Neutralizing antibody response during acute and chronic hepatitis C virus infection

Little is known about the role of Abs in determining the outcome of hepatitis C virus (HCV) infection. By using infectious retroviral pseudotypes bearing HCV glycoproteins, we measured neutralizing Ab (nAb) responses during acute and chronic HCV infection. In seven acutely infected health care workers, only two developed a nAb response that failed to associate with viral clearance. In contrast, the majority of chronically infected patients had nAbs. To determine the kinetics of strain-specific and crossreactive nAb emergence, we studied patient H, the source of the prototype genotype 1a H77 HCV strain. An early weak nAb response, specific for the autologous virus, was detected at seroconversion. However, neutralization of heterologous viruses was detected only between 33 and 111 weeks of infection. We also examined the development of nAbs in 10 chimpanzees infected with H77 clonal virus. No nAb responses were detected in three animals that cleared virus, whereas strain-specific nAbs were detected in six of the seven chronically infected animals after approximately 50 weeks of infection. The delayed appearance of high titer crossreactive nAbs in chronically infected patients suggests that selective mechanism(s) may operate to prevent the appearance of these Abs during acute infection. The long-term persistence of these nAbs in chronically infected patients may regulate viral replication

De novo donor HLA-specific antibodies predict development of bronchiolitis obliterans syndrome after lung transplantation

Background Bronchiolitis obliterans syndrome (BOS) is the major cause of late graft failure after lung transplantation. The objective was to determine whether de novo donor human leukocyte antigen (HLA)-specific antibodies (DSA) are associated with the development of BOS or patient survival. Data were analyzed from 188 lung transplant recipients with a follow-up period up to 8 years. Methods HLA antibody monitoring was performed at 3-month intervals post-transplant at routine outpatient clinic attendances and during the investigation of any acute deterioration. HLA antibody data were available for 148 patients; 66 (45%) had produced HLA antibodies after transplant, of which 38 (26%) were DSA and 28 (19%) non–donor-specific HLA antibodies. Results De novo DSA was associated with development of BOS Stage 1 (BOS1; hazard ratio [HR] = 2.302, p = 0.0015), BOS2 (HR = 3.627, p < 0.0001) and BOS3 (HR = 5.736, p < 0.0001). De novo persistent DSA correlated strongly with shorter time to onset of BOS3 (HR = 6.506, p = 0.0001). There was a significant reduction in patient survival associated with de novo DSA (HR = 1.886, p = 0.047). In multivariable analyses, de novo DSA was an independent predictor for development of all stages of BOS as well as an independent predictor of poor patient survival. Conclusions De novo DSA is a major risk factor for progression to BOS and shorter patient survival. Treatments to remove antibodies or limit antibody-mediated damage could be considered when DSA are first detected. However, a randomized, controlled trial of treatment options would enable a clearer understanding of the benefits, if any, of antibody-removal therapies

Uncovering obsessive-compulsive disorder risk genes in a pediatric cohort by high-resolution analysis of copy number variation

Abstract Background Obsessive-compulsive disorder (OCD) is a heterogeneous neuropsychiatric condition, thought to have a significant genetic component. When onset occurs in childhood, affected individuals generally exhibit different characteristics from adult-onset OCD, including higher prevalence in males and increased heritability. Since neuropsychiatric conditions are associated with copy number variations (CNVs), we considered their potential role in the etiology of OCD. Methods We genotyped 307 unrelated pediatric probands with idiopathic OCD (including 174 that were part of complete parent-child trios) and compared their genotypes with those of 3861 population controls, to identify rare CNVs (<0.5 % frequency) of at least 15 kb in size that might contribute to OCD. Results We uncovered de novo CNVs in 4/174 probands (2.3 %). Our case cohort was enriched for CNVs in genes that encode targets of the fragile X mental retardation protein (nominal p = 1.85 × 10−03; FDR=0.09), similar to previous findings in autism and schizophrenia. These results also identified deletions or duplications of exons in genes involved in neuronal migration (ASTN2), synapse formation (NLGN1 and PTPRD), and postsynaptic scaffolding (DLGAP1 and DLGAP2), which may be relevant to the pathogenesis of OCD. Four cases had CNVs involving known genomic disorder loci (1q21.1-21.2, 15q11.2-q13.1, 16p13.11, and 17p12). Further, we identified BTBD9 as a candidate gene for OCD. We also sequenced exomes of ten “CNV positive” trios and identified in one an additional plausibly relevant mutation: a 13 bp exonic deletion in DRD4. Conclusions Our findings suggest that rare CNVs may contribute to the etiology of OCD.http://deepblue.lib.umich.edu/bitstream/2027.42/134675/1/11689_2016_Article_9170.pd

Isolation of Flow and Nonflow Correlations by Two- and Four-Particle Cumulant Measurements of Azimuthal Harmonics in sNN=\sqrt{s_{_{\rm NN}}} = 200 GeV Au+Au Collisions

A data-driven method was applied to measurements of Au+Au collisions at $\sqrt{s_{_{\rm NN}}} =$ 200 GeV made with the STAR detector at RHIC to isolate pseudorapidity distance $\Delta\eta$-dependent and $\Delta\eta$-independent correlations by using two- and four-particle azimuthal cumulant measurements. We identified a component of the correlation that is $\Delta\eta$-independent, which is likely dominated by anisotropic flow and flow fluctuations. It was also found to be independent of $\eta$ within the measured range of pseudorapidity $|\eta|<1$. The relative flow fluctuation was found to be $34\% \pm 2\% (stat.) \pm 3\% (sys.)$ for particles of transverse momentum $p_{T}$ less than $2$ GeV/$c$. The $\Delta\eta$-dependent part may be attributed to nonflow correlations, and is found to be $5\% \pm 2\% (sys.)$ relative to the flow of the measured second harmonic cumulant at $|\Delta\eta| > 0.7$

Beam energy dependent two-pion interferometry and the freeze-out eccentricity of pions in heavy ion collisions at STAR

We present results of analyses of two-pion interferometry in Au+Au collisions at $\sqrt{s_{NN}}$ = 7.7, 11.5, 19.6, 27, 39, 62.4 and 200 GeV measured in the STAR detector as part of the RHIC Beam Energy Scan program. The extracted correlation lengths (HBT radii) are studied as a function of beam energy, azimuthal angle relative to the reaction plane, centrality, and transverse mass ($m_{T}$) of the particles. The azimuthal analysis allows extraction of the eccentricity of the entire fireball at kinetic freeze-out. The energy dependence of this observable is expected to be sensitive to changes in the equation of state. A new global fit method is studied as an alternate method to directly measure the parameters in the azimuthal analysis. The eccentricity shows a monotonic decrease with beam energy that is qualitatively consistent with the trend from all model predictions and quantitatively consistent with a hadronic transport model.Comment: 27 pages; 27 figure

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.

Charged-to-neutral correlation at forward rapidity in Au+Au collisions at sNN\sqrt{s_{NN}}=200 GeV

Event-by-event fluctuations of the ratio of inclusive charged to photon multiplicities at forward rapidity in Au+Au collision at $\sqrt{s_{NN}}$=200 GeV have been studied. Dominant contribution to such fluctuations is expected to come from correlated production of charged and neutral pions. We search for evidences of dynamical fluctuations of different physical origins. Observables constructed out of moments of multiplicities are used as measures of fluctuations. Mixed events and model calculations are used as baselines. Results are compared to the dynamical net-charge fluctuations measured in the same acceptance. A non-zero statistically significant signal of dynamical fluctuations is observed in excess to the model prediction when charged particles and photons are measured in the same acceptance. We find that, unlike dynamical net-charge fluctuation, charge-neutral fluctuation is not dominated by correlation due to particle decay. Results are compared to the expectations based on the generic production mechanism of pions due to isospin symmetry, for which no significant (<1%) deviation is observed.Comment: 14 pages, 6 figure

Beam-energy dependence of charge separation along the magnetic field in Au+Au collisions at RHIC

Local parity-odd domains are theorized to form inside a Quark-Gluon-Plasma (QGP) which has been produced in high-energy heavy-ion collisions. The local parity-odd domains manifest themselves as charge separation along the magnetic field axis via the chiral magnetic effect (CME). The experimental observation of charge separation has previously been reported for heavy-ion collisions at the top RHIC energies. In this paper, we present the results of the beam-energy dependence of the charge correlations in Au+Au collisions at midrapidity for center-of-mass energies of 7.7, 11.5, 19.6, 27, 39 and 62.4 GeV from the STAR experiment. After background subtraction, the signal gradually reduces with decreased beam energy, and tends to vanish by 7.7 GeV. The implications of these results for the CME will be discussed.Comment: 6 pages, 4 figures, accepted by Phys. Rev. Lett (more model comparisons have been added in version 2