The molecular basis of beta-thalassemia intermedia in southern China: genotypic heterogeneity and phenotypic diversity

<p>Abstract</p> <p>Background</p> <p>The clinical syndrome of thalassemia intermedia (TI) results from the β-globin genotypes in combination with factors to produce fetal haemoglobin (HbF) and/or co-inheritance of α-thalassemia. However, very little is currently known of the molecular basis of Chinese TI patients.</p> <p>Methods</p> <p>We systematically analyzed and characterized β-globin genotypes, α-thalassemia determinants, and known primary genetic modifiers linked to the production of HbF and the aggravation of α/β imbalance in 117 Chinese TI patients. Genotype-phenotype correlations were analyzed based on retrospective clinical observations.</p> <p>Results</p> <p>A total of 117 TI patients were divided into two major groups, namely heterozygous β-thalassemia (n = 20) in which 14 were characterized as having a mild TI with the Hb levels of 68-95 g/L except for five co-inherited ααα^anti-3.7triplication and one carried a dominant mutation; and β-thalassemia homozygotes or compound heterozygotes for β-thalassemia and other β-globin defects in which the β⁺-thalassemia mutation was the most common (49/97), hemoglobin E (HbE) variants was second (27/97), and deletional hereditary persistence of fetal hemoglobin (HPFH) or δβ-thalassemia was third (11/97). Two novel mutations, Term CD+32(A→C) and Cap+39(C→T), have been detected.</p> <p>Conclusions</p> <p>Chinese TI patients showed considerable heterogeneity, both phenotypically and genotypically. The clinical outcomes of our TI patients were mostly explained by the genotypes linked to the β- and α-globin gene cluster. However, for a group of 14 patients (13 β⁰/β^Nand 1 β⁺/β^N) with known heterozygous mutations of β-thalassemia and three with homozygous β-thalassemia (β⁰/β⁰), the existence of other causative genetic determinants is remaining to be molecularly defined.</p

Studies of di-jet survival and surface emission bias in Au+Au collisions via angular correlations with respect to back-to-back leading hadrons

We report first results from an analysis based on a new multi-hadron correlation technique, exploring jet-medium interactions and di-jet surface emission bias at RHIC. Pairs of back-to-back high transverse momentum hadrons are used for triggers to study associated hadron distributions. In contrast with two- and three-particle correlations with a single trigger with similar kinematic selections, the associated hadron distribution of both trigger sides reveals no modification in either relative pseudo-rapidity or relative azimuthal angle from d+Au to central Au+Au collisions. We determine associated hadron yields and spectra as well as production rates for such correlated back-to-back triggers to gain additional insights on medium properties.Comment: By the STAR Collaboration. 6 pages, 2 figure

System size and energy dependence of near-side di-hadron correlations

Two-particle azimuthal ($\Delta\phi$) and pseudorapidity ($\Delta\eta$) correlations using a trigger particle with large transverse momentum ($p_T$) in $d$+Au, Cu+Cu and Au+Au collisions at $\sqrt{s_{{NN}}}$ =\xspace 62.4 GeV and 200~GeV from the STAR experiment at RHIC are presented. The \ns correlation is separated into a jet-like component, narrow in both $\Delta\phi$ and $\Delta\eta$, and the ridge, narrow in $\Delta\phi$ but broad in $\Delta\eta$. Both components are studied as a function of collision centrality, and the jet-like correlation is studied as a function of the trigger and associated $p_T$. The behavior of the jet-like component is remarkably consistent for different collision systems, suggesting it is produced by fragmentation. The width of the jet-like correlation is found to increase with the system size. The ridge, previously observed in Au+Au collisions at $\sqrt{s_{{NN}}}$ = 200 GeV, is also found in Cu+Cu collisions and in collisions at $\sqrt{s_{{NN}}}$ =\xspace 62.4 GeV, but is found to be substantially smaller at $\sqrt{s_{{NN}}}$ =\xspace 62.4 GeV than at $\sqrt{s_{{NN}}}$ = 200 GeV for the same average number of participants ($\langle N_{\mathrm{part}}\rangle$). Measurements of the ridge are compared to models.Comment: 17 pages, 14 figures, submitted to Phys. Rev.

Measurements of Dihadron Correlations Relative to the Event Plane in Au+Au Collisions at sNN=200\sqrt{s_{NN}}=200 GeV

Dihadron azimuthal correlations containing a high transverse momentum (\pt) trigger particle are sensitive to the properties of the nuclear medium created at RHIC through the strong interactions occurring between the traversing parton and the medium, i.e. jet-quenching. Previous measurements revealed a strong modification to dihadron azimuthal correlations in Au+Au collisions with respect to \pp\ and \dAu\ collisions. The modification increases with the collision centrality, suggesting a path-length dependence to the jet-quenching effect. This paper reports STAR measurements of dihadron azimuthal correlations in mid-central (20-60\%) Au+Au collisions at \snn=200~GeV as a function of the trigger particle's azimuthal angle relative to the event plane, \phis=|\phit-\psiEP|. The azimuthal correlation is studied as a function of both the trigger and associated particle \pt. The subtractions of the combinatorial background and anisotropic flow, assuming Zero Yield At Minimum (\zyam), are described. The away-side correlation is strongly modified, and the modification varies with \phis, which is expected to be related to the path-length that the away-side parton traverses. The pseudo-rapidity (\deta) dependence of the near-side correlation, sensitive to long range \deta correlations (the ridge), is also investigated. The ridge and jet-like components of the near-side correlation are studied as a function of \phis. The ridge appears to drop with increasing \phis while the jet-like component remains approximately constant. ...Comment: 50 pages, 39 figures, 6 table

Observation of the antimatter helium-4 nucleus

High-energy nuclear collisions create an energy density similar to that of the universe microseconds after the Big Bang, and in both cases, matter and antimatter are formed with comparable abundance. However, the relatively short-lived expansion in nuclear collisions allows antimatter to decouple quickly from matter, and avoid annihilation. Thus, a high energy accelerator of heavy nuclei is an efficient means of producing and studying antimatter. The antimatter helium-4 nucleus ($^4\bar{He}$), also known as the anti-{\alpha} ($\bar{\alpha}$), consists of two antiprotons and two antineutrons (baryon number B=-4). It has not been observed previously, although the {\alpha} particle was identified a century ago by Rutherford and is present in cosmic radiation at the 10% level. Antimatter nuclei with B < -1 have been observed only as rare products of interactions at particle accelerators, where the rate of antinucleus production in high-energy collisions decreases by about 1000 with each additional antinucleon. We present the observation of the antimatter helium-4 nucleus, the heaviest observed antinucleus. In total 18 $^4\bar{He}$ counts were detected at the STAR experiment at RHIC in 10$^9$ recorded Au+Au collisions at center-of-mass energies of 200 GeV and 62 GeV per nucleon-nucleon pair. The yield is consistent with expectations from thermodynamic and coalescent nucleosynthesis models, which has implications beyond nuclear physics.Comment: 19 pages, 4 figures. Submitted to Nature. Under media embarg

Measurements of D0D^{0} and D∗D^{*} Production in pp + pp Collisions at s\sqrt{s} = 200 GeV

We report measurements of charmed-hadron ($D^{0}$, $D^{*}$) production cross sections at mid-rapidity in $p$ + $p$ collisions at a center-of-mass energy of 200 GeV by the STAR experiment. Charmed hadrons were reconstructed via the hadronic decays $D^{0}\rightarrow K^{-}\pi^{+}$, $D^{*+}\rightarrow D^{0}\pi^{+}\rightarrow K^{-}\pi^{+}\pi^{+}$ and their charge conjugates, covering the $p_T$ range of 0.6$-$2.0 GeV/$c$ and 2.0$-$6.0 GeV/$c$ for $D^{0}$ and $D^{*+}$, respectively. From this analysis, the charm-pair production cross section at mid-rapidity is $d\sigma/dy|_{y=0}^{c\bar{c}}$ = 170 $\pm$ 45 (stat.) $^{+38}_{-59}$ (sys.) $\mu$b. The extracted charm-pair cross section is compared to perturbative QCD calculations. The transverse momentum differential cross section is found to be consistent with the upper bound of a Fixed-Order Next-to-Leading Logarithm calculation.Comment: 15 pages, 16 figures. Revised version submitted to Phys. Rev.

Identified hadron compositions in p+p and Au+Au collisions at high transverse momenta at sNN=200\sqrt{s_{_{NN}}} = 200 GeV

We report transverse momentum ($p_{T} \leq15$ GeV/$c$) spectra of $\pi^{\pm}$, $K^{\pm}$, $p$, $\bar{p}$, $K_{S}^{0}$, and $\rho^{0}$ at mid-rapidity in p+p and Au+Au collisions at $\sqrt{s_{_{NN}}}$ = 200 GeV. Perturbative QCD calculations are consistent with $\pi^{\pm}$ spectra in p+p collisions but do not reproduce $K$ and $p(\bar{p})$ spectra. The observed decreasing antiparticle-to-particle ratios with increasing $p_T$ provide experimental evidence for varying quark and gluon jet contributions to high-$p_T$ hadron yields. The relative hadron abundances in Au+Au at $p_{T}{}^{>}_{\sim}8$ GeV/$c$ are measured to be similar to the p+p results, despite the expected Casimir effect for parton energy loss.Comment: 6 pages, 3 figures, published at PR

An Experimental Exploration of the QCD Phase Diagram: The Search for the Critical Point and the Onset of De-confinement

The QCD phase diagram lies at the heart of what the RHIC Physics Program is all about. While RHIC has been operating very successfully at or close to its maximum energy for almost a decade, it has become clear that this collider can also be operated at lower energies down to 5 GeV without extensive upgrades. An exploration of the full region of beam energies available at the RHIC facility is imperative. The STAR detector, due to its large uniform acceptance and excellent particle identification capabilities, is uniquely positioned to carry out this program in depth and detail. The first exploratory beam energy scan (BES) run at RHIC took place in 2010 (Run 10), since several STAR upgrades, most importantly a full barrel Time of Flight detector, are now completed which add new capabilities important for the interesting physics at BES energies. In this document we discuss current proposed measurements, with estimations of the accuracy of the measurements given an assumed event count at each beam energy.Comment: 59 pages, 78 figure

9p21 loss confers a cold tumor immune microenvironment and primary resistance to immune checkpoint therapy

Immune checkpoint therapy (ICT) provides substantial clinical benefits to cancer patients, but a large proportion of cancers do not respond to ICT. To date, the genomic underpinnings of primary resistance to ICT remain elusive. Here, we performed immunogenomic analysis of data from TCGA and clinical trials of anti-PD-1/PD-L1 therapy, with a particular focus on homozygous deletion of 9p21.3 (9p21 loss), one of the most frequent genomic defects occurring in ~13% of all cancers. We demonstrate that 9p21 loss confers "cold" tumor-immune phenotypes, characterized by reduced abundance of tumor-infiltrating leukocytes (TILs), particularly, T/B/NK cells, altered spatial TILs patterns, diminished immune cell trafficking/activation, decreased rate of PD-L1 positivity, along with activation of immunosuppressive signaling. Notably, patients with 9p21 loss exhibited significantly lower response rates to ICT and worse outcomes, which were corroborated in eight ICT trials of >1,000 patients. Further, 9p21 loss synergizes with PD-L1/TMB for patient stratification. A "response score" was derived by incorporating 9p21 loss, PD-L1 expression and TMB levels in pre-treatment tumors, which outperforms PD-L1, TMB, and their combination in identifying patients with high likelihood of achieving sustained response from otherwise non-responders. Moreover, we describe potential druggable targets in 9p21-loss tumors, which could be exploited to design rational therapeutic interventions

Inclusive charged hadron elliptic flow in Au + Au collisions at sNN\sqrt{s_{NN}} = 7.7 - 39 GeV

A systematic study is presented for centrality, transverse momentum ($p_T$) and pseudorapidity ($\eta$) dependence of the inclusive charged hadron elliptic flow ($v_2$) at midrapidity($|\eta| < 1.0$) in Au+Au collisions at $\sqrt{s_{NN}}$ = 7.7, 11.5, 19.6, 27 and 39 GeV. The results obtained with different methods, including correlations with the event plane reconstructed in a region separated by a large pseudorapidity gap and 4-particle cumulants ($v_2{4}$), are presented in order to investigate non-flow correlations and $v_2$ fluctuations. We observe that the difference between $v_2{2}$ and $v_2{4}$ is smaller at the lower collision energies. Values of $v_2$, scaled by the initial coordinate space eccentricity, $v_{2}/\varepsilon$, as a function of $p_T$ are larger in more central collisions, suggesting stronger collective flow develops in more central collisions, similar to the results at higher collision energies. These results are compared to measurements at higher energies at the Relativistic Heavy Ion Collider ($\sqrt{s_{NN}}$ = 62.4 and 200 GeV) and at the Large Hadron Collider (Pb + Pb collisions at $\sqrt{s_{NN}}$ = 2.76 TeV). The $v_2(p_T)$ values for fixed $p_T$ rise with increasing collision energy within the $p_T$ range studied ($< 2 {\rm GeV}/c$). A comparison to viscous hydrodynamic simulations is made to potentially help understand the energy dependence of $v_{2}(p_{T})$. We also compare the $v_2$ results to UrQMD and AMPT transport model calculations, and physics implications on the dominance of partonic versus hadronic phases in the system created at Beam Energy Scan (BES) energies are discussed.Comment: 20 pages, 12 figures. Version accepted by PR