Linking the serotonin transporter gene, family environments, hippocampal volume and depression onset: a prospective imaging gene × environment analysis

A single imaging gene-environment (IGxE) framework that is able to simultaneously model genetic, neurobiological, and environmental influences on psychopathology outcomes is needed to improve understanding of how complex interrelationships between allelic variation, differences in neuroanatomy or neuroactivity, and environmental experience affect risk for psychiatric disorder. In a longitudinal study of adolescent development we demonstrate the utility of such an IGxE framework by testing whether variation in parental behavior at age 12 altered the strength of an imaging genetics pathway, involving an indirect association between allelic variation in the serotonin transporter gene to variation in hippocampal volume and consequent onset of major depressive disorder by age 18. Results were consistent with the presence of an indirect effect of the serotonin transporter S-allele on depression onset via smaller left and right hippocampal volumes that was significant only in family environments involving either higher levels of parental aggression or lower levels of positive parenting. The previously reported finding of S-allele carriers' increased risk of depression in adverse environments may, therefore, be partly because of the effects of these environments on a neurobiological pathway from the serotonin transporter gene to depression onset that proceeds through variation in hippocampal volume. 

Novel rickettsia in ticks, Tasmania, Australia

A novel rickettsia was detected in Ixodes tasmani ticks collected from Tasmanian devils. A total of 55% were positive for the citrate synthase gene by quantitative PCR. According to current criteria for rickettsia speciation, this new rickettsia qualifies as Candidatus Rickettsia tasmanensis, named after the location of its detection.

The more pieces, the better the puzzle: sperm concentration increases gametic compatibility

The genetic benefits individuals receive from mate choice have been the focus of numerous studies, with several showing support for both intrinsic genetic benefits and compatibility effects on fertilization success and offspring viability. However, the robustness of these effects have rarely been tested across an ecologically relevant environmental gradient. In particular, sperm environment is a crucial factor determining fertilization success in many species, especially those with external fertilization. Here, we test the importance of sperm environment in mediating compatibility-based selection on fertilization using a factorial breeding design. We detected a significant intrinsic male effect on fertilization success at only one of four sperm concentrations. Compatibility effects were significant at the two highest sperm concentrations and, interestingly, the magnitude of the compatibility effect consistently increased with sperm concentration. This suggests that females are able to modify the probability of sperm-egg fusion as the amount of sperm available increases.

FTO genotype and weight loss: systematic review and meta-analysis of 9563 individual participant data from eight randomised controlled trials

OBJECTIVE:  To assess the effect of the FTO genotype on weight loss after dietary, physical activity, or drug based interventions in randomised controlled trials.

DESIGN:  Systematic review and random effects meta-analysis of individual participant data from randomised controlled trials.

DATA SOURCES:  Ovid Medline, Scopus, Embase, and Cochrane from inception to November 2015.

ELIGIBILITY CRITERIA FOR STUDY SELECTION:  Randomised controlled trials in overweight or obese adults reporting reduction in body mass index, body weight, or waist circumference by FTO genotype (rs9939609 or a proxy) after dietary, physical activity, or drug based interventions. Gene by treatment interaction models were fitted to individual participant data from all studies included in this review, using allele dose coding for genetic effects and a common set of covariates. Study level interactions were combined using random effect models. Metaregression and subgroup analysis were used to assess sources of study heterogeneity.

RESULTS:  We identified eight eligible randomised controlled trials for the systematic review and meta-analysis (n=9563). Overall, differential changes in body mass index, body weight, and waist circumference in response to weight loss intervention were not significantly different between FTO genotypes. Sensitivity analyses indicated that differential changes in body mass index, body weight, and waist circumference by FTO genotype did not differ by intervention type, intervention length, ethnicity, sample size, sex, and baseline body mass index and age category.

CONCLUSIONS:  We have observed that carriage of the FTO minor allele was not associated with differential change in adiposity after weight loss interventions. These findings show that individuals carrying the minor allele respond equally well to dietary, physical activity, or drug based weight loss interventions and thus genetic predisposition to obesity associated with the FTO minor allele can be at least partly counteracted through such interventions.

Modeling gene-environment interaction in longitudinal data : risk for neuroticism due to interaction between maternal care and the Dopamine 4 Receptor gene (DRD4)

The purpose of this study was to investigate risk for neuroticism due to the joint action of low maternal care and compromised mesocorticolimbic ‘reward’ system function linked to a variable number tandem repeat (VNTR) in the dopamine 4 receptor gene (DRD4). Data were drawn from the Victorian Adolescent Health Cohort Study, a longitudinal study of the health and well-being of 2,000 young Australians followed from adolescence to young adulthood across 8 waves from 14- to 28-years. Genetic risk was defined by carriage of at least one copy of the 7-repeat allele or derivative alleles 5, 6, and 8 (labeled 7R+). Neuroticism was assessed in adolescence and young adulthood. We observed an approximately fourfold increase in the odds of reporting neurotic symptoms in carriers of the 7R+ disposition who reported low maternal care compared with non-carriers who reported high maternal care. The percentage of risk attributable to mechanisms in which both factors played a role was 35%. Findings are discussed in terms of implications for prevention.

Gene-environment interaction in problematic substance use : interaction between DRD4 and insecure attachments

To investigate the combined effect of an exon III variable number tandem repeat in the dopamine receptor gene (DRD4) and insecure attachment style on risk for tobacco, cannabis and alcohol use problems in young adulthood. It was hypothesized that (1) individuals with 5, 6, 7 or 8 repeats (labelled 7R+) would be at increased risk for problematic drug use, and (2) risk for drug use would be further increased in individuals with 7R+ repeats who also have a history of insecure parent–child attachment relations. Data were drawn from the Victorian Adolescent Health Cohort Study, an eight-wave longitudinal study of adolescent and young adult development. DRD4 genotypes were available for 839 participants. Risk attributable to the combined effects of 7R+ genotype and insecure attachments was evaluated within a sufficient causes framework under the assumptions of additive interaction using a two-by-four table format with a common reference group. 7R+ alleles were associated with higher tobacco, cannabis and alcohol use (binging). Insecure attachments were associated with higher tobacco and cannabis use but lower alcohol use. For tobacco, there was evidence of interaction for anxious but not avoidant attachments. For cannabis, there was evidence of interaction for both anxious and avoidant attachments, although the interaction for anxious attachments was more substantial. There is no evidence of interaction for binge drinking. Results are consistent with a generic reward deficit hypothesis of drug addiction for which the 7R+ disposition may play a role. Interaction between 7R+ alleles and attachment insecurity may intensify risk for problematic tobacco and cannabis use.

Alteration of GSH level, gene expression and cell transformation in NIH3T3 cells by chronic exposure to low dose of arsenic

It is well established that arsenic toxicity is postulated to be primarily due to the binding of As(III) to sulfhydryl-containing enzymes. However, the mechanism of carcinogenesis induced by arsenic is still unclear. The interaction of arsenic with GSH and related enzymes seems a very important issue regarding mechanism of arsenical induced toxicity or carcinogenesis. The purpose of this work is to investigate the effect of chronic exposure to low dose of As(III) on GSH level, gene expression and cell transformation in NIH3T3 cells. The results showed that long-term, low dose arsenic treatment makes 3T3 cell more resistant to acute arsenic treatment. There were morphology changes after long-term arsenic treatment. First, partially immortalized 3T3 cell became immortalized. In addition, the cells were doubling more quickly than the control cells and attained higher density than the control cells at confluence. Second, cells treated with 0.1 µ.M As(III) exhibited anchorage-independent growth. Arsenic could enhance GSH level at 0.5 -10 µM dose of arsenic in 24 h treatment and decrease it at 25 µM and above. In long-term treatment with low dose of arsenic, GSH levels were decreased. As(I1I) can increase both glutathione S-transferase (GST) and glutathione reductase (GR) activities at low dose (0.5-10 M), but decreased GST and GR activities at 25 M and higher dose of arsenic, while in long-term As(III) treatment, GST and GR activities are increased. Both long-term and short-term treatments with As(III) can induce GR gene expression. GPx mRNA levels were decreased both in acute and chronic arsenic treated cells. Chronic treatment with As(III) also decreased the p53 mRNA level. Taken together, our results suggest that As(III) can alter GST, GR enzyme activities as well as GSH level and related gene expression both in long-term and short-term treatment but in a different manner in different doses. Alteration of cellular GSH level by As(III) might play all important role in gene expression and arsenic induced cell transformation.

Lupin kernel fiber consumption modifies fecal microbiota in healthy men as determined by rRNA gene flourescent in situ by hybridization

Background Changes in the composition of gastrointestinal microbiota by dietary interventions using pro- and prebiotics provide opportunity for improving health and preventing disease. However, the capacity of lupin kernel fiber (LKFibre), a novel legume-derived food ingredient, to act as a prebiotic and modulate the colonic microbiota in humans needed investigation.

Aim of the study The present study aimed to determine the effect of LKFibre on human intestinal microbiota by quantitative fluorescent in situ hybridization (FISH) analysis.

Design A total of 18 free-living healthy males between the ages of 24 and 64 years consumed a control diet and a LKFibre diet (containing an additional 17–30 g/day fiber beyond that of the control—incorporated into daily food items) for 28 days with a 28-day washout period in a single-blind, randomized, crossover dietary intervention design.
Methods Fecal samples were collected for 3 days towards the end of each diet and microbial populations analyzed by FISH analysis using 16S rRNA gene-based oligonucleotide probes targeting total and predominant microbial populations.

Results Significantly higher levels of Bifidobacterium spp. (P = 0.001) and significantly lower levels of the clostridia group of C. ramosum, C. spiroforme and C. cocleatum (P = 0.039) were observed on the LKFibre diet compared with the control. No significant differences between the LKFibre and the control diet were observed for total bacteria, Lactobacillus spp., the Eubacterium spp., the C. histolyticum/C. lituseburense group and the Bacteroides–Prevotella group.
Conclusions Ingestion of LKFibre stimulated colonic bifidobacteria growth, which suggests that this dietary fiber may be considered as a prebiotic and may beneficially contribute to colon health.

Correction of a mouse model of Menkes disease by the human Menkes gene

The brindled mouse is an accurate model of the fatal human X-linked copper deficiency disorder, Menkes disease. Males carrying the mutant allele of the Menkes gene orthologue Atp7a die in the second week of life. To determine whether the genetic defect in the brindled mice could be corrected by expression of the human Menkes gene, male transgenic mice expressing ATP7A from the chicken β-actin composite promoter (CAG) were mated with female carriers of the brindled mutation (Atp7aMo-br). Mutant males carrying the transgene survived and were fertile but the copper defect was not completely corrected. Unexpectedly males corrected with one transgenic line (T25#5) were mottled and resembled carrier females, this effect appeared to be caused by mosaic expression of the transgene. In contrast, males corrected with another line (T22#2) had agouti coats. Copper concentrations in tissues of the rescued mutants also resembled those of the heterozygous females, with high levels in kidney (84.6 ± 4.9 μg/g in corrected males vs. 137.0 ± 44.3 μg/g in heterozygotes) and small intestine (15.6 ± 2.5 μg/g in corrected males vs. 15.7 ± 2.8 μg/g in heterozygotes). The results show that the Menkes defect in mice is corrected by the human Menkes gene and that adequate correction is obtained even when the transgene expression does not match that of the endogenous gene.

Differential regulation of Adiponectin receptor gene expression by Adiponectin and Leptin in Myotubes derived from obese and diabetic individuals

Objective: This study aimed to investigate the regulation of adiponectin receptors 1 (AdipoR1) and 2 (AdipoR2) gene expression in primary skeletal muscle myotubes, derived from human donors, after exposure to globular adiponectin (gAd) and leptin. Research Methods and Procedures: Four distinct primary cell culture groups were established [ Lean, Obese, Diabetic, Weight Loss (Wt Loss); n = 7 in each] from rectus abdominus muscle biopsies obtained from surgical patients. Differentiated myotube cultures were exposed to gAd (0.1 mug/mL) or leptin (2.5 mug/mL) for 6 hours. AdipoR1 and AdipoR2 gene expression was measured by real-time polymerase chain reaction analysis. Results: AdipoR1 mRNA expression in skeletal muscle myotubes derived from Lean subjects (p < 0.05) was stimulated 1.8-fold and 2.5-fold with gAd and leptin, respectively. No increase in AdipoR1 gene expression was measured in myotubes derived from Obese, Diabetic, or Wt Loss subjects. AdipoR2 mRNA expression was unaltered after gAd and leptin exposure in all myotube groups. Discussion: Adiponectin and leptin are rapid and potent stimulators of AdipoR1 in myotubes derived from lean healthy individuals. This effect was abolished in myotubes derived from obese, obese diabetic subjects, and obese-prone individuals who had lost significant weight after bariatric surgery. The incapacity of skeletal muscle of obese and diabetic individuals to respond to exogenous adiponectin and leptin may be further suppressed as a result of impaired regulation of the AdipoR1 gene.

Activation of the selenopritein SEPS1 gene expression by pro-inflammatory cytokines in Hep G2 cells

SEPS1 (also called selenoprotein S, SelS) plays an important role in the production of inflammatory cytokines and its expression is activated by endoplasmic reticulum (ER) stress. In this report, we have identified two binding sites for the nuclear factor kappa B in the human SEPS1 promoter. SEPS1 gene expression, protein levels and promoter activity were all increased 2–3-fold by TNF-α and IL-1β in HepG2 cells. We have also confirmed that the previously proposed ER stress response element GGATTTCTCCCCCGCCACG in the SEPS1 proximate promoter is fully functional and responsive to ER stress. However, concurrent treatment of HepG2 cells with IL-1β and ER stress produced no additive effect on SEPS1 gene expression. We conclude that SEPS1 is a new target gene of NF-κB. Together with our previous findings that SEPS1 may regulate cytokine production in macrophage cells, we propose a regulatory loop between cytokines and SEPS1 that plays a key role in control of the inflammatory response.

Identifying cis-regulatory elements by statistical analysis and phylogenetic footprinting and analyzing their coexistence and related gene ontology

Discovery of cis-regulatory elements in gene promoters is a highly challenging research issue in computational molecular biology. This paper presents a novel approach to searching putative cis-regulatory elements in human promoters by first finding 8-mer sequences of high statistical significance from gene promoters of humans, mice, and Drosophila melanogaster, respectively, and then identifying the most conserved ones across the three species (phylogenetic footprinting). In this study, a conservation analysis on both closely related species (humans and mice) and distantly related species (humans/mice and Drosophila) is conducted not only to examine more candidates but also to improve the prediction accuracy. We have found 124 putative cis-regulatory elements and grouped these into 20 clusters. The investigation on the coexistence of these clusters in human gene promoters reveals that SP1, EGR, and NRF-1 are the dominant clusters appearing in the combinatorial combination of up to five clusters. Gene Ontology (GO) analysis also shows that many GO categories of transcription factors binding to these cis-regulatory elements match the GO categories of genes whose promoters contain these elements. Compared with previous research, the contribution of this study lies not only in the finding of new cis-regulatory elements, but also in its pioneering exploration on the coexistence of discovered elements and the GO relationship between transcription factors and regulated genes. This exploration verifies the putative cis-regulatory elements that have been found from this study and also gives new insight on the regulation mechanisms of gene expression.