Biomedical subjects

John G Raynes

Publications and source records attributed to John G Raynes.

4 recordsLinked to original sources

PubMed2002

Specific interactions between sense and complementary peptides: the basis for the proteomic code.

The discovery of the genetic code was one of the milestone events in biology: a conserved, universal code defining the primary amino acid sequences of all proteins of all organisms. However, this code has been thought to be limited, unable to provide additional information appropriate to defining the three-dimensional structure and function of these proteins. This raises important questions. Can there be more to the genetic code? Is there a code embedded within the code? Does a two-dimensional genetic code exist? In our view, the answer to all three of these questions is a qualified "yes". This review describes how sense and complementary peptides coded for by mutually complementary nucleic acid sequences are capable of interacting specifically, thereby suggesting the existence of a second, two-dimensional genetic code (proteomic code). Theories attempting to explain such specific interactions between sense and complementary peptides are discussed including the Mekler-Idlis (M-I) pair theory that suggests that each codon-directed amino acid residue in a sense peptide may make a specific pair-wise interaction with the corresponding complementary codon-directed residue in the complementary peptide. In effect, through-space interactions between pairs of amino acid residues are suggested as being specified by the genetic code and its complement. The biological implications of sense/complementary peptide interactions are potentially vast but still to be fully understood and appreciated. That such peptide/peptide interactions could provide the basis for understanding and constructing the proteomic code remains to be properly established but research to date suggests that we should be able to make a start in that direction.

Amino Acids↗

PubMed2002

C-reactive protein-mediated phagocytosis and phospholipase D signalling through the high-affinity receptor for immunoglobulin G (FcgammaRI).

C-reactive protein (CRP) is the prototypic acute-phase protein in man which performs innate immune functions. CRP-mediated phagocytosis may be indirect, through activation of complement and complement receptors, or direct, through receptors for the Fc portion of immunoglobulin G (IgG; FcgammaRs) or even a putative CRP-specific receptor. No strong evidence has been shown to indicate which receptors may be responsible for phagocytosis or signalling responses. Using BIAcore technology, we confirm that CRP binds directly to the extracellular portion of FcgammaRI with a threefold higher affinity than IgG (KD = 0.81 x 10-9 m). Binding is Ca2+ dependent and is inhibited by IgG1 but not by phosphorylcholine (PC). CRP opsonization (using CRP concentrations within the normal human serum range) of PC-conjugated sheep erythrocytes increased phagocytosis of these particles by COS-7 cells transfected with FcgammaRI-II chimaera or FcgammaRI/gamma-chain. Interferon-gamma-treated U937 cells, which signal through FcgammaRI to activate phospholipase D (PLD) in response to cross-linked IgG, were also activated by CRP without any requirement for further cross-linking. These studies indicate that CRP is capable of binding to and cross-linking FcgammaRI thereby resulting in PLD activation and increased phagocytosis. Uptake by FcgammaRI has been reported to promote various acquired immune responses suggesting that CRP could act in a similar way.

Animals↗

PubMed2002

Activation of p38 mitogen-activated protein kinase attenuates Leishmania donovani infection in macrophages.

Leishmania-induced macrophage dysfunctions have been correlated with altered signaling events. In this work, we report that SB203580, a specific inhibitor of p38 mitogen-activated protein kinases (MAPK), increases Leishmania donovani survival in human peripheral blood mononuclear macrophages. Consistent with this finding, activation of p38 and c-jun N-terminal kinase (JNK) MAPK signaling pathways by anisomycin significantly reduced parasite survival within these cells. However, the majority of the effect was seen in a 50% reduction in the percentage of macrophages infected, with little effect on the highly infected macrophages. The observed effect was likely to be due to the p38 MAPK pathway since SB203580 was able to completely reverse the effect of anisomycin. These findings suggest that the previously reported p38 MAPK inhibition by Leishmania infection may be partially overcome by anisomycin. Similar effects were observed in pretreated macrophages or in treatment of infected macrophages. These results suggests that p38 MAPK activation may have a potential therapeutic value in the treatment of visceral leishmaniasis.

Animals↗

PubMedDate not supplied

C-reactive protein-mediated phagocytosis of Leishmania donovani promastigotes does not alter parasite survival or macrophage responses.

C-reactive protein (CRP) is an acute phase protein that binds to surface structures of a number of different organisms. Leishmania donovani express CRP ligand when first entering the mammalian host and CRP has been shown to alter macrophage function. The aim of this study was to investigate the functional significance of CRP-mediated uptake of L. donovani on survival of the parasite within human macrophages and macrophage cell responses to the infection. CRP opsonized L. donovani uptake was inhibitable by including excess CRP in the fluid phase, suggesting Fc receptor usage rather than indirect complement-mediated uptake. Comparing equivalent initial infection loads, parasite survival over 72 h within peripheral blood derived macrophages (PBMs) and differentiated U937 cells was unaltered by CRP. Whereas CRP increased macrophage responses to phosphorylcholine coated erythrocytes, no significant alteration in tumour necrosis factor-alpha, interleukin (IL)-10 or IL-12 production from PBMs was observed between CRP opsonized or unopsonized L. donovani promastigotes. Thus, in contrast to other systems, where CRP opsonization results in macrophage activation, Leishmania can use CRP to improve infection without inducing detrimental macrophage activation.

Animals↗