Emotion moderates the association between \u3ci\u3eHTR2A\u3c/i\u3e (rs6313) genotype and antisaccade latency

The serotonin system is heavily involved in cognitive and emotional control processes. Previous work has typically investigated this system’s role in control processes separately for cognitive and emotional domains, yet it has become clear the two are linked. The present study, therefore, examined whether variation in a serotonin receptor gene (HTR2A, rs6313) moderated effects of emotion on inhibitory control. An emotional antisaccade task was used in which participants looked toward (prosaccade) or away (antisaccade) from a target presented to the left or right of a happy, angry, or neutral face. Overall, antisaccade latencies were slower for rs6313 C allele homozygotes than T allele carriers, with no effect of genotype on prosaccade latencies. Thus, C allele homozygotes showed relatively weak inhibitory control but intact reflexive control. Importantly, the emotional stimulus was either present during target presentation (overlap trials) or absent (gap trials). The gap effect (slowed latency in overlap versus gap trials) in antisaccade trials was larger with angry versus neutral faces in C allele homozygotes. This impairing effect of negative valence on inhibitory control was larger in C allele homozygotes than T allele carriers, suggesting that angry faces disrupted/ competed with the control processes needed to generate an antisaccade to a greater degree in these individuals. The genotype difference in the negative valence effect on antisaccade latency was attenuated when trial N-1 was an antisaccade, indicating top-down regulation of emotional influence. This effect was reduced in C/C versus T/_ individuals, suggesting a weaker capacity to downregulate emotional processing of task-irrelevant stimuli

Impulsiveness Mediates the Association between \u3ci\u3eGABRA2\u3c/i\u3e SNPs and Lifetime Alcohol Problems

Genetic variants in GABRA2 have previously been shown to be associated with alcohol measures, electroencephalography (EEG) β waves and impulsiveness-related traits. Impulsiveness is a behavioral risk factor for alcohol and other substance abuse. Here, we tested association between 11 variants in GABRA2 with NEO-impulsiveness and problem drinking. Our sample of 295 unrelated adult subjects was from a community of families with at least one male with DSM-IV alcohol use diagnosis, and from a socioeconomically comparable control group. Ten GABRA2 SNPs (single-nucleotide polymorphisms) were associated with the NEO-impulsiveness (P \u3c 0.03). The alleles associated with higher impulsiveness correspond to the minor alleles identified in previous alcohol dependence studies. All ten SNPs are in linkage disequilibrium (LD) with each other and represent one effect on impulsiveness. Four SNPs and the corresponding haplotype from intron 3 to intron 4 were also associated with Lifetime Alcohol Problems Score (LAPS, P \u3c 0.03) (not corrected for multiple testing). Impulsiveness partially mediates (22.6% average) this relation between GABRA2 and LAPS. Our results suggest that GABRA2 variation in the region between introns 3 and 4 is associated with impulsiveness and this effect partially influences the development of alcohol problems, but a direct effect of GABRA2 on problem drinking remains. A potential functional SNP rs279827, located next to a splice site, is located in the most significant region for both impulsiveness and LAPS. The high degree of LD among nine of these SNPs and the conditional analyses we have performed suggest that all variants represent one signal

Birth Cohort Differences in Features of Antisocial Alcoholism among Men and Women

Background: This study examines the relations between birth cohort, gender, and family history of alcohol problems on alcohol dependence, and on the endorsement of alcohol abuse/dependence symptoms related to antisocial behavior. Methods: Men (n = 1365) and women (n = 625) were recruited from the community, hospitals, and other treatment sites and were given a structured diagnostic interview. Data were analyzed by using logistic regression. Results: Age of first regular alcohol use was lower in more recent birth cohorts for both men and women, with those born in the most recent cohort reporting earliest regular use. The decline across cohort was more dramatic in women than in men. For those participants with a diagnosis of alcohol dependence, being born in a more recent cohort was associated with increased risk of dependence onset before age 25. Among those participants with onset of alcohol dependence before age 25 (nmen = 400; nwomen = 51), being born in a more recent cohort was associated with increased risk of fights while drinking, police involvement, and drunk driving trouble as well as with increased risk for a diagnosis of abuse or dependence on another drug. Conclusions: These results suggest that the prevalence of antisocial alcoholism may be increasing for both men and women. These data exemplify how societal change may affect expression of underlying vulnerability for traits thought to be genetically influenced

Nexus of Despair: A Network Analysis of Suicidal Ideation among Veterans

The objective of this study was to estimate a network model of risk and resilience factors of suicidal ideation among veterans. Two network models of suicidal ideation among Operation Iraqi Freedom/ Operation Enduring Freedom/Operation New Dawn veterans (N = 276) incorporated key disorders, traumatic stress, and resilience constructs to contextualize suicidal ideation. Childhood trauma was positively connected with suicidal ideation and harassment and inversely connected with social support and distress tolerance. This exemplifies long-lasting associations between childhood trauma and revictimization, emotion regulation, and ability to form supportive social relationships. A subsequent model including lower-order facets indicated that combat trauma was predominantly associated with posttraumatic stress disorder–intrusion symptoms. This study highlights the importance of addressing both risk and resilience to reduce suicide risk among veterans and increases understanding of factors that contribute to suicidal ideation

PTSD Symptoms and Alcohol-Related Problems among Veterans: Temporal Associations and Vulnerability

Posttraumatic stress disorder (PTSD) is associated with elevated risk of both alcohol use disorder (AUD) and related conduct problems, which are associated with behavioral and emotional dysregulation. We conducted an intensive longitudinal burst design study with 10 weeks of experience sampling over the course of 1.5 years with 250 veterans of recent conflicts. We tested time-series models of daily associations between posttraumatic stress symptoms (PTSS), alcohol dependence syndrome, and conduct problems. Exacerbations of PTSS predicted higher dependence syndrome and conduct problems the next day. This effect was significant after controlling for both concurrent (i.e., same-day) associations between drinking and the outcomes as well as the strength of associations between the outcomes from one day to the next (i.e., autoregression). Affect lability and disinhibition were hypothesized vulnerability factors increasing the strength of within-person predictors of dependence syndrome and conduct problems. Lability and disinhibition were associated with greater dependence syndrome symptoms and conduct problems over the follow-up period. Consistent with expectation, lability rather than disinhibition increased the association between drinking and dependence syndrome as well as the strength of association between dependence syndrome symptoms from one day to the next. Moderating effects of disinhibition in the conduct problems model were not significant. Importantly, results indicated reciprocal associations over time. Lability potentiated the association between dependence syndrome symptoms and next-day PTSS, whereas disinhibition potentiated the association between conduct problems and next-day PTSS. Results demonstrate complex dynamic associations between PTSS, AUD symptoms, and conduct problems over time indicative of broad regulatory impairments

SLC30A3 Responds to Glucose- and Zinc Variations in ß-Cells and Is Critical for Insulin Production and In Vivo Glucose-Metabolism During ß-Cell Stress

BACKGROUND:Ion transporters of the Slc30A- (ZnT-) family regulate zinc fluxes into sub-cellular compartments. beta-cells depend on zinc for both insulin crystallization and regulation of cell mass. METHODOLOGY/PRINCIPAL FINDINGS:This study examined: the effect of glucose and zinc chelation on ZnT gene and protein levels and apoptosis in beta-cells and pancreatic islets, the effects of ZnT-3 knock-down on insulin secretion in a beta-cell line and ZnT-3 knock-out on glucose metabolism in mice during streptozotocin-induced beta-cell stress. In INS-1E cells 2 mM glucose down-regulated ZnT-3 and up-regulated ZnT-5 expression relative to 5 mM. 16 mM glucose increased ZnT-3 and decreased ZnT-8 expression. Zinc chelation by DEDTC lowered INS-1E insulin content and insulin expression. Furthermore, zinc depletion increased ZnT-3- and decreased ZnT-8 gene expression whereas the amount of ZnT-3 protein in the cells was decreased. Zinc depletion and high glucose induced apoptosis and necrosis in INS-1E cells. The most responsive zinc transporter, ZnT-3, was investigated further; by immunohistochemistry and western blotting ZnT-3 was demonstrated in INS-1E cells. 44% knock-down of ZnT-3 by siRNA transfection in INS-1E cells decreased insulin expression and secretion. Streptozotocin-treated mice had higher glucose levels after ZnT-3 knock-out, particularly in overt diabetic animals. CONCLUSION/SIGNIFICANCE:Zinc transporting proteins in beta-cells respond to variations in glucose and zinc levels. ZnT-3, which is pivotal in the development of cellular changes as also seen in type 2 diabetes (e.g. amyloidosis in Alzheimer's disease) but not previously described in beta-cells, is present in this cell type, up-regulated by glucose in a concentration dependent manner and up-regulated by zinc depletion which by contrast decreased ZnT-3 protein levels. Knock-down of the ZnT-3 gene lowers insulin secretion in vitro and affects in vivo glucose metabolism after streptozotocin treatment

Zinc transporter gene expression is regulated by pro-inflammatory cytokines: a potential role for zinc transporters in beta-cell apoptosis?

<p>Abstract</p> <p>Background</p> <p>β-cells are extremely rich in zinc and zinc homeostasis is regulated by zinc transporter proteins. β-cells are sensitive to cytokines, interleukin-1β (IL-1β) has been associated with β-cell dysfunction and -death in both type 1 and type 2 diabetes. This study explores the regulation of zinc transporters following cytokine exposure.</p> <p>Methods</p> <p>The effects of cytokines IL-1β, interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α) on zinc transporter gene expression were measured in INS-1-cells and rat pancreatic islets. Being the more sensitive transporter, we further explored ZnT8 (Slc30A8): the effect of ZnT8 over expression on cytokine induced apoptosis was investigated as well as expression of the insulin gene and two apoptosis associated genes, BAX and BCL2.</p> <p>Results</p> <p>Our results showed a dynamic response of genes responsible for β-cell zinc homeostasis to cytokines: IL-1β down regulated a number of zinc-transporters, most strikingly ZnT8 in both islets and INS-1 cells. The effect was even more pronounced when mixing the cytokines. TNF-α had little effect on zinc transporter expression. IFN-γ down regulated a number of zinc transporters. Insulin expression was down regulated by all cytokines. ZnT8 over expressing cells were more sensitive to IL-1β induced apoptosis whereas no differences were observed with IFN-γ, TNF-α, or a mixture of cytokines.</p> <p>Conclusion</p> <p>The zinc transporting system in β-cells is influenced by the exposure to cytokines. Particularly ZnT8, which has been associated with the development of diabetes, seems to be cytokine sensitive.</p

Resveratrol Acts Not through Anti-Aggregative Pathways but Mainly via Its Scavenging Properties against Aβ and Aβ-Metal Complexes Toxicity

It has been recently suggested that resveratrol can be effective in slowing down Alzheimer's disease (AD) development. As reported in many biochemical studies, resveratrol seems to exert its neuro-protective role through inhibition of β-amyloid aggregation (Aβ), by scavenging oxidants and exerting anti-inflammatory activities. In this paper, we demonstrate that resveratrol is cytoprotective in human neuroblastoma cells exposed to Aβ and or to Aβ-metal complex. Our findings suggest that resveratrol acts not through anti-aggregative pathways but mainly via its scavenging properties