Common variants show predicted polygenic effects on height in the tails of the distribution, except in extremely short individuals

Common genetic variants have been shown to explain a fraction of the inherited variation for many common diseases and quantitative traits, including height, a classic polygenic trait. The extent to which common variation determines the phenotype of highly heritable traits such as height is uncertain, as is the extent to which common variation is relevant to individuals with more extreme phenotypes. To address these questions, we studied 1,214 individuals from the top and bottom extremes of the height distribution (tallest and shortest ∼1.5%), drawn from ∼78,000 individuals from the HUNT and FINRISK cohorts. We found that common variants still influence height at the extremes of the distribution: common variants (49/141) were nominally associated with height in the expected direction more often than is expected by chance (p<5×10⁻²⁸), and the odds ratios in the extreme samples were consistent with the effects estimated previously in population-based data. To examine more closely whether the common variants have the expected effects, we calculated a weighted allele score (WAS), which is a weighted prediction of height for each individual based on the previously estimated effect sizes of the common variants in the overall population. The average WAS is consistent with expectation in the tall individuals, but was not as extreme as expected in the shortest individuals (p<0.006), indicating that some of the short stature is explained by factors other than common genetic variation. The discrepancy was more pronounced (p<10⁻⁶) in the most extreme individuals (height<0.25 percentile). The results at the extreme short tails are consistent with a large number of models incorporating either rare genetic non-additive or rare non-genetic factors that decrease height. We conclude that common genetic variants are associated with height at the extremes as well as across the population, but that additional factors become more prominent at the shorter extreme.     

Predicting the effects of climate change on population connectivity and genetic diversity of an imperiled freshwater mussel,Cumberlandia monodonta (Bivalvia: Margaritiferidae), in riverine systems

In the face of global climate change, organisms may respond to temperature increases by shifting their ranges poleward or to higher altitudes. However, the direction of range shifts in riverine systems is less clear. Because rivers are dendritic networks, there is only one dispersal route from any given location to another. Thus, range shifts are only possible if branches are connected by suitable habitat, and stream‐dwelling organisms can disperse through these branches. We used Cumberlandia monodonta (Bivalvia: Unionoida: Margaritiferidae) as a model species to investigate the effects of climate change on population connectivity because a majority of contemporary populations are panmictic. We combined ecological niche models (ENMs) with population genetic simulations to investigate the effects of climate change on population connectivity and genetic diversity of C. monodonta. The ENMs were constructed using bioclimatic and landscape data to project shifts in suitable habitat under future climate scenarios. We then used forward‐time simulations to project potential changes in genetic diversity and population connectivity based on these range shifts. ENM results under current conditions indicated long stretches of highly suitable habitat in rivers where C. monodonta persists; populations in the upper Mississippi River remain connected by suitable habitat that does not impede gene flow. Future climate scenarios projected northward and headwater‐ward range contraction and drastic declines in habitat suitability for most extant populations throughout the Mississippi River Basin. Simulations indicated that climate change would greatly reduce genetic diversity and connectivity across populations. Results suggest that a single, large population of C. monodonta will become further fragmented into smaller populations, each of which will be isolated and begin to differentiate genetically. Because C. monodonta is a widely distributed species and purely aquatic, our results suggest that persistence and connectivity of stream‐dwelling organisms will be significantly altered in response to future climate change.     

The effect of maternal omega-3 long-chain polyunsaturated fatty acid (n-3 LCPUFA) supplementation during pregnancy and/or lactation on body fat mass in the offspring: a systematic review of animal studies

Dietary n-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) reduce adipogenesis and lipogenesis in adult rodents, but it is not clear whether an increased n-3 LCPUFA supply during the perinatal period influences body fat mass in the offspring. This systematic review aimed to evaluate the existing evidence from animal studies, which have addressed this question. Medline was searched for relevant articles. Studies were included if they involved maternal n-3 PUFA or LCPUFA supplementation and measured fat mass in the offspring. The design and quality of each study was assessed. Only four animal studies met our inclusion criteria. Three studies reported a lower fat mass in offspring of n-3 LCPUFA supplemented dams, however only one of these studies confined the intervention to the perinatal period. The dose of n-3 PUFA, the nature of the control treatment, the approaches used and outcomes assessed differed between studies. This review highlights the paucity of robust animal data as to the effect of increased n-3 LCPUFA exposure during the perinatal period alone, on body fat mass in the offspring and calls for further studies.     

The artificial incubation of crayfish eggs: review and report from an experimental study concerning the effects of offspring origin (maternal or artificial incubation) on the survival and growth of juvenile signal crayfish (Pacifastacus leniusculus, Astacidae)

The development of artificial incubation techniques in astacid crayfish has attracted attention from scientists in many countries ever since the nineteenth century. It is only in the last few years that these techniques, along with studies on egg storage and transport, have provided reliable options for improving the reproductive phase in farming. The juveniles produced need to be reared until they reach a sufficient size both for restocking and for growing purposes. In view of the current level of knowledge of rearing juvenile astacids, two 80-day experiments were carried out under controlled conditions to compare the survival and growth of Stage 2 juvenile signal crayfish (Pacifastacus leniusculus) from two origins: maternal or artificial incubation. In the first experiment, three treatments were tested: juveniles from artificially incubated eggs with formaldehyde treatments, juveniles from maternal incubation and a mixture from both origins (50% each). Survival rates ranged from 87.8% to 93.3% with no significant differences among treatments. Crayfish from artificial incubation grew significantly faster (11.47 mm carapace length (CL), 373.80 mg weight) than crayfish from maternal incubation. In the second experiment, a bifactorial design included four treatments: the crayfish was derived from artificial or from maternal incubation and was fed once a day or twice a day. Final survival rates ranged from 68.89% to 77.78%, with no significant differences among treatments. Crayfish from artificial incubation grew significantly faster than crayfish from maternal incubation. The highest CL (14.54 mm) and weight (780.13 mg) were reached by the juveniles from artificial incubation that were fed once a day. No significant differences were found between the two feeding frequencies. Results showed that artificial incubation with formaldehyde treatments had no harmful effects and made it feasible to get a better performance from the juveniles obtained.     

Effect of maternal tobacco smoking or exposure to second-hand smoke on the levels of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) in urine of mother and the first urine of newborn

Tobacco smoking during pregnancy is associated with a variety of negative consequences not only for the mother, but also for the developing fetus. Many studies have shown that carcinogens contained in tobacco smoke permeate across the placenta, and are found in fetus. The aim of the study was to determine the prenatal exposure to tobacco-specific carcinogenic N-nitrosamines on the basis of measurements of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) in urine of smoking and second-hand smoke (SHS) exposed women and in the first urine of their newborns. A questionnaire documenting demographics and socio-economical data, smoking habits and exposure to SHS was completed by 121 delivering women near or at term. Maternal concentrations of cotinine and NNAL were measured in urine of the mother and the first urine of her newborn infant by liquid chromatography tandem mass spectrometry (LC/MS/MS). The mean concentration of cotinine was 439.2 ng/mg creatinine and NNAL concentration in urine of smoking women was 74.0 pg/mg creatinine, and for her newborn 78.6 pg/mg creatinine. Among mothers exposed to SHS, cotinine and NNAL mean concentration were 23.1 ng/mg creatinine, and 26.4 pg/mg creatinine. In newborns of SHS exposed mothers during pregnancy the mean concentration of NNAL was 34.1 pg/mg creatinine, respectively. Active tobacco smoking as well as passive exposure to smoking during pregnancy is an important source of tobacco specific N-nitrosamines to the fetuses as evidenced by increased concentrations of this carcinogen. Determination of NNAL in maternal urine samples can be a useful biomarker of prenatal exposure of newborn to carcinogenic nitrosamines.     

Urinary metabonomics study on the protective effects of ergosta-4,6,8(14),22-tetraen-3-one on chronic renal failure in rats using UPLC Q-TOF/MS and a novel MSE data collection technique

Ergosta-4,6,8(14),22-tetraen-3-one (ergone), isolated from the medicinal fungus Polyporus umbellatus, has been proven to prevent the progression of renal injury and the subsequent renal fibrosis. UPLC Q-TOF/MS was employed to investigate the metabonomic characteristics of adenine-induced chronic renal failure (CRF) and the proactive effects of ergone. The significant difference of the metabolic profiling was observed from ergone-treated group compared with the CRF model group during the 10-day and 20-day study periods by using the principal components analysis (PCA). The significant difference of the ergone-treated group in metabolic profiling was also observed between 10-day and 20-day study periods. The time-dependent tendency in ergone-treated group from day 10 to 20 was obtained, indicating the time-dependent recovery effect of ergone on CRF rats. Some significantly changed metabolites like creatinine, proline, adrenosterone, taurine, creatine, phenylalanine, ornithine, dopamine, kynurenine, kynurenic acid and 3-O-methyldopa have been identified during the 20-day study period. These biochemical changes are related to the disturbance in energy metabolism and amino acid metabolism, which are helpful to further understand the CRF and the therapeutic mechanism of ergone. This work suggests that this metabonomic approach could be used as a potentially powerful tool to investigate the biochemical changes of certain physiopathological conditions, such as metabolic syndrome, as an early diagnostic measure.     

Specific ion influences on self-association of pyruvate dehydrogenase kinase isoform 2 (PDHK2), binding of PDHK2 to the L2 lipoyl domain, and effects of the lipoyl group-binding site inhibitor, Nov3r

Association of the PDHK2 and GST-L2 (glutathione-S-transferase fused to the inner lipoyl domain (L2) of dihydrolipoyl acetyltransferase (E2)) dimers was enhanced by K+ with higher affinity K+ binding than occurs at the PDHK2 active site. Supporting a distinct K+ binding site, the NH4+ ion did not effectively replace K+ in aiding GST-L2 binding. With 50 mM K+, Pi enhanced interference by ADP, ATP, or pyruvate of PDHK2 binding to GST-L2. The inclusion of Pi with ADP or ATP plus pyruvate greatly hindered PDHK2 binding to GST-L2 and promoted PDHK2 forming a tetramer. Reciprocally, GST-L2 interference with ATP/ADP binding also required elevated K+ and was increased by Pi. Potent inhibition by Nov3r of E2-activated PDHK2 activity (IC50 of approximately 7.8 nM) required elevated K+ and Pi. Nov3r only modestly inhibited the low activity of PDHK2 without E2. By binding at the lipoyl group binding site, Nov3r prevented PDHK2 binding to E2 and GST-L2. Nov3r interfered with high-affinity binding of ADP and pyruvate via a Pi-dependent mechanism. Thus, GST-L2 binding to PDHK2 is supported by K+ binding at a site distinct from the active site. Pi makes major contributions to ligands interfering with PDHK2 binding to GST-L2, the conversion of PDHK2 dimer to a tetramer, and Nov3r (an acetyl-lipoate analog) interfering with binding of ADP and pyruvate. Pi is suggested to facilitate transmission within PDHK2 of the stimulatory signal of acetylation from the distal lipoyl-group binding site to the active site.     

Design and synthesis of 5-[(2-chloro-6-fluorophenyl)acetylamino]-3-(4-fluorophenyl)-4-(4-pyrimidinyl)isoxazole (AKP-001), a novel inhibitor of p38 MAP kinase with reduced side effects based on the antedrug concept

Inhibitors of p38 mitogen-activated protein (MAP) kinase, which are closely involved in the production of inflammatory cytokines, are considered promising curative drugs for chronic inflammatory disorders. However, there is also a growing concern regarding its systemic side effects. To reduce the occurrence of side effects, we have identified a novel p38 MAP kinase inhibitor that shows properties of an antedrug, which imparts its effect solely on the inflammatory site and is metabolically inactivated right after. We have designed isoxazole derivatives through the addition of a fresh interacting fourth site to the structure of the prototypical p38 MAP kinase inhibitor that harbors three point interactive sites. The derivative 26d (AKP-001) shows excellent p38 MAP kinase inhibitory activity and a high selectivity for various kinases. Its rapid metabolism has been confirmed in rats. Moreover, 26d has been shown to be effective in animal models of inflammatory bowel disease.     

Comparative effects of three 1,4-dihydropyridine derivatives [OSI-1210, OSI-1211 (etaftoron), and OSI-3802] on rat liver mitochondrial bioenergetics and on the physical properties of membrane lipid bilayers: relevance to the length of the alkoxyl chain in positions 3 and 5 of the DHP ring

The 1,4-dihydropyridines OSI-1210, OSI-1211 (etaftoron), and OSI-3802 are compounds with similar chemical structure. They differ by the length of the alkoxyl chain in positions 3 and 5 of the dihydropyridine (DHP) ring and by their pharmacological action characteristics. However, as far as we know, a clear relationship between the effects of these compounds and the length of the alkoxyl chain in positions 3 and 5 of the DHP has not been established. The goal of this study was to compare the influence of OSI-1210, OSI-1211 (etaftoron), and OSI-3802 on rat liver mitochondrial bioenergetics and on the physical properties of membrane lipid bilayers, correlating their actions with the length of the alkoxyl chain in positions 3 and 5 of the DHP ring. Using either glutamate/malate or succinate as respiratory substrates, all the compounds, in concentrations of up to 500 microM, depressed state 3 and uncoupled respiration, respiratory control (RCR) and ADP/O ratios, and phosphorylation rate, whereas state 4 respiration was stimulated. However, the stimulatory effect on state 4 induced by OSI-3802, the compound with the longest chain in positions 3 and 5 of the DHP ring, as well as its inhibitory effects on RCR and ADP/O ratios and phosphorylation rate were more pronounced than that induced by OSI-1210 and OSI-1211 (etaftoron), the compounds with the shortest and intermediate chains, respectively. Moreover, OSI-3802 maximized state 4 stimulation and minimized RCR and ADP/O ratios, and phosphorylation rate at a concentration of 100 microM, whereas low graduate effects were detected with OSI-1210 and OSI-1211 (etaftoron) for concentrations of up to 500 microM. At low concentrations (< or =30 microM), OSI-3802, like its analogue OSI-1212 (cerebrocrast), reduced the phase transition temperature, the cooperative unit size, and the enthalpy associated with the phase transition temperature of dimyristoylphosphatidylcholine (DMPC) membrane bilayers. A good correlation was established between the effects of 200 microM OSI-1210, OSI-1211 (etaftoron), and OSI-3802 on glutamate/malate- and succinate-dependent RCR of rat liver mitochondria and on the enthalpy change (Delta H) for the thermotropic profile of DMPC membrane bilayers at a 0.2 drug/DMPC molar ratio, indicating that the changes induced by these compounds on both mitochondrial membrane integrity and physical properties of DMPC membrane bilayers are strongly related to the length of the alkoxyl chain in positions 3 and 5 of the DHP ring. A putative relationship between membrane physical perturbation, bioenergetics impairment and the molecular characteristics of the compounds will be established as an approach to better understand their differentiated toxicological and pharmacological actions.