Steered molecular dynamics simulations of ligand–receptor interaction in lipocalins

Retinol binding protein (RBP) and an engineered lipocalin, DigA16, have been studied using molecular dynamics simulations. Special emphasis has been placed on explaining the ligand–receptor interaction in RBP–retinol and DigA16–digoxigenin complexes, and steered molecular dynamics simulations of 10–20 ns have been carried out for the ligand expulsion process. Digoxigenin is bound deep inside the cavity of DigA16 and forms several stable hydrogen bonds in addition to the hydrophobic van der Waals interaction with the aromatic side-chains. Four crystalline water molecules inside the ligand-binding cavity remain trapped during the simulations. The strongly hydrophobic receptor site of RBP differs considerably from DigA16, and the main source of ligand attraction comes from the phenyl side-chains. The hydrogen bonds between digoxigenin and DigA16 cause the rupture forces on ligand removal in DigA16 and RBP to differ. The mutated DigA16 residues contribute approximately one-half of the digoxigenin interaction energy with DigA16 and, of these, the energetically most important are residues His35, Arg58, Ser87, Tyr88, and Phe114. Potential “sensor loops” were found for both receptors. These are the outlier loops between residues 114–121 and 63–67 for DigA16 and RBP, respectively, and they are located near the entrance of the ligand-binding cavity. Especially, the residues Glu119 (DigA16) and Leu64 (RBP) are critical for sensing. The ligand binding energies have been estimated based on the linear response approximation of binding affinity by using a previous parametrization for retinoids and RBP.     

Aviation noise does not impair the reproductive success of farmed blue foxes

The aim of our study was to assess the effects of aviation noise on reproduction and cub mortality in farmed blue foxes. Eighty artificially inseminated blue fox vixens (45 primiparous and 35 multiparous) were exposed to aviation noise on 5 days when they were pregnant or had cubs. The noise during the exposures varied from 85 to 121 dB (L(AFmax)). Vixens (45 primiparous and 34 multiparous) on a farm without flight action acted as controls. Cubs were counted 1, 3, 7, 14 and 49 days postpartum and at the beginning of July. Litter size (cubs per whelped vixen), reproductive performance (cubs per mated vixen) and cub losses (lost cubs per whelped vixen) were analyzed from both experimental farms (A and C). The flight action had no effect on reproductive success. Reproductive performance in primiparous vixens was 4.2+/-3.8 and 4.3+/-3.6 cubs (ns, Mann-Whitney U-test) in the control and aviation group, respectively, while in multiparous vixens the corresponding figures were 7.1+/-4.4 and 7.3+/-3.8 cubs (ns). In general, litter size declined from birth to weaning (in primiparous vixens from 8.1+/-3.8 to 5.4+/-3.2 cubs, and in multiparous from 9.7+/-3.8 to 7.2+/-3.8 cubs, P<0.001, GLM for repeated measures). The decline was greater in primiparous than in multiparous vixens (P<0.01). There were no differences in total cub losses between the experimental groups (ns). Accordingly, the present results show that exposure to severe and repeated aviation noise does not impair the reproductive success of farmed blue foxes.     

Huntington disease in Finland: a molecular and genealogical study

Summary Huntington disease (HD) is found at exceptionally low frequency in the Finnish population. In this population, linkage disequilibrium was earlier established with markers from the D4S10 and D4S43 loci. We now report a continuation to the restriction fragment length polymorphism haplotype analysis, in combination with a genealogical study of all the Finnish HD families. When the HD pedigrees were systematically traced to the 18th century, only one consanguinity was found, and a high percentage (28%) of the families had foreign ancestors. The majority of the Finnish ancestors were localized to border regions or trade centers of the country following the old postal routes. The observed high risk haplotypes formed with markers from the D4S10 and D4S43 loci were evenly distributed among the HD families in different geographical locations. Consequently, the HD gene(s) has most probably arrived in Finland on several occasions via foreign immigrants during the last few centuries.     

Novel Thermophilic Sulfate-Reducing Bacteria from a Geothermally Active Underground Mine in Japan

Thermophilic sulfate-reducing bacteria were enriched from samples obtained from a geothermal underground mine in Japan. The enrichment cultures contained bacteria affiliated with the genera Desulfotomaculum, Thermanaeromonas, Thermincola, Thermovenabulum, Moorella, “Natronoanaerobium,” and Clostridium. Two novel thermophilic sulfate-reducing strains, RL50JIII and RL80JIV, affiliated with the genera Desulfotomaculum and Thermanaeromonas, respectively, were isolated.     

The Drosophila calcipressin sarah is required for several aspects of egg activation

Activation of mature oocytes initiates development by releasing the prior arrest of female meiosis, degrading certain maternal mRNAs while initiating the translation of others, and modifying egg coverings. In vertebrates and marine invertebrates, the fertilizing sperm triggers activation events through a rise in free calcium within the egg. In insects, egg activation occurs independently of sperm and is instead triggered by passage of the egg through the female reproductive tract ; it is unknown whether calcium signaling is involved. We report here that mutations in sarah, which encodes an inhibitor of the calcium-dependent phosphatase calcineurin, disrupt several aspects of egg activation in Drosophila. Eggs laid by sarah mutant females arrest in anaphase of meiosis I and fail to fully polyadenylate and translate bicoid mRNA. Furthermore, sarah mutant eggs show elevated cyclin B levels, indicating a failure to inactivate M-phase promoting factor (MPF). Taken together, these results demonstrate that calcium signaling is involved in Drosophila egg activation and suggest a molecular mechanism for the sarah phenotype. We also find the conversion of the sperm nucleus into a functional male pronucleus is compromised in sarah mutant eggs, indicating that the Drosophila egg's competence to support male pronuclear maturation is acquired during activation.     

Application of the Red List Index as an indicator of habitat change

For the first time ever, the International Union for Conservation of Nature Red List Index for habitat types was calculated for an entire country, Finland. The RLIs were based on species threat assessments from 2000 and 2010 and included habitat definitions for all 10,131 species of 12 organism groups. The RLIs were bootstrapped to track statistically significant changes. The RLI changes of species grouped by habitats were negative for all habitat types except for forests and rural biotopes which showed a stable trend. Trends of beetles and true bugs were positive in rural and forest habitats. Other 16 observed trends of species group and habitat combinations were negative. Several trends observed were in accordance with studies focusing on particular taxa and habitats, and drivers for their change. This study demonstrates the usefulness of the RLI as a tool for observing habitat change based on species threat assessment data.     

Ten-Year Mortality and Cardiovascular Morbidity in the Finnish Diabetes Prevention Study—Secondary Analysis of the Randomized Trial

Background

The Finnish Diabetes Prevention Study (DPS) was a randomized controlled trial, which showed that it is possible to prevent type 2 diabetes by lifestyle changes. The aim of the present study was to examine whether the lifestyle intervention had an effect on the ten-year mortality and cardiovascular morbidity in the DPS participants originally randomized either into an intervention or control group. Furthermore, we compared these results with a population-based cohort comprising individuals of varying glucose tolerance states.

Methods and Findings

Middle-aged, overweight people with IGT (n = 522) were randomized into intensive intervention (including physical activity, weight reduction and dietary counseling), or control “mini-intervention” group. Median length of the intervention period was 4 years and the mean follow-up was 10.6 years. The population-based reference study cohort included 1881 individuals (1570 with normal glucose tolerance, 183 with IGT, 59 with screen-detected type 2 diabetes, 69 with previously known type 2 diabetes) with the mean follow-up of 13.8 years. Mortality and cardiovascular morbidity data were collected from the national Hospital Discharge Register and Causes of Death Register. Among the DPS participants who consented for register linkage (n = 505), total mortality (2.2 vs. 3.8 per 1000 person years, hazard ratio HR = 0.57, 95% CI 0.21–1.58) and cardiovascular morbidity (22.9 vs. 22.0 per 1000 person years, HR = 1.04, 95% CI 0.72–1.51) did not differ significantly between the intervention and control groups. Compared with the population-based cohort with impaired glucose tolerance, adjusted HRs were 0.21 (95% CI 0.09–0.52) and 0.39 (95% CI 0.20–0.79) for total mortality, and 0.89 (95% CI 0.62–1.27) and 0.87 (0.60–1.27) for cardiovascular morbidity in the intervention and control groups of the DPS, respectively. The risk of death in DPS combined cohort was markedly lower than in FINRISK IGT cohort (adjusted HR 0.30, 95% CI 0.17–0.54), but there was no significant difference in the risk of CVD (adjusted HR 0.88, 95% CI 0.64–1.21).

Conclusions

Lifestyle intervention among persons with IGT did not decrease cardiovascular morbidity during the first 10 years of follow-up. However, the statistical power may not be sufficient to detect small differences between the intervention and control groups. Low total mortality among participants of the DPS compared with individuals with IGT in the general population could be ascribed to a lower cardiovascular risk profile at baseline and regular follow-up.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00518167","term_id":"NCT00518167"}}NCT00518167     

Sex differences in heritability of BMI: a comparative study of results from twin studies in eight countries.

Body mass index (BMI), a simple anthropometric measure, is the most frequently used measure of adiposity and has been instrumental in documenting the worldwide increase in the prevalence of obesity witnessed during the last decades. Although this increase in overweight and obesity is thought to be mainly due to environmental changes, i.e., sedentary lifestyles and high caloric diets, consistent evidence from twin studies demonstrates high heritability and the importance of genetic differences for normal variation in BMI. We analysed self-reported data on BMI from approximately 37,000 complete twin pairs (including opposite sex pairs) aged 20-29 and 30-39 from eight different twin registries participating in the GenomEUtwin project. Quantitative genetic analyses were conducted and sex differences were explored. Variation in BMI was greater for women than for men, and in both sexes was primarily explained by additive genetic variance in all countries. Sex differences in the variance components were consistently significant. Results from analyses of opposite sex pairs also showed evidence of sex-specific genetic effects suggesting there may be some differences between men and women in the genetic factors that influence variation in BMI. These results encourage the continued search for genes of importance to the body composition and the development of obesity. Furthermore, they suggest that strategies to identify predisposing genes may benefit from taking into account potential sex specific effects.