Purine and pyrimidine nucleotides play critical roles in DNA and RNA synthesis as well as in membrane lipid biosynthesis and protein glycosylation. They are necessary for the development and survival ...of mature T lymphocytes. Activation of T lymphocytes is associated with an increase of purine and pyrimidine pools. However, the question of how purine vs pyrimidine nucleotides regulate proliferation, cell cycle, and survival of primary T lymphocytes following activation has not yet been specifically addressed. This was investigated in the present study by using well-known purine (mycophenolic acid, 6-mercaptopurine) and pyrimidine (methotrexate, 5-fluorouracil) inhibitors, which are used in neoplastic diseases or as immunosuppressive agents. The effect of these inhibitors was analyzed according to their time of addition with respect to the initiation of mitogenic activation. We showed that synthesis of both purine and pyrimidine nucleotides is required for T cell proliferation. However, purine and pyrimidine nucleotides differentially regulate the cell cycle since purines control both G(1) to S phase transition and progression through the S phase, whereas pyrimidines only control progression from early to intermediate S phase. Furthermore, inhibition of pyrimidine synthesis induces apoptosis whatever the time of inhibitor addition whereas inhibition of purine nucleotides induces apoptosis only when applied to already cycling T cells, suggesting that both purine and pyrimidine nucleotides are required for survival of cells committed into S phase. These findings reveal a hitherto unknown role of purine and pyrimidine de novo synthesis in regulating cell cycle progression and maintaining survival of activated T lymphocytes.
Charmonium production in γA, pA and AA Gerland, L
Journal of physics. G, Nuclear and particle physics,
01/2004, Volume:
30, Issue:
1
Journal Article, Conference Proceeding
We discuss the production of charmonium states in antiproton–nucleus collisions at the ψ′ threshold. It is explained that measurements in p¯A collisions will allow to get new information about the ...strengths of the inelastic J/ψN and ψ′N interaction, on the production of Λc and D¯ in charmonium–nucleon interactions and for the first time about the nondiagonal transitions ψ′N→J/ψN. The inelastic J/ψ-nucleon cross section is extracted from the comparison of hadron–nucleus collisions with hadron–nucleon collisions. We extract the total J/ψ-nucleon cross section from photon–nucleon collisions by accounting for the color transparency phenomenon within the frame of the GVDM (generalized vector meson dominance model). We evaluate within the GVDM the inelastic ψ′-nucleon cross section as well as the cross section for the nondiagonal transitions. Predictions for the ratio of J/ψ to ψ′ yields in antiproton–nucleus scatterings close to the threshold of ψ′ production for different nuclear targets are presented.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, SAZU, SBCE, UL, UM, UPCLJ, UPUK
We argue that the distribution of hadrons near the longitudinal light cone in central high-energy pA collisions is computable in weak coupling QCD. This is because the density of gluons per unit ...transverse area in the dense target at saturation provides an intrinsic semihard momentum scale, Q(s). We predict that the longitudinal distribution of (anti)baryons and mesons steepens with increasing energy and atomic number of the target and that the transverse momentum distribution broadens. We show that the evolution of high moments of the longitudinal net baryon distribution with Q(s) is determined by the anomalous dimension gamma(qq).
Full text
Available for:
CMK, CTK, FMFMET, IJS, NUK, PNG, UM
We perform an event-by-event analysis of the transverse momentum distribution of final state particles in central Pb(160 AGeV)+Pb collisions within a microscopic non-equilibrium transport model ...(UrQMD). Strong influence of rescattering is found. The extracted momentum distributions show less fluctuations in A+A collisions than in p+p reactions. This is in contrast to simplified p+p extrapolations and random walk models.
Full text
Available for:
IJS, IMTLJ, KILJ, KISLJ, NUK, SAZU, SBCE, UL, UM, UPCLJ, UPUK
Mycophenolic acid (MPA), the active metabolite of the immunosuppressive drug mycophenolate mofetil, is a selective inhibitor of inosine 5'-monophosphate dehydrogenase type II, a de novo purine ...nucleotide synthesis enzyme expressed in T and B lymphocytes and up-regulated upon cell activation. In this study, we report that the blockade of guanosine nucleotide synthesis by MPA inhibits mitogen-induced proliferation of PBL, an effect fully reversed by addition of guanosine and shared with mizoribine, another inhibitor of inosine 5'-monophosphate dehydrogenase. Because MPA does not inhibit early TCR-mediated activation events, such as CD25 expression and IL-2 synthesis, we investigated how it interferes with cytokine-dependent proliferation and survival. In activated lymphoblasts that are dependent on IL-2 or IL-15 for their proliferation, MPA does not impair signaling events such as of the extracellular signal-regulated kinase 2 and Stat5 phosphorylation, but inhibits down-regulation of the cyclin-dependent kinase inhibitor p27(Kip1). Therefore, in activated lymphoblasts, MPA specifically interferes with cytokine-dependent signals that control cell cycle and blocks activated T cells in the mid-G(1) phase of the cell cycle. Although it blocks IL-2-mediated proliferation, MPA does not inhibit cell survival and Bcl-x(L) up-regulation by IL-2 or other cytokines whose receptors share the common gamma-chain (CD132). Finally, MPA does not interfere with IL-2-dependent acquisition of susceptibility to CD95-mediated apoptosis and degradation of cellular FLIP. Therefore, MPA has unique functional properties not shared by other immunosuppressive drugs interfering with IL-2R signaling events such as rapamycin and CD25 mAbs.
PDF
