An islet-specific pulse of TGF-β abrogates CTL function and promotes β cell survival independent of Foxp3+ T cells

Effective therapies that prevent chronic inflammation from developing into type 1 diabetes remain elusive. In this study, we show that expression of TGF-β for just 1 wk in inflamed islets of NOD mice significantly delays diabetes development. Time course studies demonstrated that the brief TGF-β pulse protects only if administered when extensive β cell destruction has occurred. Surprisingly, TGF-β-mediated protection is not linked to enhanced Foxp3(+) regulatory T cell activity or to decreased intrapancreatic presentation of islet Ags. Instead, TGF-β disables the transition of primed autoreactive CD8(+) T cells to cytotoxic effectors and decreases generation, or maintenance, of CD8(+) memory T cells within the pancreas, significantly impairing their diabetogenic capacity.     

Position-specific suppression and enhancement of HIV-1 integrase reactions by minor groove benzo[a]pyrene diol epoxide deoxyguanine adducts: implications for molecular interactions between integrase and substrates

The viral protein HIV-1 integrase is required for insertion of the viral genome into human chromosomes and for viral replication. Integration proceeds in two consecutive integrase-mediated reactions: 3'-processing and strand transfer. To investigate the DNA minor groove interactions of integrase relative to known sites of integrase action, we synthesized oligodeoxynucleotides containing single covalent adducts of known absolute configuration derived from trans-opening of benzo-[a]pyrene 7,8-diol 9,10-epoxide by the exocyclic 2-amino group of deoxyguanosine at specific positions in a duplex sequence corresponding to the terminus of the viral U5 DNA. Because the orientations of the hydrocarbon in the minor groove are known from NMR solution structures of duplex oligonucleotides containing these deoxyguanosine adducts, a detailed analysis of the relationship between the position of minor groove ligands and integrase interactions is possible. Adducts placed in the DNA minor groove two or three nucleotides from the 3'-processing site inhibited both 3'-processing and strand transfer. Inosine substitution showed that the guanine 2-amino group is required for efficient 3'-processing at one of these positions and for efficient strand transfer at the other. Mapping of the integration sites on both strands of the DNA substrates indicated that the adducts both inhibit strand transfer specifically at the minor groove bound sites and enhance integration at sites up to six nucleotides away from the adducts. These experiments demonstrate the importance of position-specific minor groove contacts for both the integrase-mediated 3'-processing and strand transfer reactions.     

Obesity and Quality of Life: Mediating Effects of Pain and Comorbidities

Objective: To estimate the association between body mass index (BMI) and health‐related quality of life (HRQL) and examine whether joint pain and obesity‐related comorbidities mediate the BMI‐HRQL association. Research Methods and Procedures: Population‐based survey data from the 1999 Behavioral Risk Factor Surveillance Survey. Adults (N = 155, 989) were classified according to BMI as underweight (<18.5 kg/m²), desirable weight (18.5 to 24.9 kg/m²), overweight (25 to 29.9 kg/m²), obese class I (30 to 34.9 kg/m²), obese class II (35 to 39.9 kg/m²), and obese class III (≥40 kg/m²). Data including general health status, unhealthy days in the past 30 caused by physical problems and mental problems, and total unhealthy days in the past 30 were collected. Results: After adjusting for age, sex, race, smoking, education, and income, we observed J‐shaped associations between BMI and HRQL. Compared with desirable weight adults, underweight, overweight, and obesity classes I, II, and III adults [odds ratio (OR) = 1.57, 1.19, 1.95, 2.72, and 4.36, respectively] were significantly (p < 0.001) more likely to report fair/poor general health status. For unhealthy days caused by physical problems, the corresponding ORs were 1.51, 1.15, 1.66, 2.27, and 3.61 (p < 0.001). For unhealthy days caused by mental problems, the ORs were 1.35, 1.14 1.43, 1.57, and 2.25 (p < 0.001). For total unhealthy days, the corresponding ORs were 1.27, 1.09, 1.37, 1.73, and 2.46 (p < 0.01). Adding joint pain and obesity‐related comorbidities into models attenuated BMI‐HRQL associations. Discussion: Associations between BMI and HRQL indices were J‐shaped. Joint pain and comorbidities may mediate BMI‐HRQL associations.     

Detection of ruminal bacteria that degrade toxic dihydroxypyridine compounds produced from mimosine.

Leucaena leucocephala, a tropical leguminous shrub, contains a toxic amino acid, mimosine. Successful utilization of leucaena as a ruminant forage depends on colonization of the rumen by bacteria that degrade dihydroxypyridines (DHP), which are toxic intermediates in the metabolism of mimosine. Populations in the rumina of animals in some parts of the world, however, do not include bacteria that are able to carry out this degradation. We thus describe tests for the presence of DHP degraders in ruminal populations that are based on degradation (loss) of DHP compounds from culture media. Results obtained with the tests indicate that DHP degraders were not part of microbial populations in the rumina of cattle, sheep, and goats in Iowa, while most rumen samples examined from animals from the Virgin Islands and Haiti contained DHP degraders. These results confirm and extend the findings of others about geographic limits to the distribution of these important ruminal bacteria.     

Effect of nutritionally induced liveweight differences on ovulation rates and the population of ovarian follicles in ewes

Differential feeding prior to the onset of the breeding season resulted in mean liveweight differences of 12 kg in two groups of Romney ewes. This difference was maintained while ovulation rates and the population of externally visible ovarian follicles were measured. The ovulation rate at first oestrus was significantly higher in the high liveweight group but there was no difference between groups thereafter. High liveweight ewes had consistently higher mean follicle scores at all stages of the oestrous cycle. Mean follicle score was lower following the third oestrus than following first oestrus (P < 0.01).     

Do Leptin Levels Predict Weight Gain?—A 5-Year Follow-Up Study in Mauritius

Objective : To investigate whether relative baseline leptin levels predict long-term changes in adiposity and/or its distribution. Research Methods and Procedures : In a longitudinal study of 2888 nondiabetic Mauritians aged 25 years to 74 years who participated in population-based surveys in 1987 and 1992, changes in body mass index (BMI), waist/hip ratio (WHR), and waist circumference were compared between “hyperleptinemic,” “normoleptinemic,” and “hypoleptinemic” groups. “Relative leptin levels” were calculated as standardized residuals from the regression of log₁₀ leptin on baseline BMI to provide a leptin measure independent of BMI. Analyses were performed within each sex. A linear regression model was used to assess the effect of standardized residuals on changes in BMI, WHR, and waist circumference, independent of baseline BMI, age, fasting insulin, and ethnicity. Results : After adjusting for age and baseline BMI by analysis of covariance, there was no difference in changes in BMI, WHR, or waist circumference between men with low, normal, or high relative leptin levels. Among women, there was a significant difference in ΔWHR across leptin groups, such that the largest increase occurred in the “normal” leptin group. For both men and women, the linear regression models explained ?10% of variation in dependent variables, and the only significant independent variables were age, BMI, and being of Chinese origin, compared with Indian origin. Discussion : These findings do not support a role for leptin concentration in predicting weight gain or changes in fat distribution in adults over a 5-year period.     

Kairomonal Responses of Natural Enemies and Associates of the Southern Ips (Coleoptera: Curculionidae: Scolytinae) to Ipsdienol, Ipsenol and Cis-Verbenol

Bark beetle infested pines are an ephemeral habitat utilized by a diverse assemblage of insects. Although many bark beetle insect associates have little or no measurable impact on bark beetle brood production, some reduce brood production by either competing with brood for the limited phloem tissue or by feeding on brood. Several studies have observed synchrony between the colonization of hosts by bark beetles and the arrival of insect associates. Some insect associates mediate synchrony with bark beetle mass attacks with kairomonal responses to bark beetle aggregation pheromones. The objectives of this study were to document the community of Coleoptera associated with the southern Ips (Ips avulsus, Ips calligraphus and Ips grandicollis) and to test the hypothesis that synchrony of insect associates with the southern Ips is mediated by kairomonal responses to aggregation pheromones. A large community of Coleoptera (109 species) was recorded from traps baited with southern Ips pheromones. A significant treatment effect was observed for the guilds of meristem feeders, natural enemies and woodborers. The southern Ips pheromone ipsenol was broadly attractive to meristem feeders, natural enemies and woodborers and in general blends were more attractive than individual compounds. These results demonstrate that a diverse community of Coleoptera is associated with the southern Ips and that several members of this community facilitate synchrony with kairomonal responses to southern Ips aggregation pheromones.     

PHI-1 induced enhancement of myosin phosphorylation in chicken smooth muscle

Herein, we provide evidence that in chicken smooth muscle, G-protein stimulation by a Rho-kinase pathway leads to an increase in myosin light chain phosphorylation. Additionally, G-protein stimulation did not increase MYPT1 phosphorylation at Thr695 or Thr850, and CPI-17, was not expressed in chicken smooth muscle. However, PHI-1 was present in chicken smooth muscle tissues. Both agonist and GTP(gamma)S stimulation result in an increase in PHI-1 phosphorylation, which is inhibited by inhibitors to both Rho-kinase (Y-27632) and (PKC) GF109203x. These data suggest that PHI-1 may act as a CPI-17 analog in chicken smooth muscle and inhibit myosin phosphatase activity during G-protein stimulation to produce Ca2+ sensitization.     

Observations on the Vietnam Palo Alto strain of Plasmodium vivax in two species of Aotus monkeys

Thirty-three splenectomized Aotus lemurinus griseimembra monkeys with no previous experience with malaria were infected with the Vietnam Palo Alto strain of Plasmodium vivax. The median maximum parasite count was 280,000/microl. Nine splenectomized monkeys with previous infection with Plasmodium falciparum had median maximum parasite counts of 120,000/microl. Splenectomized Aotus nancymai monkeys supported infections at a lower level. Transmission via the bites of Anopheles dirus mosquitoes was obtained in a splenectomized A. lemurinus griseimembra, with a prepatent period of 31 days. It is estimated that between 1.5 x 10(8) and 1.6 x 10(9) parasites can be removed from an infected animal for molecular or diagnostic antigenic studies.