The Functional DRD3 Ser9Gly Polymorphism (rs6280) Is Pleiotropic, Affecting Reward as Well as Movement

Abnormalities of motivation and behavior in the context of reward are a fundamental component of addiction and mood disorders. Here we test the effect of a functional missense mutation in the dopamine 3 receptor (DRD3) gene (ser9gly, rs6280) on reward-associated dopamine (DA) release in the striatum. Twenty-six healthy controls (HCs) and 10 unmedicated subjects with major depressive disorder (MDD) completed two positron emission tomography (PET) scans with [11C]raclopride using the bolus plus constant infusion method. On one occasion subjects completed a sensorimotor task (control condition) and on another occasion subjects completed a gambling task (reward condition). A linear regression analysis controlling for age, sex, diagnosis, and self-reported anhedonia indicated that during receipt of unpredictable monetary reward the glycine allele was associated with a greater reduction in D2/3 receptor binding (i.e., increased reward-related DA release) in the middle (anterior) caudate (p<0.01) and the ventral striatum (p<0.05). The possible functional effect of the ser9gly polymorphism on DA release is consistent with previous work demonstrating that the glycine allele yields D3 autoreceptors that have a higher affinity for DA and display more robust intracellular signaling. Preclinical evidence indicates that chronic stress and aversive stimulation induce activation of the DA system, raising the possibility that the glycine allele, by virtue of its facilitatory effect on striatal DA release, increases susceptibility to hyperdopaminergic responses that have previously been associated with stress, addiction, and psychosis

Future therapeutic targets in rheumatoid arthritis?

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by persistent joint inflammation. Without adequate treatment, patients with RA will develop joint deformity and progressive functional impairment. With the implementation of treat-to-target strategies and availability of biologic therapies, the outcomes for patients with RA have significantly improved. However, the unmet need in the treatment of RA remains high as some patients do not respond sufficiently to the currently available agents, remission is not always achieved and refractory disease is not uncommon. With better understanding of the pathophysiology of RA, new therapeutic approaches are emerging. Apart from more selective Janus kinase inhibition, there is a great interest in the granulocyte macrophage-colony stimulating factor pathway, Bruton's tyrosine kinase pathway, phosphoinositide-3-kinase pathway, neural stimulation and dendritic cell-based therapeutics. In this review, we will discuss the therapeutic potential of these novel approaches

Possible Associations of NTRK2 Polymorphisms with Antidepressant Treatment Outcome: Findings from an Extended Tag SNP Approach

Background: Data from clinical studies and results from animal models suggest an involvement of the neurotrophin system in the pathology of depression and antidepressant treatment response. Genetic variations within the genes coding for the brain-derived neurotrophic factor (BDNF) and its key receptor Trkb (NTRK2) may therefore influence the response to antidepressant treatment. Methods: We performed a single and multi-marker association study with antidepressant treatment outcome in 398 depressed Caucasian inpatients participating in the Munich Antidepressant Response Signature (MARS) project. Two Caucasian replication samples (N = 249 and N = 247) were investigated, resulting in a total number of 894 patients. 18 tagging SNPs in the BDNF gene region and 64 tagging SNPs in the NTRK2 gene region were genotyped in the discovery sample; 16 nominally associated SNPs were tested in two replication samples. Results: In the discovery analysis, 7 BDNF SNPs and 9 NTRK2 SNPs were nominally associated with treatment response. Three NTRK2 SNPs (rs10868223, rs1659412 and rs11140778) also showed associations in at least one replication sample and in the combined sample with the same direction of effects ($P_{corr}$ = .018, $P_{corr}$ = .015 and $P_{corr}$ = .004, respectively). We observed an across-gene BDNF-NTRK2 SNP interaction for rs4923468 and rs1387926. No robust interaction of associated SNPs was found in an analysis of BDNF serum protein levels as a predictor for treatment outcome in a subset of 93 patients. Conclusions/Limitations: Although not all associations in the discovery analysis could be unambiguously replicated, the findings of the present study identified single nucleotide variations in the BDNF and NTRK2 genes that might be involved in antidepressant treatment outcome and that have not been previously reported in this context. These new variants need further validation in future association studies

A new practical method to evaluate the Joule-Thomson coefficient for natural gases

© 2017, The Author(s). The Joule–Thomson (JT) phenomenon, the study of fluid temperature changes for a given pressure change at constant enthalpy, has great technological and scientific importance for designing, maintenance and prediction of hydrocarbon production. The phenomenon serves vital role in many facets of hydrocarbon production, especially associated with reservoir management such as interpretation of temperature logs of production and injection well, identification of water and gas entry locations in multilayer production scenarios, modelling of thermal response of hydrocarbon reservoirs and prediction of wellbore flowing temperature profile. The purpose of this study is to develop a new method for the evaluation of JT coefficient, as an essential parameter required to account the Joule–Thomson effects while predicting the flowing temperature profile for gas production wells. To do this, a new correction factor, CNM, has been developed through numerical analysis and proposed a practical method to predict CNM which can simplify the prediction of flowing temperature for gas production wells while accounting the Joule–Thomson effect. The developed correlation and methodology were validated through an exhaustive survey which has been conducted with 20 different gas mixture samples. For each sample, the model has been run for a wide range of temperature and pressure conditions, and the model was rigorously verified by comparison of the results estimated throughout the study with the results obtained from HYSYS and Peng–Robinson equation of state. It is observed that model is very simple and robust yet can accurately predict the Joule–Thomson effect

Genetic Characterization of a Core Set of a Tropical Maize Race Tuxpeño for Further Use in Maize Improvement

The tropical maize race Tuxpeño is a well-known race of Mexican dent germplasm which has greatly contributed to the development of tropical and subtropical maize gene pools. In order to investigate how it could be exploited in future maize improvement, a panel of maize germplasm accessions was assembled and characterized using genome-wide Single Nucleotide Polymorphism (SNP) markers. This panel included 321 core accessions of Tuxpeño race from the International Maize and Wheat Improvement Center (CIMMYT) germplasm bank collection, 94 CIMMYT maize lines (CMLs) and 54 U.S. Germplasm Enhancement of Maize (GEM) lines. The panel also included other diverse sources of reference germplasm: 14 U.S. maize landrace accessions, 4 temperate inbred lines from the U.S. and China, and 11 CIMMYT populations (a total of 498 entries with 795 plants). Clustering analyses (CA) based on Modified Rogers Distance (MRD) clearly partitioned all 498 entries into their corresponding groups. No sub clusters were observed within the Tuxpeño core set. Various breeding strategies for using the Tuxpeño core set, based on grouping of the studied germplasm and genetic distance among them, were discussed. In order to facilitate sampling diversity within the Tuxpeño core, a minicore subset of 64 Tuxpeño accessions (20% of its usual size) representing the diversity of the core set was developed, using an approach combining phenotypic and molecular data. Untapped diversity represents further use of the Tuxpeño landrace for maize improvement through the core and/or minicore subset available to the maize community

Substance abuse treatment client experience in an employed population: results of a client survey

<p>Abstract</p> <p>Background</p> <p>Understanding client perspectives on treatment is increasingly recognized as key to improving care. Yet information on the perceptions and experiences of workers with private insurance coverage who receive help for substance use conditions is relatively sparse, particularly in managed behavioral health care organization (MBHO) populations. Furthermore, the role of several factors including prior service use has not been fully explored.</p> <p>Methods</p> <p>Employees covered by a large MBHO who had received substance abuse services in the past year were surveyed (146 respondents completed the telephone survey and self-reported service use).</p> <p>Results</p> <p>The most common reasons for entering treatment were problems with health; home, family or friends; or work. Prior treatment users reported more reasons for entering treatment and more substance use-related work impairment. The majority of all respondents felt treatment helped a lot or some. One quarter reported getting less treatment than they felt they needed.</p> <p>Discussion and conclusions</p> <p>Study findings point to the need to tailor treatment for prior service users and to recognize the role of work in treatment entry and outcomes. Perceived access issues may be present even among insured clients already in treatment.</p

Prioritization and Evaluation of Depression Candidate Genes by Combining Multidimensional Data Resources

Large scale and individual genetic studies have suggested numerous susceptible genes for depression in the past decade without conclusive results. There is a strong need to review and integrate multi-dimensional data for follow up validation. The present study aimed to apply prioritization procedures to build-up an evidence-based candidate genes dataset for depression.Depression candidate genes were collected in human and animal studies across various data resources. Each gene was scored according to its magnitude of evidence related to depression and was multiplied by a source-specific weight to form a combined score measure. All genes were evaluated through a prioritization system to obtain an optimal weight matrix to rank their relative importance with depression using the combined scores. The resulting candidate gene list for depression (DEPgenes) was further evaluated by a genome-wide association (GWA) dataset and microarray gene expression in human tissues.A total of 5,055 candidate genes (4,850 genes from human and 387 genes from animal studies with 182 being overlapped) were included from seven data sources. Through the prioritization procedures, we identified 169 DEPgenes, which exhibited high chance to be associated with depression in GWA dataset (Wilcoxon rank-sum test, p = 0.00005). Additionally, the DEPgenes had a higher percentage to express in human brain or nerve related tissues than non-DEPgenes, supporting the neurotransmitter and neuroplasticity theories in depression.With comprehensive data collection and curation and an application of integrative approach, we successfully generated DEPgenes through an effective gene prioritization system. The prioritized DEPgenes are promising for future biological experiments or replication efforts to discover the underlying molecular mechanisms for depression

Biology of Francisella tularensis Subspecies holarctica Live Vaccine Strain in the Tick Vector Dermacentor variabilis

Background: The c-proteobacterium Francisella tularensis is the etiologic agent of seasonal tick-transmitted tularemia epizootics in rodents and rabbits and of incidental infections in humans. The biology of F. tularensis in its tick vectors has not been fully described, particularly with respect to its quanta and duration of colonization, tissue dissemination, and transovarial transmission. A systematic study of the colonization of Dermacentor variabilis by the F. tularensis subsp. holarctica live vaccine strain (LVS) was undertaken to better understand whether D. variabilis may serve as an inter-epizootic reservoir for F. tularensis. Methodology/Principal Findings: Colony-reared larva, nymph, and adult D. variabilis were artificially fed LVS via glass capillary tubes fitted over the tick mouthparts, and the level of colonization determined by microbial culture. Larvae and nymphs were initially colonized with 8.860.8610 1 and 1.160.03610 3 CFU/tick, respectively. Post-molting, a significant increase in colonization of both molted nymphs and adults occurred, and LVS persisted in 42 % of molted adult ticks at 126 days post-capillary tube feeding. In adult ticks, LVS initially colonized the gut, disseminated to hemolymph and salivary glands by 21 days, and persisted up to 165 days. LVS was detected in the salivary secretions of adult ticks after four days post intra-hemocoelic inoculation, and LVS recovered from salivary gland was infectious to mice with an infectious dose 50 % of 3 CFU. LVS in gravid female ticks colonized via the intra-hemocoelic route disseminated to the ovaries and then t

A Whole-Genome SNP Association Study of NCI60 Cell Line Panel Indicates a Role of Ca2+ Signaling in Selenium Resistance

Epidemiological studies have suggested an association between selenium intake and protection from a variety of cancer. Considering this clinical importance of selenium, we aimed to identify the genes associated with resistance to selenium treatment. We have applied a previous methodology developed by our group, which is based on the genetic and pharmacological data publicly available for the NCI60 cancer cell line panel. In short, we have categorized the NCI60 cell lines as selenium resistant and sensitive based on their growth inhibition (GI50) data. Then, we have utilized the Affymetrix 125K SNP chip data available and carried out a genome-wide case-control association study for the selenium sensitive and resistant NCI60 cell lines. Our results showed statistically significant association of four SNPs in 5q33–34, 10q11.2, 10q22.3 and 14q13.1 with selenium resistance. These SNPs were located in introns of the genes encoding for a kinase-scaffolding protein (AKAP6), a membrane protein (SGCD), a channel protein (KCNMA1), and a protein kinase (PRKG1). The knock-down of KCNMA1 by siRNA showed increased sensitivity to selenium in both LNCaP and PC3 cell lines. Furthermore, SNP-SNP interaction (epistasis) analysis indicated the interactions of the SNPs in AKAP6 with SGCD as well as SNPs in AKAP6 with KCNMA1 with each other, assuming additive genetic model. These genes were also all involved in the Ca2+ signaling, which has a direct role in induction of apoptosis and induction of apoptosis in tumor cells is consistent with the chemopreventive action of selenium. Once our findings are further validated, this knowledge can be translated into clinics where individuals who can benefit from the chemopreventive characteristics of the selenium supplementation will be easily identified using a simple DNA analysis