Biomedical subjects

F Simpson

Publications and source records attributed to F Simpson.

21 records · Page 2Linked to original sources

PubMedDate not supplied

Phosphatidylinositol-4,5-bisphosphate is required for endocytic coated vesicle formation.

Receptor-mediated endocytosis via clathrin-coated vesicles has been extensively studied and, while many of the protein players have been identified, much remains unknown about the regulation of coat assembly and the mechanisms that drive vesicle formation [1]. Some components of the endocytic machinery interact with inositol polyphosphates and inositol lipids in vitro, implying a role for phosphatidylinositols in vivo [2] [3]. Specifically, the adaptor protein complex AP2 binds phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2), PtdIns(3)P, PtdIns(3,4,5)P3 and inositol phosphates. Phosphatidylinositol binding regulates AP2 self-assembly and the interactions of AP2 complexes with clathrin and with peptides containing endocytic motifs [4] [5]. The GTPase dynamin contains a pleckstrin homology (PH) domain that binds PtdIns(4,5)P2 and PtdIns(3,4,5)P3 to regulate GTPase activity in vitro [6] [7]. However, no direct evidence for the involvement of phosphatidylinositols in clathrin-mediated endocytosis exists to date. Using well-characterized PH domains as high affinity and high specificity probes in combination with a perforated cell assay that reconstitutes coated vesicle formation, we provide the first direct evidence that PtdIns(4,5)P2 is required for both early and late events in endocytic coated vesicle formation.

Adaptor Protein Complex 2↗

PubMedDate not supplied

Immunological and in-vivo neurological studies on a benzoic acid-specific T cell-derived antigen-binding molecule from the serum of a toluene-sensitive patient.

T-cell-derived antigen-binding molecules (TABMs) specific for benzoic acid were isolated from the serum of a toluene-sensitive patient. The resulting purified TABMs (BA-TABMs) did not contain immunoglobulin G and were associated with the cytokine transforming growth factor-beta (TGF-beta). BA-TABMs bound to benzoic acid conjugated to human serum albumin (BA-HSA), as well as to other chemicals conjugated to human serum albumin-including dinitrophenol and oxazolone. The binding of BA-TABMs to the conjugated chemicals increased the level of detectable TGF-beta, and a similar effect was observed with the unconjugated chemicals, benzoic acid and 2,4-dinitrophenol glycine. The increase in TGF-beta was critically dependent on the ratio between BA-TABMs and the conjugated or unconjugated chemicals; the increase was optimum at intermediate concentrations and absent at low and high concentrations. The authors used an established animal model in vivo and demonstrated that TGF-beta enhanced the inflammatory response induced by the release of neuropeptides from sensory nerves; this enhancement occurred in a dose-dependent manner. The BA-TABMs also enhanced this neurogenic inflammatory response in a dose-dependent manner, and this effect was blocked by anti-TGF-beta antibody. When the authors added either BA-HSA or benzoic acid, the effect of BA-TABMs on neurogenic inflammation was further enhanced at intermediate concentrations of antigen and was unaltered or reduced at higher concentrations. TABMs specific to particular chemicals, as a result of their association with cytokines (e.g., TGF-beta), may be implicated in symptom production in chemically sensitive patients.

Adult↗

PubMedDate not supplied

Clinical and immunological responses in subjects sensitive to solvents.

Twenty patients proved sensitive to a 15-min exposure to 15 ppm toluene. We assessed patients neuropsychologically before and after toluene exposure, and they had impaired cognitive functioning characterized by a deterioration in short- and long-term memory and psychomotor coordination. We measured total immunoglobin G and T-cell antigen-binding molecules against an antigen prepared by conjugation of para-aminobenzoic acid to human serum albumin in 20 patients and 16 controls. There was no significant difference in the immunoglobulin G levels to the antigen in the 2 groups, but the levels of T-cell antigen-binding molecules against the para-aminobenzoic acid conjugated to human serum albumin were elevated significantly in subjects sensitive to toluene. We also found significant associations between T-cell antigen-binding molecule levels and (a) decreased performance on the STROOP (Colour Word) test, (b) a shift in focal length following toluene exposure, (c) clinical assessment of disability, and (d) longer histories of chemical exposure. The measurement of T-cell antigen-binding molecules against chemical haptens may be valuable in the assessment of patients who are sensitive to chemicals.

Adult↗