multi-strange baryons in Au+Au collisions at sqrts = 200 GeV compared to pp interactions at the same energy. The strange baryon yields in Au+Au collisions, then scaled down by the number of participating nucleons, are enhanced relative to those measured in pp reactions. The enhancement observed increases with the strangeness content of the baryon, and increases for all strange baryons with collision centrality. The enhancement is qualitatively similar to that observed at lower collision energy sqrts =17.3 GeV. The previous observations are for the bulk production, while at intermediate pT, 1 < pT< 4 GeV/c, the strange baryons even exceed binary scaling from pp yields.Comment: 7 pages, 4 figures. Printed in PR