Indirect genetic effects and the spread of infectious disease: are we capturing the full heritable variation underlying disease prevalence?

Reducing disease prevalence through selection for host resistance offers a desirable alternative to chemical treatment. Selection for host resistance has proven difficult, however, due to low heritability estimates. These low estimates may be caused by a failure to capture all the relevant genetic variance in disease resistance, as genetic analysis currently is not taylored to estimate genetic variation in infectivity. Host infectivity is the propensity of transmitting infection upon contact with a susceptible individual, and can be regarded as an indirect effect to disease status. It may be caused by a combination of physiological and behavioural traits. Though genetic variation in infectivity is difficult to measure directly, Indirect Genetic Effect (IGE) models, also referred to as associative effects or social interaction models, allow the estimation of this variance from more readily available binary disease data (infected/non-infected). We therefore generated binary disease data from simulated populations with known amounts of variation in susceptibility and infectivity to test the adequacy of traditional and IGE models. Our results show that a conventional model fails to capture the genetic variation in infectivity inherent in populations with simulated infectivity. An IGE model, on the other hand, does capture some of the variation in infectivity. Comparison with expected genetic variance suggests that there is scope for further methodological improvement, and that potential responses to selection may be greater than values presented here. Nonetheless, selection using an index of estimated direct and indirect breeding values was shown to have a greater genetic selection differential and reduced future disease risk than traditional selection for resistance only. These findings suggest that if genetic variation in infectivity substantially contributes to disease transmission, then breeding designs which explicitly incorporate IGEs might help reduce disease prevalence.     

Study on genetic variations of PPARα gene and its effects on thermal tolerance in Chinese Holstein

Peroxisome proliferator-activated receptor alpha (PPARα) regulates responses to chemical or physical stress in part by altering expression of genes involved in proteome maintenance. In this research, polymerase chain reaction (PCR) technique was used to amplify 766 and 589 bp fragments of intron 3 and 7 of PPARα gene in Chinese Holstein (n = 771). Sequencing results showed that three novel single nucleotide polymorphisms (SNPs) were identified at position 44087 (G/A), 65550 (G/A), and 65676(G/A) in the PPARα gene. PCR–restriction fragment length polymorphism technology was used to genotype the three SNPs. Association analysis showed that cows with H1H8 (P < 0.05), H2H8 (P < 0.01), H5H7 (P < 0.05), H5H8 (P < 0.05), and H8H8 (P < 0.05) haplotype combinations had lower potassium content in erythrocytes than those with H2H6 haplotype combination. Cows with H1H8, and H8H8 haplotype combinations had lower decrease rate of milk yield than those with H2H6 and H6H8 haplotype combinations (P < 0.05). Cows with H2H8 and H8H8 haplotype combinations had lower rectal temperature than those with H5H8 and H7H7 haplotype combinations (P < 0.05). In conclusion, H8H8 haplotype combination may be advantageous for heat resistance traits in Chinese Holstein cattle.     

When can refuges mediate the genetic effects of fire regimes? A simulation study of the effects of topography and weather on neutral and adaptive genetic diversity in fire‐prone landscapes

Understanding how landscape heterogeneity mediates the effects of fire on biodiversity is increasingly important under global changes in fire regimes. We used a simulation experiment to investigate how fire regimes interact with topography and weather to shape neutral and selection‐driven genetic diversity under alternative dispersal scenarios, and to explore the conditions under which microrefuges can maintain genetic diversity of populations exposed to recurrent fire. Spatial heterogeneity in simulated fire frequency occurred in topographically complex landscapes, with fire refuges and fire‐prone “hotspots” apparent. Interannual weather variability reduced the effect of topography on fire patterns, with refuges less apparent under high weather variability. Neutral genetic diversity was correlated with long‐term fire frequency under spatially heterogeneous fire regimes, being higher in fire refuges than fire‐prone areas, except under high dispersal or low fire severity (low mortality). This generated different spatial genetic structures in fire‐prone and fire‐refuge components of the landscape, despite similar dispersal. In contrast, genetic diversity was only associated with time since the most recent fire in flat landscapes without predictable refuges and hotspots. Genetic effects of selection driven by fire‐related conditions depended on selection pressure, migration distance and spatial heterogeneity in fire regimes. Allele frequencies at a locus conferring higher fitness under successional environmental conditions followed a pattern of “temporal adaptation” to contemporary conditions under strong selection pressure and high migration. However, selected allele frequencies were correlated with spatial variation in long‐term mean fire frequency (relating to environmental predictability) under weak dispersal, low selection pressure and strong spatial heterogeneity in fire regimes.     

Can we optimise the exercise training prescription to maximise improvements in mitochondria function and content?

Background

While there is agreement that exercise is a powerful stimulus to increase both mitochondrial function and content, we do not know the optimal training stimulus to maximise improvements in mitochondrial biogenesis.

Scope of review

This review will focus predominantly on the effects of exercise on mitochondrial function and content, as there is a greater volume of published research on these adaptations and stronger conclusions can be made.

Major conclusions

The results of cross-sectional studies, as well as training studies involving rats and humans, suggest that training intensity may be an important determinant of improvements in mitochondrial function (as determined by mitochondrial respiration), but not mitochondrial content (as assessed by citrate synthase activity). In contrast, it appears that training volume, rather than training intensity, may be an important determinant of exercise-induced improvements in mitochondrial content. Exercise-induced mitochondrial adaptations are quickly reversed following a reduction or cessation of physical activity, highlighting that skeletal muscle is a remarkably plastic tissue. Due to the small number of studies, more research is required to verify the trends highlighted in this review, and further studies are required to investigate the effects of different types of training on the mitochondrial sub-populations and also mitochondrial adaptations in different fibre types. Further research is also required to better understand how genetic variants influence the large individual variability for exercise-induced changes in mitochondrial biogenesis.

General significance

The importance of mitochondria for both athletic performance and health underlines the importance of better understanding the factors that regulate exercise-induced changes in mitochondrial biogenesis. This article is part of a Special Issue entitled Frontiers of Mitochondrial Research.     

Implications of exercise training in mtDNA defects--use it or lose it?

Whether regular exercise is beneficial or should be avoided is a question currently unsettled in patients with heteroplasmic mitochondrial DNA (mtDNA) disorders of skeletal muscle. Deleterious effects of habitual physical inactivity superimposed upon impaired mitochondrial oxidative phosphorylation may contribute to varying degrees of exercise intolerance in these patients. Endurance exercise training is widely known to improve exercise capacity in healthy subjects and various chronic-disease patient populations. Although we have shown that beneficial physiological and biochemical responses to training increase exercise tolerance in patients with mtDNA defects, knowledge of the muscle adaptive response to endurance training within the setting of mitochondrial heteroplasmy remains limited. In order to determine advisability of endurance training as therapy, it remains to be established whether potential endurance training-induced increases in mutant mtDNA levels may be offset by increases in absolute wild-type mtDNA levels, and whether chronic inactivity leads to a selective down-regulation of wild-type mtDNA. Resistance training utilizes a different adaptive exercise approach to induce the transfer of normal mitochondrial templates from satellite cells to mature muscle fibers of patients with sporadic mtDNA disorders. The efficacy and safety of this approach needs to be further established. Our current inability to clearly advise patients to "use it or lose it" underscores the immediate urgency of studying the effects of exercise on skeletal muscle of patients with heteroplasmic mtDNA defects.     

Ex vivo and in vivo effects of isofagomine on acid β-glucosidase variants and substrate levels in Gaucher disease

Isofagomine (IFG) is an acid β-glucosidase (GCase) active site inhibitor that acts as a pharmacological chaperone. The effect of IFG on GCase function was investigated in GCase mutant fibroblasts and mouse models. IFG inhibits GCase with K(i) ～30 nM for wild-type and mutant enzymes (N370S and V394L). Fibroblasts treated with IFG at μM concentrations showed enhancement of WT and mutant GCase activities and protein levels. Administration of IFG (30 mg/kg/day) to the mice homozygous for GCase mutations (V394L, D409H, or D409V) led to increased GCase activity in visceral tissues and brain extracts. IFG effects on GCase stability and substrate levels were evaluated in a mouse model (hG/4L/PS-NA) that has doxycycline-controlled human WT GCase (hGCase) expression driven by a liver-specific promoter and is also homozygous for the IFG-responsive V394L GCase. Both human and mouse GCase activity and protein levels were increased in IFG-treated mice. The liver-secreted hGCase in serum was stabilized, and its effect on the lung and spleen involvement was enhanced by IFG treatment. In 8-week IFG-treated mice, the accumulated glucosylceramide and glucosylsphingosine were reduced by 75 and 33%, respectively. Decreases of storage cells were correlated with >50% reductions in substrate levels. These results indicate that IFG stabilizes GCase in tissues and serum and can reduce visceral substrates in vivo.     

Inferring landscape effects on dispersal from genetic distances: how far can we go?

Functional connectivity affects demography and gene dynamics in fragmented populations. Besides species-specific dispersal ability, the connectivity between local populations is affected by the landscape elements encountered during dispersal. Documenting these effects is thus a central issue for the conservation and management of fragmented populations. In this study, we compare the power and accuracy of three methods (partial correlations, regressions and Approximate Bayesian Computations) that use genetic distances to infer the effect of landscape upon dispersal. We use stochastic individual-based simulations of fragmented populations surrounded by landscape elements that differ in their permeability to dispersal. The power and accuracy of all three methods are good when there is a strong contrast between the permeability of different landscape elements. The power and accuracy can be further improved by restricting analyses to adjacent pairs of populations. Landscape elements that strongly impede dispersal are the easiest to identify. However, power and accuracy decrease drastically when landscape complexity increases and the contrast between the permeability of landscape elements decreases. We provide guidelines for future studies and underline the needs to evaluate or develop approaches that are more powerful.     

Trio under threat: can we secure the future of rhinos,elephants and tigers in Malaysia?

Three of Malaysia’s endangered large mammal species are experiencing contrasting futures. Populations of the Sumatran rhino (Dicerorhinus sumatrensis) have dwindled to critically low numbers in Peninsular Malaysia (current estimates need to be revised) and the state of Sabah (less than 40 individuals estimated). In the latter region, a bold intervention involving the translocation of isolated rhinos is being developed to concentrate them into a protected area to improve reproduction success rates. For the Asian elephant (Elephas maximus), recently established baselines for Peninsular Malaysia (0.09 elephants/km² estimated from one site) and Sabah (between 0.56 and 2.15 elephants/km² estimated from four sites) seem to indicate globally significant populations based on dung count surveys. Similar surveys are required to monitor elephant population trends at these sites and to determine baselines elsewhere. The population status of the Malayan tiger (Panthera tigris jacksoni) in Peninsular Malaysia, however, remains uncertain as only a couple of scientifically defensible camera-trapping surveys (1.66 and 2.59 tigers/100 km² estimated from two sites) have been conducted to date. As conservation resources are limited, it may be prudent to focus tiger monitoring and protection efforts in priority areas identified by the National Tiger Action Plan for Malaysia. Apart from reviewing the conservation status of rhinos, elephants and tigers and threats facing them, we highlight existing and novel conservation initiatives, policies and frameworks that can help secure the long-term future of these iconic species in Malaysia.     

Adiponectin and cardiovascular disease: state of the art?

The cardiometabolic syndrome, associated with increased cardiovascular disease risk in the industrialized world, is estimated to affect one in four adults. Although the mechanisms linking obesity and cardiovascular disease remain unclear, research continues to unravel the molecular pathways behind this pandemic. Adipose tissue has emerged as a metabolically active participant in mediating vascular complications, serving as an active endocrine and paracrine organ secreting adipokines, which participate in diverse metabolic processes. Among these adipokines is adiponectin, which seems to possess antiatherogenic and anti-inflammatory effects and may be protective against cardiovascular disease development. The current review describes the pathophysiology of adiponectin in atherosclerotic disease.     

Do ACE and CKMM gene variations have potent effects on physical performance in inactive male adolescents?

Molecular Biology Reports - We studied to ascertain whether the ACE and/or CKMM genotypes independently influence the baseline level of some sport performances in 613 inactive male adolescents...     

Fish communities on the world's warmest reefs: what can they tell us about the effects of climate change in the future?

To examine the role of climatic extremes in structuring reef fish communities in the Arabian region, reef fish communities were visually surveyed at four sites within the southern Persian Gulf (also known as the Arabian Gulf and The Gulf), where sea-surface temperatures are extreme (range: 12-35° C annually), and these were compared with communities at four latitudinally similar sites in the biogeographically connected Gulf of Oman, where conditions are more moderate (range: 22-31° C annually). Although sites were relatively similar in the cover and composition of coral communities, substantial differences in the structure and composition of associated fish assemblages were apparent. Fish assemblages in the southern Persian Gulf held significantly lower estimates of abundance, richness and biomass, with significantly higher abundances of smaller sized individuals than Gulf of Oman assemblages. Functionally, southern Persian Gulf sites held significantly lower abundances of nearly all the common fish trophic guilds found on Gulf of Oman sites, although higher abundances of herbivorous grazers were apparent. These results suggest the potential for substantial changes in the structure of reef-associated fish communities, independent of changes in habitat within an environment of increasing fluctuations in oceanic climate.     

Assessing the additive and dominance genetic effects of vegetative propagation ability in Eucalyptus—influence of modeling on genetic gain

To study the genetic determinism of propagation by cutting, 2,115 individuals of 83 full-sib families of the Eucalyptus urophylla?×?Eucalyptus grandis hybrid were used as stock plants and propagated by cuttings. Shoot production (PROD) and cutting success (CUT) were measured in two periods corresponding to the dry and rainy seasons. The experiments showed a significant effect of propagation period, suggesting the combined influence of environmental conditions and physiological state of stock plants. Using the linear mixed model (LMM) and the generalized one (GLMM) to take into account the non-normal distribution, the additive and dominance variances were estimated. They were significantly different from zero for PROD and CUT, as was the interaction between genetic effects and periods. The dominance variance was equal or higher than additive variance for both traits (1?σ ² _D /σ ² _A ?h ² _ss?=?0.182 and H ² _sl?=?0.443) but high with GLMM (h ² _ss?=?0.431 and H ² _sl?=?0.891). For CUT, the same trend was observed for variances but the genetic control was weaker with heritabilities smaller than 0.3. The selection accuracy (r) was affected by the statistical model, r?=?0.94 and r?=?0.42 for PROD using LMM and GLMM, respectively. Genetic correlations between PROD, CUT, and the field growth of clones at 25 months were relatively low. These results are important elements to consider for breeding strategies that target genetic gain for both field growth and cutting success.     

Effect of TNF-α and IL-1β genetic variants on the development of myocardial infarction in Turkish population

Tumor necrosis factor-alpha (TNF-α) and interleukin 1 beta (IL-1β) genetic variants which resulting in TNF-α and IL-1 overproduction may increase susceptibility to autoimmune diseases such as atherosclerosis. We have studied the association of TNF-α G308A and IL-1β (+3953) C/T polymorphism with myocardial infarction in Turkish population. 143 patients with myocardial infarction and 213 age-matched healthy controls were included in the study. In univariant analysis, the frequencies of IL-1β, TNF-α genotype or allele, and haplotype of C:A and T:A were significantly elevated in patients when compared with those of controls. GA genotype of TNF-α, T allele of IL-1β and A of TNF-α allele seem to be risk factors for myocardial infarction. In contrast, CC genotype of IL-1β and GG genotype of TNF-α have protective effect against myocardial infarction. In multivariate logistic regression analysis, TNF-α A allele, gender and smoking were associated with myocardial infarction. In conclusion, we can state that TNF-α A allele might be associated with myocardial infarction.     

Is the future blue-green or brown? The effects of extreme events on phytoplankton dynamics in a semi-arid man-made lake

Aquatic Ecology - In arid and semi-arid regions, a hydrological regime characterized by an annual cycle of drought and rainy seasons changes the volume and retention time of reservoirs. Such...     

Neurochemical dementia diagnostics in Alzheimer's disease: where are we now and where are we going?

Neurochemical dementia diagnostics (NDD) is a routine laboratory tool used in the diagnostic process for patients with neurodegenerative disorders, such as Alzheimer's disease. Currently, two groups of biomarkers analyzed in the cerebrospinal fluid are considered - namely amyloid-β peptides and Tau proteins - along with the hyperphosphorylated forms of the latter (pTau). Current directions in the development of NDD include the following: search for novel biomarkers with improved analytical or diagnostic performance; optimization of the analysis of the biomarkers already available (e.g., by improved quality control and interlaboratory comparison of results); applications of novel technologies enabling better management of patient samples; and search for biomarkers in the blood. This article presents the state-of-the-art in the field of cerebrospinal fluid-based NDD, and also summarizes some of the hypotheses of how the future development of NDD tools might look.