Inflammatory modulation of exercise salience: using hormesis to return to a healthy lifestyle

Most of the human population in the western world has access to unlimited calories and leads an increasingly sedentary lifestyle. The propensity to undertake voluntary exercise or indulge in spontaneous physical exercise, which might be termed "exercise salience", is drawing increased scientific attention. Despite its genetic aspects, this complex behaviour is clearly modulated by the environment and influenced by physiological states. Inflammation is often overlooked as one of these conditions even though it is known to induce a state of reduced mobility. Chronic subclinical inflammation is associated with the metabolic syndrome; a largely lifestyle-induced disease which can lead to decreased exercise salience. The result is a vicious cycle that increases oxidative stress and reduces metabolic flexibility and perpetuates the disease state. In contrast, hormetic stimuli can induce an anti-inflammatory phenotype, thereby enhancing exercise salience, leading to greater biological fitness and improved functional longevity. One general consequence of hormesis is upregulation of mitochondrial function and resistance to oxidative stress. Examples of hormetic factors include calorie restriction, extreme environmental temperatures, physical activity and polyphenols. The hormetic modulation of inflammation, and thus, exercise salience, may help to explain the highly heterogeneous expression of voluntary exercise behaviour and therefore body composition phenotypes of humans living in similar obesogenic environments.

Label-free enrichment of avian Leucocytozoon using flow cytometric sorting

The group of haemosporidian parasites is of general interest to basic and applied science, since several species infect mammals, leading to malaria and associated disease symptoms. Although the great majority of haemosporidian parasites appear in bird hosts, as in the case of Leucocytozoon buteonis, there is little genomic information about genetic aspects of their co-evolution with hosts. Consequently, there is a high need for parasite-enrichment strategies enabling further analyses of the genomes, namely without exposure to DNA-intercalating dyes. Here, we used flow cytometry without an additional labelling step to enrich L. buteonis from infected buzzard blood. A specific, defined area of two-dimensional scattergramms was sorted and the fraction was further analysed. The successful enrichment of L. buteonis in the sorted fraction was demonstrated by Giemsa-staining and qPCR revealing a clear increase of parasite-specific genes, while host-specific genes were significantly decreased. This is the first report describing a labelling-free enrichment approach of L. buteonis from infected buzzard blood. The enrichment of parasites presented here is free of nucleic acid-intercalating dyes which may interfere with fluorescence-based methods or subsequent sequencing approaches.

Genetic association analysis of vitamin D pathway with obesity traits

Objective:Observational studies have examined the link between vitamin D deficiency and obesity traits. Some studies have reported associations between vitamin D pathway genes such as VDR, GC and CYP27B1 with body mass index (BMI) and waist circumference (WC); however, the findings have been inconsistent. Therefore, we investigated the involvement of vitamin D metabolic pathway genes in obesity-related traits in a large population-based study.Methods:We undertook a comprehensive analysis between 100 tagging single nucleotide polymorphisms (tagSNPs) in genes encoding for DHCR7, CYP2R1, VDBP, CYP27B1, CYP27A1, CYP24A1, VDR and RXRG, and obesity traits in 5224 participants (aged 45 years) in the 1958 British birth cohort (1958BC). We further extended our analyses to investigate the associations between SNPs and obesity traits using the summary statistics from the GIANT (Genetic Investigation of Anthropometric Traits) consortium (n=123 865).Results:In the 1958BC (n=5224), after Bonferroni correction, none of the tagSNPs were associated with obesity traits except for one tagSNP from CYP24A1 that was associated with waist-hip ratio (WHR) (rs2296239, P=0.001). However, the CYP24A1 SNP was not associated with BMI-adjusted WHR (WHRadj) in the 1958BC (rs2296239, P=1.00) and GIANT results (n=123 865, P=0.18). There was also no evidence for an interaction between the tagSNPs and obesity on BMI, WC, WHR and WHRadj in the 1958BC. In the GIANT consortium, none of the tagSNPs were associated with obesity traits.Conclusions:Despite a very large study, our findings suggest that the vitamin D pathway genes are unlikely to have a major role in obesity-related traits in the general population.

Direct versus indirect sexual selection: genetic basis of colour, size and recruitment in a wild bird

Indirect and direct models of sexual selection make different predictions regarding the quantitative genetic relationships between sexual ornaments and fitness. Indirect models predict that ornaments should have a high heritability and that strong positive genetic covariance should exist between fitness and the ornament. Direct models, on the other hand, make no such assumptions about the level of genetic variance in fitness and the ornament, and are therefore likely to be more important when environmental sources of variation are large. Here we test these predictions in a wild population of the blue tit (Parus caeruleus), a species in which plumage coloration has been shown to be under sexual selection. Using 3 years of cross-fostering data from over 250 breeding attempts, we partition the covariance between parental coloration and aspects of nestling fitness into a genetic and environmental component. Contrary to indirect models of sexual selection, but in agreement with direct models, we show that variation in coloration is only weakly heritable (h(2) < 0.11), and that two components of offspring fitness-nestling size and fledgling recruitment-are strongly dependent on parental effects, rather than genetic effects. Furthermore, there was no evidence of significant positive genetic covariation between parental colour and offspring traits. Contrary to direct benefit models, however, we find little evidence that variation in colour reliably indicates the level of parental care provided by either males or females. Taken together, these results indicate that the assumptions of indirect models of sexual selection are not supported by the genetic basis of the traits reported on here.

Output risk aspects of genetically modified crop technology in South Africa

Technology involving genetic modification of crops has the potential to make a contribution to rural poverty reduction in many developing countries. Thus far, insecticide-producing 'Bt' varieties of cotton have been the main GM crops under cultivation in developing nations. Several studies have evaluated the farm-level performance of Bt varieties in comparison to conventional ones by estimating production technology, and have mostly found Bt technology to be very successful in raising output and/or reducing insecticide input. However, the production risk properties of this technology have not been studied, although they are likely to be important to risk-averse smallholders. This study investigates the output risk aspects of Bt technology using a three-year farm-level dataset on smallholder cotton production in Makhathini flats, Kwa-Zulu Natal, South Africa. Stochastic dominance and stochastic production function estimation methods are used to examine the risk properties of the two technologies. Results indicate that Bt technology increases output risk by being most effective when crop growth conditions are good, but being less effective when conditions are less favourable. However, in spite of its risk increasing effect, the mean output performance of Bt cotton is good enough to make it preferable to conventional technology even for risk-averse smallholders.

Review: intellectual property aspects of plant transformation

One of the recurring themes of the debates concerning the application of genetic transformation technology has been the role of Intellectual Property Rights (IPR). This term covers both the content of patents and the confidential expertise usually related to methodology and referred to as 'Trade Secrets'. This review explains the concepts behind patent protection, and discusses the wide-ranging scope of existing patents that cover all aspects of transgenic technology, from selectable markers and novel promoters to methods of gene introduction. Although few of the patents in this area have any real commercial value, there are a small number of key patents that restrict the 'freedom to operate' of new companies seeking to exploit the methods. Over the last 20 years, these restrictions have forced extensive cross-licensing between ag-biotech companies and have been one of the driving forces behind the consolidation of these companies. Although such issues are often considered of little interest to the academic scientist working in the public sector, they are of great importance in any discussion of the role of 'public-good breeding' and of the relationship between the public and private sectors.

Genetic variation in a chilean endangered endemic: Gomortega keule (Molina) Baillon

Gomortega keule (Molina) Baillon is an endangered, rare species, the only representative of its genus, and endemic to Central Chile. Populations of this tree are now fragmented and few individuals can be found in any of them. Genetic diversity was studied in 33 individuals from three populations in Cauquenes, a coastal mountain area (35°58'S-72°41'W). Fifteen InterSimple Sequence Repeat primers were used to determine the degree of similarity between and within populations. This revealed that 30% of the variation exhibited was between populations while 70% was within; nevertheless individuals were clearly clustered in a pattern which reflected a narrow base of diversity. Three other species from the Laurales order were used in order to provide an external reference as to the degree of diversity. In addition, an external wild population from the native species, Peumus boldus, was used to verify the utility of the markers. We show that the primers are effective in quickly giving an estimate of the degree of diversity of a population, thus giving important topical information relevant to preserving endangered species. Aspects of the conservation and management policy for the species in order to maintain the remaining populations and to preserve the genetic resources are discussed.

The genetic basis of resistance to anticoagulants in rodents

Anticoagulant compounds, i.e., derivatives of either 4-hydroxycoumarin (e.g., warfarin, bromadiolone) or indane-1,3-dione (e.g., diphacinone, chlorophacinone), have been in worldwide use as rodenticides for > 50 years. These compounds inhibit blood coagulation by repression of the vitamin K reductase reaction (VKOR). Anticoagulant-resistant rodent populations have been reported from many countries and pose a considerable problem for pest control. Resistance is transmitted as an autosomal dominant trait although, until recently, the basic genetic mutation was unknown. Here, we report on the identification of eight different mutations in the VKORC1 gene in resistant laboratory strains of brown rats and house mice and in wild-caught brown rats from various locations in Europe with five of these mutations affecting only two amino acids (Tyr139Cys, Tyr139Ser, Tyr139Phe and Leu128Gln, Leu128Ser). By recombinant expression of VKORC1 constructs in HEK293 cells we demonstrate that mutations at Tyr139 confer resistance to warlarin at variable degrees while the other mutations, in addition, dramatically reduce VKOR activity. Our data strongly argue for at least seven independent mutation events in brown rats and two in mice. They suggest that mutations in VKORC1 are the genetic basis of anticoagulant resistance in wild populations of rodents, although the mutations alone do not explain all aspects of resistance that have been reported. We hypothesize that these mutations, apart from generating structural changes in the VKORC1 protein, may induce compensatory mechanisms to maintain blood clotting. Our findings provide the basis for a DNA-based field monitoring of anticoagulant resistance in rodents.

Analytical and compositional aspects of isoflavones in food and their biological effects

This paper provides an overview of analytical techniques used to determine isoflavones (IFs) in foods and biological fluids with main emphasis on sample preparation methods. Factors influencing the content of IFs in food including processing and natural variability are summarized and an insight into IF databases is given. Comparisons of dietary intake of IFs in Asian and Western populations, in special subgroups like vegetarians, vegans, and infants are made and our knowledge on their absorption, distribution, metabolism, and excretion by the human body is presented. The influences of the gut microflora, age, gender, background diet, food matrix, and the chemical nature of the IFs on the metabolism of IFs are described. Potential mechanisms by which IFs may exert their actions are reviewed, and genetic polymorphism as determinants of biological response to soy IFs is discussed. The effects of IFs on a range of health outcomes including atherosclerosis, breast, intestinal, and prostate cancers, menopausal symptoms, bone health, and cognition are reviewed on the basis of the available in vitro, in vivo animal and human data.

Dietary, physiological, genetic and pathological influences on postprandial lipid metabolism

Most of diurnal time is spent in a postprandial state due to successive meal intakes during the day. As long as the meals contain enough fat, a transient increase in triacylglycerolaemia and a change in lipoprotein pattern occurs. The extent and kinetics of such postprandial changes are highly variable and are modulated by numerous factors. This review focuses on factors affecting postprandial lipoprotein metabolism and genes, their variability and their relationship with intermediate phenotypes and risk of CHD. Postprandial lipoprotein metabolism is modulated by background dietary pattern as well as meal composition (fat amount and type, carbohydrate, protein, fibre, alcohol) and several lifestyle conditions (physical activity, tobacco use), physiological factors (age, gender, menopausal status) and pathological conditions (obesity, insulin resistance, diabetes mellitus). The roles of many genes have been explored in order to establish the possible implications of their variability in lipid metabolism and CHD risk. The postprandial lipid response has been shown to be modified by polymorphisms within the genes for apo A-I, A-IV, AN, E, B, C-I and C-III, lipoprotein lipase, hepatic lipase, fatty acid binding and transport proteins, microsomal trigyceride transfer protein and scavenger receptor class B type I. Overall, the variability in postprandial response is important and complex, and the interactions between nutrients or dietary or meal compositions and gene variants need further investigation. The extent of present knowledge and needs for future studies are discussed in light of ongoing developments in nutrigenetics.

Endocannabinoid receptor antagonists: potential for obesity treatment

Obesity has been described as a global epidemic. Its increasing prevalence is matched by growing costs, not only to the health of the individual, but also to the medical services required to treat a range of obesity-related diseases. In most instances, obesity is a product of progressively less energetic lifestyles and the over-consumption of readily available, palatable, and highly caloric foods. Past decades have seen massive investment in the search for effective anti-obesity therapies, so far with limited success. An important part of the process of developing new pharmacologic treatments for obesity lies in improving our understanding of the psychologic and physiologic processes that govern appetite and bodyweight regulation. Recent discoveries concerning the endogenous cannabinoids are beginning to give greater insight into these processes. Current research indicates that endocannabinoids may be key to the appetitive and consummatory aspects of eating motivation, possibly mediating the craving for and enjoyment of the most desired, most fattening foods. Additionally, endocannabinoids appear to modulate central and peripheral processes associated with fat and glucose metabolism. Selective cannabinoid receptor antagonists have been shown to suppress the motivation to eat, and preferentially reduce the consumption of palatable, energy-dense foods. Additionally, these agents act to reduce adiposity through metabolic mechanisms that are independent of changes in food intake. Given the current state of evidence, we conclude that the endocannabinoids represent an exciting target for new anti-obesity therapies.

Increasing detection rate of user-to-root attacks using genetic algorithms

An extensive set of machine learning and pattern classification techniques trained and tested on KDD dataset failed in detecting most of the user-to-root attacks. This paper aims to provide an approach for mitigating negative aspects of the mentioned dataset, which led to low detection rates. Genetic algorithm is employed to implement rules for detecting various types of attacks. Rules are formed of the features of the dataset identified as the most important ones for each attack type. In this way we introduce high level of generality and thus achieve high detection rates, but also gain high reduction of the system training time. Thenceforth we re-check the decision of the user-to- root rules with the rules that detect other types of attacks. In this way we decrease the false-positive rate. The model was verified on KDD 99, demonstrating higher detection rates than those reported by the state- of-the-art while maintaining low false-positive rate.

Causal relationship between obesity and vitamin D status: bi-directional mendelian randomization analysis of multiple cohorts

BACKGROUND: Obesity is associated with vitamin D deficiency, and both are areas of active public health concern. We explored the causality and direction of the relationship between body mass index (BMI) and 25-hydroxyvitamin D [25(OH)D] using genetic markers as instrumental variables (IVs) in bi-directional Mendelian randomization (MR) analysis. METHODS AND FINDINGS: We used information from 21 adult cohorts (up to 42,024 participants) with 12 BMI-related SNPs (combined in an allelic score) to produce an instrument for BMI and four SNPs associated with 25(OH)D (combined in two allelic scores, separately for genes encoding its synthesis or metabolism) as an instrument for vitamin D. Regression estimates for the IVs (allele scores) were generated within-study and pooled by meta-analysis to generate summary effects. Associations between vitamin D scores and BMI were confirmed in the Genetic Investigation of Anthropometric Traits (GIANT) consortium (n = 123,864). Each 1 kg/m(2) higher BMI was associated with 1.15% lower 25(OH)D (p = 6.52×10⁻²⁷). The BMI allele score was associated both with BMI (p = 6.30×10⁻⁶²) and 25(OH)D (-0.06% [95% CI -0.10 to -0.02], p = 0.004) in the cohorts that underwent meta-analysis. The two vitamin D allele scores were strongly associated with 25(OH)D (p≤8.07×10⁻⁵⁷ for both scores) but not with BMI (synthesis score, p = 0.88; metabolism score, p = 0.08) in the meta-analysis. A 10% higher genetically instrumented BMI was associated with 4.2% lower 25(OH)D concentrations (IV ratio: -4.2 [95% CI -7.1 to -1.3], p = 0.005). No association was seen for genetically instrumented 25(OH)D with BMI, a finding that was confirmed using data from the GIANT consortium (p≥0.57 for both vitamin D scores). CONCLUSIONS: On the basis of a bi-directional genetic approach that limits confounding, our study suggests that a higher BMI leads to lower 25(OH)D, while any effects of lower 25(OH)D increasing BMI are likely to be small. Population level interventions to reduce BMI are expected to decrease the prevalence of vitamin D deficiency.

Candidate genes for obesity-susceptibility show enriched association within a large genome-wide association study for BMI

Before the advent of genome-wide association studies (GWASs), hundreds of candidate genes for obesity-susceptibility had been identified through a variety of approaches. We examined whether those obesity candidate genes are enriched for associations with body mass index (BMI) compared with non-candidate genes by using data from a large-scale GWAS. A thorough literature search identified 547 candidate genes for obesity-susceptibility based on evidence from animal studies, Mendelian syndromes, linkage studies, genetic association studies and expression studies. Genomic regions were defined to include the genes ±10 kb of flanking sequence around candidate and non-candidate genes. We used summary statistics publicly available from the discovery stage of the genome-wide meta-analysis for BMI performed by the genetic investigation of anthropometric traits consortium in 123 564 individuals. Hypergeometric, rank tail-strength and gene-set enrichment analysis tests were used to test for the enrichment of association in candidate compared with non-candidate genes. The hypergeometric test of enrichment was not significant at the 5% P-value quantile (P = 0.35), but was nominally significant at the 25% quantile (P = 0.015). The rank tail-strength and gene-set enrichment tests were nominally significant for the full set of genes and borderline significant for the subset without SNPs at P < 10(-7). Taken together, the observed evidence for enrichment suggests that the candidate gene approach retains some value. However, the degree of enrichment is small despite the extensive number of candidate genes and the large sample size. Studies that focus on candidate genes have only slightly increased chances of detecting associations, and are likely to miss many true effects in non-candidate genes, at least for obesity-related traits.

A genome-wide association meta-analysis identifies new childhood obesity loci

Multiple genetic variants have been associated with adult obesity and a few with severe obesity in childhood; however, less progress has been made in establishing genetic influences on common early-onset obesity. We performed a North American, Australian and European collaborative meta-analysis of 14 studies consisting of 5,530 cases (≥95th percentile of body mass index (BMI)) and 8,318 controls (<50th percentile of BMI) of European ancestry. Taking forward the eight newly discovered signals yielding association with P < 5 × 10(-6) in nine independent data sets (2,818 cases and 4,083 controls), we observed two loci that yielded genome-wide significant combined P values near OLFM4 at 13q14 (rs9568856; P = 1.82 × 10(-9); odds ratio (OR) = 1.22) and within HOXB5 at 17q21 (rs9299; P = 3.54 × 10(-9); OR = 1.14). Both loci continued to show association when two extreme childhood obesity cohorts were included (2,214 cases and 2,674 controls). These two loci also yielded directionally consistent associations in a previous meta-analysis of adult BMI(1).