Shared HLA antigens and reproductive performance among Hutterites.

Shared histocompatibility antigens between spouses may affect reproductive outcome adversely as a result of prenatal selection against compatible fetuses. Evidence from both animal and human studies suggest that histocompatible fetuses may not initiate a maternal immunologic response that prevents rejection of the embryo. Therefore, parents sharing HLA antigens may produce compatible fetuses and consequently experience a greater frequency of early fetal losses and show poorer reproductive outcome than couples not sharing antigens. In the Hutterites, an inbred human isolate that proscribes contraception, we tested the hypothesis that couples sharing HLA antigens have poorer reproductive outcomes than couples who do not. The Hutterites are characterized by high fertility and large family sizes. Couples that share zero (no. = 21), one (no. = 15), and more than one (no. = 10) HLA-A or HLA-B antigens were compared for reproductive performance. Median intervals between births were larger among couples that share more than one antigen in eight of 11 intervals examined. In addition, the median intervals from marriage to first, fifth, and tenth birth were consistently larger among couples that share more than one antigen. Differences among the groups appear to become larger with increasing parity, suggesting that the effect of histocompatibility on reproductive performance becomes more evident in later pregnancies. These differences in reproductive performance between couples that share zero, one, or more than one HLA-A or HLA-B antigens may have significant evolutionary consequences. However, our results demonstrate that sharing HLA antigens does not preclude normal pregnancy and caution should be exercised before concluding that shared HLA antigens are solely responsible for repeated fetal losses.     

On processes determining the vertical stability of surface waters in the marginal ice zone of the north-western Weddell Sea and their relationship with phytoplankton bloom development

Summary Ice-edge-related phytoplankton blooms following the retreating sea-ice in the marginal ice zone are frequently observed phenomena. Such blooms are generally short-lived and are followed by a strong decrease in the chlorophyll concentration towards the open ocean, generally explained by the degradation of the vertical stability. Solar heating and ice melting, which control the stability of the surface water of the north-western Weddell Sea during sea-ice retreat in spring were analysed in order to relate the spatial features of the phytoplankton ice-edge bloom in 1988 to the density field. Solar heating has little effect on the density of seawater in ice-covered areas because the thermal expansion coefficient is very low close to the freezing temperature. Outside the marginal ice zone, the temperature effect on stratification increases and the combined contribution of melting and heating on buoyancy input to the surface layer is roughly constant. As a consequence, the low phytoplankton stocks in the open ocean adjacent to the marginal ice zone, after an initial bloom peak following the retreating ice in spring, are not necessarily caused by deep turbulent mixing, in contrast to what is often assumed.Data presented here were collected during the European Polarstern Study (EPOS) sponsored by the European Science Foundation     

Effects of diazepam on photosynthesis,respiration, rubidium uptake,and finestructure of Scenedesmus obliquus in synchronous cultures

Effects of diazepam (Valium) on photosynthesis, chlorophyll/photosynthesis ratios, respiration, uptake of rubidium ions, and ultrastructure of Scenedesmus obliquus synchronized by a light-dark regimen of \(14:\overline {10}\) hrs were determined. 80 and 160 μM diazepam, added to the nutrient medium at the start of the light-dark change (i.e., start of the cell cycle) gradually reduced rates of photosynthesis below the initial rates from the beginning of the experiment. Contents of chlorophyll, however, remained nearly unaffected. Consequently, the diazepam-treated cells had a higher chlorophyll/photosynthesis ratio—also with regard to respiration in order to calculate the gross photosynthesis. The occurrence of photorespiration cannot be assumed. The net influx or rubidium was slightly reduced by 100 μM diazepam 0.5 and 2.0 hrs after the start of the cell cycle and was strongly inhibited after 5 to 14 hrs. 80 and 160 μM diazepam caused separation of thylakoids, formation of giant mitochondria and enlargement of vacuoles. The results are discussed and it is finally suggested that diazepam acts on different membrane systems. Furthermore an ATP deficiency cannot be excluded.     

Engineering the Fc region of immunoglobulin G to modulate in vivo antibody levels

We have engineered the Fc region of a human immunoglobulin G (IgG) to generate a mutated antibody that modulates the concentrations of endogenous IgGs in vivo. This has been achieved by targeting the activity of the Fc receptor, FcRn, which serves through its IgG salvage function to maintain and regulate IgG concentrations in the body. We show that an IgG whose Fc region was engineered to bind with higher affinity and reduced pH dependence to FcRn potently inhibits FcRn-IgG interactions and induces a rapid decrease of IgG levels in mice. Such FcRn blockers (or 'Abdegs,' for antibodies that enhance IgG degradation) may have uses in reducing IgG levels in antibody-mediated diseases and in inducing the rapid clearance of IgG-toxin or IgG-drug complexes.     

Gene-environment interaction effects on the development of immune responses in the 1st year of life

Asthma is a common disease that results from both genetic and environmental risk factors. Children attending day care in the 1st year of life have lower risks for developing asthma, although the mechanism for this "day care" effect is largely unknown. We investigated the interactions between day care exposure in the 1st 6 mo of life and genotypes for 72 polymorphisms at 45 candidate loci and their effects on cytokine response profiles and on the development of atopic phenotypes in the 1st year of life in the Childhood Onset of Asthma (COAST) cohort of children. Six interactions (at four polymorphisms in three loci) with "day care" that had an effect on early-life immune phenotypes were significant at P<.001. The estimated false-discovery rate was 33%, indicating that an estimated four P values correspond to true associations. Moreover, the "day care" effect at some loci was accounted for by the increased number of viral infections among COAST children attending day care, whereas interactions at other loci were independent of the number of viral infections, indicating the presence of additional risk factors associated with day care environment. This study identified significant gene-environment interactions influencing the early patterning of the immune system and the subsequent development of asthma and highlights the importance of considering environmental risk factors in genetic analyses.     

Variation in ITGB3 has sex-specific associations with plasma lipoprotein(a) and whole blood serotonin levels in a population-based sample

A recent genome-scan identified the Leu33Pro polymorphism in the 3 integrin (ITGB3) gene as a quantitative trait locus for whole blood serotonin level in a large Hutterite pedigree. Because both the Leu33Pro polymorphism and the serotonin system have been implicated in cardiovascular disease (CVD) risk and treatment response, we studied additional variation in ITGB3 and its relationship to intermediate phenotypes associated with CVD in the same population. We examined associations between 15 single nucleotide polymorphisms (SNPs) across ITGB3 and five CVD-related traits in the Hutterites: plasma levels of high density lipoprotein-cholesterol (HDL-c), triglycerides (TG), low density lipoprotein-cholesterol (LDL-c), and lipoprotein(a) [Lp(a)] and blood pressure or hypertension. Seven of these SNPs in ITGB3 were associated with whole blood serotonin. Among the intermediate CVD-related phenotypes, only Lp(a) was associated with multiple ITGB3 SNPs, five of which were also associated with serotonin. A sex-stratified analysis revealed that the association between ITGB3 and Lp(a) is present only in females, whereas the association between ITGB3 and serotonin is concentrated in males. Our results suggest that variation in ITGB3 in addition to Leu33Pro could contribute to susceptibility to CVD and serotonin in a sex-specific manner.     

HLA and mate choice in humans.

Evidence from studies in rodents suggests that mate selection is influenced by major-histocompatibility-complex haplotypes, with preferences for dissimilar partners. This study was initiated to determine whether avoidance of a mate with the same HLA haplotype as one's own might be occurring in the Hutterites, a North American reproductive isolate of European ancestry, notable for their large sibships, communal lifestyle, and limited number of five-locus HLA haplotypes (HLA-A, -B, -C, -DR, and -DQ). HLA haplotypes were known for 411 Hutterite couples. The number of couples expected to match for a haplotype was calculated in two ways: first, from population genotype frequencies, with account being taken of the nonrandom mating pattern with respect to colony lineages, and, second, from computer simulations using conservative founder assumptions and the exact genealogy of the 411 couples. We observed fewer matches for HLA haplotypes between spouses than expected (first method, P = .005; second method, P = .020-.067). Among couples who did match for a haplotype, the matched haplotype was inherited from the mother in 29 cases and from the father in 50 cases (P = .018). These results are consistent with the conclusion that Hutterite mate choice is influenced by HLA haplotypes, with an avoidance of spouses with haplotypes that are the same as one's own.     

Demographic components of gene frequency change in free-ranging macaques on Cayo Santiago

Gene frequency profiles from January 1973 to January 1977 for three polymorphic loci were examined in Cayo Santiago rhesus social groups. The effects of demographic components (i.e., births, deaths, immigrations, emigrations, and group fission and fusion) on total change in gene frequencies are assessed. Allelic frequencies at the carbonic anhydrase II, 6-phosphogluconate dehydrogenase, and transferrin loci were analyzed in four social groups. In the two groups that underwent fission and fusion during the study period, the timing of these processes was related to the largest short-term changes in gene frequences. However, immigration and emigration had the greatest effect on total change in gene frequency in all groups during the study period. The relative importance of births and deaths in producing gene frequency change varied among the social groups. These results suggest that the relative importance of the demographic components of gene frequency change in primate populations is determined by behavioral patterns and ecological conditions specific to the population considered.     

Root Growth and Oxygen Relations at Low Water Potentials. Impact of Oxygen Availability in Polyethylene Glycol Solutions

Polyethylene glycol (PEG), which is often used to impose low water potentials (ψ_w) in solution culture, decreases O₂ movement by increasing solution viscosity. We investigated whether this property causes O₂ deficiency that affects the elongation or metabolism of maize (Zea mays L.) primary roots. Seedlings grown in vigorously aerated PEG solutions at ambient solution O₂ partial pressure (pO₂) had decreased steady-state root elongation rates, increased root-tip alanine concentrations, and decreased root-tip proline concentrations relative to seedlings grown in PEG solutions of above-ambient pO₂ (alanine and proline accumulation are responses to hypoxia and low ψ_w, respectively). Measurements of root pO₂ were made using an O₂ microsensor to ensure that increased solution pO₂ did not increase root pO₂ above physiological levels. In oxygenated PEG solutions that gave maximal root elongation rates, root pO₂ was similar to or less than (depending on depth in the tissue) pO₂ of roots growing in vermiculite at the same ψ_w. Even without PEG, high solution pO₂ was necessary to raise root pO₂ to the levels found in vermiculite-grown roots. Vermiculite was used for comparison because it has large air spaces that allow free movement of O₂ to the root surface. The results show that supplemental oxygenation is required to avoid hypoxia in PEG solutions. Also, the data suggest that the O₂ demand of the root elongation zone may be greater at low relative to high ψ_w, compounding the effect of PEG on O₂ supply. Under O₂-sufficient conditions root elongation was substantially less sensitive to the low ψ_w imposed by PEG than that imposed by dry vermiculite.