New class I and II HLA alleles strongly associated with opposite patterns of progression to AIDS.

The genetics of resistance to infection by HIV-1 cohort consists of 200 slow and 75 rapid progressors to AIDS corresponding to the extremes of HIV disease outcome of 20,000 Caucasians of European descent. A comprehensive analysis of HLA class I and class II genes in this highly informative cohort has identified HLA alleles associated with fast or slow progression, including several not described previously. A quantitative analysis shows an overall HLA influence independent of and equal in magnitude (for the protective effect) to the effect of the CCR5-Delta32 mutation. Among HLA class I genes, A29 (p = 0.001) and B22 (p < 0.0001) are significantly associated with rapid progression, whereas B14 (p = 0.001) and C8 (p = 0.004) are significantly associated with nonprogression. The class I alleles B27, B57, C14 (protective), and C16, as well as B35 (susceptible), are also influential, but their effects are less robust. Influence of class II alleles was only observed for DR11. These results confirm the influence of the immune system on disease progression and may have implications on peptide-based vaccine development.     

Tomoscintigraphy for detecting gastrointestinal and medullary thyroid cancers: first clinical results using radiolabelled monoclonal antibodies against carcinoembryonic antigen.

Transaxial tomoscintigraphy (or single-photon emission computerised tomography) was used to detect secondary deposits of carcinoma in 17 patients who had been injected with iodine-131-labelled monoclonal antibodies against carcinoembryonic antigen. Of 17 tumor sites studied by tomoscintigraphy 16 were detected (sensitivity 94%); five sites had a volume smaller than 10 cm3. Tomoscintigraphy also detected three unknown tumour deposits later confirmed by surgery or radiology. In contrast, when 21 tumour sites in the same patients were studied by rectilinear scintigraphy, only nine tumour sites were detected (sensitivity 43%), of which eight had a volume larger than 50 cm3.     

Localization by immunofluorescence of a gastrin-like substance in the brain of the rainbow trout,Salmo gairdneri

Summary With the aid of an indirect immunofluorescence technique neurones containing a gastrin-like substance were identified in the brain of Salmo gairdneri. The perikarya of these neurones appear to be located along the periventricular part of the nucleus lateralis tuberis between the hypophysial stalk and the most rostral tip of the saccus vasculosus. The fibres of these perikarya run rostrally toward the hypophysis, where they can be followed in the protrusions of the neurohypophysis into the proximal pars distalis. Here the bundle of immunoreactive fibres divides into numerous smaller bundles and into single fibres. Immunohistochemical specificity tests have shown this immunoreactive substance to belong to the gastrin group, sharing an antigenic determinant with cholecystokinin (CCK) and pentagastrin (common aminoacid sequence Trp-Met-Asp-Phe). A possible function of these gastrin (or CCK)-containing neurones in the rainbow trout is discussed.     

Characterization of transducin from bovine retinal rod outer segments. Participation of the amino-terminal region of T alpha in subunit interaction

The GTP-induced dissociation of T alpha from T beta gamma initiates the release of transducin from photolyzed rhodopsin and the subsequent activation of the cGMP phosphodiesterase. In this study, site-specific proteolysis and immunoprecipitation were used to map the domain of T alpha that interacts with T beta gamma. We found that Staphylococcus aureus V8 protease rapidly removes a small fragment from T alpha under native conditions, resulting in the formation of a single 38-kDa polypeptide (T alpha'). Under the same conditions, T beta gamma remains intact. A 4.5-fold decrease in the rate of T alpha cleavage by S. aureus protease was observed in the presence of T beta gamma, suggesting T beta gamma binding blocks the protease-sensitive site on T alpha. Amino acid sequence analysis indicated that T alpha' is derived from the cleavage of T alpha at Glu-21. The ability of T alpha' to interact with and activate the retinal phosphodiesterase is not diminished. However, T alpha' is unable to participate in T beta gamma-dependent activities such as the light-stimulated binding of guanine nucleotides, binding to photoexcited rhodopsin, and ADP-ribosylation catalyzed by pertussis toxin. Moreover, the anti-T alpha monoclonal antibody TF16 was able to precipitate T beta gamma in the presence of T alpha, but not with either T alpha' or T alpha-guanosine 5'-O-(3-thiotriphosphate). We conclude that the amino-terminal region of T alpha participates in T beta gamma interaction and discuss our results with respect to the known structure and function of transducin.     

Melanocortin‐1 receptor structure and functional regulation

The melanogenic actions of the melanocortins are mediated by the melanocortin‐1 receptor (MC1R). MC1R is a member of the G‐protein‐coupled receptors (GPCR) superfamily expressed in cutaneous and hair follicle melanocytes. Activation of MC1R by adrenocorticotrophin or α‐melanocyte stimulating hormone is positively coupled to the cAMP signaling pathway and leads to a stimulation of melanogenesis and a switch from the synthesis of pheomelanins to the production of eumelanic pigments. The functional behavior of the MC1R agrees with emerging concepts in GPCR signaling including dimerization, coupling to more than one signaling pathway and a high agonist‐independent constitutive activity accounting for inverse agonism phenomena. In addition, MC1R displays unique properties such as an unusually high number of natural variants often associated with clearly visible phenotypes and the occurrence of endogenous peptide antagonists. Therefore MC1R is an ideal model to study GPCR function. Here we review our current knowledge of MC1R structure and function, with emphasis on information gathered from the analysis of natural variants. We also discuss recent data on the regulation of MC1R function by paracrine and endocrine factors and by external stimuli such as ultraviolet light.     

Phosphatidylinositol inhibits microtubule assembly by binding to microtubule-associated protein 2 at a single, specific, high-affinity site.

The effects of various anionic phospholipids on the in vitro assembly of MAP2/tubulin microtubules has been examined. We show that the potency to inhibit is related to the polarity of the phospholipids and that this is consistent with a mode of action involving the sequencing of microtubule-associated proteins (MAPs) by nonspecific electrostatic interactions. The inhibitory potency of phosphatidylinositol (PI) is, however, considerably larger than predicted by this model. The effects of PI on MAP2/tubulin microtubule assembly have therefore been examined in greater detail by preparing phosphatidylcholine (PC) liposomes doped with increasing amounts of PI. We show that when the PI is sufficiently dispersed by dilution with PC, it inhibits microtubule assembly by binding to MAP2 with an apparent stoichiometry, after correction for the bilamellar nature of the liposomes, of 1:1 mol.mol-1 PI:MAP2. Furthermore, we show that the Kd of this interaction is in the submicromolar range.     

Disruption of energy metabolism and smoltification during exposure of juvenile atlantic salmon (Salmo salar) to low pH

Juvenile Atlantic salmon were held for 76 days at pH 4.7 during the period when the final stages of smoltification normally occur. Control salmon (pH 6.5) had significant increases in weight, length and liver somatic index which were not observed in those held at low pH. Condition factor decreased in both groups but to a significantly greater extent in the low pH group. After 15 days levels of ADP and glucose were higher and AEC, CP and glycogen were lower in muscles of salmon exposed to low pH. These qualitative differences were maintained until the end of the experiment. ATP and total adenylate concentrations in muscle were lower after 62 days of exposure to low pH compared to controls. The levels of ATP, total adenylates, AEC and glucose were consistently higher in livers of salmon exposed to low pH than those of controls. There were no differences in liver concentrations of AMP, CP and glycogen between the two treatments or with time of exposure within each treatment. The results suggest that exposure of juvenile Atlantic salmon to low pH increased gluconeogenesis and decreased food intake to the detriment of growth.