Cesium-Coated Halide Perovskites as a Photocathode Material: Modeling Insights.

Photocathodes emit electrons when illuminated, a process utilized across many technologies. Cutting-edge applications require a set of operating conditions that are not met with current photocathode materials. Meanwhile, halide perovskites have been studied extensively and have shown a lot of promise for a wide variety of optoelectronic applications. Well-documented halide perovskite properties such as inexpensive growth techniques, improved carrier mobility, low trap density, and tunable direct band gaps make them promising candidates for next-generation photocathode materials. Here, we use density functional theory to explore the possible application of pure inorganic perovskites (CsPbBr3 and CsPbI3) as photocathodes. It is determined that the addition of a Cs coating improved the performance by lowering the work function anywhere between 1.5 and 3 eV depending on the material, crystal surface, and surface coverage. A phenomenological model, modified from that developed by Gyftopoulos and Levine, is used to predict the reduction in work function with Cs coverage. The results of this work aim to guide the further experimental development of Cs-coated halide perovskites for photocathode materials.

Acute rhinosinusitis: When to prescribe an antibiotic.

Yes, the majority of antibiotics prescribed for acute rhinosinusitis are unnecessary, but when should you prescribe one and which one(s) should you use?

Molecular Correlates of Topiramate and GRIK1 rs2832407 Genotype in Pluripotent Stem Cell-Derived Neural Cultures.

BACKGROUND: There is growing evidence that the anticonvulsant topiramate is efficacious in reducing alcohol consumption. Further, an intronic single nucleotide polymorphism (rs2832407, C A) in the GRIK1 gene, which encodes the GluK1 subunit of the excitatory kainate receptor, predicted topiramate's effectiveness in reducing heavy drinking in a clinical trial. The molecular correlates of GRIK1 genotype that may relate to topiramate's ability to reduce drinking remain unknown. METHODS: We differentiated induced pluripotent stem cells (iPSCs) characterized by GRIK1 rs2832407 genotype from 8 A/A and 8 C/C donors into forebrain-lineage neural cultures. Our differentiation protocol yielded mixed neural cultures enriched for glutamatergic neurons. Basal mRNA expression of the GRIK1 locus was examined via quantitative polymerase chain reaction (qPCR). The effects of acute topiramate exposure on excitatory spontaneous synaptic activity were examined via whole-cell patch-clamp electrophysiology. Results were compared and contrasted between iPSC donor genotypes. RESULTS: Although characterization of the GRIK1 locus revealed no effect of rs2832407 genotype on GRIK1 isoform mRNA expression, a significant difference was observed on GRIK1 antisense-2 expression, which was greater in C/C neural cultures. Differential effects of acute exposure to 5 µM topiramate were observed on spontaneous synaptic activity in A/A versus C/C neurons, with a smaller reduction in excitatory event frequency observed in C/C donor neurons. CONCLUSIONS: This work highlights the use of iPSC technologies to study pharmacogenetic treatment effects in psychiatric disorders and furthers our understanding of the molecular effects of topiramate exposure in human neural cells.

Histone Deacetylase (HDAC) Gene Family in Allotetraploid Cotton and Its Diploid Progenitors: In Silico Identification, Molecular Characterization, and Gene Expression Analysis under Multiple Abiotic Stresses, DNA Damage and Phytohormone Treatments.

Histone deacetylases (HDACs) play a significant role in a plant's development and response to various environmental stimuli by regulating the gene transcription. However, HDACs remain unidentified in cotton. In this study, a total of 29 HDACs were identified in allotetraploid Gossypium hirsutum, while 15 and 13 HDACs were identified in Gossypium arboretum and Gossypium raimondii, respectively. Gossypium HDACs were classified into three groups (reduced potassium dependency 3 (RPD3)/HDA1, HD2-like, and Sir2-like (SRT) based on their sequences, and Gossypium HDACs within each subgroup shared a similar gene structure, conserved catalytic domains and motifs. Further analysis revealed that Gossypium HDACs were under a strong purifying selection and were unevenly distributed on their chromosomes. Gene expression data revealed that G. hirsutum HDACs were differentially expressed in various vegetative and reproductive tissues, as well as at different developmental stages of cotton fiber. Furthermore, some G. hirsutum HDACs were co-localized with quantitative trait loci (QTLs) and single-nucleotide polymorphism (SNPs) of fiber-related traits, indicating their function in fiber-related traits. We also showed that G. hirsutum HDACs were differentially regulated in response to plant hormones (abscisic acid (ABA) and auxin), DNA damage agent (methyl methanesulfonate (MMS)), and abiotic stresses (cold, salt, heavy metals and drought), indicating the functional diversity and specification of HDACs in response to developmental and environmental cues. In brief, our results provide fundamental information regarding G. hirsutum HDACs and highlight their potential functions in cotton growth, fiber development and stress adaptations, which will be helpful for devising innovative strategies for the improvement of cotton fiber and stress tolerance.

Differential effects of nicotine delivery rate on subjective drug effects, urges to smoke, heart rate and blood pressure in tobacco smokers.

RATIONALE: The nicotine delivery rate is a key feature of tobacco product design, yet there have been limited human studies examining the effects of nicotine as a function of delivery rate. OBJECTIVE: We developed an intravenous nicotine infusion protocol to evaluate differential effects of nicotine delivery rate on subjective drug effects, smoking urges, abstinence symptoms, heart rate, and blood pressure. METHODS: Eighteen non-treatment seeking, overnight abstinent male and female smokers (18 to 30 years old), who smoked ≥ 5 cigarettes per day for the past year completed four sessions, in which they were randomly assigned to a saline infusion, or a 1 mg per 70-kg body weight dose of nicotine delivered over 1, 5, or 10 min at rates of 0.24, 0.048, or 0.024 µg/kg/s, respectively. RESULTS: Smoking urges, as assessed by the Brief Questionnaire of Smoking Urges, were reduced relative to placebo for the 1- and 5-min infusion, but not the 10-min infusion. Although the 1- and 5-min infusions reduced smoking urges to a similar extent, the 1-min infusion induced a greater heart rate and blood pressure increase. Changes to subjective drug effects, heart rate, and blood pressure delineate the differential effects of nicotine delivery rate for these outcomes. CONCLUSIONS: We have characterized the delivery rate-response curve for a nicotine dose that is roughly the amount of nicotine (~ 1 mg) delivered by smoking a standard tobacco cigarette. Our findings reinforce the importance of nicotine delivery rate when evaluating the potential effects of nicotine from tobacco products.

Modulation of "Protective" Nicotine Perception and Use Profile by Flavorants: Preliminary Findings in E-cigarettes.

INTRODUCTION: Characterizing flavors are widely available in e-cigarettes and motivate initiation and continued use. Flavors may enhance appeal and facilitate development of addiction to tobacco products through modulation of tobacco products' reinforcing or aversive actions. Palatable flavors (eg, fruit) may increase appeal through primary reinforcing properties. Menthol's cooling and anesthetic effects may increase appeal by counteracting nicotine's aversive effects. Genetics provide a method for modeling individual differences in sensitivity to nicotine's effects. A common polymorphism, rs16969968, encoded in the α5 nicotinic acetylcholine receptor subunit gene (CHRNA5), is a well-recognized marker for smoking risk and reduces sensitivity to nicotine aversiveness. METHODS: This pilot study tested how flavors impacted e-cigarette appeal and self-administration. In a single testing day, cigarette smokers (N = 32; 94% menthol-smokers) self-administered e-cigarettes containing e-liquids differing in nicotine level (0 mg/mL, 24 mg/mL) and flavor (unflavored, menthol, fruit-flavored) within directed and ad libitum e-cigarette paradigms. Subjective drug effects, number of puffs, rs16969968 genotype, plasma nicotine, and menthol glucuronide levels were collected. RESULTS: Menthol partially ameliorated nicotine aversiveness; fruit did not. In nicotine's absence, fruit flavor increased self-reported preference and ad libitum use relative to menthol-containing or unflavored e-liquids. Individuals with high-smoking-risk rs16969968 genotype (N = 7) reported greater craving alleviation following directed administration of nicotine-containing e-liquids, showed a trend rating nicotine-containing e-liquids as less harsh, and self-administered more nicotine during ad libitum compared to individuals with low-smoking-risk genotype (N = 23). CONCLUSIONS: While menthol countered aversiveness of nicotine-containing e-liquids, fruit flavor increased appeal of nicotine-free e-liquids. These preliminary findings suggest menthol and fruit flavor increase e-cigarettes' appeal through distinct mechanisms. IMPLICATIONS: This study provides a detailed characterization of the effects of flavors (unflavored, menthol, fruit), nicotine (0 mg/mL, 24 mg/mL) and their interactions on the subjective drug effects and ad libitum self-administration of e-cigarettes. Genetics were used to assess these effects in higher-smoking-risk (diminished sensitivity to nicotine aversiveness) and lower-risk groups. Findings could inform impact of regulation of flavors or nicotine in e-cigarettes, and their impacts on vulnerable sub-populations.

Comparative Genome-wide Analysis and Expression Profiling of Histone Acetyltransferase (HAT) Gene Family in Response to Hormonal Applications, Metal and Abiotic Stresses in Cotton.

Post-translational modifications are involved in regulating diverse developmental processes. Histone acetyltransferases (HATs) play vital roles in the regulation of chromation structure and activate the gene transcription implicated in various cellular processes. However, HATs in cotton, as well as their regulation in response to developmental and environmental cues, remain unidentified. In this study, 9 HATs were identified from Gossypium raimondi and Gossypium arboretum, while 18 HATs were identified from Gossypium hirsutum. Based on their amino acid sequences, Gossypium HATs were divided into three groups: CPB, GNAT, and TAFII250. Almost all the HATs within each subgroup share similar gene structure and conserved motifs. Gossypium HATs are unevenly distributed on the chromosomes, and duplication analysis suggests that Gossypium HATs are under strong purifying selection. Gene expression analysis showed that Gossypium HATs were differentially expressed in various vegetative tissues and at different stages of fiber development. Furthermore, all the HATs were differentially regulated in response to various stresses (salt, drought, cold, heavy metal and DNA damage) and hormones (abscisic acid (ABA) and auxin (NAA)). Finally, co-localization of HAT genes with reported quantitative trait loci (QTL) of fiber development were reported. Altogether, these results highlight the functional diversification of HATs in cotton growth and fiber development, as well as in response to different environmental cues. This study enhances our understanding of function of histone acetylation in cotton growth, fiber development, and stress adaptation, which will eventually lead to the long-term improvement of stress tolerance and fiber quality in cotton.

Genome mapping of quantitative trait loci (QTL) controlling domestication traits of intermediate wheatgrass (Thinopyrum intermedium).

Allohexaploid (2n = 6x = 42) intermediate wheatgrass (Thinopyrum intermedium), abbreviated IWG, is an outcrossing perennial grass belonging to the tertiary gene pool of wheat. Perenniality would be valuable option for grain production, but attempts to introgress this complex trait from wheat-Thinopyrum hybrids have not been commercially successful. Efforts to breed IWG itself as a dual-purpose forage and grain crop have demonstrated useful progress and applications, but grain yields are significantly less than wheat. Therefore, genetic and physical maps have been developed to accelerate domestication of IWG. Herein, these maps were used to identify quantitative trait loci (QTLs) and candidate genes associated with IWG grain production traits in a family of 266 full-sib progenies derived from two heterozygous parents, M26 and M35. Transgressive segregation was observed for 17 traits related to seed size, shattering, threshing, inflorescence capacity, fertility, stem size, and flowering time. A total of 111 QTLs were detected in 36 different regions using 3826 genotype-by-sequence markers in 21 linkage groups. The most prominent QTL had a LOD score of 15 with synergistic effects of 29% and 22% over the family means for seed retention and percentage of naked seeds, respectively. Many QTLs aligned with one or more IWG gene models corresponding to 42 possible domestication orthogenes including the wheat Q and RHT genes. A cluster of seed-size and fertility QTLs showed possible alignment to a putative Z self-incompatibility gene, which could have detrimental grain-yield effects when genetic variability is low. These findings elucidate pathways and possible hurdles in the domestication of IWG.

Alcohol-responsive genes identified in human iPSC-derived neural cultures.

Alcohol use contributes to numerous diseases and injuries. The nervous system is affected by alcohol in diverse ways, though the molecular mechanisms of these effects are not clearly understood. Using human-induced pluripotent stem cells (iPSCs), we developed a neural cell culture model to identify the mechanisms of alcohol's effects. iPSCs were generated from fibroblasts and differentiated into forebrain neural cells cultures that were treated with 50 mM alcohol or sham conditions (same media lacking alcohol) for 7 days. We analyzed gene expression using total RNA sequencing (RNA-seq) for 34 samples derived from 10 subjects and for 10 samples from 5 subjects in an independent experiment that had intermittent exposure to the same dose of alcohol. We also analyzed genetic effects on gene expression and conducted a weighted correlation network analysis. We found that differentiated neural cell cultures have the capacity to recapitulate gene regulatory effects previously observed in specific primary neural tissues and identified 226 genes that were differentially expressed (FDR < 0.1) after alcohol treatment. The effects on expression included decreases in INSIG1 and LDLR, two genes involved in cholesterol homeostasis. We also identified a module of 58 co-expressed genes that were uniformly decreased following alcohol exposure. The majority of these effects were supported in independent alcohol exposure experiments. Enrichment analysis linked the alcohol responsive genes to cell cycle, notch signaling, and cholesterol biosynthesis pathways, which are disrupted in several neurological disorders. Our findings suggest that there is convergence between these disorders and the effects of alcohol exposure.

The Cholinergic System as a Treatment Target for Opioid Use Disorder.

Opioid overdoses recently became the leading cause of accidental death in the US, marking an increase in the severity of the opioid use disorder (OUD) epidemic that is impacting global health. Current treatment protocols for OUD are limited to opioid medications, including methadone, buprenorphine, and naltrexone. While these medications are effective in many cases, new treatments are required to more effectively address the rising societal and interpersonal costs associated with OUD. In this article, we review the opioid and cholinergic systems, and examine the potential of acetylcholine (ACh) as a treatment target for OUD. The cholinergic system includes enzymes that synthesize and degrade ACh and receptors that mediate the effects of ACh. ACh is involved in many central nervous system functions that are critical to the development and maintenance of OUD, such as reward and cognition. Medications that target the cholinergic system have been approved for the treatment of Alzheimer's disease, tobacco use disorder, and nausea. Clinical and preclinical studies suggest that medications such as cholinesterase inhibitors and scopolamine, which target components of the cholinergic system, show promise for the treatment of OUD and further investigations are warranted.

Risk Locus Identification Ties Alcohol Withdrawal Symptoms to SORCS2.

BACKGROUND: Efforts to promote the cessation of harmful alcohol use are hindered by the affective and physiological components of alcohol withdrawal (AW), which can include life-threatening seizures. Although previous studies of AW and relapse have highlighted the detrimental role of stress, little is known about genetic risk factors. METHODS: We conducted a genome-wide association study of AW symptom count in uniformly assessed subjects with histories of serious AW, followed by additional genotyping in independent AW subjects. RESULTS: The top association signal for AW severity was in sortilin family neurotrophin receptor gene SORCS2 on chromosome 4 (European American meta-analysis n = 1,478, p = 4.3 × 10-9 ). There were no genome-wide significant findings in African Americans (n = 1,231). Bioinformatic analyses were conducted using publicly available high-throughput transcriptomic and epigenomic data sets, showing that in humans SORCS2 is most highly expressed in the nervous system. The identified SORCS2 risk haplotype is predicted to disrupt a stress hormone-modulated regulatory element that has tissue-specific activity in human hippocampus. We used human neural lineage cells to demonstrate in vitro a causal relationship between stress hormone levels and SORCS2 expression, and show that SORCS2 levels in culture are increased upon ethanol exposure and withdrawal. CONCLUSIONS: Taken together, these findings indicate that the pathophysiology of withdrawal may involve the effects of stress hormones on neurotrophic factor signaling. Further investigation of these pathways could produce new approaches to managing the aversive consequences of abrupt alcohol cessation.

Biochemical, demographic, and self-reported tobacco-related predictors of the acute heart rate response to nicotine in smokers.

Understanding the stimulatory effects of nicotine on cardiovascular function in humans is of great interest given the wide-spread use of different forms of combustible and smokeless products that deliver nicotine. An intravenous nicotine infusion procedure was used to evaluate factors associated with the acute heart rate (HR) response to nicotine (0.5 mg per 70 kg bodyweight) in a sample of 213 smokers. We tested for differential response to nicotine based on demographic characteristics (race [European American vs African America], sex, body mass index and age); a set of blood-based biomarkers (baseline nicotine, cotinine and cortisol levels and nicotine metabolite ratio); and a set of self-reported measures related to tobacco use. Nicotine infusion was first noted to increase HR approximately 10 beats per minute (95% CI: 7.8-12.3) one minute post-infusion, and 13 beats per minute (95% CI: 11.0-15.2) two minutes post-infusion. Higher cortisol, lower nicotine levels, higher nicotine metabolite ratio, being female and greater withdrawal symptoms were independently associated with a potentiated increase in HR 1 or 2 min after nicotine infusion. Factors associated with the acute HR effects of nicotine warrant further investigation given their potential to inform the development of nicotine delivery systems as tobacco harm reduction approaches for smokers.

Phenome-wide association study for CYP2A6 alleles: rs113288603 is associated with hearing loss symptoms in elderly smokers.

To identify novel phenotypic associations related to Cytochrome P450 Family 2 Subfamily A Member 6 (CYP2A6), we investigated the human phenome in a total of 11,271 individuals. Initially, we conducted a phenome-wide association study in 3,401 nicotine-exposed elderly subjects considering 358 phenotypic traits. We identified a significant association between CYP2A6 rs113288603 and hearing loss symptoms (p = 5.75 × 10-5). No association was observed in a sample of 3,245 nicotine-unexposed individuals from the same discovery cohort, consistent with the conclusion that the finding is related to CYP2A6 involvement in nicotine metabolism. Consistent results were obtained (p < 0.1) in an independent sample of 2,077 nicotine-exposed elderly subjects, and similarly, no significance was observed in the nicotine-unexposed sample (n = 2,548) of the replication cohort. Additional supporting evidence for this association was provided by gene expression data: rs113288603 is associated with increased CYP2A6 expression in cerebellar hemispheres (p = 7.8 × 10-4). There is a well-known correlation between smoking and age-related hearing loss. Cigarette smoking is associated with structural changes in the brain and CYP2A6 mediates these changes. In this context, the regulatory role of rs113288603 in cerebellum appears to be consistent with the known involvement of this brain region in auditory function.

Roegneria alashanica Keng: a species with the StStStYStY genome constitution.

The genome constitution of tetraploid Roegneria alashanica Keng has been in question for a long time. Most scientific studies have suggested that R. alashanica had two versions of the St genome, St1St2, similar to that of Pseudoroegneria elytrigioides (C. Yen & J.L. Yang) B.R. Lu. A study, however, concluded that R. alashanica had the StY genome formula typical for tetraploid species of Roegneria. For the present study, R. alashanica, Elymus longearistatus (Bioss.) Tzvelev (StY genomes), Pseudoroegneria strigosa (M. Bieb.) Á. Löve (St), Pseudoroegneria libanoctica (Hackel) D.R. Dewey (St), and Pseudoroegneria spicata (Pursh) Á. Löve (St) were screened for the Y-genome specific marker B14(F+R)269. All E. longearistatus plants expressed intense bands specific to the Y genome. Only 6 of 10 R. alashanica plants exhibited relatively faint bands for the STS marker. Previously, the genome in species of Pseudoroegneria exhibiting such faint Y-genome specific marker was designated as StY. Based on these results, R. alashanica lacks the Y genome in E. longearistatus but likely possess two remotely related St genomes, St and StY. According to its genome constitution, R. alashanica should be classified in the genus Pseudoroenera and given the new name Pseudoroegneria alashanica (Keng) R.R.-C. Wang and K.B. Jensen.

Genetic risk variants for social anxiety.

Social anxiety is a neurobehavioral trait characterized by fear and reticence in social situations. Twin studies have shown that social anxiety has a heritable basis, shared with neuroticism and extraversion, but genetic studies have yet to demonstrate robust risk variants. We conducted genomewide association analysis (GWAS) of subjects within the Army Study To Assess Risk and Resilience in Servicemembers (Army STARRS) to (i) determine SNP-based heritability of social anxiety; (ii) discern genetic risk loci for social anxiety; and (iii) determine shared genetic risk with neuroticism and extraversion. GWAS were conducted within ancestral groups (EUR, AFR, LAT) using linear regression models for each of the three component studies in Army STARRS, and then meta-analyzed across studies. SNP-based heritability for social anxiety was significant (h2g = 0.12, P = 2.17 × 10-4 in EUR). One meta-analytically genomewide significant locus was seen in each of EUR (rs708012, Chr 6: BP 36965970, P = 1.55 × 10-8 ; beta = 0.073) and AFR (rs78924501, Chr 1: BP 88406905, P = 3.58 × 10-8 ; beta = 0.265) samples. Social anxiety in Army STARRS was significantly genetically correlated (negatively) with extraversion (rg = -0.52, se = 0.22, P = 0.02) but not with neuroticism (rg = 0.05, se = 0.22, P = 0.81) or with an anxiety disorder factor score (rg = 0.02, se = 0.32, P = 0.94) from external GWAS meta-analyses. This first GWAS of social anxiety confirms a genetic basis for social anxiety, shared with extraversion but possibly less so with neuroticism. © 2017 Wiley Periodicals, Inc.

Differential transferability of EST-SSR primers developed from the diploid species Pseudoroegneria spicata, Thinopyrum bessarabicum, and Thinopyrum elongatum.

Simple sequence repeat technology based on expressed sequence tag (EST-SSR) is a useful genomic tool for genome mapping, characterizing plant species relationships, elucidating genome evolution, and tracing genes on alien chromosome segments. EST-SSR primers developed from three perennial diploid species of Triticeae, Pseudoroegneria spicata (Pursh) Á. Löve (having St genome), Thinopyrum bessarabicum (Savul. & Rayss) Á. Löve (Jb = Eb = J), and Thinopyrum elongatum (Host) D.R. Dewey (Je = Ee = E), were used to produce amplicons in these three species to (i) assess relative transferability, (ii) identify polymorphic species-specific markers, and (iii) determine genome relationships among the three species. Because of the close relationship between Jb and Je genomes, EST-SSR primers derived from Th. bessarabicum and Th. elongatum had greater transferability to each other than those derived from the St-genome P. spicata. A large number of polymorphic species- and genome-specific EST-SSR amplicons were identified that will be used for construction of genetic maps of these diploid species, and tracing economically useful genes in breeding or gene transfer programs in various species of Triticeae.

A Review of Genome-Wide Association Studies of Stimulant and Opioid Use Disorders.

Substance use disorders (SUD) are a major contributor to disability and disease burden worldwide. Risk for developing SUDs is influenced by variation in the genome. Identifying the genetic variants that influence SUD risk may help us to understand the biological mechanisms for the disorders and improve treatments. Genome-wide association studies (GWAS) have been successful in identifying many regions of the genome associated with common human disorders. Here, findings from recent GWAS of SUDs that involve illicit substances will be reviewed. Several GWAS have been reported, including studies on opioid and stimulant use disorder (cocaine and methamphetamine). Several of these GWAS report associations that are biologically interesting and statistically robust. Replication of the associations in independent samples and functional studies to understand the basis for the statistical associations will be important next steps.

Genome-wide Association Studies of Posttraumatic Stress Disorder in 2 Cohorts of US Army Soldiers.

IMPORTANCE: Posttraumatic stress disorder (PTSD) is a prevalent, serious public health concern, particularly in the military. The identification of genetic risk factors for PTSD may provide important insights into the biological foundation of vulnerability and comorbidity. OBJECTIVE: To discover genetic loci associated with the lifetime risk for PTSD in 2 cohorts from the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS). DESIGN, SETTING, AND PARTICIPANTS: Two coordinated genome-wide association studies of mental health in the US military contributed participants. The New Soldier Study (NSS) included 3167 unique participants with PTSD and 4607 trauma-exposed control individuals; the Pre/Post Deployment Study (PPDS) included 947 unique participants with PTSD and 4969 trauma-exposed controls. The NSS data were collected from February 1, 2011, to November 30, 2012; the PDDS data, from January 9 to April 30, 2012. The primary analysis compared lifetime DSM-IV PTSD cases with trauma-exposed controls without lifetime PTSD. Data were analyzed from March 18 to December 27, 2015. MAIN OUTCOMES AND MEASURES: Association analyses for PTSD used logistic regression models within each of 3 ancestral groups (European, African, and Latino American) by study, followed by meta-analysis. Heritability and genetic correlation and pleiotropy with other psychiatric and immune-related disorders were estimated. RESULTS: The NSS population was 80.7% male (6277 of 7774 participants; mean [SD] age, 20.9 [3.3] years); the PPDS population, 94.4% male (5583 of 5916 participants; mean [SD] age, 26.5 [6.0] years). A genome-wide significant locus was found in ANKRD55 on chromosome 5 (rs159572; odds ratio [OR], 1.62; 95% CI, 1.37-1.92; P = 2.34 × 10-8) and persisted after adjustment for cumulative trauma exposure (adjusted OR, 1.64; 95% CI, 1.39-1.95; P = 1.18 × 10-8) in the African American samples from the NSS. A genome-wide significant locus was also found in or near ZNF626 on chromosome 19 (rs11085374; OR, 0.77; 95% CI, 0.70-0.85; P = 4.59 × 10-8) in the European American samples from the NSS. Similar results were not found for either single-nucleotide polymorphism in the corresponding ancestry group from the PPDS sample, in other ancestral groups, or in transancestral meta-analyses. Single-nucleotide polymorphism-based heritability was nonsignificant, and no significant genetic correlations were observed between PTSD and 6 mental disorders or 9 immune-related disorders. Significant evidence of pleiotropy was observed between PTSD and rheumatoid arthritis and, to a lesser extent, psoriasis. CONCLUSIONS AND RELEVANCE: In the largest genome-wide association study of PTSD to date, involving a US military sample, limited evidence of association for specific loci was found. Further efforts are needed to replicate the genome-wide significant association with ANKRD55-associated in prior research with several autoimmune and inflammatory disorders-and to clarify the nature of the genetic overlap observed between PTSD and rheumatoid arthritis and psoriasis.

Intravenous Nicotine Self-Administration in Smokers: Dose-Response Function and Sex Differences.

Sex differences in the sensitivity to nicotine may influence vulnerability to tobacco dependence. The goal of this study was to investigate the dose-response function for the reinforcing and subjective effects of intravenous nicotine in male and female smokers. Tobacco-dependent subjects (12 male and 14 female) participated in four experimental sessions in which they received sample infusions of saline and nicotine (0.1, 0.2, 0.3, or 0.4 mg doses) in a randomized double-blind crossover design. During each session, subjects first received the sample infusions, and heart rate (HR), blood pressure, and subjective stimulatory, pleasurable and aversive responses were monitored. Immediately following the sample infusions, subjects self-administered either nicotine or saline in six double-blind forced-choice trials. A sex by dose interaction was observed in the nicotine choice paradigm. Nicotine self-administration rate was negatively correlated with nicotine dose in males (males displayed choice preference for low doses of nicotine over high doses of nicotine), but no significant relationship between dose and choice preference was evident in females. Relative to placebo, sample doses of nicotine increased heart rate and blood pressure, and induced stimulatory, pleasurable, and aversive subjective effects. Diastolic blood pressure increased dose dependently in males, but not in females. These findings, which demonstrate sex differences in nicotine self-administration for doses that are near to the reinforcement threshold, suggest that male and female smokers may respond differently to the changes in nicotine doses available for self-administration.