Evolution of diversity at the major histocompatibility complex

Recent evidence from both population data and DNA sequence analyses indicates that the unprecedented genetic diversity found at MHC loci is selectively maintained in contemporary natural populations, although the strength and nature of this selection are currently unclear. Due to the critical role played by MHC molecules in immune recognition, it is generally assumed that some form of parasite-driven selection is operating. However, the general failure to implicate MHC in the susceptibility to specific infectious diseases has been troubling, and may indicate that selection is too weak to detect directly. Alternatively, strong selection can be reconciled by a variety of factors including the amplification of minor (disease-based) vigor differences into large fitness differences by intraspecific competition, or non-disease-based selection such as mating preferences and selective abortion.     

Exchange of fluorinated glucose across the red-cell membrane measured by 19F-n.m.r. magnetization transfer.

The 19F n.m.r. spectrum of 3-fluoro-3-deoxy-D-glucose (3FG) in a red-cell suspension was observed to contain separate resonances from the intra- and extra-cellular populations of both the alpha- and beta-anomers. This phenomenon was used with an n.m.r. spin-transfer procedure to measure the rate of exchange of the anomers across the human red-cell membrane under equilibrium-exchange conditions at 37 degrees C. The beta-anomer crossed the membrane significantly more quickly than the alpha-anomer. At a total 3FG concentration of 9.3 mM; the first-order rate constants for the efflux of the alpha- and beta-anomers were 0.41 +/- 0.15 and 0.88 +/- 0.20 s-1 respectively. The measurable 3FG exchange was inhibited by 75 and 100% respectively by the glucose-transport inhibitors cytochalasin B and phloretin. Glucose inhibited the exchange of 3FG, and the results were consistent with glucose and 3FG binding to the hexose-transport protein with similar affinity.     

Switch and Bait: Probing the Discriminative Basis of Odor Identification via Recognition Memory

When people misidentify everyday odors, as they often do, theirerrors may conceivably lie in faulty perceptions or in faultyaccess to the names. Discussions of the matter usually focuson the latter, as if people had no problems with perceptualaccuracy. (The problem of faulty access may get attention becauseits high subjective impact makes it particularly memorable,when it does occur.) However, studies have demonstrated breakdownsin ability to discriminate quality, from which it follows thatpeople will misidentify items through perceptual confusions.Furthermore, misidentifications often contain considerable informationabout the identities of items, as if people simply did not perceivethe items accurately, but perhaps fuzzily or with some perceptualbias. Recognition memory, with a 2-day interval between inspectionand test, provided a vehicle to address two questions on thistopic: (i) Would people notice that we had switched items andhad presented for recognition items that matched their misidentificationsrather than the original items inspected? (ii) Would peoplenot only fall for the false bait, but actually identify theswitched items correctly, and thereby imply that they were ‘tuned’to perceive those odors? People commonly failed to notice theswitches, i.e. took the bait and commonly identified the switcheditems with veridical names. Although subject to further study,the outcome suggests that when people give such names as garlicfor vinegar, orange for lime, soy sauce for molasses and manyothers, the errors often lie largely at a perceptual stage ofprocessing, i.e. at input rather than output. Chem. Senses 21:35–44, 1996.     

Neutralization sensitivity of human immunodeficiency virus type 1 is determined in part by the cell in which the virus is propagated.

Neutralizing antibody responses to human immunodeficiency virus type 1 (HIV-1) vary widely and have not been reproducibly associated with prognosis or disease progression. We have found that both low-passage clinical isolates and laboratory-adapted strains of HIV-1 have different sensitivities to neutralization by the same antiserum, depending on the host cell in which the viral stock is prepared. One such isolate (VL069) grown in H9 cells was neutralized by 20 human sera at a geometric mean titer of 1:2,047; this same isolate prepared in peripheral blood mononuclear cell (PBMC) culture was neutralized at a mean titer of < 1:10 by the same sera. Adsorption and mixing experiments indicated that neither antibody to H9 cell components nor blocking by excess viral antigen was responsible for the differences observed. This host cell effect is rapidly reversible upon passage of the virus from PBMCs to H9 cells and back into PBMCs. In contrast, the neutralization characteristics remained remarkably stable over extended culture in PBMCs. Two laboratory strains and five clinical isolates were evaluated in expanded studies of this phenomenon. While the neutralization characteristics of most of the strains studied were affected by the host cell in which the strain was propagated, two of the strains (one clinical isolate and one laboratory strain) appeared antigenically unaffected by their cell of origin. Host cell effect was also evident in neutralization by monoclonal antibodies directed against the CD4-binding region and the V2, V3, and gp41 regions. Possible mechanisms for this host cell effect include (i) mutation during passaging; (ii) selection in different host cells of different subpopulations of the (uncloned) viral stock; and (iii) cell-specific posttranslational modifications. To explore these possibilities, the V3 through V5 region of gp120 was sequenced in preparations made by passing VL069 into H9 cells and into PBMCs; HIVMN grown in CEM-SS cells and in PBMCs was also sequenced. In both cases, a few amino acid changes outside the V3 region were found. Studies are currently under way to assess the significance of these changes.     

Effects of Congenital Infection of Sheep with Border Disease Virus on Myelin Proteins

Abstract— Border disease (BD) of sheep is caused by a virus in the genus Pestivirus that results in decreased myelination throughout the CMS when acquired congenitally. Pregnant ewes were inoculated with BD virus at 50 days of gestation, and myelin proteins were quantified in several regions of the CNS during prenatal and postnatal development of infected lambs for comparison with age-matched controls. Newborn field-infected lambs were also examined. Myelin basic protein (MBP), proteolipid protein (PLP), myelin-associated glycoprotein (MAG), and 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP) were measured by densitometric scanning of western blots. Deficiencies in the myelin proteins were detected as early as 116 days of gestation, and the deficiencies of myelin proteins were most pronounced in the cerebellum at all ages examined. PLP and MBP increased from 10–30% of normal in cerebellar white matter at birth to 40–60% of normal at 6 months, suggesting some catch-up in the amount of compact myelin with development. MAG and CNP were between 70 and 80% of control levels in the cerebellum at birth and at 6 months. Similar results were obtained for the corpus callosum and spinal cord of infected lambs, but the deficiencies of myelin proteins were not as great. A common finding in all regions examined was that MBP and PLP were reduced more than MAG and CNP. This is probably explained by a greater deficit of compact myelin, in which MBP and PLP are localized, than of associated oli-godendroglial membranes, in which MAG and CNP are concentrated. Similar results have been obtained in several dysmyelinating mutants, pointing to common factors in virally and genetically caused hypomyelination. Key Words: Border disease—Myelin—Hypomyelination—Development—Sheeo.     

HYBRIDIZATION AS A DISPERSAL MECHANISM

An example from the genus Eucalyptus is used to argue that hybridization may be of evolutionary significance as a means of gene dispersal where seed dispersal is limited. A previous study of regeneration of E. risdonii and E. amygdalina indicated that the current selective regime was favoring E. risaonii. However, the dispersal of E. risdonii by seeds is shown to be limited (s, = 4.6 m). By comparison, the flow of E. risdonii genes into the range of E. amygdalina by pollen dispersal and F₁ hybridization is widespread (s_p = 82 m). While the actual level of hybridization is low, interspecific hybridization effectively doubles the dispersal of E. risdonii genes into the range of E. amygdalina. This pollen flow can have a significant genetic impact, since isolated hybrids or patches of abnormal phenotypes have been found 200–300 m from the species boundary. Based on lignotuber size, some of these patches appear to have been founded by F₁ hybrids. The frequency of E. risdonii types in the patches appears to increase with patch size suggesting that there is selection for this phenotype in subsequent generations. E. risdonii-like individuals were recovered in the progeny from both intermediate and E. risdonii backcross phenotypes. These results suggest that E. risdonii may invade suitable habitat islands within the E. amygdalina forest, independently of seed migration, by long-distance pollen migration followed by selection for the gene combinations of the pollen parent.