ON T CELL FATE DECISIONS: RETINOL, METABOLISM AND ITREG DIFFERENTIATION

The mammalian immune system is equipped to both eliminate pathogenic microorganisms and tumors, while remaining in homeostasis with commensal species at mucosal surfaces and tolerant towards self. Suppressor regulatory T cells (Tregs) are a major sentinel of this immunological tolerance. Induced Tregs (iTregs) arise in the periphery following the integration of cues from the metabolites, cytokines, etc. which make up its milieu. Dysregulation of iTreg development, function or homing underlies the etiology of many autoimmune diseases and immunopathologies. The amelioration or prevention of multiple murine disease models by boosting Treg cell numbers foreshadows clinical efficacy of iTreg therapy, but an incomplete understanding of Treg development has thus far prevented successful translation. Therefore, we considered the basic biology of T cell fate decision making from two unique, but integrated angles. First, we show that the stimulation of PPARγ in human T cells upregulates RDH10, a molecule which catalyzes the rate limiting step in the oxidation of retinol to transcriptionally active all-trans retinoic acid (ATRA), a positive regulator of iTreg development. This functionally intact pathway endows T cells the ability to autonomously sense and respond to retinoid signals present during Treg development and at tissue sites. Next, we asked questions about how T cells sense nutrient and oxygen availability as they differentiate. Tregs lacking the serine/threonine kinase PINK1 have limited activation-induced phosphorylation of Akt and oxidative phosphorylation rates, and reduced suppressor function. Notably, the uncoupling of iTreg function from normal FoxP3 expression reinforces the recent hypothesis that the PI3K/Akt/mTORC1 axis and metabolic checkpoints are decisive players in the acquisition of suppressor activity. Ultimately, the studies described herein converge on Akt and metabolism, and contribute to our understanding of how T cells integrate diverse signals present during fate determinism, provoking future Treg based therapeutics

Possible Evidence of Disoriented Chiral Condensates from the Anomaly in Omega and AntiOmega Abundances at the SPS

No conventional picture of nucleus-nucleus collisions has yet been able to explain the abundance of Omega and AntiOmega in central collisions between Pb nuclei at 158 A GeV at the CERN SPS. We argue that such a deviation from predictions of statistical thermal models and numerical simulations is evidence that they are produced as topological defects in the form of skyrmions arising from the formation of disoriented chiral condensates. The estimated domain size falls in the right range to be consistent with the so far non-observation of DCC from the distribution of neutral pions.Comment: paper presented at the ICPAQGP-2001, Jaipur, Indi

Is Anomalous Production of Omega and anti-Omega Evidence for Disoriented Chiral Condensates?

No conventional picture of nucleus-nucleus collisions has yet been able to explain the abundance of Omega and anti-Omega hyperons in central collisions between Pb nuclei at 158 A GeV at the CERN SPS. We argue that this is evidence that they are produced as topological defects arising from the formation of disoriented chiral condensates (DCC) with an average domain size of about 2 fm.Comment: version 2 containing formulas, accepted by PR

Diffuse Traumatic Brain Injury Induces Prolonged Immune Sysregulation and Potentiates Hyperalgesia Following a Peripheral Immune Challenge

Background: Nociceptive and neuropathic pain occurs as part of the disease process after traumatic brain injury (TBI) in humans. Central and peripheral inflammation, a major secondary injury process initiated by the traumatic brain injury event, has been implicated in the potentiation of peripheral nociceptive pain. We hypothesized that the inflammatory response to diffuse traumatic brain injury potentiates persistent pain through prolonged immune dysregulation. Results: To test this, adult, male C57BL/6 mice were subjected to midline fluid percussion brain injury or to sham procedure. One cohort of mice was analyzed for inflammation-related cytokine levels in cortical biopsies and serum along an acute time course. In a second cohort, peripheral inflammation was induced seven days after surgery/injury with an intraplantar injection of carrageenan. This was followed by measurement of mechanical hyperalgesia, glial fibrillary acidic protein and Iba1 immunohistochemical analysis of neuroinflammation in the brain, and flow cytometric analysis of T-cell differentiation in mucosal lymph. Traumatic brain injury increased interleukin-6 and chemokine ligand 1 levels in the cortex and serum that peaked within 1–9 h and then resolved. Intraplantar carrageenan produced mechanical hyperalgesia that was potentiated by traumatic brain injury. Further, mucosal T cells from brain-injured mice showed a distinct deficiency in the ability to differentiate into inflammation-suppressing regulatory T cells (Tregs). Conclusions: We conclude that traumatic brain injury increased the inflammatory pain associated with cutaneous inflammation by contributing to systemic immune dysregulation. Regulatory T cells are immune suppressors and failure of T cells to differentiate into regulatory T cells leads to unregulated cytokine production which may contribute to the potentiation of peripheral pain through the excitation of peripheral sensory neurons. In addition, regulatory T cells are identified as a potential target for therapeutic rebalancing of peripheral immune homeostasis to improve functional outcome and decrease the incidence of peripheral inflammatory pain following traumatic brain injury

Giant QCD K-factors beyond NLO

Hadronic observables in Z+jet events can be subject to large NLO corrections at TeV scales, with K-factors that even reach values of order 50 in some cases. We develop a method, LoopSim, by which approximate NNLO predictions can be obtained for such observables, supplementing NLO Z+jet and NLO Z+2-jet results with a unitarity-based approximation for missing higher loop terms. We first test the method against known NNLO results for Drell-Yan lepton pt spectra. We then show our approximate NNLO results for the Z+jet observables. Finally we examine whether the LoopSim method can provide useful information even in cases without giant K-factors, with results for observables in dijet events that can be compared to early LHC data.Comment: 38 pages, 13 figures; v2 includes additional reference

Dynamical Evolution of the Scalar Condensate in Heavy Ion Collisions

We derive the effective coarse-grained field equation for the scalar condensate of the linear sigma model in a simple and straightforward manner using linear response theory. The dissipative coefficient is calculated at tree level on the basis of the physical processes of sigma-meson decay and of thermal sigma-mesons and pions knocking sigma-mesons out of the condensate. The field equation is solved for hot matter undergoing either one or three dimensional expansion and cooling in the aftermath of a high energy nuclear collision. The results show that the time constant for returning the scalar condensate to thermal equilibrium is of order 2 fm/c.Comment: 19 pages, 3 figures are embedded at the end. The effect of the time dependence of the condensate v is included in this revised version. Numerical work is redone accordingl

Dynamical Color Correlations in a SU(2)cSU(2)_c Quark Exchange Model of Nuclear Matter

The quark exchange model is a simple realization of an adiabatic approximation to the strong-coupling limit of Quantum Chromodynamics (QCD): the quarks always coalesce into the lowest energy set of flux tubes. Nuclear matter is thus modeled in terms of its quarks. We wish to study the correlations imposed by total wavefunction antisymmetry when color degrees of freedom are included. To begin with, we have considered one-dimensional matter with a $SU(2)$ color internal degree of freedom only. We proceed by constructing a totally antisymmetric, color singlet {\it Ansatz} characterized by a variational parameter $\lambda$ (which describes the length scale over which two quarks in the system are clustered into hadrons) and by performing a variational Monte Carlo calculation of the energy to optimize $\lambda$ for a fixed density. We calculate the $q-q$ correlation function as well, and discuss the qualitative differences between the system at low and high density.Comment: 32 pages in REVTeX, IU/NTC 93-28, FSU-SCRI-93-161. The postscript file, including 12 figures, is available via anonymous ftp from ftp.scri.fsu.edu in /pub/jorgep/magic.p

How To Find Charm in Nuclear Collisions at RHIC and LHC

Measurements of dilepton production from charm decay and Drell-Yan processes respectively probe the gluon and sea quark distributions in hadronic collisions. In nucleus-nucleus collisions, these hard scattering processes constitute a `background' to thermal contributions from the hot matter produced by the collision. To determine the magnitude and behavior of this background, we calculate the hard scattering contribution to dilepton production in nuclear collisions at RHIC and LHC at next to leading order in perturbative QCD. Invariant mass, rapidity and transverse momentum distributions are presented. We compare these results to optimistic hydrodynamic estimates of the thermal dilepton production. We find that charm production from hard scattering is by far the dominant contribution. Experiments therefore can measure the gluon distribution in the nuclear target and projectile and, consequently, can provide new information on gluon shadowing. We then illustrate how experimental cuts on the rapidity gap between the leptons can aid in reducing the charm background, thereby enhancing thermal information.Comment: 32 pages, latex, 19 figure

Antiproton Production in 11.5 A GeV/c Au+Pb Nucleus-Nucleus Collisions

We present the first results from the E864 collaboration on the production of antiprotons in 10% central 11.5 A GeV/c Au+Pb nucleus collisions at the Brookhaven AGS. We report invariant multiplicities for antiproton production in the kinematic region 1.4<y<2.2 and 50<p_T<300 MeV/c, and compare our data with a first collision scaling model and previously published results from the E878 collaboration. The differences between the E864 and E878 antiproton measurements and the implications for antihyperon production are discussed.Comment: 4 pages, 4 figures; accepted for publication in Physical Review Letter

Event shapes in e+e- annihilation and deep inelastic scattering

This article reviews the status of event-shape studies in e+e- annihilation and DIS. It includes discussions of perturbative calculations, of various approaches to modelling hadronisation and of comparisons to data.Comment: Invited topical review for J.Phys.G; 40 pages; revised version corrects some nomenclatur