QCD and strongly coupled gauge theories: challenges and perspectives.

We highlight the progress, current status, and open challenges of QCD-driven physics, in theory and in experiment. We discuss how the strong interaction is intimately connected to a broad sweep of physical problems, in settings ranging from astrophysics and cosmology to strongly coupled, complex systems in particle and condensed-matter physics, as well as to searches for physics beyond the Standard Model. We also discuss how success in describing the strong interaction impacts other fields, and, in turn, how such subjects can impact studies of the strong interaction. In the course of the work we offer a perspective on the many research streams which flow into and out of QCD, as well as a vision for future developments.

Low oxygen tension enhances hepatitis C virus replication.

Low oxygen tension exerts a significant effect on the replication of several DNA and RNA viruses in cultured cells. In vitro propagation of hepatitis C virus (HCV) has thus far been studied under atmospheric oxygen levels despite the fact that the liver tissue microenvironment is hypoxic. In this study, we investigated the efficiency of HCV production in actively dividing or differentiating human hepatoma cells cultured under low or atmospheric oxygen tensions. By using both HCV replicons and infection-based assays, low oxygen was found to enhance HCV RNA replication whereas virus entry and RNA translation were not affected. Hypoxia signaling pathway-focused DNA microarray and real-time quantitative reverse transcription-PCR (qRT-PCR) analyses revealed an upregulation of genes related to hypoxic stress, glycolytic metabolism, cell growth, and proliferation when cells were kept under low (3% [vol/vol]) oxygen tension, likely reflecting cell adaptation to anaerobic conditions. Interestingly, hypoxia-mediated enhancement of HCV replication correlated directly with the increase in anaerobic glycolysis and creatine kinase B (CKB) activity that leads to elevated ATP production. Surprisingly, activation of hypoxia-inducible factor alpha (HIF-α) was not involved in the elevation of HCV replication. Instead, a number of oncogenes known to be associated with glycolysis were upregulated and evidence that these oncogenes contribute to hypoxia-mediated enhancement of HCV replication was obtained. Finally, in liver biopsy specimens of HCV-infected patients, the levels of hypoxia and anaerobic metabolism markers correlated with HCV RNA levels. These results provide new insights into the impact of oxygen tension on the intricate HCV-host cell interaction.

High levels of HCV core+1 antibodies in HCV patients with hepatocellular carcinoma.

The core region of the hepatitis C virus (HCV) genome possesses an overlapping ORF that has been shown to encode a protein, known as the alternate reading frame protein (ARFP), F or core+1. The biological role of this protein remains elusive, as it appears to be non-essential for virus replication. However, a number of independent studies have shown that the ARFP/F/core+1 protein elicits humoral and cellular immune responses in HCV-infected individuals and interacts with important cellular proteins. To assess the significance of the core+1 humoral response in HCV-infected patients, we examined the prevalence of anti-core+1 antibodies in sera from patients with hepatocellular carcinoma (HCC) in comparison with chronically HCV-infected individuals without HCC. We produced two HCV core+1 histidine-tagged recombinant proteins for genotypes 1a (aa 11-160) and 1b (aa 11-144), as well as a non-tagged highly purified recombinant core+1/S protein (aa 85-144) of HCV-1b. Using an in-house ELISA, we tested the prevalence of core+1 antibodies in 45 patients with HCC in comparison with 47 chronically HCV-infected patients without HCC and 77 negative-control sera. More than 50 % of the serum samples from HCC patients reacted with all core+1 antigens, whereas <26 % of the sera from the non-HCC HCV-infected individuals tested positive. No core+1-specific reactivity was detected in any of the control samples. In conclusion, the high occurrence of anti-core+1 antibodies in the serum of HCC patients suggests a role for the ARFP/F/core+1 protein in the pathogenesis of HCC.

Transforming growth factor-beta-regulated expression of genes in macrophages implicated in the control of cholesterol homoeostasis.

The regulation of macrophage cholesterol homoeostasis is of crucial importance in the pathogenesis of atherosclerosis, an underlying cause of heart attack and stroke. Several recent studies have revealed a critical role for the cytokine TGF-beta (transforming growth factor-beta), a key regulator of the immune and inflammatory responses, in atherogenesis. We discuss here the TGF-beta signalling pathway and its role in this disease along with the outcome of our recent studies on the action of the cytokine on the expression of key genes implicated in the uptake or efflux of cholesterol by macrophages and the molecular mechanisms underlying such regulation.

Omega- and Omega+ production in central Pb + Pb collisions at 40 and 158A GeV.

Results are presented on Omega production in central Pb+Pb collisions at 40 and 158A GeV beam energy. For the first time in heavy ion reactions, rapidity distributions and total yields were measured for the sum Omega(-) + Omega(+) at 40A GeV and for Omega(-) and Omega(+) separately at 158A GeV. The yields are strongly underpredicted by the string-hadronic UrQMD model but agree better with predictions from hadron gas models.

System-size dependence of strangeness production in nucleus-nucleus collisions at squareroot[sNN]=17.3 GeV.

Emission of pi+/-, K+/-, phi, and Lambda was measured in near-central C+C and Si+Si collisions at 158 AGeV beam energy. Together with earlier data for p+p, S+S, and Pb+Pb, the system-size dependence of relative strangeness production in nucleus-nucleus collisions is obtained. Its fast rise and the saturation observed at about 60 participating nucleons can be understood as the onset of the formation of coherent systems of increasing size.

Lambda and lambda production in central Pb-Pb collisions at 40, 80, and 158A GeV.

Production of Lambda and Antilambda hyperons was measured in central Pb-Pb collisions at 40, 80, and 158A GeV beam energy on a fixed target. Transverse mass spectra and rapidity distributions are given for all three energies. The Lambda/pi ratio at midrapidity and in full phase space shows a pronounced maximum between the highest BNL Alternating Gradient Synchrotron and 40A GeV CERN Super Proton Synchrotron energies, whereas the Lambda/pi ratio exhibits a monotonic increase.

Evidence for an exotic S= -2, Q= -2 baryon resonance in proton-proton collisions at the CERN SPS.

Results of resonance searches in the Xi(-)pi(-), Xi(-)pi(+), Xi;(+)pi(-), and Xi;(+)pi(+) invariant mass spectra in proton-proton collisions at sqrt[s]=17.2 GeV are presented. Evidence is shown for the existence of a narrow Xi(-)pi(-) baryon resonance with mass of 1.862+/-0.002 GeV/c(2) and width below the detector resolution of about 0.018 GeV/c(2). The significance is estimated to be above 4.2sigma. This state is a candidate for the hypothetical exotic Xi(--)(3/2) baryon with S=-2, I=3 / 2, and a quark content of (dsdsu). At the same mass, a peak is observed in the Xi(-)pi(+) spectrum which is a candidate for the Xi(0)(3/2) member of this isospin quartet with a quark content of (dsus[-]d). The corresponding antibaryon spectra also show enhancements at the same invariant mass.

Molecular characterization of the Xenopus CCAAT-enhancer binding protein beta gene promoter.

Transcription factors belonging to the CCAAT-enhancer binding protein (C/EBP) family play key roles in the regulation of genes implicated in the control of growth, differentiation, metabolism, and inflammation. The recent limited studies on the promoter regions of C/EBP genes, particularly C/EBPalpha, have indicated the potential existence of species-specific regulatory mechanisms. It is therefore essential that the promoter regions of different C/EBP genes from a wide range of species are investigated in detail. As an important step toward this goal, we report here the characterization of the Xenopus laevis C/EBPbeta gene promoter. Sequence analysis showed that the 1.6-kb promoter region contained putative binding sites for several transcription factors that have previously been implicated in the regulation of the C/EBPs, including C/EBP, CREB, Myb, STAT, and USF. The -288/+91 promoter region was capable of directing high levels of expression in the hepatoma Hep3B cell line. In addition, this minimal promoter could be autoregulated by both C/EBPalpha and C/EBPbeta and activated by lipopolysaccharide, interleukin-6 and CREB. These results therefore demonstrate that several aspects of C/EBPbeta regulation in mammals have been highly conserved in amphibians. However, a comparison of C/EBPbeta gene promoters characterized to date does indicate the existence of species-specific differences in autoregulation.

Event-by-event fluctuations of the Kaon-to-Pion ratio in central Pb+Pb collisions at 158 GeV per nucleon.

We present the first measurement of fluctuations from event to event in the production of strange particles in collisions of heavy nuclei. The ratio of charged kaons to charged pions is determined for individual central Pb+Pb collisions. After accounting for the fluctuations due to detector resolution and finite number statistics we derive an upper limit on genuine nonstatistical fluctuations, which could be related to a first- or second-order QCD phase transition. Such fluctuations are shown to be very small.

Analysis of the Xenopus laevis CCAAT-enhancer binding protein alpha gene promoter demonstrates species-specific differences in the mechanisms for both auto-activation and regulation by Sp1.

Transcription factors belonging to the CCAAT-enhancer binding protein (C/EBP) family have been implicated in the regulation of gene expression during differentiation, development and disease. Autoregulation is relatively common in the modulation of C/EBP gene expression and the murine and human C/EBPalpha genes have been shown to be auto-activated by different mechanisms. In the light of this finding, it is essential that autoregulation of C/EBPalpha genes from a wider range of different species be investigated in order to gauge the degree of commonality, or otherwise, that may exist. We report here studies that investigate the regulation of the Xenopus laevis C/EBPalpha gene (xC/EBPalpha). The -1131/+41 promoter region was capable of directing high levels of expression in both the human hepatoma Hep3B and the Xenopus kidney epithelial A6 cell lines, and was auto-activated by expression vectors specifying for xC/EBPalpha or xC/EBPss. Deletion analysis showed that the -321/+41 sequence was sufficient for both the constitutive promoter activity and auto-activation and electrophoretic mobility shift assays identified the interaction of C/EBPs and Sp1 to this region. Although deletion of either the C/EBP or the Sp1 site drastically reduced the xC/EBPalpha promoter activity, multimers of only the C/EBP site could confer autoregulation to a heterologous SV40 promoter. These results indicate that, in contrast to the human promoter and in common with the murine gene, the xC/EBPalpha promoter was subject to direct autoregulation. In addition, we demonstrate a novel species-specific action of Sp1 in the regulation of C/EBPalpha expression, with the factor able to repress the murine promoter but activate the Xenopus gene.

Three-pion interferometry results from central Pb+Pb collisions at 158A GeV/c.

Three-particle correlations have been measured for identified pi(-) from central 158A GeV Pb+Pb collisions by the WA98 experiment at CERN. A substantial contribution of the genuine three-body correlation has been found as expected for a mainly chaotic and symmetric source.

Cytokine-mediated differential regulation of macrophage activator protein-1 genes.

The regulation of macrophage activator protein-1 (AP-1) gene expression by LPS and cytokines is of potentially crucial importance in the pathogenesis of several diseases. The action of LPS and four cytokines on AP-1 gene expression in the murine macrophage J774.2 cell line was, therefore, studied. Exposure of the cells to IL-6 produced no changes in the mRNA levels of all AP-1 members studied. In contrast, the expression of JunB, c-jun and c-fos, but not JunD, was increased by LPS, TNF-alpha, IFN-gamma and IL-1, albeit with different kinetics and magnitude of induction. Electrophoretic mobility shift assays showed a close correlation between the expression of the AP-1 genes and the functional AP-1 DNA binding activity and, additionally, demonstrated the participation of heterodimeric interactions between the different members. These studies provide insights into the potential mechanisms that may be involved in the mediator-specific modulation of AP-1 regulated macrophage gene expression.