Sample records for val di maso

  1. A Verification Method for MASOES.

    PubMed

    Perozo, N; Aguilar Perozo, J; Terán, O; Molina, H

    2013-02-01

    MASOES is a 3agent architecture for designing and modeling self-organizing and emergent systems. This architecture describes the elements, relationships, and mechanisms, both at the individual and the collective levels, that favor the analysis of the self-organizing and emergent phenomenon without mathematically modeling the system. In this paper, a method is proposed for verifying MASOES from the point of view of design in order to study the self-organizing and emergent behaviors of the modeled systems. The verification criteria are set according to what is proposed in MASOES for modeling self-organizing and emerging systems and the principles of the wisdom of crowd paradigm and the fuzzy cognitive map (FCM) theory. The verification method for MASOES has been implemented in a tool called FCM Designer and has been tested to model a community of free software developers that works under the bazaar style as well as a Wikipedia community in order to study their behavior and determine their self-organizing and emergent capacities.

  2. The Vibrio alginolyticus T3SS effectors, Val1686 and Val1680, induce cell rounding, apoptosis and lysis of fish epithelial cells

    PubMed Central

    Zhao, Zhe; Liu, Jinxin; Deng, Yiqin; Huang, Wen; Ren, Chunhua; Call, Douglas R.; Hu, Chaoqun

    2018-01-01

    ABSTRACT Vibrio alginolyticus is a Gram-negative bacterium that is an opportunistic pathogen of both marine animals and people. Its pathogenesis likely involves type III secretion system (T3SS) mediated induction of rapid apoptosis, cell rounding and osmotic lysis of infected eukaryotic cells. Herein, we report that effector proteins, Val1686 and Val1680 from V. alginolyticus, were responsible for T3SS-mediated death of fish cells. Val1686 is a Fic-domain containing protein that not only contributed to cell rounding by inhibiting Rho guanosine triphosphatases (GTPases), but was requisite for the induction of apoptosis because the deletion mutant (Δval1686) was severely weakened in its ability to induce cell rounding and apoptosis in fish cells. In addition, Val1686 alone was sufficient to induce cell rounding and apoptosis as evidenced by the transfection of Val1686 into fish cells. Importantly, the Fic-domain essential for cell rounding activity was equally important to activation of apoptosis of fish cells, indicating that apoptosis is a downstream event of Val1686-dependent GTPase inhibition. V. alginolyticus infection likely activates JNK and ERK pathways with sequential activation of caspases (caspase-8/-10, -9 and -3) and subsequent apoptosis. Val1680 contributed to T3SS-dependent lysis of fish cells in V. alginolyticus, but did not induce autophagy as has been reported for its homologue (VopQ) in V. parahaemolyticus. Together, Val1686 and Val1680 work together to induce apoptosis, cell rounding and cell lysis of V. alginolyticus-infected fish cells. These findings provide new insights into the mechanism of cell death caused by T3SS of V. alginolyticus. PMID:29252102

  3. Sweet Taste Receptor TAS1R2 Polymorphism (Val191Val) Is Associated with a Higher Carbohydrate Intake and Hypertriglyceridemia among the Population of West Mexico

    PubMed Central

    Ramos-Lopez, Omar; Panduro, Arturo; Martinez-Lopez, Erika; Roman, Sonia

    2016-01-01

    Some high-carbohydrate diets may lead to obesity and multiple metabolic disorders, including hypertriglyceridemia (HTG). This lipid abnormality is considered an important risk factor for cardiovascular disease and type 2 diabetes. The sweet taste receptor TAS1R2 polymorphism (Ile191Val) has been reported to be associated with carbohydrate intake. The aim of this study was to analyze the association of the TAS1R2 gene polymorphism with carbohydrate intake and HTG among the population of West Mexico. In a cross-sectional study, 441 unrelated subjects were analyzed for TAS1R2 genotypes (Ile/Ile, Ile/Val and Val/Val) by an allelic discrimination assay. Biochemical tests and a three-day food record were assessed. The Val/Val genotype carriers had a higher intake of total carbohydrates, fiber and servings of cereals and vegetables than the other genotype carriers. The Val/Val genotype conferred a higher risk for HTG than the Ile/Val and Ile/Ile genotypes (OR = 3.26, 95%CI 1.35–7.86, p = 0.006 and OR = 2.61, 95%CI 1.12–6.07, p = 0.02, respectively). Furthermore, the Val/Val genotype was associated with approximately 30% higher triglycerides compared with Ile/Val and Ile/Ile genotypes (β = 44.09, 95%CI 9.94–78.25, p = 0.01 and β = 45.7, 95%CI 10.85–80.54, p = 0.01, respectively). In conclusion, the Val/Val genotype of TAS1R2 was associated with a higher carbohydrate intake and HTG. PMID:26907331

  4. CoalVal-A coal resource valuation program

    USGS Publications Warehouse

    Rohrbacher, Timothy J.; McIntosh, Gary E.

    2010-01-01

    CoalVal is a menu-driven Windows program that produces cost-of-mining analyses of mine-modeled coal resources. Geological modeling of the coal beds and some degree of mine planning, from basic prefeasibility to advanced, must already have been performed before this program can be used. United States Geological Survey mine planning is done from a very basic, prefeasibility standpoint, but the accuracy of CoalVal's output is a reflection of the accuracy of the data entered, both for mine costs and mine planning. The mining cost analysis is done by using mine cost models designed for the commonly employed, surface and underground mining methods utilized in the United States. CoalVal requires a Microsoft Windows? 98 or Windows? XP operating system and a minimum of 1 gigabyte of random access memory to perform operations. It will not operate on Microsoft Vista?, Windows? 7, or Macintosh? operating systems. The program will summarize the evaluation of an unlimited number of coal seams, haulage zones, tax entities, or other area delineations for a given coal property, coalfield, or basin. When the reader opens the CoalVal publication from the USGS website, options are provided to download the CoalVal publication manual and the CoalVal Program. The CoalVal report is divided into five specific areas relevant to the development and use of the CoalVal program: 1. Introduction to CoalVal Assumptions and Concepts. 2. Mine Model Assumption Details (appendix A). 3. CoalVal Project Tutorial (appendix B). 4. Program Description (appendix C). 5. Mine Model and Discounted Cash Flow Formulas (appendix D). The tutorial explains how to enter coal resource and quality data by mining method; program default values for production, operating, and cost variables; and ones own operating and cost variables into the program. Generated summary reports list the volume of resource in short tons available for mining, recoverable short tons by mining method; the seam or property being mined

  5. Characterization of glycidol-hemoglobin adducts as biomarkers of exposure and in vivo dose

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Honda, Hiroshi, E-mail: honda.hiroshi@kao.co.jp; Törnqvist, Margareta; Nishiyama, Naohiro

    2014-03-15

    Hemoglobin adducts have been used as biomarkers of exposure to reactive chemicals. Glycidol, an animal carcinogen, has been reported to form N-(2,3-dihydroxy-propyl)valine adducts to hemoglobin (diHOPrVal). To support the use of these adducts as markers of glycidol exposure, we investigated the kinetics of diHOPrVal formation and its elimination in vitro and in vivo. Five groups of rats were orally administered a single dose of glycidol ranging from 0 to 75 mg/kg bw, and diHOPrVal levels were measured 24 h after administration. A dose-dependent increase in diHOPrVal levels was observed with high linearity (R{sup 2} = 0.943). Blood sampling at differentmore » time points (1, 10, 20, or 40 days) from four groups administered glycidol at 12 mg/kg bw suggested a linear decrease in diHOPrVal levels compatible with the normal turnover of rat erythrocytes (life span, 61 days), with the calculated first-order elimination rate constant (k{sub el}) indicating that the diHOPrVal adduct was chemically stable. Then, we measured the second-order rate constant (k{sub val}) for the reaction of glycidol with N-terminal valine in rat and human hemoglobin in in vitro experiments with whole blood. The k{sub val} was 6.7 ± 1.1 and 5.6 ± 1.3 (pmol/g globin per μMh) in rat and human blood, respectively, indicating no species differences. In vivo doses estimated from k{sub val} and diHOPrVal levels were in agreement with the area under the (concentration–time) curve values determined in our earlier toxicokinetic study in rats. Our results indicate that diHOPrVal is a useful biomarker for quantification of glycidol exposure and for risk assessment. - Highlight: • Glycidol-hemoglobin adduct (diHOPrVal) was characterized for exposure evaluation. • We studied the kinetics of diHOPrVal formation and elimination in vitro and in vivo. • Dose dependent formation and chemical stability were confirmed in the rat study. • In vivo dose (AUC) of glycidol could be estimated from diHOPrVal

  6. Ha-ras(val12) induces HSP70b transcription via the HSE/HSF1 system, but HSP70b expression is suppressed in Ha-ras(val12)-transformed cells.

    PubMed

    Stanhill, A; Levin, V; Hendel, A; Shachar, I; Kazanov, D; Arber, N; Kaminski, N; Engelberg, D

    2006-03-09

    Heat shock proteins (Hsps) are overexpressed in many tumors, but are downregulated in some tumors. To check for a direct effect of Ha-Ras(val12) on HSP70 transcription, we transiently expressed the oncoprotein in Rat1 fibroblasts and monitored its effect on HSP70b promoter-driven reporter gene. We show that expression of Ha-Ras(val12) induced this promoter. Promoter analysis via systematic deletions and point mutations revealed that Ha-Ras(val12) induces HSP70b transcription via heat shock elements (HSEs). Also, Ha-Ras(val12) induction of HSE-mediated transcription was dramatically reduced in HSF1-/- cells. Yet, residual effect of Ha-Ras(val12) that was still measured in HSF1-/- cells suggests that some of the Ha-Ras(val12) effect is Hsf1-independent. When HSF1-/- cells, stably expressing Ha-Ras(val12), were grown on soft agar only small colonies were formed suggesting a role for heat shock factor 1 (Hsf1) in Ha-Ras(val12)-mediated transformation. Although Ha-ras(Val12) seems to be an inducer of HSP70's expression, we found that in Ha-ras(Val12-)transformed fibroblasts expression of this gene is suppressed. This suppression is correlated with higher sensitivity of Ha-ras(val12)-transformed cells to heat shock. We suggest that Ha-ras(Val12) is involved in Hsf1 activation, thereby inducing the cellular protective response. Cells that repress this response are perhaps those that acquire the capability to further proliferate and become transformed clones.

  7. Association of Catechol-O-methyltransferase polymorphism Val158Met and mammographic density: A meta-analysis.

    PubMed

    Kallionpää, Roope A; Uusitalo, Elina; Peltonen, Juha

    2017-08-15

    The Val158Met polymorphism in catechol-O-methyltransferase (COMT) enzyme reduces the methylation of catechol estrogens, which may affect mammographic density. High mammographic density is a known risk factor of breast cancer. Our aim was to perform meta-analysis of the effect of COMT Val158Met polymorphism on mammographic density. Original studies reporting data on mammographic density, stratified by the presence of COMT Val158Met polymorphism, were identified and combined using genetic models Met/Val vs. Val/Val, Met/Met vs. Val/Val, Val/Met+Met/Met vs. Val/Val (dominant model) and Met/Met vs. Val/Met+Val/Val (recessive model). Subgroup analyses by breast cancer status, menopausal status and use of hormone replacement therapy (HRT) were also performed. Eight studies were included in the meta-analysis. The overall effect in percent mammographic density was -1.41 (CI -2.86 to 0.05; P=0.06) in the recessive model. Exclusion of breast cancer patients increased the effect size to -1.93 (CI -3.49 to -0.37; P=0.02). The results suggested opposite effect of COMT Val158Met for postmenopausal users of HRT versus premenopausal women or postmenopausal non-users of HRT. COMT Val158Met polymorphism may be associated with mammographic density at least in healthy women. Menopausal status and HRT should be taken into account in future studies to avoid masking of the underlying effects. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. 3. VAL CAMERA CAR, VIEW OF CAMERA CAR AND TRACK ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    3. VAL CAMERA CAR, VIEW OF CAMERA CAR AND TRACK WITH THE VAL TO THE RIGHT, LOOKING NORTHEAST. - Variable Angle Launcher Complex, Camera Car & Track, CA State Highway 39 at Morris Reservior, Azusa, Los Angeles County, CA

  9. Cathecol-O-methyl transferase Val158Met genotype is not a risk factor for conversion disorder.

    PubMed

    Armagan, E; Almacıoglu, M L; Yakut, T; Köse, A; Karkucak, M; Köksal, O; Görükmez, O

    2013-03-19

    Alterations in catechol-O-methyltransferase (COMT) activity are involved in various types of neurological disorders. We examined a possible association between the COMT Val158Met polymorphism and conversion disorder in a study of 48 patients with conversion disorder and 48 control patients. In the conversion disorder group, 31 patients were Val/Met heterozygotes, 15 patients were Val/Val homozygotes and 2 patients were Met/Met homozygotes. In the control group, 32 patients were Val/Met heterozygotes and 16 patients were Val/Val homozygotes. There was no significant difference between the groups. We conclude that the COMT Val158Met genotype is quite common in Turkey and that it is not a risk factor for conversion disorder in the Turkish population.

  10. HER2 Ile655Val polymorphism contributes to breast cancer risk: evidence from 27 case-control studies.

    PubMed

    Lu, Su; Wang, Zhanwei; Liu, Hong; Hao, Xishan

    2010-12-01

    Proto-oncogene HER2 (also known as erbB-2 or neu) plays an important role in the carcinogenesis and the prognosis of breast cancer. Many epidemiological studies have been conducted to explore the association between the HER2 Ile655Val polymorphism and breast cancer risk. However, inconsistency existed in the results. Therefore, we performed a meta-analysis of 27 published case-control studies including 11,504 cases and 12,538 controls. We assessed the strength of the association by crude odds ratios (ORs) with 95% confidence intervals (CIs) and reached a result that HER2 Ile655Val polymorphism was associated with an increased breast cancer risk in overall populations (for Ile/Val vs. Ile/Ile: OR = 1.05, 95% CI = 1.00-1.12, P = 0.07 for heterogeneity; for the dominant model Ile/Val + Val/Val vs. Ile/Ile: OR = 1.10, 95% CI = 1.01-1.20, P = 0.01 for heterogeneity). In subgroup analysis by ethnicity, we found a significant association among Africans (for Val/Val vs. Ile/Ile: OR = .78, 95% CI = 1.94-39.72, P = 0.35 for heterogeneity; for the recessive model Val/Val vs. Ile/Val +Ile/Ile: OR = 8.60, 95% CI = 1.92-38.48, P = 0.31 for heterogeneity) and Asians (for Ile/Val vs. Ile/Ile: OR = 1.18, 95% CI = 1.01-1.39, P = 0.41 for heterogeneity; for the dominant model Val/Val + Ile/Val vs. Ile/Ile: OR = 1.18, 95% CI = 1.01-1.38, P = 0.27 for heterogeneity). In conclusion, our meta-analysis suggests that HER2 Ile 655Val polymorphism may contribute to breast cancer risk.

  11. Genetic contribution of catechol-O-methyltransferase polymorphism (Val158Met) in children with chronic tension-type headache.

    PubMed

    Fernández-de-las-Peñas, César; Ambite-Quesada, Silvia; Rivas-Martínez, Inés; Ortega-Santiago, Ricardo; de-la-Llave-Rincón, Ana Isabel; Fernández-Mayoralas, Daniel M; Pareja, Juan A

    2011-10-01

    Our aim was to investigate the relationship between Val158Met polymorphisms, headache, and pressure hypersensitivity in children with chronic tension-type headache (CTTH). A case-control study with blinded assessor was conducted. Seventy children with CTTH associated with pericranial tenderness and 70 healthy children participated. After amplifying Val158Met polymorphism by polymerase chain reactions, we assessed genotype frequencies and allele distributions. We classified children according to their Val158Met polymorphism: Val/Val, Val/Met, Met/Met. Pressure pain thresholds (PPT) were bilaterally assessed over the temporalis, upper trapezius, second metacarpal, and tibialis anterior muscles. The distribution of Val158Met genotypes was not significantly different (p = 0.335), between children with CTTH and healthy children, and between boys and girls (p = 0.872). Children with CTTH with the Met/Met genotype showed a longer headache history compared with those with Met/Val (p = 0.001) or Val/Val (p = 0.002) genotype. Children with CTTH with Met/Met genotype showed lower PPT over upper trapezius and temporalis muscles than children with CTTH with Met/Val or Val/Val genotype (p < 0.01). The Val158Met catechol-O-methyltransferase (COMT) polymorphism does not appear to be involved in predisposition to suffer from CTTH in children; nevertheless, this genetic factor may be involved in the phenotypic expression, as pressure hypersensitivity was greater in those CTTH children with the Met/Met genotype.

  12. The influence of COMT Val158Met genotype on the character dimension cooperativeness in healthy females

    PubMed Central

    Baeken, Chris; Claes, Stephan; De Raedt, Rudi

    2014-01-01

    Objectives Although the Val158Met catechol-O-methyltransferase (COMT) gene has been linked with the temperament dimension Novelty Seeking (NS), new insights in this polymorphism might point to a major role for character features as well. Given that individual life experiences may influence Val158 and Met158 allele carriers differently it has been suggested that the character trait cooperativeness could be implicated. Case report A homogeneous group of eighty right-handed Caucasian healthy female university students were assessed with the TCI and genotyped for the COMT Val158Met polymorphism (rs4680). Gene determination showed that eighteen were Val158 homozygotes, forty-four Val/Met158 heterozygotes, and eighteen were Met158 homozygotes. All were within the same age range and never documented to have suffered from any neuropsychiatric illness. Bonferroni corrected non-parametric analyses showed that only for the character scale cooperativeness Val158 homozygotes displayed significant higher scores when compared to Met158 homozygotes. No significant differences on cooperativeness scores were found between Val158 and Val/Met158 carriers or between Met158 and Val/Met158 carriers. No differences were observed for the COMT Val158Met polymorphism and the other temperament and character scales. Conclusions Our findings support the assumption that the Val158Met single nucleotide polymorphism (SNP) influences character traits and not only temperament. Our results add to the notion that Val158 homozygotes are considered to be helpful and empathic and it suggest that these cooperativeness character traits are related to the dopaminergic system. PMID:25161818

  13. Paradoxical visuomotor adaptation to reversed visual input is predicted by BDNF Val66Met polymorphism

    PubMed Central

    Barton, Brian; Treister, Andrew; Humphrey, Melanie; Abedi, Garen; Cramer, Steven C.; Brewer, Alyssa A.

    2014-01-01

    Brain-derived neurotrophic factor (BDNF) is the most abundant neurotrophin in the brain, influencing neural development, plasticity, and repair (Chen et al., 2004; Thoenen, 1995). The BDNF gene contains a single-nucleotide polymorphism (SNP) called Val66Met. The Met allele interferes with intracellular BDNF-trafficking, decreases activity-dependent BDNF secretion, and consequently is often associated with a shift from plasticity to stability in neural circuits (Egan et al., 2003). We investigated the behavioral consequences of the presence of the Met allele by comparing how 40 heterozygous subjects with the Val/Met genotype and 35 homozygous subjects with the Val/Val genotype performed on visuomotor tasks (reaching and navigation) under two conditions: normal vision and completely left-right reversed vision. As expected, subjects did not differ in their short-term ability to learn the tasks with normal vision (p = 0.58). Intuitively, it would be expected that homozygous Val/Val subjects with a propensity for greater BDNF-induced activity-dependent plasticity would learn new tasks more quickly than heterozygous Val/Met subjects with decreased BDNF secretion (Gilbert, Li, & Piech, 2009). However, we found the opposite here. When short-term mechanisms of visuomotor adaptation were engaged to compensate for the misalignment of visual and somatomotor information created by the left-right reversal of vision, heterozygous Val/Met subjects learned significantly more quickly than their homozygous Val/Val counterparts (p = 0.027). Our results demonstrate the paradoxical finding that the presence of the Met allele, which is thought to promote cortical stability, here improves immediate visuomotor adaptation to left–right-reversed visual input. PMID:25104829

  14. The functional BDNF Val66Met polymorphism affects functions of pre-attentive visual sensory memory processes.

    PubMed

    Beste, Christian; Schneider, Daniel; Epplen, Jörg T; Arning, Larissa

    2011-01-01

    The brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, is involved in nerve growth and survival. Especially, a single nucleotide polymorphism (SNP) in the BDNF gene, Val66Met, has gained a lot of attention, because of its effect on activity-dependent BDNF secretion and its link to impaired memory processes. We hypothesize that the BDNF Val66Met polymorphism may have modulatory effects on the visual sensory (iconic) memory performance. Two hundred and eleven healthy German students (106 female and 105 male) were included in the data analysis. Since BDNF is also discussed to be involved in the pathogenesis of depression, we additionally tested for possible interactions with depressive mood. The BDNF Val66Met polymorphism significantly influenced iconic-memory performance, with the combined Val/Met-Met/Met genotype group revealing less time stability of information stored in iconic memory than the Val/Val group. Furthermore, this stability was positively correlated with depressive mood exclusively in the Val/Val genotype group. Thus, these results show that the BDNF Val66Met polymorphism has an effect on pre-attentive visual sensory memory processes. Copyright © 2010 Elsevier Ltd. All rights reserved.

  15. Geochemical signature of permanent and ephemeral thermal springs in Val di Cornia, Central Italy

    NASA Astrophysics Data System (ADS)

    Pierotti, Lisa; Pennisi, Maddalena; Muti, Antonio; Gherardi, Fabrizio

    2014-05-01

    In the Val di Cornia area, several permanent thermal springs outflow. They belong to the hydrothermal system of Campiglia Marittima and have been exploited since longtime for the therapeutic properties of the discharged waters. With an average outflow of 250 L/sec, Calidario (36.3±0.2° C) is the most important permanent spring of the area. Periodically, i.e. about every 10 years, a number of ephemeral thermo-mineral springs in Bagnarello (46±0.2° C) and Monte Peloso (42.2±0.3° C) area, spontaneously reactivate over short time periods (several weeks to few months), with a maximum discharge of 150±20 L/sec. This phenomenon is generally induced by intensive rainfall events. In this contribution, we present new geochemical analyses of waters discharged from Calidario and the ephemeral springs reactivated at the beginning of 2001 and at the end of 2010. These new data are then compared to previous analyses to investigate geochemical variations over a 30-years period. Both ephemeral and permanent thermal springs have Ca-SO4 geochemical signature, typical of groundwaters circulating through the carbonate-evaporitic complexes of the Tuscan Nappe (Mesozoic age). Clear salinity trends are identified, with TDS increasing from Calidario to Monte Peloso and Bagnarello springs, up to a maximum of about 3000 ppm. Chemical speciation indicates that most of the thermal waters are close to saturation with respect to fluorite and gypsum/anhydrite, with solute geothermometers indicating possible equilibrium temperature of 50-55° C for Monte Peloso and Bagnarello waters, respectively. Higher temperatures, up to 75° C, were inferred by assuming equilibrium at depth with the aluminosilicates of the regional Basement (phyllitic formations of Paleozoic age), below the evaporites of the Tuscan Nappe (Triassic age). With δ18O and δ2H values of -6.4 (±0.2)o and -38.9 (±2.9)o respectively, the ephemeral springs have a steady stable isotope composition, comparable to permanent

  16. Association between the Catechol O-Methyltransferase (COMT) Val158met Polymorphism and Different Dimensions of Impulsivity

    PubMed Central

    Malloy-Diniz, Leandro Fernandes; Lage, Guilherme Menezes; Campos, Simone Becho; de Paula, Jonas Jardim; de Souza Costa, Danielle; Romano-Silva, Marco Aurélio; de Miranda, Débora Marques; Correa, Humberto

    2013-01-01

    Background Impulsivity is a multidimensional construct which has been associated with dopaminergic neurotransmission. Nonetheless, until this moment, few studies addressed the relationship between different types of impulsivity and the single nucleotide polymorphism caused by a substitution of valine (val) with methionine (met) in the 158 codon of the Catechol-o-Methyltransferase gene (COMT-val158met). The present study aimed to investigate the association between val158met COMT polymorphism and impulsive behavior measured by two neuropsychological tests. Methodology/Principal Findings We administered two neuropsychological tests, a Continuous Performance Task and the Iowa Gambling Task were applied to 195 healthy participants to characterize their levels of motor, attentional and non-planning impulsivity. Then, subjects were grouped by genotype, and their scores on impulsivity measures were compared. There were no significant differences between group scores on attentional and motor impulsivity. Those participants who were homozygous for the met allele performed worse in the Iowa Gambling Task than val/val and val/met subjects. Conclusions/Significance Our results suggest that met allele of val158met COMT polymorphism is associated with poor performance in decision-making/cognitive impulsivity task. The results reinforce the hypothesis that val and met alleles of the val158met polymorphism show functional dissociation and are related to different prefrontal processes. PMID:24039968

  17. Modulation of the COMT Val(158)Met polymorphism on resting-state EEG power.

    PubMed

    Solís-Ortiz, Silvia; Pérez-Luque, Elva; Gutiérrez-Muñoz, Mayra

    2015-01-01

    The catechol-O-methyltransferase (COMT) Val(158)Met polymorphism impacts cortical dopamine (DA) levels and may influence cortical electrical activity in the human brain. This study investigated whether COMT genotype influences resting-state electroencephalogram (EEG) power in the frontal, parietal and midline regions in healthy volunteers. EEG recordings were conducted in the resting-state in 13 postmenopausal healthy woman carriers of the Val/Val genotype and 11 with the Met/Met genotype. The resting EEG spectral absolute power in the frontal (F3, F4, F7, F8, FC3 and FC4), parietal (CP3, CP4, P3 and P4) and midline (Fz, FCz, Cz, CPz, Pz and Oz) was analyzed during the eyes-open and eyes-closed conditions. The frequency bands considered were the delta, theta, alpha1, alpha2, beta1 and beta2. EEG data of the Val/Val and Met/Met genotypes, brain regions and conditions were analyzed using a general linear model analysis. In the individuals with the Met/Met genotype, delta activity was increased in the eyes-closed condition, theta activity was increased in the eyes-closed and in the eyes-open conditions, and alpha1 band, alpha2 band and beta1band activity was increased in the eyes-closed condition. A significant interaction between COMT genotypes and spectral bands was observed. Met homozygote individuals exhibited more delta, theta and beta1 activity than individuals with the Val/Val genotype. No significant interaction between COMT genotypes and the resting-state EEG regional power and conditions were observed for the three brain regions studied. Our findings indicate that the COMT Val(158)Met polymorphism does not directly impact resting-state EEG regional power, but instead suggest that COMT genotype can modulate resting-state EEG spectral power in postmenopausal healthy women.

  18. Modulation of the COMT Val158Met polymorphism on resting-state EEG power

    PubMed Central

    Solís-Ortiz, Silvia; Pérez-Luque, Elva; Gutiérrez-Muñoz, Mayra

    2015-01-01

    The catechol-O-methyltransferase (COMT) Val158Met polymorphism impacts cortical dopamine (DA) levels and may influence cortical electrical activity in the human brain. This study investigated whether COMT genotype influences resting-state electroencephalogram (EEG) power in the frontal, parietal and midline regions in healthy volunteers. EEG recordings were conducted in the resting-state in 13 postmenopausal healthy woman carriers of the Val/Val genotype and 11 with the Met/Met genotype. The resting EEG spectral absolute power in the frontal (F3, F4, F7, F8, FC3 and FC4), parietal (CP3, CP4, P3 and P4) and midline (Fz, FCz, Cz, CPz, Pz and Oz) was analyzed during the eyes-open and eyes-closed conditions. The frequency bands considered were the delta, theta, alpha1, alpha2, beta1 and beta2. EEG data of the Val/Val and Met/Met genotypes, brain regions and conditions were analyzed using a general linear model analysis. In the individuals with the Met/Met genotype, delta activity was increased in the eyes-closed condition, theta activity was increased in the eyes-closed and in the eyes-open conditions, and alpha1 band, alpha2 band and beta1band activity was increased in the eyes-closed condition. A significant interaction between COMT genotypes and spectral bands was observed. Met homozygote individuals exhibited more delta, theta and beta1 activity than individuals with the Val/Val genotype. No significant interaction between COMT genotypes and the resting-state EEG regional power and conditions were observed for the three brain regions studied. Our findings indicate that the COMT Val158Met polymorphism does not directly impact resting-state EEG regional power, but instead suggest that COMT genotype can modulate resting-state EEG spectral power in postmenopausal healthy women. PMID:25883560

  19. Association of the F13A1 Val34Leu polymorphism and recurrent pregnancy loss: A meta-analysis.

    PubMed

    Jung, Jae Hyun; Kim, Jae-Hoon; Song, Gwan Gyu; Choi, Sung Jae

    2017-08-01

    Factor XIII (FXIII) plays role in stabilizing the linkage between fibrins during blood clotting and has been implicated in recurrent pregnancy loss (RPL). The relationship between the Val34Leu polymorphism in F13A1, which encodes the enzymatic subunit of FXIII, and RPL is unclear. The aim of this meta-analysis was to evaluate the association betweenF13A1 Val34Leu and the risk of RPL. We performed a meta-analysis of 11 studies involving 1092 cases and 678 controls using published literature from PubMed and Embase. We detected an association in recessive (Val/Val vs. Val/Leu+Leu/Leu; OR=0.71, 95% CI=0.51-0.99, P=0.04), and one of the two co-dominant (Val/Val vs. Val/Leu; OR=0.71, 95% CI=0.52-0.98, P=0.03) models of in heritance. Subgroup analysis revealed that the F13A1 Val34Leu polymorphism was associated with RPL in Asians (Val vs. Leu; OR=0.53, CI=0.33-0.85, P=0.01). However, there was no association between F13A1 Val34Leu and RPL in Europeans and South Americans. Our meta-analysis supports an association between F13A1 Val34Leu and RPL. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Association of BDNF Val66Met polymorphism with HPA and SAM axis reactivity to psychological and physical stress.

    PubMed

    Tsuru, Jusen; Tanaka, Yoshihiro; Ishitobi, Yoshinobu; Maruyama, Yoshihiro; Inoue, Ayako; Kawano, Aimi; Ikeda, Rie; Ando, Tomoko; Oshita, Harumi; Aizawa, Saeko; Masuda, Koji; Higuma, Haruka; Kanehisa, Masayuki; Ninomiya, Taiga; Akiyoshi, Jotaro

    2014-01-01

    Decreased expression of brain-derived neurotrophic factor (BDNF) is implicated in enhanced stress responses. The BDNF Val66Met polymorphism is associated with psychological changes; for example, carriers of the Met allele exhibit increased harm avoidance as well as a higher prevalence of depression and anxiety disorder. To analyze the effects of BDNF Val66Met on stress responses, we tested 226 university students (88 women and 138 men) using a social stress procedure (Trier Social Stress Test [TSST]) and an electrical stimulation stress test. Stress indices were derived from repeated measurements of salivary α-amylase, salivary cortisol, heart rate, and psychological testing during the stress tests. All subjects were genotyped for the Val66Met polymorphism (G196A). A significant three-way interaction (time [3 levels] × BDNF [Val/Val, Val/Met, Met/Met]; P<0.05) was demonstrated that revealed different salivary cortisol responses in the TSST but not in electrical stimulation. Met/Met women had stronger cortisol responses than Val/Met and Val/Val individuals in the TSST. Met/Met men exhibited stronger salivary cortisol responses than Val/Met and Val/Val individuals in the TSST. These results indicate that a common, functionally significant polymorphism in BDNF had different effects on hypothalamic-pituitary-adrenocortical axis reactivity but not on sympathetic adrenomedullary reactivity in TSST and electrical stimulation tests.

  1. BDNF Val66Met polymorphism modulates the effect of loneliness on white matter microstructure in young adults.

    PubMed

    Meng, Jie; Hao, Lei; Wei, Dongtao; Sun, Jiangzhou; Li, Yu; Qiu, Jiang

    2017-12-01

    Loneliness is a common experience. Susceptibility to loneliness is a stable trait and is heritable. Previous studies have suggested that loneliness may impact regional gray matter density and brain activation to social stimuli, but its relation to white matter structure and how it may interact with genetic factors remains unclear. In this study, we investigated whether and how a common polymorphism (Val66Met) in the brain-derived neurotrophic factor gene modulated the association between loneliness and white matter microstructure in 162 young adults. The tract-based spatial statistics analyses revealed that the relationships between loneliness and white matter microstructures were significantly different between Val/Met heterozygotes and Val/Val homozygotes. Specifically, loneliness was significantly correlated with reduced fractional anisotropy and increased radial diffusivity in widespread white matter fibers within Val/Met heterozygotes. It was also significantly correlated with increased radial diffusivity in Met/Met genotypes but showed no significant association with white matter measures in Val/Val genotypes. Furthermore, the associations between loneliness and fractional anisotropy (or radial diffusivity) in Val/Met heterozygotes turned out to be global effects. These results provide evidence that loneliness may interact with the BDNF Val66Met polymorphism to shape the microstructures of white matter, and the Val/Met heterozygotes may be more susceptible to social environment. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. The influence of COMT Val¹⁵⁸Met genotype on the character dimension cooperativeness in healthy females.

    PubMed

    Baeken, Chris; Claes, Stephan; De Raedt, Rudi

    2014-07-01

    Although the Val(158)Met catechol-O-methyltransferase (COMT) gene has been linked with the temperament dimension Novelty Seeking (NS), new insights in this polymorphism might point to a major role for character features as well. Given that individual life experiences may influence Val(158) and Met(158) allele carriers differently it has been suggested that the character trait cooperativeness could be implicated. A homogeneous group of eighty right-handed Caucasian healthy female university students were assessed with the TCI and genotyped for the COMT Val(158)Met polymorphism (rs4680). Gene determination showed that eighteen were Val(158) homozygotes, forty-four Val/Met(158) heterozygotes, and eighteen were Met(158) homozygotes. All were within the same age range and never documented to have suffered from any neuropsychiatric illness. Bonferroni corrected non-parametric analyses showed that only for the character scale cooperativeness Val(158) homozygotes displayed significant higher scores when compared to Met(158) homozygotes. No significant differences on cooperativeness scores were found between Val(158) and Val/Met(158) carriers or between Met(158) and Val/Met(158) carriers. No differences were observed for the COMT Val(158)Met polymorphism and the other temperament and character scales. Our findings support the assumption that the Val(158)Met single nucleotide polymorphism (SNP) influences character traits and not only temperament. Our results add to the notion that Val(158) homozygotes are considered to be helpful and empathic and it suggest that these cooperativeness character traits are related to the dopaminergic system.

  3. Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism affects sympathetic tone in a gender-specific way.

    PubMed

    Chang, Chuan-Chia; Chang, Hsin-An; Chen, Tien-Yu; Fang, Wen-Hui; Huang, San-Yuan

    2014-09-01

    The Val/Val genotype of the brain-derived neurotrophic factor (BDNF) polymorphism (Val66Met) has been reported to affect human anxiety-related phenotypes. Substantial research has demonstrated that anxiety is associated with sympathetic activation, while sex steroid hormones have been shown to exert differential actions in regulating BDNF expression. Thus, we examined whether the BDNF variant modulates autonomic function in a gender-dependent manner. From 708 adults initially screened for medical and psychiatric illnesses, a final cohort of 583 drug-free healthy Han Chinese (355 males, 228 females; age 34.43±8.42 years) was recruited for BDNF genotyping (Val/Val: 136, 23.3%, Val/Met: 294, 50.4%, and Met/Met: 153, 26.2%). Time- and frequency-domain analyses of heart rate variability (HRV) were used to assess autonomic outflow to the heart. Significant genotype-by-gender interaction effects were found on HRV indices. Even after adjusting for possible confounders, male participants bearing the Val/Val genotype had significant increases in low frequency (LF), LF% and LF/high frequency (HF) ratio, indicating altered sympathovagal balance with increased sympathetic modulation, compared to male Met/Met homozygotes. Females, however, showed an opposite but non-significant pattern. These results suggest that the studied BDNF polymorphism is associated with sympathetic control in a gender-specific way. The findings here support the view that male subjects with the Val/Val genotype have increased risk of anxiety by association with sympathetic activation. Copyright © 2014 Elsevier Ltd. All rights reserved.

  4. Vals Cape, New Guinea

    NASA Image and Video Library

    1994-09-30

    STS068-261-062 (30 September-11 October 1994) --- Vals Cape (left) is the prominent point of the island of New Guinea (Indonesia's Irian Jaya) that juts southwest into the Arafura Sea, pointing towards Australia. The part of New Guinea in this northwest-looking view is entirely low-lying swampland with very low population density. The Digul River, snaking across the middle of the view, drains the high mountain chain, which runs along the spine of the island.

  5. Synthetic approaches to peptides containing the L-Gln-L-Val-D(S)-Dmt motif.

    PubMed

    Suaifan, Ghadeer A R Y; Arafat, Tawfiq; Threadgill, Michael D

    2007-05-15

    The pseudoprolines S-Dmo (5,5-dimethyl-4-oxaproline) and R-Dmt (5,5-dimethyl-4-thiaproline) have been used to study the effects of forcing a fully cis conformation in peptides. Synthesis of peptides containing these (which have the same configuration as L-Pro) is straightforward. However, synthesis of peptides containing S-Dmt is difficult, owing to the rapid cyclisation of L-Aaa-S-Dmt amides and esters to form the corresponding diketopiperazines (DKP); thus the intermediacy of L-Aaa-S-Dmt amides and esters must be avoided in the synthetic sequence. Peptides containing the L-Gln-L-Val-D(S)-Dmt motif are particularly difficult, owing to the insolubility of coupling partners containing Gln. Introduction of Gln as N-Boc-pyroglutamate overcame the latter difficulty and the dipeptide active ester BocPygValOC(6)F(5) coupled in good yield with S-DmtOH. BocPygVal-S- DmtNH(CH(2))(2)C(6)H(4)NO(2) was converted quantitatively to BocGlnVal-S-DmtNH(CH(2))(2)C(6)H(4)NO(2) with ammonia, demonstrating the utility of this approach. Two peptide derivatives (CbzSerLysLeuGlnVal-S-DmtNH(CH(2))(2)C(6)H(4)NO(2) and CbzSerSerLysLeuGlnVal-S- DmtNH(CH(2))(2)C(6)H(4)NO(2)) were assembled, using these new methods of coupling a dipeptide acid active ester with S-DmtOH and introduction of Gln as Pyg, followed by conventional peptide couplings. The presence of the Val caused these peptides to be cleaved very slowly by prostate-specific antigen (PSA) at Leu Gln, rather than the expected Gln Val.

  6. Geomorphological survey and remote sensing analysis: a multidisciplinary approach to reconstruct triggering factors of a DSGSD in Maso Corto (South Tyrol, Italy)

    NASA Astrophysics Data System (ADS)

    Amato, Gabriele; Fubelli, Giandomenico; Piccin, Gianluca; Chinellato, Giulia; Iasio, Christian; Mosna, David; Morelli, Corrado

    2015-04-01

    In the Alpine regions, it is essential and urgent to define an improved and specific set of monitoring methods for the evolution of instability phenomena in order to avoid the closure of the installations because of the occurrence of natural calamities and to ensure the safety of citizens. In this context the SloMove Project aims at consolidate know-how of the ordinary monitoring applications of surface movements, evaluate their pros and cons and optimize the expected technical procedures of investigation. Within the SloMove project, an experimental composite monitoring has been carried out in the touristic site of Maso Corto (South Tyrol, Italy). Structural-Geomorphological Survey, GPS measurements and Time series analysis of SAR Interferometry data have been integrated. The purposes of this experiment are: 1) to reconstruct the geomorphological dynamics and their state of activity; 2) to provide considerations on the role of permafrost as an influential factor for landslide activity. Structural-Geomorphological survey highlighted control of structural asset of the outcropping lithologies on geomorphological markers, such as trenches, counterscarps, outcropping sliding surfaces. The area is characterized by metamorphic rocks, affected by foliation oriented between N350 and N30. Moreover, joints due to frost thaw activity are common in the shallow portions and the presence of two sets of tectonics fractures (N45, 45°-60° and N360, sub-vertical) has been recognized. In order to evaluate the state of permafrost, rock glaciers in the area have been investigated. SAR interferometry data have been processed by TRE® through the SqueeSAR™ analysis using Radarsat and Envisat images acquired during a period between 2003 and 2009. GPS surveys were carried out through the technique of Rapid-Static Relative Positioning during the summer months of 2012 and 2013. Data shows that an area of 2km2, north of Maso Corto, is affected by a Deep Seated Gravitational Slide

  7. BDNF val66met Polymorphism Affects Aging of Multiple Types of Memory

    PubMed Central

    Kennedy, Kristen M.; Reese, Elizabeth D.; Horn, Marci M.; Sizemore, April N.; Unni, Asha K.; Meerbrey, Michael E.; Kalich, Allan G.; Rodrigue, Karen M.

    2014-01-01

    The BDNF val66met polymorphism (rs6265) influences activity-dependent secretion of brain-derived neurotrophic factor in the synapse, which is crucial for learning and memory. Individuals homozygous or heterozygous for the met allele have lower BDNF secretion than val homozygotes and may be at risk for reduced declarative memory performance, but it remains unclear which types of declarative memory may be affected and how aging of memory across the lifespan is impacted by the BDNF val66met polymorphism. This cross-sectional study investigated the effects of BDNF polymorphism on multiple indices of memory (item, associative, prospective, subjective complaints) in a lifespan sample of 116 healthy adults aged 20-93 years. Advancing age showed a negative effect on item, associative and prospective memory, but not on subjective memory complaints. For item and prospective memory, there were significant age x BDNF group interactions, indicating the adverse effect of age on memory performance across the lifespan was much stronger in the BDNF met carriers than for the val homozygotes. BDNF met carriers also endorsed significantly greater subjective memory complaints, regardless of age, and showed a trend (p < .07) toward poorer associative memory performance compared to val homozygotes. These results suggest that genetic predisposition to the availability of brain-derived neurotrophic factor, by way of the BDNF val66met polymorphism, exerts an influence on multiple indices of episodic memory – in some cases in all individuals regardless of age (subjective memory and perhaps associative memory), in others as an exacerbation of age-related differences in memory across the lifespan (item and prospective memory). PMID:25264352

  8. BDNF val66met polymorphism affects aging of multiple types of memory.

    PubMed

    Kennedy, Kristen M; Reese, Elizabeth D; Horn, Marci M; Sizemore, April N; Unni, Asha K; Meerbrey, Michael E; Kalich, Allan G; Rodrigue, Karen M

    2015-07-01

    The BDNF val66met polymorphism (rs6265) influences activity-dependent secretion of brain-derived neurotrophic factor in the synapse, which is crucial for learning and memory. Individuals homozygous or heterozygous for the met allele have lower BDNF secretion than val homozygotes and may be at risk for reduced declarative memory performance, but it remains unclear which types of declarative memory may be affected and how aging of memory across the lifespan is impacted by the BDNF val66met polymorphism. This cross-sectional study investigated the effects of BDNF polymorphism on multiple indices of memory (item, associative, prospective, subjective complaints) in a lifespan sample of 116 healthy adults aged 20-93 years. Advancing age showed a negative effect on item, associative and prospective memory, but not on subjective memory complaints. For item and prospective memory, there were significant age×BDNF group interactions, indicating the adverse effect of age on memory performance across the lifespan was much stronger in the BDNF met carriers than for the val homozygotes. BDNF met carriers also endorsed significantly greater subjective memory complaints, regardless of age, and showed a trend (p<.07) toward poorer associative memory performance compared to val homozygotes. These results suggest that genetic predisposition to the availability of brain-derived neurotrophic factor, by way of the BDNF val66met polymorphism, exerts an influence on multiple indices of episodic memory - in some cases in all individuals regardless of age (subjective memory and perhaps associative memory), in others as an exacerbation of age-related differences in memory across the lifespan (item and prospective memory). This article is part of a Special Issue entitled Memory & Aging. Copyright © 2014 Elsevier B.V. All rights reserved.

  9. Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism interacts with gender to influence cortisol responses to mental stress.

    PubMed

    Jiang, Rong; Babyak, Michael A; Brummett, Beverly H; Siegler, Ilene C; Kuhn, Cynthia M; Williams, Redford B

    2017-05-01

    Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism has been associated with cortisol responses to stress with gender differences reported, although the findings are not entirely consistent. To evaluate the role of Val66Met genotype and gender on cortisol responses to stress, we conducted a 45-min mental stress protocol including four tasks and four rest periods. Blood cortisol was collected for assay immediately before and after each task and rest period. A significant two-way interaction of Val66Met genotype×gender (P=0.022) was observed on the total area under the curve (AUC), a total cortisol response over time, such that the Val/Val genotype was associated with a larger cortisol response to stress as compared to the Met group in women but not in men. Further contrast analyses between the Val/Val and Met group for each stress task showed a similar increased cortisol pattern among women Val/Val genotype but not among men. The present findings indicate the gender differences in the effect of Val66Met genotype on the cortisol responses to stress protocol, and extend the evidence for the importance of gender and the role of Val66Met in the modulation of stress reactivity and subsequent depression prevalence. Further studies and the underlying mechanism need to be investigated, which may provide an insight for prevention, intervention, and treatment strategies that target those at high risk. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. Brain-Derived Neurotrophic Factor (BDNF) Val66Met Polymorphism Interacts with Gender to Influence Cortisol Responses to Mental Stress

    PubMed Central

    Jiang, Rong; Babyak, Michael A.; Brummett, Beverly H.; Siegler, Ilene C.; Kuhn, Cynthia M.; Williams, Redford B.

    2017-01-01

    Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism has been associated with cortisol responses to stress with gender differences reported, although the findings are not entirely consistent. To evaluate the role of Val66Met genotype and gender on cortisol responses to stress, we conducted a 45-min mental stress protocol including four tasks and four rest periods. Blood cortisol was collected for assay immediately before and after each task and rest period. A significant two-way interaction of Val66Met genotype × gender (P = 0.022) was observed on the total area under the curve (AUC), a total cortisol response over time, such that the Val/Val genotype was associated with a larger cortisol response to stress as compared to the Met group in women but not in men. Further contrast analyses between the Val/Val and Met group for each stress task showed a similar increased cortisol pattern among women Val/Val genotype but not among men. The present findings indicate the gender differences in the effect of Val66Met genotype on the cortisol responses to stress protocol, and extend the evidence for the importance of gender and the role of Val66Met in the modulation of stress reactivity and subsequent depression prevalence. Further studies and the underlying mechanism need to be investigated, which may provide an insight for prevention, intervention, and treatment strategies that target those at high risk. PMID:28249185

  11. Catechol-O-Methyltransferase Val158Met Polymorphism on Striatum Structural Covariance Networks in Alzheimer's Disease.

    PubMed

    Chang, Chiung-Chih; Tsai, Shih-Jen; Chen, Nai-Ching; Huang, Chi-Wei; Hsu, Shih-Wei; Chang, Ya-Ting; Liu, Mu-En; Chang, Wen-Neng; Tsai, Wan-Chen; Lee, Chen-Chang

    2018-06-01

    The catechol-O-methyltransferase enzyme metabolizes dopamine in the prefrontal axis, and its genetic polymorphism (rs4680; Val158Met) is a known determinant of dopamine signaling. In this study, we investigated the possible structural covariance networks that may be modulated by this functional polymorphism in patients with Alzheimer's disease. Structural covariance networks were constructed by 3D T1 magnetic resonance imaging. The patients were divided into two groups: Met-carriers (n = 91) and Val-homozygotes (n = 101). Seed-based analysis was performed focusing on triple-network models and six striatal networks. Neurobehavioral scores served as the major outcome factors. The role of seed or peak cluster volumes, or a covariance strength showing Met-carriers > Val-homozygotes were tested for the effect on dopamine. Clinically, the Met-carriers had higher mental manipulation and hallucination scores than the Val-homozygotes. The volume-score correlations suggested the significance of the putaminal seed in the Met-carriers and caudate seed in the Val-homozygotes. Only the dorsal-rostral and dorsal-caudal putamen interconnected peak clusters showed covariance strength interactions (Met-carriers > Val-homozygotes), and the peak clusters also correlated with the neurobehavioral scores. Although the triple-network model is important for a diagnosis of Alzheimer's disease, our results validated the role of the dorsal-putaminal-anchored network by the catechol-O-methyltransferase Val158Met polymorphism in predicting the severity of cognitive and behavior in subjects with Alzheimer's disease.

  12. Interacting effect of BDNF Val66Met polymorphism and stressful life events on adolescent depression.

    PubMed

    Chen, J; Li, X; McGue, M

    2012-11-01

    There is a strong etiological link between brain-derived neurotrophic factor and depression, but the neurocellular mechanisms and gene-environment interactions remain obscure. This study investigated whether one functional polymorphism in the brain-derived neurotrophic factor gene (BDNF Val66Met) modulates the influence of stressful life events on adolescent depressive symptoms. A total of 780 pairs of ethnic Han Chinese adolescent twins, 11-17 years of age, were randomly assigned to one of two subgroups (twin1 and twin2). All subjects were genotyped as Val/Val, Val/Met or Met/Met, and assessed for depressive symptoms using the Children's Depression Inventory. The level of environmental stress was estimated by the frequency of stressful life events using the Life Events Checklist. The frequency of stressful life events was significantly correlated with depressive symptoms (twin1: β = 0.21, P = 0.01; twin2: β = 0.27, P < 0.01), but there was no significant main effect of the BDNF Val66Met genotype on depressive symptoms. In both subgroups, however, the interaction between the BDNF Val66Met genotype and stressful life event frequency was significant (twin1: β = 0.19, P = 0.01; twin2: β = 0.15, P = 0.04); individuals with one or two Val alleles demonstrated a greater susceptibility to both the detrimental effects of higher stress and the beneficial effects of lower stress compared to the Met/Met genotype. These findings support the 'differential-susceptibility' hypothesis, whereby the BDNF Val allele modulates the influence of environmental stress on depression by enhancing the neuroplastic response to all life events. © 2012 The Authors. Genes, Brain and Behavior © 2012 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society.

  13. Structural basis of DNA target recognition by the B3 domain of Arabidopsis epigenome reader VAL1

    PubMed Central

    Sasnauskas, Giedrius; Kauneckaitė, Kotryna; Siksnys, Virginijus

    2018-01-01

    Abstract Arabidopsis thaliana requires a prolonged period of cold exposure during winter to initiate flowering in a process termed vernalization. Exposure to cold induces epigenetic silencing of the FLOWERING LOCUS C (FLC) gene by Polycomb group (PcG) proteins. A key role in this epigenetic switch is played by transcriptional repressors VAL1 and VAL2, which specifically recognize Sph/RY DNA sequences within FLC via B3 DNA binding domains, and mediate recruitment of PcG silencing machinery. To understand the structural mechanism of site-specific DNA recognition by VAL1, we have solved the crystal structure of VAL1 B3 domain (VAL1-B3) bound to a 12 bp oligoduplex containing the canonical Sph/RY DNA sequence 5′-CATGCA-3′/5′-TGCATG-3′. We find that VAL1-B3 makes H-bonds and van der Waals contacts to DNA bases of all six positions of the canonical Sph/RY element. In agreement with the structure, in vitro DNA binding studies show that VAL1-B3 does not tolerate substitutions at any position of the 5′-TGCATG-3′ sequence. The VAL1-B3–DNA structure presented here provides a structural model for understanding the specificity of plant B3 domains interacting with the Sph/RY and other DNA sequences. PMID:29660015

  14. Suicide attempt, clinical correlates, and BDNF Val66Met polymorphism in chronic patients with schizophrenia.

    PubMed

    Xia, Haisen; Zhang, Guangya; Du, Xiangdong; Zhang, Yingyang; Yin, Guangzhong; Dai, Jing; He, Man-Xi; Soares, Jair C; Li, Xiaosi; Zhang, Xiang Yang

    2018-02-01

    Recent evidence suggests the role of brain-derived neurotrophic factor (BDNF) in the pathophysiology of suicidal behavior. Because schizophrenia patients usually have high suicide rates and numerous studies have suggested that BDNF may contribute to the psychopathology of schizophrenia, we hypothesized that the functional polymorphism of BDNF (Val66Met) was associated with suicide attempts in patients with schizophrenia in a Chinese Han population. This polymorphism was genotyped in 825 chronic schizophrenia patients with (n = 123) and without (n = 702) suicide attempts and 445 healthy controls without a history of suicide attempts using a case-control design. The schizophrenia symptoms were assessed by the Positive and Negative Syndrome Scale. There were no significant differences in BDNF Val66Met genotype and allele distributions between the patients and healthy controls. However, we found the Val allele (p = .023) and the Val/Val genotypes (p = .058) to be associated with a history of suicide attempts. Moreover, some clinical characteristics, including age and cigarettes smoked each day, interacted with the BDNF gene variant and appeared to play an important role in suicide attempts among schizophrenia patients. The BDNF Val66Met polymorphism itself and its interaction with some clinical variables may influence suicide attempts among schizophrenia patients. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

  15. cDNA, deduced polypeptide structure and chromosomal assignment of human pulmonary surfactant proteolipid, SPL(pVal)

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Glasser, S.W.; Korfhagen, T.R.; Weaver, T.E.

    1988-01-05

    In hyaline membrane disease of premature infants, lack of surfactant leads to pulmonary atelectasis and respiratory distress. Hydrophobic surfactant proteins of M/sub r/ = 5000-14,000 have been isolated from mammalian surfactants which enhance the rate of spreading and the surface tension lowering properties of phospholipids during dynamic compression. The authors have characterized the amino-terminal amino acid sequence of pulmonary proteolipids from ether/ethanol extracts of bovine, canine, and human surfactant. Two distinct peptides were identified and termed SPL(pVal) and SPL(Phe). An oligonucleotide probe based on the valine-rich amino-terminal amino acid sequence of SPL(pVal) was utilized to isolate cDNA and genomic DNAmore » encoding the human protein, termed surfactant proteolipid SPL(pVal) on the basis of its unique polyvaline domain. The primary structure of a precursor protein of 20,870 daltons, containing the SPL(pVal) peptide, was deduced from the nucleotide sequence of the cDNAs. Hybrid-arrested translation and immunoprecipitation of labeled translation products of human mRNA demonstrated a precursor protein, the active hydrophobic peptide being produced by proteolytic processing. Two classes of cDNAs encoding SPL(pVal) were identified. Human SPL(pVal) mRNA was more abundant in the adult than in fetal lung. The SPL(pVal) gene locus was assigned to chromosome 8.« less

  16. The BDNF Val66Met polymorphism regulates glucocorticoid-induced corticohippocampal remodeling and behavioral despair

    PubMed Central

    Notaras, M; Du, X; Gogos, J; van den Buuse, M; Hill, R A

    2017-01-01

    The BDNF Val66Met polymorphism has been associated with sensitivity to stress and affective disorders. We therefore sought to model the inter-causality of these relationships under controlled laboratory conditions. We subjected humanized BDNF Val66Met (hBDNFVal66Met) transgenic mice to a history of stress, modeled by chronic late-adolescent corticosterone (CORT) exposure, before evaluating affective-related behavior using the forced-swim test (FST) in adulthood. While hBDNFMet/Met mice had a depression-like phenotype in the FST irrespective of CORT, hBDNFVal/Val wildtype mice had a resilient phenotype but developed an equally robust depressive-like phenotype following CORT. A range of stress-sensitive molecules were studied across the corticohippocampal axis, and where genotype differences occurred following CORT they tended to inversely coincide with the behavior of the hBDNFVal/Val group. Notably, tyrosine hydroxylase was markedly down-regulated in the mPFC of hBDNFVal/Val mice as a result of CORT treatment, which mimicked expression levels of hBDNFMet/Met mice and the FST behavior of both groups. The expression of calretinin, PSD-95, and truncated TrkB were also concomitantly reduced in the mPFC of hBDNFVal/Val mice by CORT. This work establishes BDNFVal66Met genotype as a regulator of behavioral despair, and identifies new biological targets of BDNF genetic variation relevant to stress-inducible disorders such as depression. PMID:28926000

  17. The catechol-O-methyltransferase (COMT) Val158Met genotype modulates working memory-related dorsolateral prefrontal response and performance in bipolar disorder.

    PubMed

    Miskowiak, K W; Kjaerstad, H L; Støttrup, M M; Svendsen, A M; Demant, K M; Hoeffding, L K; Werge, T M; Burdick, K E; Domschke, K; Carvalho, A F; Vieta, E; Vinberg, M; Kessing, L V; Siebner, H R; Macoveanu, J

    2017-05-01

    Cognitive dysfunction affects a substantial proportion of patients with bipolar disorder (BD), and genetic-imaging paradigms may aid in the elucidation of mechanisms implicated in this symptomatic domain. The Val allele of the functional Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene is associated with reduced prefrontal cortex dopamine and exaggerated working memory-related prefrontal activity. This functional magnetic resonance imaging (fMRI) study investigated for the first time whether the COMT Val158Met genotype modulates prefrontal activity during spatial working memory in BD. Sixty-four outpatients with BD in full or partial remission were stratified according to COMT Val158Met genotype (ValVal [n=13], ValMet [n=34], and MetMet [n=17]). The patients completed a spatial n-back working memory task during fMRI and the Cambridge Neuropsychological Test Automated Battery (CANTAB) Spatial Working Memory test outside the scanner. During high working memory load (2-back vs 1-back), Val homozygotes displayed decreased activity relative to ValMet individuals, with Met homozygotes displaying intermediate levels of activity in the right dorsolateral prefrontal cortex (dlPFC) (P=.016). Exploratory whole-brain analysis revealed a bilateral decrease in working memory-related dlPFC activity in the ValVal group vs the ValMet group which was not associated with differences in working memory performance during fMRI. Outside the MRI scanner, Val carriers performed worse in the CANTAB Spatial Working Memory task than Met homozygotes (P≤.006), with deficits being most pronounced in Val homozygotes. The association between Val allelic load, dlPFC activity and WM impairment points to a putative role of aberrant PFC dopamine tonus in the cognitive impairments in BD. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  18. BDNF Val66Met polymorphism is associated with abnormal interhemispheric transfer of a newly acquired motor skill.

    PubMed

    Morin-Moncet, Olivier; Beaumont, Vincent; de Beaumont, Louis; Lepage, Jean-Francois; Théoret, Hugo

    2014-05-01

    Recent data suggest that the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene can alter cortical plasticity within the motor cortex of carriers, which exhibits abnormally low rates of cortical reorganization after repetitive motor tasks. To verify whether long-term retention of a motor skill is also modulated by the presence of the polymorphism, 20 participants (10 Val66Val, 10 Val66Met) were tested twice at a 1-wk interval. During each visit, excitability of the motor cortex was measured by transcranial magnetic stimulations (TMS) before and after performance of a procedural motor learning task (serial reaction time task) designed to study sequence-specific learning of the right hand and sequence-specific transfer from the right to the left hand. Behavioral results showed a motor learning effect that persisted for at least a week and task-related increases in corticospinal excitability identical for both sessions and without distinction for genetic group. Sequence-specific transfer of the motor skill from the right hand to the left hand was greater in session 2 than in session 1 only in the Val66Met genetic group. Further analysis revealed that the sequence-specific transfer occurred equally at both sessions in the Val66Val genotype group. In the Val66Met genotype group, sequence-specific transfer did not occur at session 1 but did at session 2. These data suggest a limited impact of Val66Met polymorphism on the learning and retention of a complex motor skill and its associated changes in corticospinal excitability over time, and a possible modulation of the interhemispheric transfer of procedural learning. Copyright © 2014 the American Physiological Society.

  19. The UK Earth System Models Marine Biogeochemical Evaluation Toolkit, BGC-val

    NASA Astrophysics Data System (ADS)

    de Mora, Lee

    2017-04-01

    The Biogeochemical Validation toolkit, BGC-val, is a model and grid independent python-based marine model evaluation framework that automates much of the validation of the marine component of an Earth System Model. BGC-val was initially developed to be a flexible and extensible system to evaluate the spin up of the marine UK Earth System Model (UKESM). However, the grid-independence and flexibility means that it is straightforward to adapt the BGC-val framework to evaluate other marine models. In addition to the marine component of the UKESM, this toolkit has been adapted to compare multiple models, including models from the CMIP5 and iMarNet inter-comparison projects. The BGC-val toolkit produces multiple levels of analysis which are presented in a simple to use interactive html5 document. Level 1 contains time series analyses, showing the development over time of many important biogeochemical and physical ocean metrics, such as the Global primary production or the Drake passage current. The second level of BGC-val is an in-depth spatial analyses of a single point in time. This is a series of point to point comparison of model and data in various regions, such as a comparison of Surface Nitrate in the model vs data from the world ocean atlas. The third level analyses are specialised ad-hoc packages to go in-depth on a specific question, such as the development of Oxygen minimum zones in the Equatorial Pacific. In additional to the three levels, the html5 document opens with a Level 0 table showing a summary of the status of the model run. The beta version of this toolkit is available via the Plymouth Marine Laboratory Gitlab server and uses the BSD 3 clause license.

  20. Brain-Derived Neurotrophic Factor Val66Met Human Polymorphism Impairs the Beneficial Exercise-Induced Neurobiological Changes in Mice.

    PubMed

    Ieraci, Alessandro; Madaio, Alessandro I; Mallei, Alessandra; Lee, Francis S; Popoli, Maurizio

    2016-12-01

    Several studies have shown that exercise improves cognitive functions and emotional behaviors. Positive effects of exercise have been associated with enhanced brain plasticity, adult hippocampal neurogenesis, and increased levels of brain-derived neurotrophic factor (BDNF). However, a substantial variability of individual response to exercise has been described, which may be accounted for by individual genetic variants. Here, we have assessed whether and how the common human BDNF Val66Met polymorphism influences the neurobiological effects modulated by exercise in BDNF Val66Met knock-in male mice. Wild-type (BDNF Val/Val ) and homozygous BDNF Val66Met (BDNF Met/Met ) male mice were housed in cages equipped with or without running wheels for 4 weeks. Changes in behavioral phenotype, hippocampal adult neurogenesis, and gene expression were evaluated in exercised and sedentary control mice. We found that exercise reduced the latency to feed in the novelty suppressed feeding and the immobility time in the forced swimming test in BDNF Val/Val but not in BDNF Met/Met mice. Hippocampal neurogenesis was reduced in BDNF Met/Met mice compared with BDNF Val/Val mice. BDNF Met/Met mice had lower basal BDNF protein levels in the hippocampus, which was not recovered following exercise. Moreover, exercise-induced expression of total BDNF, BDNF splice variants 1, 2, 4, 6 and fibronectin type III domain-containing protein 5 (FNDC5) mRNA levels were absent or reduced in the dentate gyrus of BDNF Met/Met mice. Exercise failed to enhance PGC-1α and FNDC5 mRNA levels in the BDNF Met/Met muscle. Overall these results indicate that, in adult male mice, the BDNF Val66Met polymorphism impairs the beneficial behavioral and neuroplasticity effects induced by physical exercise.

  1. THE FUNDUS PHENOTYPE ASSOCIATED WITH THE p.Ala243Val BEST1 MUTATION.

    PubMed

    Khan, Kamron N; Islam, Farrah; Moore, Anthony T; Michaelides, Michel

    2018-03-01

    To describe a highly recognizable and reproducible retinal phenotype associated with a specific BEST1 mutation-p.Ala243Val. Retrospective review of consecutive cases where genetic testing has identified p.Ala243Val BEST1 as the cause of disease. Electronic patient records were used to extract demographic, as well as functional and anatomical data. These data were compared with those observed with the most common BEST1 genotype, p.Arg218Cys. Eight individuals (six families) were identified with the p.Ala243Val BEST1 mutation and seven patients with the pathologic variant p.Arg218Cys. No patients with mutation of codon 243 knowingly had a family history of retinal disease, whereas all patients with the p.Arg218Cys variant did. The maculopathy was bilateral in all cases. The p.Ala243Val mutation was associated with a pattern dystrophy-type appearance, most visible with near-infrared reflectance and fundus autofluorescence imaging. This phenotype was never observed with any other genotype. This mutation was associated with an older median age of symptom onset (median = 42, interquartile range = 22) compared with those harboring the p.Arg218Cys mutation (median = 18, interquartile range = 12; Mann-Whitney U test; P < 0.05). Despite their older age, the final recorded acuity seemed to be better in the p.Ala243Val group (median = 0.55, interquartile range = 0.6475; median = 0.33, interquartile range = 0.358), although this did not reach statistical significance (Mann-Whitney U test; P > 0.05). The mutation p.Ala243Val is associated with highly recognizable and reproducible pattern dystrophy-like phenotype. Patients develop symptoms at a later age and tend to have better preservation of electrooculogram amplitudes.

  2. Spontaneous abortion and functional polymorphism (Val16Ala) in the manganese SOD gene.

    PubMed

    Eskafi Sabet, E; Salehi, Z; Khodayari, S; Sabouhi Zarafshan, S; Zahiri, Z

    2015-02-01

    Spontaneous abortion is the most common complication of early pregnancy. Genetic factors have been hypothesised to play a role in spontaneous abortion. Since it is possible that the balance of oxidants and antioxidants can be affected by different genetic variants, gene polymorphisms have been proposed as a susceptibility factor that increases the chance of miscarriage. Manganese superoxide dismutase is an important antioxidant enzyme encoded by manganese superoxide dismutase (MnSOD) gene. The aim of this experiment was to assess whether Val16Ala polymorphism of MnSOD gene is associated with miscarriage in northern Iran. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used for genotyping. Statistical analyses were conducted using the χ(2)-test. The genetic distributions did not differ significantly between cases and controls, however slightly more Val/Val genotypes were found among the patients compared with control subjects (p = 0.059). No correlation was observed between susceptibility to abortion and MnSOD Val16Ala polymorphism. Larger population-based studies are needed for clarifying the relationship between abortion and MnSOD genotypes.

  3. Association between the COMT Val158Met polymorphism and fibromyalgia susceptibility and fibromyalgia impact questionnaire score: a meta-analysis.

    PubMed

    Lee, Young Ho; Kim, Jae-Hoon; Song, Gwan Gyu

    2015-01-01

    The aim of this study was to explore whether the catechol-O-methyltransferase (COMT) Val158Met polymorphism is associated with susceptibility to fibromyalgia and fibromyalgia impact questionnaire (FIQ) score in fibromyalgia patients. We conducted a meta-analysis of the associations of the COMT Val158Met polymorphism with fibromyalgia risk as well as FIQ score in fibromyalgia patients. A total of 993 fibromyalgia patients and 778 controls from 10 studies on the COMT Val158Met polymorphism and 538 fibromyalgia patients from 5 studies on the COMT Val158Met polymorphism and FIQ score were included in this meta-analysis. The meta-analysis revealed an association between fibromyalgia and the COMT Met/Met + Val/Met genotype in all study subjects (odds ratio (OR) 1.635, 95 % confidence interval (CI) 1.029-2.597, p = 0.037). However, stratification by ethnicity indicated no association between the Met/Met + Val/Met genotype and fibromyalgia in the European and Turkish populations (OR 1.202, 95 % CI 0.876-1.649, p = 0.255; OR 2.132, 95 % CI 0.764-5.949, p = 0.148, respectively). Analysis using other genetic models showed no association between the COMT Val158Met polymorphism and fibromyalgia. The meta-analysis also revealed that the FIQ score was significantly higher in individuals with the COMT Met/Met genotype than in those with the Val/Val genotype [weighted mean difference (WMD) = 14.39, 95 % CI 3.316-25.48, p = 0.011] and the Val/Met genotype (WMD = 5.108, 95 % CI 2.212-4.891, p = 0.021). This meta-analysis identified an association between fibromyalgia risk and the COMT Val158Met polymorphism as well as the FIQ score in fibromyalgia patients.

  4. Peripheral vascular reactivity and serum BDNF responses to aerobic training are impaired by the BDNF Val66Met polymorphism.

    PubMed

    Lemos, José R; Alves, Cleber R; de Souza, Sílvia B C; Marsiglia, Julia D C; Silva, Michelle S M; Pereira, Alexandre C; Teixeira, Antônio L; Vieira, Erica L M; Krieger, José E; Negrão, Carlos E; Alves, Guilherme B; de Oliveira, Edilamar M; Bolani, Wladimir; Dias, Rodrigo G; Trombetta, Ivani C

    2016-02-01

    Besides neuronal plasticity, the neurotrophin brain-derived neurotrophic factor (BDNF) is also important in vascular function. The BDNF has been associated with angiogenesis through its specific receptor tropomyosin-related kinase B (TrkB). Additionally, Val66Met polymorphism decreases activity-induced BDNF. Since BDNF and TrkB are expressed in vascular endothelial cells and aerobic exercise training can increase serum BDNF, this study aimed to test the hypotheses: 1) Serum BDNF levels modulate peripheral blood flow; 2) The Val66Met BDNF polymorphism impairs exercise training-induced vasodilation. We genotyped 304 healthy male volunteers (Val66Val, n = 221; Val66Met, n = 83) who underwent intense aerobic exercise training on a running track three times/wk for 4 mo. We evaluated pre- and post-exercise training serum BDNF and proBDNF concentration, heart rate (HR), mean blood pressure (MBP), forearm blood flow (FBF), and forearm vascular resistance (FVR). In the pre-exercise training, BDNF, proBDNF, BDNF/proBDNF ratio, FBF, and FVR were similar between genotypes. After exercise training, functional capacity (V̇o2 peak) increased and HR decreased similarly in both groups. Val66Val, but not Val66Met, increased BDNF (interaction, P = 0.04) and BDNF/proBDNF ratio (interaction, P < 0.001). Interestingly, FBF (interaction, P = 0.04) and the FVR (interaction, P = 0.01) responses during handgrip exercise (HG) improved in Val66Val compared with Val66Met, even with similar responses of HR and MBP. There were association between BDNF/proBDNF ratio and FBF (r = 0.64, P < 0.001) and FVR (r = -0.58, P < 0.001) during HG exercise. These results show that peripheral vascular reactivity and serum BDNF responses to exercise training are impaired by the BDNF Val66Met polymorphism and such responsiveness is associated with serum BDNF concentrations in healthy subjects. Copyright © 2016 the American Physiological Society.

  5. Brain-derived neurotrophic factor Val66Met polymorphism and dexamethasone/CRH test results in depressed patients.

    PubMed

    Schüle, Cornelius; Zill, Peter; Baghai, Thomas C; Eser, Daniela; Zwanzger, Peter; Wenig, Nadine; Rupprecht, Rainer; Bondy, Brigitta

    2006-09-01

    Data suggest that both neurotrophic and hypothalamic-pituitary-adrenocortical (HPA) systems are involved in the pathophysiology of depression. The aim of the present study was to investigate whether the non-conservative brain-derived neurotrophic factor (BDNF) Val66Met polymorphism has an impact on HPA axis activity in depressed patients. At admission, the dexamethasone/CRH (DEX/CRH) test was performed in 187 drug-free in-patients suffering from major depression or depressed state of bipolar disorder (DSM-IV criteria). Moreover, genotyping of BDNF Val66Met polymorphism was carried out using the fluorescence resonance energy transfer method (FRET). Homozygous carriers of the Met/Met genotype showed a significantly higher HPA axis activity during the DEX/CRH test than patients carrying the Val/Val or Val/Met genotype (ACTH, cortisol). Our results further contribute to the hypothesized association between HPA axis dysregulation and reduced neuroplasticity in depression and are consistent with the assumption that BDNF is a stress-responsive intercellular messenger modifying HPA axis activity.

  6. [Association of Val66Met polymorphism of brain-derived neurotrophic factor gene with cognitive impairment and clinical symptoms in first episode schizophrenia].

    PubMed

    Zhang, Chengcheng; Gu, Xiaochu; Wang, Qiang; Li, Mingli; Deng, Wei; Guo, Wanjun; Zhao, Liansheng; Ma, Xiaohong; Li, Tao

    2017-08-10

    To assess the association of cognitive impairment and clinical symptoms in first-episode schizophrenia with the Val66Met (rs6265) polymorphism of brain-derived neurotrophic factor (BDNF) gene. For 87 patients with first-episode schizophrenia and 76 healthy controls, the Val66Met polymorphism was determined with a Taqman Assay-on-Demand method. Wechsler intelligence test was carried out for all participants. Correlation of cognitive impairment with clinical severity was also analyzed. The patients were significantly lower in total IQ, verbal IQ and performance IQ compared to the controls. The lower total IQ (F=4.59, P= 0.01) and verbal IQ (F=4.44, P=0.01) were influenced by genetic factors and diagnostic interaction. The vertal IQ of Val/Val patients was significantly lower than those of Val/Met and Met/Met carriers. For the control group, the verbal IQ of Met/Met carriers was lower than that of Val/Met carriers, and the total IQ of Met/Met carriers was lower than those of Val/Met and Val/Val carriers. For the patient group, the total IQ of Val/Val carriers was negatively correlated with positive symptoms (r=-0.65, P=0.03) and thought disorders (r=-0.61, P=0.02). Cognitive impairment in first-episode schizophrenic patients is associated with the Val66Met polymorphism of the BDNF gene, and has an important clinical relevance.

  7. Association of glutathione S-transferase pi (GSTP1) Ile105Val polymorphism with the risk of skin cancer: a meta-analysis.

    PubMed

    Zhou, Cheng-Fan; Ma, Tai; Zhou, Deng-Chuan; Shen, Tong; Zhu, Qi-Xing

    2015-08-01

    Numerous epidemiological studies have evaluated the association of Glutathione S-transferase P1 (GSTP1) Ile105Val polymorphism with the risk of skin cancer. However, the results remain inconclusive. To derive a more precise estimation of the association between the GSTP1 Ile105Val polymorphism and skin cancer risk, a meta-analysis was performed. A comprehensive search was conducted to identify the eligible studies. We used odds ratios (ORs) with 95 % confidence intervals (CIs) to assess the association of GSTP1 Ile105Val polymorphism with skin cancer risk. Thirteen case-control studies in nine articles, which included a total of 1504 cases and 2243 controls. Overall, we found that GSTP1 Ile105Val polymorphism was not associated with skin cancer risk. Furthermore, subgroup analysis by histological types showed that GSTP1 Ile105Val polymorphism was associated with risks of malignant melanoma under the dominant model (Val/Val + Val/Ile vs. Ile/Ile: OR 1.230, 95 % CI 1.017-1.488, P = 0.033). However, lack of association between GSTP1 Ile105Val polymorphism and BCC and SCC risk in all genetic models. Our meta-analysis suggested that the GSTP1 Ile105Val polymorphism might be associated with increased risk of malignant melanoma in Caucasian population.

  8. The Val158Met COMT polymorphism is a modifier of the age at onset in Parkinson's disease with a sexual dimorphism

    PubMed Central

    Klebe, Stephan; Golmard, Jean-Louis; Nalls, Michael A; Saad, Mohamad; Singleton, Andrew B; Bras, Jose M; Hardy, John; Simon-Sanchez, Javier; Heutink, Peter; Kuhlenbäumer, Gregor; Charfi, Rim; Klein, Christine; Hagenah, Johann; Gasser, Thomas; Wurster, Isabel; Lesage, Suzanne; Lorenz, Delia; Deuschl, Günther; Durif, Franck; Pollak, Pierre; Damier, Philippe; Tison, François; Durr, Alexandra; Amouyel, Philippe; Lambert, Jean-Charles; Tzourio, Christophe; Maubaret, Cécilia; Charbonnier-Beaupel, Fanny; Tahiri, Khadija; Vidailhet, Marie; Martinez, Maria; Brice, Alexis; Corvol, Jean-Christophe

    2013-01-01

    The catechol-O-methyltranferase (COMT) is one of the main enzymes that metabolise dopamine in the brain. The Val158Met polymorphism in the COMT gene (rs4680) causes a trimodal distribution of high (Val/Val), intermediate (Val/Met) and low (Met/Met) enzyme activity. We tested whether the Val158Met polymorphism is a modifier of the age at onset (AAO) in Parkinson's disease (PD). The rs4680 was genotyped in a total of 16 609 subjects from five independent cohorts of European and North American origin (5886 patients with PD and 10 723 healthy controls). The multivariate analysis for comparing PD and control groups was based on a stepwise logistic regression, with gender, age and cohort origin included in the initial model. The multivariate analysis of the AAO was a mixed linear model, with COMT genotype and gender considered as fixed effects and cohort and cohort-gender interaction as random effects. COMT genotype was coded as a quantitative variable, assuming a codominant genetic effect. The distribution of the COMT polymorphism was not significantly different in patients and controls (p=0.22). The Val allele had a significant effect on the AAO with a younger AAO in patients with the Val/Val (57.1±13.9, p=0.03) than the Val/Met (57.4±13.9) and the Met/Met genotypes (58.3±13.5). The difference was greater in men (1.9 years between Val/Val and Met/Met, p=0.007) than in women (0.2 years, p=0.81). Thus, the Val158Met COMT polymorphism is not associated with PD in the Caucasian population but acts as a modifier of the AAO in PD with a sexual dimorphism: the Val allele is associated with a younger AAO in men with idiopathic PD. PMID:23408064

  9. COMT val158met and 5-HTTLPR Genetic Polymorphisms Moderate Executive Control in Cannabis Users

    PubMed Central

    Verdejo-García, Antonio; Beatriz Fagundo, Ana; Cuenca, Aida; Rodriguez, Joan; Cuyás, Elisabet; Langohr, Klaus; de Sola Llopis, Susana; Civit, Ester; Farré, Magí; Peña-Casanova, Jordi; de la Torre, Rafael

    2013-01-01

    The adverse effects of cannabis use on executive functions are still controversial, fostering the need for novel biomarkers able to unveil individual differences in the cognitive impact of cannabis consumption. Two common genetic polymorphisms have been linked to the neuroadaptive impact of Δ9-tetrahydrocannabinol (THC) exposure and to executive functions in animals: the catechol-O-methyltransferase (COMT) gene val158met polymorphism and the SLC6A4 gene 5-HTTLPR polymorphism. We aimed to test if these polymorphisms moderate the harmful effects of cannabis use on executive function in young cannabis users. We recruited 144 participants: 86 cannabis users and 58 non-drug user controls. Both groups were genotyped and matched for genetic makeup, sex, age, education, and IQ. We used a computerized neuropsychological battery to assess different aspects of executive functions: sustained attention (CANTAB Rapid Visual Information Processing Test, RVIP), working memory (N-back), monitoring/shifting (CANTAB ID/ED set shifting), planning (CANTAB Stockings of Cambridge, SOC), and decision-making (Iowa Gambling Task, IGT). We used general linear model-based analyses to test performance differences between cannabis users and controls as a function of genotypes. We found that: (i) daily cannabis use is not associated with executive function deficits; and (ii) COMT val158met and 5-HTTLPR polymorphisms moderate the link between cannabis use and executive performance. Cannabis users carrying the COMT val/val genotype exhibited lower accuracy of sustained attention, associated with a more strict response bias, than val/val non-users. Cannabis users carrying the COMT val allele also committed more monitoring/shifting errors than cannabis users carrying the met/met genotype. Finally, cannabis users carrying the 5-HTTLPR s/s genotype had worse IGT performance than s/s non-users. COMT and SLC6A4 genes moderate the impact of cannabis use on executive functions. PMID:23449176

  10. Interaction between job stress and the BDNF Val66Met polymorphism affects depressive symptoms in Chinese healthcare workers.

    PubMed

    He, Shu-Chang; Wu, Shuang; Wang, Chao; Du, Xiang-Dong; Yin, Guangzhong; Jia, Qiufang; Zhang, Yingyang; Wang, Li; Soares, Jair C; Zhang, Xiang Yang

    2018-08-15

    Chronic exposure to job-related stress can lead to depression and BDNF polymorphism may play an important role in this process. The role of the stress × BDNF Val66Met interaction in depression has been studied widely using childhood stress, but few studies have utilized chronic stress in adulthood as a moderator. This study was to examine the chronic stress × BDNF Val66Met interaction in job-related depression in the healthcare workers in a Chinese Han population, which has not been reported yet. Using a cross-sectional design, 243 doctors and nurses were recruited from a general hospital in Beijing, and were assessed for depression with Self-rating Depression Scale (SDS), and the stress using the House and Rizzo's Work Stress Scale. The BDNF Val66Met polymorphism was genotyped. There was a significant positive association between job stress and depressive scores (p < 0.001). No significant main effect of the BDNF Val66Met genotype on depressive symptoms was observed (p > 0.05). A statistically significant interaction between BDNF Val66Met and job stress on depressive symptoms was found (p < 0.05); individuals with Val/Val genotype showed a higher SDS score than Met allele carriers only in the low-stress group, without significant differences in SDS score between the BDNF Val66Met subgroups in medium- or high-stress group. Limitations include cross-sectional study design, the small sample size only in healthcare workers and only one polymorphism in BDNF gene was analyzed. Our results suggest a close relationship between job-related stress and depression, and the interaction of the BDNF Val66Met polymorphism and chronic stress in adulthood may impact the depressive symptoms. Copyright © 2018. Published by Elsevier B.V.

  11. The BDNF Val66Met polymorphism affects HPA-axis reactivity to acute stress.

    PubMed

    Alexander, Nina; Osinsky, Roman; Schmitz, Anja; Mueller, Eva; Kuepper, Yvonne; Hennig, Juergen

    2010-07-01

    Growing evidence suggests that individual differences in HPA-axis reactivity to psychosocial stress are partly due to heritable influences. However, knowledge about the role of specific genetic variants remains very limited to date. Since brain-derived neurotrophic factor (BDNF) not only exhibits neurotrophic actions but is also involved in the regulation of hypothalamic neuropeptides, we investigated the role of a common functional polymorphism within the BDNF gene (BDNF Val66Met) in the context of endocrine and cardiovascular stress reactivity. Healthy male adults (N=100) were genotyped and exposed to a standardized laboratory stress task (Public Speaking). Saliva cortisol and self-reported mood levels were obtained at 6 time points prior to the stressor and during an extended recovery period. Furthermore, heart rate reactivity as an indicator of sympathetic activation was monitored continuously during the experimental procedure. We report a small, but significant effect of the BDNF Val66Met polymorphism on stress reactivity. More precisely, carriers of the met-allele showed a significantly attenuated HPA-axis and cardiovascular reactivity to the psychosocial stressor compared to subjects with the val/val genotype. Furthermore, the diminished physiological response in met-allele carriers was also attended by significantly lower self-reported ratings of perceived stress and nervousness. Our findings of a diminished endocrine and cardiovascular stress response in healthy male adults is consistent with a previously published study and adds further evidence for a crucial role of the BDNF Val66Met polymorphism in the modulation of stress reactivity. Copyright 2010. Published by Elsevier Ltd.

  12. Brain-derived neurotrophic factor Val66Met polymorphism and alcohol-related phenotypes.

    PubMed

    Nedic, Gordana; Perkovic, Matea Nikolac; Sviglin, Korona Nenadic; Muck-Seler, Dorotea; Borovecki, Fran; Pivac, Nela

    2013-01-10

    Alcoholism is a chronic psychiatric disorder affecting neural pathways that regulate motivation, stress, reward and arousal. Brain-derived neurotrophic factor (BDNF) regulates mood, response to stress and interacts with neurotransmitters and stress systems involved in reward pathways and addiction. Aim of the study was to evaluate the association between a single nucleotide polymorphism (BDNF Val66Met or rs6265) and alcohol related phenotypes in Caucasian patients. In ethnically homogenous Caucasian subjects of the Croatian origin, the BDNF Val66Met genotype distribution was determined in 549 male and 126 female patients with alcohol dependence and in 655 male and 259 female healthy non-alcoholic control subjects. Based on the structured clinical interview, additional detailed clinical interview, the Brown-Goodwin Scale, the Hamilton Rating Scale for Depression and the Clinical Global Impression scores, alcoholic patients were subdivided into those with or without comorbid depression, aggression, delirium tremens, withdrawal syndrome, early/late onset of alcohol abuse, prior suicidal attempt during lifetime, current suicidal behavior, and severity of alcohol dependence. The results showed no significant association between BDNF Val66Met variants and alcohol dependence and/or any of the alcohol related phenotypes in either Caucasian women, or men, with alcohol dependence. There are few limitations of the study. The overall study sample size was large (N=1589) but not well-powered to detect differences in BDNF Val66Met genotype distribution between studied groups. Healthy control women were older than female alcoholic patients. Only one BDNF polymorphism (rs6265) was studied. In conclusion, these data do not support the view that BDNF Val66Met polymorphism correlates with the specific alcohol related phenotypes in ethnically homogenous medication-free Caucasian subjects with alcohol dependence. Copyright © 2012 Elsevier Inc. All rights reserved.

  13. Ferrimagnetism and disorder of epitaxial Mn2-xCoxVAl Heusler compound thin films

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Meinert, Markus; Schmalhorst, Jan-Michael; Reiss, Gunter

    The quaternary full Heusler compound Mn{sub 2-x}Co{sub x}VAl with x = 1 is predicted to be a half-metallic antiferromagnet. Thin films of the quaternary compounds with x = 0-2 were prepared by dc and RF magnetron co-sputtering on heated MgO (0 0 1) substrates. The magnetic structure was examined by x-ray magnetic circular dichroism and the chemical disorder was characterized by x-ray diffraction. Ferrimagnetic coupling of V to Mn was observed for Mn{sub 2}VAl (x = 0). For x = 0.5, we also found ferrimagnetic order with V and Co antiparallel to Mn. The observed reduced magnetic moments are interpretedmore » with the help of band structure calculations in the coherent potential approximation. Mn{sub 2}VAl is very sensitive to disorder involving Mn, because nearest-neighbour Mn atoms couple antiferromagnetically. Co{sub 2}VAl has B2 order and has reduced magnetization. In the cases with x {ge} 0.9 conventional ferromagnetism was observed, closely related to the atomic disorder in these compounds.« less

  14. Stress-related methylation of the catechol-O-methyltransferase Val 158 allele predicts human prefrontal cognition and activity.

    PubMed

    Ursini, Gianluca; Bollati, Valentina; Fazio, Leonardo; Porcelli, Annamaria; Iacovelli, Luisa; Catalani, Assia; Sinibaldi, Lorenzo; Gelao, Barbara; Romano, Raffaella; Rampino, Antonio; Taurisano, Paolo; Mancini, Marina; Di Giorgio, Annabella; Popolizio, Teresa; Baccarelli, Andrea; De Blasi, Antonio; Blasi, Giuseppe; Bertolino, Alessandro

    2011-05-04

    DNA methylation at CpG dinucleotides is associated with gene silencing, stress, and memory. The catechol-O-methyltransferase (COMT) Val(158) allele in rs4680 is associated with differential enzyme activity, stress responsivity, and prefrontal activity during working memory (WM), and it creates a CpG dinucleotide. We report that methylation of the Val(158) allele measured from peripheral blood mononuclear cells (PBMCs) of Val/Val humans is associated negatively with lifetime stress and positively with WM performance; it interacts with stress to modulate prefrontal activity during WM, such that greater stress and lower methylation are related to reduced cortical efficiency; and it is inversely related to mRNA expression and protein levels, potentially explaining the in vivo effects. Finally, methylation of COMT in prefrontal cortex and that in PBMCs of rats are correlated. The relationship of methylation of the COMT Val(158) allele with stress, gene expression, WM performance, and related brain activity suggests that stress-related methylation is associated with silencing of the gene, which partially compensates the physiological role of the high-activity Val allele in prefrontal cognition and activity. Moreover, these results demonstrate how stress-related DNA methylation of specific functional alleles impacts directly on human brain physiology beyond sequence variation.

  15. The association between COMT Val158Met polymorphism and migraine risk: A meta-analysis.

    PubMed

    Liao, Yao-Jun; Jiang, Jing-Ru; Jin, San-Qing

    2017-05-01

    Background The COMT Val158Met polymorphism has long been regarded as a risk factor for migraine. The possible association between COMT Val158Met polymorphism and migraine has been evaluated in several studies, but the results are not consistent. Therefore, we conduct this meta-analysis to address these issues. Methods The WEB OF SCIENCE and EMBASE databases were searched for eligible studies. The odds ratio (OR) with the corresponding 95% confidence interval (CI) was calculated to estimate the strength of the association between COMT Val158Met polymorphism and migraine. Results Five studies with 979 cases and 1870 controls were ultimately included in the present meta-analysis. The overall data showed no significant association between COMT Val158Met polymorphism and migraine in the multiplicative model (OR = 0.97, 95% CI: 0.78-1.21, p = 0.805) and dominant model (OR = 1.05, 95% CI: 0.75-1.48, p = 0.773), neither in the additive model (OR = 0.97, 95% CI: 0.77-1.23, p = 0.817) nor in the recessive model (OR = 0.88, 95% CI: 0.71-1.09, p = 0.246). In subgroup analysis, both for Caucasian and Asian populations, no statistically significant associations were observed in any genetic models. Conclusions Our meta-analysis suggested that the COMT Val158Met polymorphism was not associated with migraine risk.

  16. Platyhelminth Venom Allergen-Like (VAL) proteins: revealing structural diversity, class-specific features and biological associations across the phylum

    PubMed Central

    CHALMERS, IAIN W.; HOFFMANN, KARL F.

    2012-01-01

    SUMMARY During platyhelminth infection, a cocktail of proteins is released by the parasite to aid invasion, initiate feeding, facilitate adaptation and mediate modulation of the host immune response. Included amongst these proteins is the Venom Allergen-Like (VAL) family, part of the larger sperm coating protein/Tpx-1/Ag5/PR-1/Sc7 (SCP/TAPS) superfamily. To explore the significance of this protein family during Platyhelminthes development and host interactions, we systematically summarize all published proteomic, genomic and immunological investigations of the VAL protein family to date. By conducting new genomic and transcriptomic interrogations to identify over 200 VAL proteins (228) from species in all 4 traditional taxonomic classes (Trematoda, Cestoda, Monogenea and Turbellaria), we further expand our knowledge related to platyhelminth VAL diversity across the phylum. Subsequent phylogenetic and tertiary structural analyses reveal several class-specific VAL features, which likely indicate a range of roles mediated by this protein family. Our comprehensive analysis of platyhelminth VALs represents a unifying synopsis for understanding diversity within this protein family and a firm context in which to initiate future functional characterization of these enigmatic members. PMID:22717097

  17. The BDNF Val66Met polymorphism and plasma brain-derived neurotrophic factor levels in Han Chinese heroin-dependent patients.

    PubMed

    Chen, Shiou-Lan; Lee, Sheng-Yu; Chang, Yun-Hsuan; Wang, Tzu-Yun; Chen, Shih-Heng; Chu, Chun-Hsien; Chen, Po See; Yang, Yen Kuang; Hong, Jau-Shyong; Lu, Ru-Band

    2015-02-02

    BDNF and its gene polymorphism may be important in synaptic plasticity and neuron survival, and may become a key target in the physiopathology of long-term heroin use. Thus, we investigated the relationships between brain-derived neurotrophic factor (BDNF) plasma concentrations and the BDNF Val66Met nucleotide polymorphism (SNP) in heroin-dependent patients. The pretreatment expression levels of plasma BDNF and the BDNF Val66Met SNP in 172 heroin-dependent patients and 102 healthy controls were checked. BDNF levels were significantly lower in patients (F = 52.28, p < 0.0001), but the distribution of the SNP was not significantly different. Nor were plasma BDNF levels significantly different between Met/Met, Met/Val, and Val/Val carriers in each group, which indicated that the BDNF Val66Met SNP did not affect plasma BDNF levels in our participants. In heroin-dependent patients, plasma BDNF levels were negatively correlated with the length of heroin dependency. Long-term (>15 years) users had significantly lower plasma BDNF levels than did short-term (<5 years) users. We conclude that plasma BDNF concentration in habitual heroin users are not affected by BDNF Val66Met gene variants, but by the length of the heroin dependency.

  18. The BDNF Val66Met polymorphism and plasma brain-derived neurotrophic factor levels in Han Chinese heroin-dependent patients

    PubMed Central

    Chen, Shiou-Lan; Lee, Sheng-Yu; Chang, Yun-Hsuan; Wang, Tzu-Yun; Chen, Shih-Heng; Chu, Chun-Hsien; Chen, Po See; Yang, Yen Kuang; Hong, Jau-Shyong; Lu, Ru-Band

    2015-01-01

    BDNF and its gene polymorphism may be important in synaptic plasticity and neuron survival, and may become a key target in the physiopathology of long-term heroin use. Thus, we investigated the relationships between brain-derived neurotrophic factor (BDNF) plasma concentrations and the BDNF Val66Met nucleotide polymorphism (SNP) in heroin-dependent patients. The pretreatment expression levels of plasma BDNF and the BDNF Val66Met SNP in 172 heroin-dependent patients and 102 healthy controls were checked. BDNF levels were significantly lower in patients (F = 52.28, p < 0.0001), but the distribution of the SNP was not significantly different. Nor were plasma BDNF levels significantly different between Met/Met, Met/Val, and Val/Val carriers in each group, which indicated that the BDNF Val66Met SNP did not affect plasma BDNF levels in our participants. In heroin-dependent patients, plasma BDNF levels were negatively correlated with the length of heroin dependency. Long-term (>15 years) users had significantly lower plasma BDNF levels than did short-term (<5 years) users. We conclude that plasma BDNF concentration in habitual heroin users are not affected by BDNF Val66Met gene variants, but by the length of the heroin dependency. PMID:25640280

  19. Effect of Fe-V nonstoichiometry on electrical and thermoelectric properties of Fe2VAl films

    NASA Astrophysics Data System (ADS)

    Kudo, Kohei; Yamada, Shinya; Chikada, Jinichiro; Shimanuki, Yuta; Nakamura, Yoshiaki; Hamaya, Kohei

    2018-04-01

    We study the effect of Fe-V nonstoichiometry on electrical and thermoelectric properties of Fe2VAl films. We find that temperature dependence of electrical resistivity and carrier type for Fe2- x V1+ x Al films are similar to those for bulk samples reported previously. In addition, the electrical and thermoelectric properties can be modulated by varying x. These results indicate that the electronic band structure having a pseudo gap at around the Fermi level is demonstrated even in thin-film Fe2VAl samples. This study will lead to further improvement in thermoelectric properties of the thin-film Fe2VAl.

  20. Protective Effect of Val129-PrP against Bovine Spongiform Encephalopathy but not Variant Creutzfeldt-Jakob Disease

    PubMed Central

    Fernández-Borges, Natalia; Espinosa, Juan Carlos; Marín-Moreno, Alba; Aguilar-Calvo, Patricia; Asante, Emmanuel A.; Kitamoto, Tetsuyuki; Mohri, Shirou; Andréoletti, Olivier

    2017-01-01

    Bovine spongiform encephalopathy (BSE) is the only known zoonotic prion that causes variant Creutzfeldt-Jakob disease (vCJD) in humans. The major risk determinant for this disease is the polymorphic codon 129 of the human prion protein (Hu-PrP), where either methionine (Met129) or valine (Val129) can be encoded. To date, all clinical and neuropathologically confirmed vCJD cases have been Met129 homozygous, with the exception of 1 recently reported Met/Val heterozygous case. Here, we found that transgenic mice homozygous for Val129 Hu-PrP show severely restricted propagation of the BSE prion strain, but this constraint can be partially overcome by adaptation of the BSE agent to the Met129 Hu-PrP. In addition, the transmission of vCJD to transgenic mice homozygous for Val129 Hu-PrP resulted in a prion with distinct strain features. These observations may indicate increased risk for vCJD secondary transmission in Val129 Hu-PrP–positive humans with the emergence of new strain features. PMID:28820136

  1. Analysis of the Association between Catechol-O-Methyltransferase Val158Met and Male Sexual Orientation.

    PubMed

    Yu, Wei; Tu, Dan; Hong, Fuchang; Wang, Jing; Liu, Xiaoli; Cai, Yumao; Xu, Ruiwei; Zhao, Guanglu; Wang, Feng; Pan, Hong; Wu, Shinan; Feng, Tiejian; Wang, Binbin

    2015-09-01

    Male sexual orientation is thought to have a genetic component. However, previous studies have failed to generate positive results from among candidate genes. Catechol-O-methyltransferase (COMT), located on chromosome 22, has six exons, spans 27 kb, and encodes a protein of 271 amino acids. COMT has an important role in regulating the embryonic levels of catecholamine neurotransmitters (such as dopamine, norepinephrine, and epinephrine) and estrogens. COMT is also thought to be related to sexual orientation. This study aimed to investigate the relationship between the COMT Val158Met variant and male sexual orientation. We performed association analysis of the COMT gene single nucleotide polymorphism, Val158Met, in 409 homosexual cases and 387 heterosexual control Chinese men. COMT polymorphism status was determined using a polymerase chain reaction-based assay. Polymerase chain reaction was performed to genotype the COMT Val158Met polymorphism. The frequency differences of the genotype and alleles distribution between the male homosexual and control groups. Significant differences, both in genotype and alleles, between male homosexual individuals and controls indicated a genetic component related to male homosexuality. The Val allele recessive model could be an interrelated genetic model of the cause of male homosexuality. The COMT Val158Met variant might be associated with male sexual orientation and a recessive model was suggested. © 2015 International Society for Sexual Medicine.

  2. Interim Assessment of the VAL Automated Guideway Transit System.

    DOT National Transportation Integrated Search

    1981-11-01

    This report describes an interim assessment of the VAL (Vehicules Automatiques Legers or Light Automated Vehicle) AGT system which is currently under construction in Lille, France, and which is to become fully operational in December 1983. This repor...

  3. BDNF Val66Met polymorphism is associated with HPA axis reactivity to psychological stress characterized by genotype and gender interactions.

    PubMed

    Shalev, Idan; Lerer, Elad; Israel, Salomon; Uzefovsky, Florina; Gritsenko, Inga; Mankuta, David; Ebstein, Richard P; Kaitz, Marsha

    2009-04-01

    A key protein in maintaining neuronal integrity throughout the life span is brain-derived neurotrophic factor (BDNF). The BDNF gene is characterized by a functional polymorphism, which has been associated with stress-related disorders such as anxiety-related syndromes and depression, prompting us to examine individual responses by Genotype and Sex to a standardized social stress paradigm. Gender differences in BDNFxstress responses were posited because estrogen induces synthesis of BDNF in several brain regions. 97 university students (51 females and 46 males) participated in a social stress procedure (Trier Social Stress Test, TSST). Indices of stress were derived from repeated measurement of cortisol, blood pressure, and heart rate during the TSST. All subjects were genotyped for the Val66Met polymorphism. Tests of within-subject effects showed a significant three-way interaction (SPSS GLM repeated measures: Time (eight levels)xBDNF (val/val, val/met)xSex: p=0.0002), which reflects gender differences in the pattern of cortisol rise and decline during the social challenge. In male subjects, val/val homozygotes showed a greater rise in salivary cortisol than val/met heterozygotes. In female subjects, there was a trend for the opposite response, which is significant when area under the curve increase (AUCi) was calculated for the val/val homozygotes to show the lowest rise. Overall, the same pattern of results was observed for blood pressure and heart rate. These results indicate that a common, functionally significant polymorphism in the BDNF gene modulates HPA axis reactivity and regulation during the TSST differently in men and women. Findings may be related to gender differences in reactivity and vulnerability to social stress.

  4. BDNF val66met polymorphism is associated with age at onset and intensity of symptoms of paranoid schizophrenia in a Polish population.

    PubMed

    Suchanek, Renata; Owczarek, Aleksander; Paul-Samojedny, Monika; Kowalczyk, Małgorzata; Kucia, Krzysztof; Kowalski, Jan

    2013-01-01

    The brain-derived neurotrophic factor (BDNF) is one of the candidate genes for schizophrenia. There is evidence that val66met polymorphism may be involved in the pathophysiology of schizophrenia. The authors genotyped val66met (rs6265) polymorphism of the BDNF gene in 208 inpatients with paranoid schizophrenia and 254 control subjects in a Polish population. There was no association between val66met polymorphism and development of paranoid schizophrenia in either men or women. However, an association was found between this polymorphism and age at onset and psychopathology of paranoid schizophrenia. Men with the val/met genotype had an earlier age at onset, and the val/val genotype predisposed to more severe symptoms, particularly on the General Psychopathology Scale of the Positive and Negative Symptoms Scale (PANSS-G). The analysis of PANSS single items has shown that patients with the val/met genotype had higher scores on a hallucinatory behavior item than those with other genotypes.

  5. 5. VAL LAUNCHER BRIDGE OVER LAUNCHER SLAB TAKEN FROM RESERVOIR ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    5. VAL LAUNCHER BRIDGE OVER LAUNCHER SLAB TAKEN FROM RESERVOIR LOOKING NORTH. - Variable Angle Launcher Complex, Variable Angle Launcher, CA State Highway 39 at Morris Reservior, Azusa, Los Angeles County, CA

  6. Modifcation of the Prolyl Ring of Val-Pro and the Impact of this Modification on b2 Ion Structure

    NASA Astrophysics Data System (ADS)

    Bernier, Matthew C.; Wysocki, Vicki H.; Gucinski, Ashley; Chamot-Rooke, Julia

    2013-06-01

    Here we present b2 ion studies on one tripeptide (VPA) and show how the addition of a fluorine or a hydroxyl group on the 3rd position of the proline ring can affect the b2 ion formation. Action IRMPD results of ValHyp (Hyp=hydroxyproline), ValFlp (Flp=trans-fluoroproline), and Valflp (flp=cis-fluoroproline) all show the presence of a strong oxazolone band in the CO region at 1900 cm-1. The presence of peaks in the diketopiperazine region between 1700 and 1800 cm-1 varies depending on which substituent is placed on the prolyl ring. Recently published data from our group showed a pair of medium sized diketopiperazine bands at 1760 and 1701 cm-1 for ValPro and we observed similarly intense bands for Valflp at 1752 and 1689 cm-1. ValHyp and ValFlp fail to show any significant diketopiperazine bands, but if zoomed in x10 a small band can be observed at 1756 cm-1 for ValHyp. From this data it is apparent that substitution of the second position prolyl ring can alter the formation of the b2 diketopiperazine ion.

  7. 7. VAL CAMERA CAR, DETAIL OF 'FLARE' OR TRAJECTORY CAMERA ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    7. VAL CAMERA CAR, DETAIL OF 'FLARE' OR TRAJECTORY CAMERA INSIDE CAMERA CAR. - Variable Angle Launcher Complex, Camera Car & Track, CA State Highway 39 at Morris Reservior, Azusa, Los Angeles County, CA

  8. 7. VAL CAMERA STATION, INTERIOR VIEW OF CAMERA MOUNT, COMMUNICATION ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    7. VAL CAMERA STATION, INTERIOR VIEW OF CAMERA MOUNT, COMMUNICATION EQUIPMENT AND STORAGE CABINET. - Variable Angle Launcher Complex, Camera Stations, CA State Highway 39 at Morris Reservior, Azusa, Los Angeles County, CA

  9. 3. VAL CONTROL STATION, VIEW OF CONTROL PANELS SHOWING MAIN ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    3. VAL CONTROL STATION, VIEW OF CONTROL PANELS SHOWING MAIN PRESSURE GAUGES, LOOKING NORTH. - Variable Angle Launcher Complex, Control Station, CA State Highway 39 at Morris Reservior, Azusa, Los Angeles County, CA

  10. The effect of the COMT val(158)met polymorphism on neural correlates of semantic verbal fluency.

    PubMed

    Krug, Axel; Markov, Valentin; Sheldrick, Abigail; Krach, Sören; Jansen, Andreas; Zerres, Klaus; Eggermann, Thomas; Stöcker, Tony; Shah, N Jon; Kircher, Tilo

    2009-12-01

    Variation in the val(158)met polymorphism of the COMT gene has been found to be associated with cognitive performance. In functional neuroimaging studies, this dysfunction has been linked to signal changes in prefrontal areas. Given the complex modulation and functional heterogeneity of frontal lobe systems, further specification of COMT gene-related phenotypes differing in prefrontally mediated cognitive performance are of major interest. Eighty healthy individuals (54 men, 26 women; mean age 23.3 years) performed an overt semantic verbal fluency task while brain activation was measured with functional magnetic resonance imaging (fMRI). COMT val(158)met genotype was determined and correlated with brain activation measured with fMRI during the task. Although there were no differences in performance, brain activation in the left inferior frontal gyrus [Brodmann area 10] was positively correlated with the number of val alleles in the COMT gene. COMT val(158)met status modulates brain activation during the language production on a semantic level in an area related to executive functions.

  11. COMT Val(158)Met genotype determines the direction of cognitive effects produced by catechol-O-methyltransferase inhibition.

    PubMed

    Farrell, Sarah M; Tunbridge, Elizabeth M; Braeutigam, Sven; Harrison, Paul J

    2012-03-15

    Catechol-O-methyltransferase (COMT) metabolizes dopamine. The COMT Val(158)Met polymorphism influences its activity, and multiple neural correlates of this genotype on dopaminergic phenotypes, especially working memory, have been reported. COMT activity can also be regulated pharmacologically by COMT inhibitors. The inverted-U relationship between cortical dopamine signaling and working memory predicts that the effects of COMT inhibition will differ according to COMT genotype. Thirty-four COMT Met(158)Met (Met-COMT) and 33 COMT Val(158)Val (Val-COMT) men were given a single 200-mg dose of the brain-penetrant COMT inhibitor tolcapone or placebo in a randomized, double-blind, between-subjects design. They completed the N-back task of working memory and a gambling task. In the placebo group, Met-COMT subjects outperformed Val-COMT subjects on the 2- back, and they were more risk averse. Tolcapone had opposite effects in the two genotype groups: it worsened N-back performance in Met-COMT subjects but enhanced it in Val-COMT subjects. Tolcapone made Met-COMT subjects less risk averse but Val-COMT subjects more so. In both tasks, tolcapone reversed the baseline genotype differences. Depending on genotype, COMT inhibition can enhance or impair working memory and increase or decrease risky decision making. To our knowledge, the data are the clearest demonstration to date that the direction of effect of a drug can be influenced by a polymorphism in its target gene. The results support the inverted-U model of dopamine function. The findings are of translational relevance, because COMT inhibitors are used in the adjunctive treatment of Parkinson's disease and are under evaluation in schizophrenia and other disorders. Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  12. BDNF-Val66Met-Polymorphism Impact on Cortical Plasticity in Schizophrenia Patients: A Proof-of-Concept Study

    PubMed Central

    Nitsche, Michael A.; Wobrock, Thomas; Bunse, Tilmann; Rein, Bettina; Herrmann, Maximiliane; Schmitt, Andrea; Nieratschker, Vanessa; Witt, Stephanie H.; Rietschel, Marcella; Falkai, Peter; Hasan, Alkomiet

    2015-01-01

    Background: Brain-derived neurotrophic factor (BDNF) has been shown to be a moderator of neuroplasticity. A frequent BDNF-polymorphism (Val66Met) is associated with impairments of cortical plasticity. In patients with schizophrenia, reduced neuroplastic responses following non-invasive brain stimulation have been reported consistently. Various studies have indicated a relationship between the BDNF-Val66Met-polymorphism and motor-cortical plasticity in healthy individuals, but schizophrenia patients have yet to be investigated. The aim of this proof-of-concept study was, therefore, to test the impact of the BDNF-Val66Met-polymorphism on inhibitory and facilitatory cortical plasticity in schizophrenia patients. Methods: Cortical plasticity was investigated in 22 schizophrenia patients and 35 healthy controls using anodal and cathodal transcranial direct-current stimulation (tDCS) applied to the left primary motor cortex. Animal and human research indicates that excitability shifts following anodal and cathodal tDCS are related to molecular long-term potentiation and long-term depression. To test motor-cortical excitability before and after tDCS, well-established single- and paired-pulse transcranial magnetic stimulation protocols were applied. Results: Our analysis revealed increased glutamate-mediated intracortical facilitation in met-heterozygotes compared to val-homozygotes at baseline. Following cathodal tDCS, schizophrenia met-heterozygotes had reduced gamma-amino-butyric-acid-mediated short-interval intracortical inhibition, whereas healthy met-heterozygotes displayed the opposite effect. The BDNF-Val66Met-polymorphism did not influence single-pulse motor-evoked potential amplitudes after tDCS. Conclusions: These preliminary findings support the notion of an association of the BDNF-Val66Met-polymorphism with observable alterations in plasticity following cathodal tDCS in schizophrenia patients. This indicates a complex interaction between inhibitory

  13. Lack of association between uncoupling protein-2 Ala55Val polymorphism and incident diabetes in the atherosclerosis risk in communities study.

    PubMed

    Bielinski, Suzette J; Pankow, James S; Boerwinkle, Eric; Bray, Molly S; Kao, W H Linda; Folsom, Aaron R

    2008-09-01

    Type 2 diabetes mellitus (T2DM) is characterized by impaired insulin secretion, peripheral insulin resistance, and increased hepatic glucose production. Genes that contribute to genetic susceptibility to T2DM function in numerous biochemical pathways. Uncoupling protein-2 (UCP2) functions as a negative regulator of insulin secretion. Animal studies show induction of UCP2 plays a pathogenic role in the progression of obesity-induced T2DM and some human studies have shown an association between a common UCP2 polymorphism, Ala55Val (rs660339), and T2DM, obesity, and resting metabolic rate with the Val/Val genotype conferring increased risk. We investigated the relationship between the Ala55Val variant and incidence of T2DM among 12,056 participants in the Atherosclerosis Risk in Communities (ARIC) Study aged 45-64 years at baseline. Incident T2DM (n = 1,406) cases were identified over 9 years of follow-up. The Val55 allele frequency was 44% in blacks and 41% in whites. The rate of T2DM per 1,000 person was 15.0, 15.6, and 15.6 yearsfor Ala/Ala, Ala/Val, and Val/Val genotypes, respectively. We found no significant association between UCP2 genotypes and incident T2DM in the whole cohort, in race-gender subgroups, or in categories of body mass index (normal, overweight and obese). The Ala55Val polymorphism of UCP2 was not associated with incident T2DM in the ARIC cohort.

  14. Cal/Val activities for DubaiSat-2 performance assessment

    NASA Astrophysics Data System (ADS)

    Bushahab, A.; Al-Mansoori, S.; Al-Suwaidi, K.; Al Matroushi, Hessa; Al-Tunaiji, E.; Al Shamsi, Meera

    2014-10-01

    Emirates Institution for Advanced Science and Technology (EIAST) was established by the Dubai Government in 2006. After three years of working together with Satrec Initiative (South Korea), EIAST was able to launch DubaiSat-1 on the 29th of July 2009. Building on the success of DubaiSat-1 and the roll out of the knowledge transfer program, UAE engineers were involved in almost 70% of the total build and design of DubaiSat-2. Targeting the commercial market, DubaiSat-2 was launched on the 21st of November 2013 for capturing 1-meter resolution images. The 1st Cal/Val phase was the most critical phase in the satellite life-time, where most of the initial measurements took place. This phase extended over the period of 25/11/2013 till 12/12/2013. Moreover, this phase included most of the relative calibration tasks, color balancing and band matching. 2nd Cal/Val phase included most of the debugging and the pointing accuracy calibration tests. This phase extended over the period of 11/02/2014 till 09/03/2014. This phase emphasized on the calibration of the pointing accuracy. The 3rd Cal/Val phase included fine tuning for the Gyro system to further increase the stability of the satellite and thus improve the pointing accuracy. Moreover, new techniques were implemented to the Pan-Sharpening and to the MTF compensation procedures to enhance the final product. This phase extended over the period of 04/05/2014 till 21/05/2014.

  15. 8. VAL CAMERA CAR, CLOSEUP VIEW OF 'FLARE' OR TRAJECTORY ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    8. VAL CAMERA CAR, CLOSE-UP VIEW OF 'FLARE' OR TRAJECTORY CAMERA ON SLIDING MOUNT. - Variable Angle Launcher Complex, Camera Car & Track, CA State Highway 39 at Morris Reservior, Azusa, Los Angeles County, CA

  16. 2. VAL CONTROL STATION, VIEW OF INTERIOR SHOWING EXTERIOR DOOR, ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    2. VAL CONTROL STATION, VIEW OF INTERIOR SHOWING EXTERIOR DOOR, WINDOWS AND CONTROL PANELS, LOOKING SOUTHEAST. - Variable Angle Launcher Complex, Control Station, CA State Highway 39 at Morris Reservior, Azusa, Los Angeles County, CA

  17. A brain-derived neurotrophic factor polymorphism Val66Met identifies fibromyalgia syndrome subgroup with higher body mass index and C-reactive protein.

    PubMed

    Xiao, Yangming; Russell, I Jon; Liu, Ya-Guang

    2012-08-01

    A common single nucleotide polymorphism (SNP) in the gene of brain-derived neurotrophic factor (BDNF) results from a substitution at position 66 from valine (Val) to methionine (Met) and may predispose to human neuropsychiatric disorders. We proposed to determine whether these BDNF gene SNPs were associated with fibromyalgia syndrome (FMS) and/or any of its typical phenotypes. Patients with FMS (N = 95) and healthy normal controls (HNC, N = 58) were studied. Serum high-sensitivity C-reactive protein (hsCRP) levels were measured using an enzyme-linked immunosorbent assay (ELISA). The BDNF SNPs were determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).The BDNF SNP distribution was 65 (68%) Val/Val, 28 (30%) Val/Met, and 2 (2%) Met/Met for FMS and 40 (69%), 17(29%), and 1 (2%) for HNC, respectively. The serum high-sensitivity C-reactive protein (hsCRP)and body mass index (BMI) in FMS were higher than in HNC. The FMS with BDNF Val66Val had significantly higher mean BMI (P = 0.0001) and hsCRP (P = 0.02) than did FMS carrying the Val66Met genotype. This pattern was not found in HNC. Phenotypic measures of subjective pain, pain threshold, depression, or insomnia did not relate to either of the BDNF SNPs in FMS. The relative distribution BDNF SNPs did not differ between FMS and HNC. The BDNF Val66Met polymorphism is not selective for FMS. The BDNF Val66Val SNP identifies a subgroup of FMS with elevated hsCRP and higher BMI. This is the first study to associate a BDNF polymorphism with a FMS subgroup phenotype.

  18. Techniques of stapler-based navigational thoracoscopic segmentectomy using virtual assisted lung mapping (VAL-MAP)

    PubMed Central

    Murayama, Tomonori; Nakajima, Jun

    2016-01-01

    Anatomical segmentectomies play an important role in oncological lung resection, particularly for ground-glass types of primary lung cancers. This operation can also be applied to metastatic lung tumors deep in the lung. Virtual assisted lung mapping (VAL-MAP) is a novel technique that allows for bronchoscopic multi-spot dye markings to provide “geometric information” to the lung surface, using three-dimensional virtual images. In addition to wedge resections, VAL-MAP has been found to be useful in thoracoscopic segmentectomies, particularly complex segmentectomies, such as combined subsegmentectomies or extended segmentectomies. There are five steps in VAL-MAP-assisted segmentectomies: (I) “standing” stitches along the resection lines; (II) cleaning hilar anatomy; (III) confirming hilar anatomy; (IV) going 1 cm deeper; (V) step-by-step stapling technique. Depending on the anatomy, segmentectomies can be classified into linear (lingular, S6, S2), V- or U-shaped (right S1, left S3, S2b + S3a), and three dimensional (S7, S8, S9, S10) segmentectomies. Particularly three dimensional segmentectomies are challenging in the complexity of stapling techniques. This review focuses on how VAL-MAP can be utilized in segmentectomy, and how this technique can assist the stapling process in even the most challenging ones. PMID:28066675

  19. Catechol-O-Methyltransferase Val158Met Polymorphism Associates with Individual Differences in Sleep Physiologic Responses to Chronic Sleep Loss

    PubMed Central

    Goel, Namni; Banks, Siobhan; Lin, Ling; Mignot, Emmanuel; Dinges, David F.

    2011-01-01

    Background The COMT Val158Met polymorphism modulates cortical dopaminergic catabolism, and predicts individual differences in prefrontal executive functioning in healthy adults and schizophrenic patients, and associates with EEG differences during sleep loss. We assessed whether the COMT Val158Met polymorphism was a novel marker in healthy adults of differential vulnerability to chronic partial sleep deprivation (PSD), a condition distinct from total sleep loss and one experienced by millions on a daily and persistent basis. Methodology/Principal Findings 20 Met/Met, 64 Val/Met, and 45 Val/Val subjects participated in a protocol of two baseline 10h time in bed (TIB) nights followed by five consecutive 4 h TIB nights. Met/Met subjects showed differentially steeper declines in non-REM EEG slow-wave energy (SWE)—the putative homeostatic marker of sleep drive—during PSD, despite comparable baseline SWE declines. Val/Val subjects showed differentially smaller increases in slow-wave sleep and smaller reductions in stage 2 sleep during PSD, and had more stage 1 sleep across nights and a shorter baseline REM sleep latency. The genotypes, however, did not differ in performance across various executive function and cognitive tasks and showed comparable increases in subjective and physiological sleepiness in response to chronic sleep loss. Met/Met genotypic and Met allelic frequencies were higher in whites than African Americans. Conclusions/Significance The COMT Val158Met polymorphism may be a genetic biomarker for predicting individual differences in sleep physiology—but not in cognitive and executive functioning—resulting from sleep loss in a healthy, racially-diverse adult population of men and women. Beyond healthy sleepers, our results may also provide insight for predicting sleep loss responses in patients with schizophrenia and other psychiatric disorders, since these groups repeatedly experience chronically-curtailed sleep and demonstrate COMT

  20. 6. VAL CAMERA CAR, DETAIL OF COMMUNICATION EQUIPMENT INSIDE CAMERA ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    6. VAL CAMERA CAR, DETAIL OF COMMUNICATION EQUIPMENT INSIDE CAMERA CAR WITH CAMERA MOUNT IN FOREGROUND. - Variable Angle Launcher Complex, Camera Car & Track, CA State Highway 39 at Morris Reservior, Azusa, Los Angeles County, CA

  1. Construction of a New Phage Integration Vector pFIV-Val for Use in Different Francisella Species.

    PubMed

    Tlapák, Hana; Köppen, Kristin; Rydzewski, Kerstin; Grunow, Roland; Heuner, Klaus

    2018-01-01

    We recently identified and described a putative prophage on the genomic island FhaGI-1 located within the genome of Francisella hispaniensis AS02-814 ( F. tularensis subsp. novicida -like 3523). In this study, we constructed two variants of a Francisella phage integration vector, called pFIV1-Val and pFIV2-Val ( Francisella Integration Vector-tRNA Val -specific), using the attL/R- sites and the site-specific integrase (FN3523_1033) of FhaGI-1, a chloramphenicol resistance cassette and a sacB gene for counter selection of transformants against the vector backbone. We inserted the respective sites and genes into vector pUC57-Kana to allow for propagation in Escherichia coli . The constructs generated a circular episomal form in E. coli which could be used to transform Francisella spp . where FIV-Val stably integrated site specifically into the tRNA Val gene of the genome, whereas pUC57-Kana is lost due to counter selection. Functionality of the new vector was demonstrated by the successfully complementation of a Francisella mutant strain. The vectors were stable in vitro and during host-cell infection without selective pressure. Thus, the vectors can be applied as a further genetic tool in Francisella research, expanding the present genetic tools by an integrative element. This new element is suitable to perform long-term experiments with different Francisella species.

  2. Schistosoma mansoni venom allergen-like protein 4 (SmVAL4) is a novel lipid-binding SCP/TAPS protein that lacks the prototypical CAP motifs

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kelleher, Alan; Darwiche, Rabih; Rezende, Wanderson C.

    2014-08-01

    The first structure of an S. mansoni venom allergen-like protein is presented. Schistosomiasis is a parasitic disease that affects over 200 million people. Vaccine candidates have been identified, including Schistosoma mansoni venom allergen-like proteins (SmVALs) from the SCP/TAPS (sperm-coating protein/Tpx/antigen 5/pathogenesis related-1/Sc7) superfamily. The first SmVAL structure, SmVAL4, was refined to a resolution limit of 2.16 Å. SmVAL4 has a unique structure that could not be predicted from homologous structures, with longer loops and an unusual C-terminal extension. SmVAL4 has the characteristic α/β-sandwich and central SCP/TAPS cavity. Furthermore, SmVAL4 has only one of the signature CAP cavity tetrad amino-acid residuesmore » and is missing the histidines that coordinate divalent cations such as Zn{sup 2+} in other SCP/TAPS proteins. SmVAL4 has a cavity between α-helices 1 and 4 that was observed to bind lipids in tablysin-15, suggesting the ability to bind lipids. Subsequently, SmVAL4 was shown to bind cholesterol in vitro. Additionally, SmVAL4 was shown to complement the in vivo sterol-export phenotype of yeast mutants lacking their endogenous CAP proteins. Expression of SmVAL4 in yeast cells lacking endogenous CAP function restores the block in sterol export. These studies suggest an evolutionarily conserved lipid-binding function shared by CAP proteins such as SmVAL4 and yeast CAP proteins such as Pry1.« less

  3. 18. VAL, DETAIL OF LAUNCHER BRIDGE ALONG THE SIDE OF ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    18. VAL, DETAIL OF LAUNCHER BRIDGE ALONG THE SIDE OF THE 32' DIAMETER LAUNCHING TUBE LOOKING SOUTHWEST. - Variable Angle Launcher Complex, Variable Angle Launcher, CA State Highway 39 at Morris Reservior, Azusa, Los Angeles County, CA

  4. Influence of COMT Val158Met polymorphism on emotional decision-making: A sex-dependent relationship?

    PubMed

    Costa, Danielle de Souza; Bechara, Antoine; de Paula, Jonas Jardim; Romano-Silva, Marco Aurélio; Correa, Humberto; Lage, Guilherme Menezes; Miranda, Débora Marques de; Malloy-Diniz, Leandro Fernandes

    2016-12-30

    The biological underpinnings of sex-related differences in decision-making are still under-explored. The COMT gene is related to sexual dimorphism and with different choices made under uncertainty, albeit no study has specifically investigated a moderation effect of sex on the association between the COMT gene and the performance on decision-making paradigms. In this study, we investigated the influence of the COMT Val 158 Met polymorphism on Iowa Gambling Task (IGT) performance depending on sex in a healthy adult sample. Participants were 192 healthy adults (84 men and 108 women). The first 40 choices in the IGT were considered decisions under ambiguity and the last 60 choices decisions under risk. To test our moderation hypothesis we used a separate regressions approach. The results revealed a sex-dependent effect of COMT Va l 158 Met polymorphism on decision-making as measured by the IGT. Val/Val women showed the best performance in the last trials of the IGT. Therefore, the COMT Val 158 Met polymorphism may be considered a genetic marker underlying sex differences in decision-making. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  5. Meta-analysis of the brain-derived neurotrophic factor gene (BDNF) Val66Met polymorphism in anxiety disorders and anxiety-related personality traits.

    PubMed

    Frustaci, Alessandra; Pozzi, Gino; Gianfagna, Francesco; Manzoli, Lamberto; Boccia, Stefania

    2008-01-01

    Brain-derived neurotrophic factor (BDNF) is potentially involved in the pathogenesis of anxiety. We carried out meta-analyses to evaluate the relationship between the BDNF Val66Met (valine, methionine) polymorphism and anxiety disorders (AD) or anxiety-related personality traits (ARPT). Medline, Embase and PsycINFO were searched up to December 2007. We investigated 3 outcomes related to BDNF Val66Met polymorphisms: (1) clinically diagnosed cases of AD; (2) ARPT in subjects without psychiatric diagnoses, assessed either by the Neuroticism scale of NEO-Personality Inventory forms (NEO-PI, NEO-PI-R, NEO-FFI), or by (3) the Harm Avoidance (HA) scale of Tridimensional Personality Questionnaire (TPQ) or its extended version Temperament and Character Inventory (TCI). Seven case-control studies were selected for AD, including 1,092 cases and 8,394 controls, while 5 cross-sectional studies for Neuroticism (n = 1,633) and 4 for HA (n = 607). Both Met/Met and Val/Met individuals, as compared to Val/Val, showed a statistically significant lower Neuroticism score [SMD = -0.24 (95% CI: -0.44, -0.04), and -0.11 (95% CI: -0.22, -0.01), respectively]. No significant association was found between BDNF Val66Met polymorphism and AD [OR = 1.13 (95% CI: 0.85-1.52) for Met/Met versus Val/Val] or HA [SMD = 0.11 (95% CI: -0.19, 0.42) for Met/Met vs. Val/Val]. The low number of studies on this topic and their limited sample size, along with the inner limits in the definition of anxiety phenotypes, suggest caution in the interpretation of these results. Larger additional studies possibly investigating the interaction with other genes and environmental exposures are required to confirm these results. 2008 S. Karger AG, Basel.

  6. The BDNF Val66Met Polymorphism Influences Reading Ability and Patterns of Neural Activation in Children

    PubMed Central

    Jasińska, Kaja K.; Molfese, Peter J.; Kornilov, Sergey A.; Mencl, W. Einar; Frost, Stephen J.; Lee, Maria; Pugh, Kenneth R.; Grigorenko, Elena L.; Landi, Nicole

    2016-01-01

    Understanding how genes impact the brain’s functional activation for learning and cognition during development remains limited. We asked whether a common genetic variant in the BDNF gene (the Val66Met polymorphism) modulates neural activation in the young brain during a critical period for the emergence and maturation of the neural circuitry for reading. In animal models, the bdnf variation has been shown to be associated with the structure and function of the developing brain and in humans it has been associated with multiple aspects of cognition, particularly memory, which are relevant for the development of skilled reading. Yet, little is known about the impact of the Val66Met polymorphism on functional brain activation in development, either in animal models or in humans. Here, we examined whether the BDNF Val66Met polymorphism (dbSNP rs6265) is associated with children’s (age 6–10) neural activation patterns during a reading task (n = 81) using functional magnetic resonance imaging (fMRI), genotyping, and standardized behavioral assessments of cognitive and reading development. Children homozygous for the Val allele at the SNP rs6265 of the BDNF gene outperformed Met allele carriers on reading comprehension and phonological memory, tasks that have a strong memory component. Consistent with these behavioral findings, Met allele carriers showed greater activation in reading–related brain regions including the fusiform gyrus, the left inferior frontal gyrus and left superior temporal gyrus as well as greater activation in the hippocampus during a word and pseudoword reading task. Increased engagement of memory and spoken language regions for Met allele carriers relative to Val/Val homozygotes during reading suggests that Met carriers have to exert greater effort required to retrieve phonological codes. PMID:27551971

  7. The BDNF Val66Met Polymorphism Influences Reading Ability and Patterns of Neural Activation in Children.

    PubMed

    Jasińska, Kaja K; Molfese, Peter J; Kornilov, Sergey A; Mencl, W Einar; Frost, Stephen J; Lee, Maria; Pugh, Kenneth R; Grigorenko, Elena L; Landi, Nicole

    2016-01-01

    Understanding how genes impact the brain's functional activation for learning and cognition during development remains limited. We asked whether a common genetic variant in the BDNF gene (the Val66Met polymorphism) modulates neural activation in the young brain during a critical period for the emergence and maturation of the neural circuitry for reading. In animal models, the bdnf variation has been shown to be associated with the structure and function of the developing brain and in humans it has been associated with multiple aspects of cognition, particularly memory, which are relevant for the development of skilled reading. Yet, little is known about the impact of the Val66Met polymorphism on functional brain activation in development, either in animal models or in humans. Here, we examined whether the BDNF Val66Met polymorphism (dbSNP rs6265) is associated with children's (age 6-10) neural activation patterns during a reading task (n = 81) using functional magnetic resonance imaging (fMRI), genotyping, and standardized behavioral assessments of cognitive and reading development. Children homozygous for the Val allele at the SNP rs6265 of the BDNF gene outperformed Met allele carriers on reading comprehension and phonological memory, tasks that have a strong memory component. Consistent with these behavioral findings, Met allele carriers showed greater activation in reading-related brain regions including the fusiform gyrus, the left inferior frontal gyrus and left superior temporal gyrus as well as greater activation in the hippocampus during a word and pseudoword reading task. Increased engagement of memory and spoken language regions for Met allele carriers relative to Val/Val homozygotes during reading suggests that Met carriers have to exert greater effort required to retrieve phonological codes.

  8. 5. VAL CAMERA CAR, DETAIL OF HOIST AT SIDE OF ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    5. VAL CAMERA CAR, DETAIL OF HOIST AT SIDE OF BRIDGE AND ENGINE CAR ON TRACKS, LOOKING NORTHEAST. - Variable Angle Launcher Complex, Camera Car & Track, CA State Highway 39 at Morris Reservior, Azusa, Los Angeles County, CA

  9. 21. VAL, DETAIL OF MUZZLE END OF LAUNCHER BRIDGE SHOWING ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    21. VAL, DETAIL OF MUZZLE END OF LAUNCHER BRIDGE SHOWING BOTH LAUNCHER TUBES TAKEN FROM RESERVOIR LOOKING NORTH. - Variable Angle Launcher Complex, Variable Angle Launcher, CA State Highway 39 at Morris Reservior, Azusa, Los Angeles County, CA

  10. 32. VAL, DETAIL SHOWING LOADING PLATFORM, PROJECTILE LOADING CAR, LAUNCHER ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    32. VAL, DETAIL SHOWING LOADING PLATFORM, PROJECTILE LOADING CAR, LAUNCHER SLAB AND UNDERSIDE OF LAUNCHER BRIDGE LOOKING SOUTHWEST. - Variable Angle Launcher Complex, Variable Angle Launcher, CA State Highway 39 at Morris Reservior, Azusa, Los Angeles County, CA

  11. Brain-Derived Neurotrophic Factor Val66Met Human Polymorphism Impairs the Beneficial Exercise-Induced Neurobiological Changes in Mice

    PubMed Central

    Ieraci, Alessandro; Madaio, Alessandro I; Mallei, Alessandra; Lee, Francis S; Popoli, Maurizio

    2016-01-01

    Several studies have shown that exercise improves cognitive functions and emotional behaviors. Positive effects of exercise have been associated with enhanced brain plasticity, adult hippocampal neurogenesis, and increased levels of brain-derived neurotrophic factor (BDNF). However, a substantial variability of individual response to exercise has been described, which may be accounted for by individual genetic variants. Here, we have assessed whether and how the common human BDNF Val66Met polymorphism influences the neurobiological effects modulated by exercise in BDNF Val66Met knock-in male mice. Wild-type (BDNFVal/Val) and homozygous BDNF Val66Met (BDNFMet/Met) male mice were housed in cages equipped with or without running wheels for 4 weeks. Changes in behavioral phenotype, hippocampal adult neurogenesis, and gene expression were evaluated in exercised and sedentary control mice. We found that exercise reduced the latency to feed in the novelty suppressed feeding and the immobility time in the forced swimming test in BDNFVal/Val but not in BDNFMet/Met mice. Hippocampal neurogenesis was reduced in BDNFMet/Met mice compared with BDNFVal/Val mice. BDNFMet/Met mice had lower basal BDNF protein levels in the hippocampus, which was not recovered following exercise. Moreover, exercise-induced expression of total BDNF, BDNF splice variants 1, 2, 4, 6 and fibronectin type III domain-containing protein 5 (FNDC5) mRNA levels were absent or reduced in the dentate gyrus of BDNFMet/Met mice. Exercise failed to enhance PGC-1α and FNDC5 mRNA levels in the BDNFMet/Met muscle. Overall these results indicate that, in adult male mice, the BDNF Val66Met polymorphism impairs the beneficial behavioral and neuroplasticity effects induced by physical exercise. PMID:27388329

  12. 2. VAL CAMERA CAR, VIEW OF CAMERA CAR AND TRACK ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    2. VAL CAMERA CAR, VIEW OF CAMERA CAR AND TRACK WITH CAMERA STATION ABOVE LOOKING WEST TAKEN FROM RESERVOIR. - Variable Angle Launcher Complex, Camera Car & Track, CA State Highway 39 at Morris Reservior, Azusa, Los Angeles County, CA

  13. 27. VAL, DETAIL OF LAUNCHER SLAB AND LAUNCHER RAIL WITH ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    27. VAL, DETAIL OF LAUNCHER SLAB AND LAUNCHER RAIL WITH 7 INCH DIAMETER HOLE FOR SUPPORT CARRIAGE LOCKING PIN. - Variable Angle Launcher Complex, Variable Angle Launcher, CA State Highway 39 at Morris Reservior, Azusa, Los Angeles County, CA

  14. The BDNF Val66Met polymorphism: relation to familiar risk of affective disorder, BDNF levels and salivary cortisol.

    PubMed

    Vinberg, Maj; Trajkovska, Viktorija; Bennike, Bente; Knorr, Ulla; Knudsen, Gitte M; Kessing, Lars V

    2009-10-01

    Brain-derived neurotrophic factor (BDNF) and the hypothalamic-pituitary-adrenal (HPA) axis are considered to play an important role in the pathophysiology of affective disorders. The aim of the present study was to investigate whether the BDNF Val66Met polymorphism is associated with a familiar risk of affective disorder and whether these genotypes affect whole blood BDNF level and salivary cortisol. In a high-risk study, healthy monozygotic and dizygotic twins with and without a co-twin (high- and low-risk twins, respectively) history of affective disorder were identified through nationwide registers. Familiar predisposition to unipolar and bipolar disorder was not associated with any specific genotype pattern of the BDNF Val66Met polymorphism, not in this sample of 124 val/val, 58 val/met and 8 met/met individuals. However, the combination of having a high familiar risk of affective disorder and the met allele was associated with a higher whole blood BDNF (p=0.02) and a higher evening cortisol level (p=0.01), but not with awakening cortisol. Individuals at high risk of affective disorders and who are carriers of the met allele of the Val66Met polymorphism may present with an enhanced stress response. The presence of a specific genotype alone may not enhance the risk of developing an affective episode. Rather, the altered stress response may be expressed only in combination with other risk variants through interactions with the environment.

  15. Analysts guide: TreeVal for Windows, Version 2.0.

    Treesearch

    R.D. Fight; J.T. Chmelik; E.A. Coulter

    2001-01-01

    TreeVal for Windows provides financial information and analysis to support silvicultural decisions in coast Douglas-fir (Pseudotsuga menziesii (Mirb.) Franco). It integrates the effect of growth and yield, management costs, harvesting costs, product and mill type, manufacturing costs, product prices, and product grade premiums. Output files from...

  16. The roles of COMT val158met status and aviation expertise in flight simulator performance and cognitive ability.

    PubMed

    Kennedy, Q; Taylor, J L; Noda, A; Adamson, M; Murphy, G M; Zeitzer, J M; Yesavage, J A

    2011-09-01

    The polymorphic variation in the val158met position of the catechol-O-methyltransferase (COMT) gene is associated with differences in executive performance, processing speed, and attention. The purpose of this study is: (1) replicate previous COMT val158met findings on cognitive performance; (2) determine whether COMT val158met effects extend to a real-world task, aircraft navigation performance in a flight simulator; and (3) determine if aviation expertise moderates any effect of COMT val158met status on flight simulator performance. One hundred seventy two pilots aged 41-69 years, who varied in level of aviation training and experience, completed flight simulator, cognitive, and genetic assessments. Results indicate that although no COMT effect was found for an overall measure of flight performance, a positive effect of the met allele was detected for two aspects of cognitive ability: executive functioning and working memory performance. Pilots with the met/met genotype benefited more from increased levels of expertise than other participants on a traffic avoidance measure, which is a component of flight simulator performance. These preliminary results indicate that COMT val158met polymorphic variation can affect a real-world task.

  17. The Roles of COMT val158met Status and Aviation Expertise in Flight Simulator Performance and Cognitive Ability

    PubMed Central

    Taylor, J. L.; Noda, A.; Adamson, M.; Murphy, G. M.; Zeitzer, J. M.; Yesavage, J. A.

    2011-01-01

    The polymorphic variation in the val158met position of the catechol-O-methyltransferase (COMT) gene is associated with differences in executive performance, processing speed, and attention. The purpose of this study is: (1) replicate previous COMT val158met findings on cognitive performance; (2) determine whether COMT val158met effects extend to a real-world task, aircraft navigation performance in a flight simulator; and (3) determine if aviation expertise moderates any effect of COMT val158met status on flight simulator performance. One hundred seventy two pilots aged 41–69 years, who varied in level of aviation training and experience, completed flight simulator, cognitive, and genetic assessments. Results indicate that although no COMT effect was found for an overall measure of flight performance, a positive effect of the met allele was detected for two aspects of cognitive ability: executive functioning and working memory performance. Pilots with the met/met genotype benefited more from increased levels of expertise than other participants on a traffic avoidance measure, which is a component of flight simulator performance. These preliminary results indicate that COMT val158met polymorphic variation can affect a real-world task. PMID:21193954

  18. Effects of Mind-Body Training on Personality and Behavioral Activation and Inhibition System According to BDNF Val66Met Polymorphism.

    PubMed

    Jung, Ye-Ha; Lee, Ul Soon; Jang, Joon Hwan; Kang, Do-Hyung

    2016-05-01

    It has been known that mind-body training (MBT) can affect personality and behavior system as well as emotional well-being, but different effects of MBT on them has not been reported according to BDNF genetic polymorphism. Healthy subjects consisted of 64 subjects and the MBT group who practiced meditation regularly consisted of 72 practitioners. Participants completed neuroticism-extraversion-openness (NEO) Five-Factor Inventory and Behavioral Activation System/Behavioral Inhibition System (BAS/BIS) scales. All subjects were genotyped for the BDNF Val66Met polymorphism. In the same genotypes of the BDNF Val/Val+Val/Met group, MBT group showed the increased Extraversion (p=0.033) and the increased Openness to Experience (p=0.004) compared to the control group. Also, in the same Met/Met carriers, MBT group exhibited the increase of Extraversion (p=0.008), the reduction of Neuroticism (p=0.002), and the increase of Openness to Experience (p=0.008) compared to the control group. In the same genotypes of the BDNF Val/Val+Val/Met group, MBT group showed the decreased BAS-Reward Responsiveness (p=0.016) and the decrease of BIS (p=0.004) compared to the control group. In the BDNF Met/Met group, MBT group increased BAS-Fun Seeking (p=0.045) and decreased BIS (p=0.013) compared to the control group. MBT would differently contribute to NEO personality and BAS/BIS according to BDNF genetic polymorphism, compensating for different vulnerable traits based on each genotype.

  19. Executive control in schizophrenia: a preliminary study on the moderating role of COMT Val158Met for comorbid alcohol and substance use disorders.

    PubMed

    Carrà, Giuseppe; Nicolini, Gabriella; Crocamo, Cristina; Lax, Annamaria; Amidani, Francesca; Bartoli, Francesco; Castellano, Filippo; Chiorazzi, Alessia; Gamba, Giulia; Papagno, Costanza; Clerici, Massimo

    2017-07-01

    A functional polymorphism in the catechol-O-methyltransferase (COMT) gene (Val158Met) appears to influence cognition in people with alcohol/substance use disorders (AUD/SUD) and in those with psychosis. To explore the potential moderating effect of these factors, a cross-sectional study was conducted, randomly recruiting subjects with DSM-IV diagnosis of schizophrenia. AUD/SUD was rigorously assessed, as well as COMT Val158Met polymorphism. Executive control functioning was measured using the Intra-Extra Dimensional Set Shift (IED). The effect of a possible interaction between comorbid AUD/SUD and COMT Val158Met polymorphism on IED scores was explored. Subjects with schizophrenia, comorbid AUD/SUD, and MetMet carriers for SNP rs4680 of the COMT gene showed worse performance on IED completed stages scores, as compared with individuals with ValVal genotype. However, among subjects without AUD/SUD, those with the MetMet variant performed better than people carrying ValVal genotype. This study is the first to date examining the impact of COMT on cognition in a highly representative sample of people with schizophrenia and comorbid AUD/SUD. Differential moderating effects of COMT Val/Met genotype variations may similarly influence executive functions in people with schizophrenia and comorbid AUD/SUD.

  20. 34. VAL, DETAIL OF STAIRS ON COUNTERWEIGHT SLAB WITH COUNTERWEIGHT ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    34. VAL, DETAIL OF STAIRS ON COUNTERWEIGHT SLAB WITH COUNTERWEIGHT CAR RAILS ON RIGHT AND PERSONNEL CAR RAILS ON LEFT. - Variable Angle Launcher Complex, Variable Angle Launcher, CA State Highway 39 at Morris Reservior, Azusa, Los Angeles County, CA

  1. MTHFR-Ala222Val and male infertility: a study in Iranian men, an updated meta-analysis and an in silico-analysis.

    PubMed

    Nikzad, Hossein; Karimian, Mohammad; Sareban, Kobra; Khoshsokhan, Maryam; Hosseinzadeh Colagar, Abasalt

    2015-11-01

    Methylenetetrahydrofolate reductase (MTHFR) functions as a main regulatory enzyme in folate metabolism. The association of MTHFR gene Ala222Val polymorphism with male infertility in an Iranian population was investigated by undertaking a meta-analysis and in-silico approach. A genetic association study included 497 men; 242 had unexplained infertility and 255 were healthy controls. Polymerase chain reaction restriction fragment length polymorphism was used for genotyping MTHFR-Ala222Val. OpenMeta[Analyst] software was used to conduct the analysis; 22 studies were identified by searching PubMed and the currently reported genetic association study. A novel in-silico approach was used to analyse the effects of Ala222Val substitution on the structure of mRNA and protein. Genetic association study revealed a significant association of MTHFR-222Val/Val genotype with oligozoospermia (OR 2.32; 95% CI, 1.12 to 4.78; P = 0.0451) and azoospermia (OR 2.59; 95% CI 1.09 to 6.17; P = 0.0314). Meta-analysis for allelic, dominant and codominant models showed a significant association between Ala222Val polymorphism and the risk of male infertility (P < 0.001). In silico-analysis showed MTHFR-Ala222Val affects enzyme structure and could also change the mRNA properties (P = 0.1641; P < 0.2 is significant). The meta-analysis suggested significant association of MTHFR-Ala222Val with risk of male infertility, especially in Asian populations. Copyright © 2015 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

  2. An isotope-dilution UPLC-MS/MS technique for the human biomonitoring of the internal exposure to glycidol via a valine adduct at the N-terminus of hemoglobin.

    PubMed

    Hielscher, Jan; Monien, Bernhard H; Abraham, Klaus; Jessel, Sönke; Seidel, Albrecht; Lampen, Alfonso

    2017-08-01

    Fatty acid esters of glycidol (glycidyl esters) are processing contaminants generated as a byproduct of the industrial deodorization of vegetable oils and fats. Oral intake of glycidyl esters leads to the release of glycidol in the gastrointestinal tract. Glycidol is carcinogenic, genotoxic and teratogenic in rodents. It is rated as probably carcinogenic to humans (IARC group 2A). The determination of internal exposure of glycidol may support the assessment of the possible human health risks related to glycidyl ester intake. For this purpose, hemoglobin adducts of glycidol may be suitable biomarkers reflecting the cumulative exposure of up to four months. We applied a modified Edman degradation to assess the glycidol adduct at the N-terminal valine, N-(2,3-dihydroxypropyl)-valine (2,3-diHOPr-Val), of hemoglobin. The modified valine was cleaved with fluorescein-5-isothiocyanate (FITC), resulting in the formation of N-(2,3-dihydroxypropyl)-valine fluorescein thiohydantoin (DHP-Val-FTH). An isotope-dilution technique was developed for the quantification of the thiohydantoin analyte by ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and DHP-Val-d 7 -FTH as reference standard. The limit of detection was 4 fmol DHP-Val-FTH per injection corresponding to 0.7pmol 2,3-diHOPr-Val/g hemoglobin. The adduct levels in blood samples of 12 non-smoking participants were in the range of 2.2-4.9pmol 2,3-diHOPr-Val/g hemoglobin. The current work presents the first isotope-dilution technique using UPLC-MS/MS for the quantification of 2,3-diHOPr-Val at the N-terminus of hemoglobin as a sensitive and convenient alternative to earlier GC-MS methods. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Neuroprotective effects of (Val8)GLP-1-Glu-PAL in the MPTP Parkinson's disease mouse model.

    PubMed

    Zhang, YanFang; Chen, YiMei; Li, Lin; Hölscher, Christian

    2015-10-15

    Glucagon-like peptide 1 (GLP-1) is a hormone and a growth factor. GLP-1 mimetics are currently on the market as treatments for type 2 diabetes. They also have shown neuroprotective properties in animal models of neurodegenerative disorders. In addition, the GLP-1 mimetic exendin-4 has shown protective effects in animal models of Parkinson's disease (PD), and a first clinical trial in PD patients showed promising results. (Val8)GLP-1-glu-PAL is a new GLP-1 analogue which has a longer biological half-life than exendin-4. We previously showed that (Val8)GLP-1-glu-PAL has neuroprotective properties. Here we tested the drug in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. MPTP was injected (30mg/kg i.p.) along with (Val8)GLP-1-glu-PAL (25nmol/kg i.p.) once-daily for 8 days. (Val8)GLP-1-glu-PAL showed good effects in preventing the MPTP-induced motor impairment (Rotarod, open field locomotion, swim test), reduction in tyrosine hydroxylase levels (dopamine synthesis) in the substantia nigra, a reduction of activated caspase 3 levels, of TUNEL positive cell numbers, of the pro-apoptotic signaling molecule BAX and an increase in the growth signaling molecule Bcl-2. The results demonstrate that (Val8)GLP-1-glu-PAL shows promise as a novel treatment of PD. Copyright © 2015 Elsevier B.V. All rights reserved.

  4. 33. VAL, DETAIL OF PERSONNEL CAR AT THE TOP OF ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    33. VAL, DETAIL OF PERSONNEL CAR AT THE TOP OF THE COUNTERWEIGHT SLAB WITH THE COUNTERWEIGHT CAR IN DISTANCE LOOKING NORTH. - Variable Angle Launcher Complex, Variable Angle Launcher, CA State Highway 39 at Morris Reservior, Azusa, Los Angeles County, CA

  5. 4. VAL PARTIAL ELEVATION SHOWING LAUNCHER BRIDGE ON SUPPORTS, LAUNCHER ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    4. VAL PARTIAL ELEVATION SHOWING LAUNCHER BRIDGE ON SUPPORTS, LAUNCHER SLAB, SUPPORT CARRIAGE, CONCRETE 'A' FRAME STRUCTURE AND CAMERA TOWER LOOKING SOUTHEAST. - Variable Angle Launcher Complex, Variable Angle Launcher, CA State Highway 39 at Morris Reservior, Azusa, Los Angeles County, CA

  6. Association between Val66Met brain-derived neurotrophic factor (BDNF) gene polymorphism and post-treatment relapse in alcohol dependence.

    PubMed

    Wojnar, Marcin; Brower, Kirk J; Strobbe, Stephen; Ilgen, Mark; Matsumoto, Halina; Nowosad, Izabela; Sliwerska, Elzbieta; Burmeister, Margit

    2009-04-01

    The purpose of this study was to examine relationships between genetic markers of central serotonin (5-HT) and dopamine function, and risk for post-treatment relapse, in a sample of alcohol-dependent patients. The study included 154 patients from addiction treatment programs in Poland, who met DSM-IV criteria for alcohol dependence. After assessing demographics, severity of alcohol use, suicidality, impulsivity, depression, hopelessness, and severity of alcohol use at baseline, patients were followed for approximately 1 year to evaluate treatment outcomes. Genetic polymorphisms in several genes (TPH2, SLC6A4, HTR1A, HTR2A, COMT, and BDNF) were tested as predictors of relapse (defined as any drinking during follow-up) while controlling for baseline measures. Of 154 eligible patients, 123 (80%) completed follow-up and 48% (n = 59) of these individuals relapsed. Patients with the Val allele in the Val66Met BDNF polymorphism and the Met allele in the Val158Met COMT polymorphism were more likely to relapse. Only the BDNF Val/Val genotype predicted post-treatment relapse [odds ratio (OR) = 2.62; p = 0.019], and time to relapse (OR = 2.57; p = 0.002), after adjusting for baseline measures and other significant genetic markers. When the analysis was restricted to patients with a family history of alcohol dependence (n = 73), the associations between the BDNF Val/Val genotype and relapse (OR = 5.76, p = 0.0045) and time to relapse (hazard ratio = 4.93, p = 0.001) were even stronger. The Val66Met BDNF gene polymorphism was associated with a higher risk and earlier occurrence of relapse among patients treated for alcohol dependence. The study suggests a relationship between genetic markers and treatment outcomes in alcohol dependence. Because a large number of statistical tests were conducted for this study and the literature on genetics and relapse is so novel, the results should be considered as hypothesis generating and need to be replicated in independent studies.

  7. Association between Val66Met Brain-Derived Neurotrophic Factor (BDNF) Gene Polymorphism and Post-Treatment Relapse in Alcohol Dependence

    PubMed Central

    Wojnar, Marcin; Brower, Kirk J.; Strobbe, Stephen; Ilgen, Mark; Matsumoto, Halina; Nowosad, Izabela; Sliwerska, Elzbieta; Burmeister, Margit

    2009-01-01

    Background The purpose of this study was to examine relationships between genetic markers of central serotonin and dopamine function, and risk for post-treatment relapse, in a sample of alcohol-dependent patients. Methods The study included 154 patients from addiction treatment programs in Poland, who met DSM-IV criteria for alcohol dependence. After assessing demographics, severity of alcohol use, suicidality, impulsivity, depression, hopelessness, and severity of alcohol use at baseline, patients were followed for approximately one year to evaluate treatment outcomes. Genetic polymorphisms in several genes (TPH2, SLC6A4, HTR1A, HTR2A, COMT, BDNF) were tested as predictors of relapse (defined as any drinking during follow-up) while controlling for baseline measures. Results Of 154 eligible patients, 123 (80%) completed follow-up and 48% (n = 59) of these individuals relapsed. Patients with the Val allele in the Val66Met BDNF polymorphism and the Met allele in the Val158Met COMT polymorphism were more likely to relapse. Only the BDNF Val/Val genotype predicted post-treatment relapse (OR = 2.62; p = 0.019), and time to relapse (OR = 2.57; p = 0.002), after adjusting for baseline measures and other significant genetic markers. When the analysis was restricted to patients with a family history of alcohol dependence (n = 73), the associations between the BDNF Val/Val genotype and relapse (OR = 5.76, p = 0.0045) and time to relapse (HR = 4.93, p = 0.001) were even stronger. Conclusions The Val66Met BDNF gene polymorphism was associated with a higher risk and earlier occurrence of relapse among patients treated for alcohol dependence. The study suggests a relationship between genetic markers and treatment outcomes in alcohol dependence. Because a large number of statistical tests were conducted for this study and the literature on genetics and relapse is so novel, the results should be considered as hypothesis generating and need to be replicated in independent studies

  8. COMT val108/158 met genotype affects neural but not cognitive processing in healthy individuals.

    PubMed

    Dennis, Nancy A; Need, Anna C; LaBar, Kevin S; Waters-Metenier, Sheena; Cirulli, Elizabeth T; Kragel, James; Goldstein, David B; Cabeza, Roberto

    2010-03-01

    The relationship between cognition and a functional polymorphism in the catechol-O-methlytransferase (COMT) gene, val108/158met, is one of debate in the literature. Furthermore, based on the dopaminergic differences associated with the COMT val108/158met genotype, neural differences during cognition may be present, regardless of genotypic differences in cognitive performance. To investigate these issues the current study aimed to 1) examine the effects of COMT genotype using a large sample of healthy individuals (n = 496-1218) and multiple cognitive measures, and using a subset of the sample (n = 22), 2) examine whether COMT genotype effects medial temporal lobe (MTL) and frontal activity during successful relational memory processing, and 3) investigate group differences in functional connectivity associated with successful relational memory processing. Results revealed no significant group difference in cognitive performance between COMT genotypes in any of the 19 cognitive measures. However, in the subset sample, COMT val homozygotes exhibited significantly decreased MTL and increased prefrontal activity during both successful relational encoding and retrieval, and reduced connectivity between these regions compared with met homozygotes. Taken together, the results suggest that although the COMT val108/158met genotype has no effect on cognitive behavioral measures in healthy individuals, it is associated with differences in neural process underlying cognitive output.

  9. The brain-derived neurotrophic factor (BDNF) gene Val66Met polymorphism affects memory performance in older adults.

    PubMed

    Azeredo, Lucas A de; De Nardi, Tatiana; Levandowski, Mateus L; Tractenberg, Saulo G; Kommers-Molina, Julia; Wieck, Andrea; Irigaray, Tatiana Q; Silva, Irênio G da; Grassi-Oliveira, Rodrigo

    2017-01-01

    Memory impairment is an important contributor to the reduction in quality of life experienced by older adults, and genetic risk factors seem to contribute to variance in age-related cognitive decline. Brain-derived neurotrophic factor (BDNF) is an important nerve growth factor linked with development and neural plasticity. The Val66Met polymorphism in the BDNF gene has been associated with impaired episodic memory in adults, but whether this functional variant plays a role in cognitive aging remains unclear. The purpose of this study was to investigate the effects of the BDNF Val66Met polymorphism on memory performance in a sample of elderly adults. Eighty-seven subjects aged > 55 years were recruited using a community-based convenience sampling strategy in Porto Alegre, Brazil. The logical memory subset of the Wechsler Memory Scale-Revised was used to assess immediate verbal recall (IVR), delayed verbal recall (DVR), and memory retention rate. BDNF Met allele carriers had lower DVR scores (p = 0.004) and a decline in memory retention (p = 0.017) when compared to Val/Val homozygotes. However, we found no significant differences in IVR between the two groups (p = 0.088). These results support the hypothesis of the BDNF Val66Met polymorphism as a risk factor associated with cognitive impairment, corroborating previous findings in young and older adults.

  10. The highly selective oxidation of cyclohexane to cyclohexanone and cyclohexanol over VAlPO4 berlinite by oxygen under atmospheric pressure.

    PubMed

    Hong, Yun; Sun, Dalei; Fang, Yanxiong

    2018-04-04

    The oxidation of cyclohexane under mild conditions occupies an important position in the chemical industry. A few soluble transition metals were widely used as homogeneous catalysts in the industrial oxidation of cyclohexane. Because heterogeneous catalysts are more manageable than homogeneous catalysts as regards separation and recycling, in our study, we hydrothermally synthesized and used pure berlinite (AlPO 4 ) and vanadium-incorporated berlinite (VAlPO 4 ) as heterogeneous catalysts in the selective oxidation of cyclohexane with molecular oxygen under atmospheric pressure. The catalysts were characterized by means of by XRD, FT-IR, XPS and SEM. Various influencing factors, such as the kind of solvents, reaction temperature, and reaction time were investigated systematically. The XRD characterization identified a berlinite structure associated with both the AlPO 4 and VAlPO 4 catalysts. The FT-IR result confirmed the incorporation of vanadium into the berlinite framework for VAlPO 4 . The XPS measurement revealed that the oxygen ions in the VAlPO 4 structure possessed a higher binding energy than those in V 2 O 5 , and as a result, the lattice oxygen was existed on the surface of the VAlPO 4 catalyst. It was found that VAlPO 4 catalyzed the selective oxidation of cyclohexane with molecular oxygen under atmospheric pressure, while no activity was detected on using AlPO 4 . Under optimum reaction conditions (i.e. a 100 mL cyclohexane, 0.1 MPa O 2 , 353 K, 4 h, 5 mg VAlPO 4 and 20 mL acetic acid solvent), a selectivity of KA oil (both cyclohexanol and cyclohexanone) up to 97.2% (with almost 6.8% conversion of cyclohexane) was obtained. Based on these results, a possible mechanism for the selective oxidation of cyclohexane over VAlPO 4 was also proposed. As a heterogeneous catalyst VAlPO 4 berlinite is both high active and strong stable for the selective oxidation of cyclohexane with molecular oxygen. We propose that KA oil is formed via a catalytic cycle

  11. 79. VIEW OF VAL FIRING RANGE LOOKING SOUTHWEST SHOWING LAUNCHER ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    79. VIEW OF VAL FIRING RANGE LOOKING SOUTHWEST SHOWING LAUNCHER BRIDGE, BARGES, SONAR BUOY RANGE AND MORRIS DAM IN BACKGROUND, June 10, 1948. - Variable Angle Launcher Complex, Variable Angle Launcher, CA State Highway 39 at Morris Reservior, Azusa, Los Angeles County, CA

  12. 76. FIRST TEST SHOT OF THE VAL AT THE DEDICATION ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    76. FIRST TEST SHOT OF THE VAL AT THE DEDICATION CEREMONIES AS SEEN FROM THE OBSERVATION DECK ABOVE THE CONTROL STATION, May 7, 1948. - Variable Angle Launcher Complex, Variable Angle Launcher, CA State Highway 39 at Morris Reservior, Azusa, Los Angeles County, CA

  13. Modification of depression by COMT val158met polymorphism in children exposed to early severe psychosocial deprivation

    PubMed Central

    Drury, Stacy S; Theall, Katherine P; Smyke, Anna T; Keats, Bronya JB; Egger, Helen L; Nelson, Charles A; Fox, Nathan A; Marshall, Peter J; Zeanah, Charles H

    2014-01-01

    Objective To examine the impact of the Catechol-O-Methyltransferase (COMT) val158met allele on depressive symptoms in young children exposed to early severe social deprivation as a result of being raised in institutions. Methods 136 children from the Bucharest Early Intervention Project (BEIP) were randomized before 31 months of age to either care as usual (CAU) in institutions or placement in newly created foster care (FCG). At 54 months of age, a psychiatric assessment using the Preschool Age Psychiatric Assessment (PAPA) was completed. DNA was collected and genotyped for the COMT val158met polymorphism. Multivariate analysis examined the relationship between COMT alleles and depressive symptoms. Results Mean level of depressive symptoms was lower among participants with the met allele compared to those with two copies of the val allele (p <0.05). Controlling for group and gender, the rate of depressive symptoms was significantly lower among participants with the met/met or the met/val genotype (adjusted relative risk (aRR) = 0.67, 95% CI = 0.45, 0.99) compared to participants with the val/val genotype, indicating an intermediate impact for heterozygotes consistent with the biological impact of this polymorphism. The impact of genotype within groups differed significantly. There was a significant protective effect of the met allele on depressive symptoms within the CAU group, however there was no relationship seen within the FCG group. Conclusions This is the first study, to our knowledge, to find evidence of a gene × environment interaction in the setting of early social deprivation. These results support the hypothesis that individual genetic differences may explain some of the variability in recovery amongst children exposed to early severe social deprivation. PMID:20403637

  14. The BDNF Val66Met polymorphism and plasma brain-derived neurotrophic factor levels in Han Chinese patients with bipolar disorder and schizophrenia.

    PubMed

    Chen, Shiou-Lan; Lee, Sheng-Yu; Chang, Yun-Hsuan; Chen, Shih-Heng; Chu, Chun-Hsien; Wang, Tzu-Yun; Chen, Po-See; Lee, I-Hui; Yang, Yen-Kuang; Hong, Jau-Shyong; Lu, Ru-Band

    2014-06-03

    Brain-derived neurotropic factor (BDNF) is widely distributed in the peripheral and central nervous systems. BDNF and its gene polymorphism may be important in synaptic plasticity and neuron survival, and may become a key target in the physiopathology of several mental illnesses. To elucidate the role of BDNF, we compared the plasma BDNF levels and the BDNF Val66Met gene variants effect in several mental disorders. We enrolled 644 participants: 177 patients with bipolar I disorder (BP-I), 190 with bipolar II disorder (BP-II), 151 with schizophrenia, and 126 healthy controls. Their plasma BDNF levels and BDNF Val66Met single nucleotide polymorphisms (SNP) were checked before pharmacological treatment. Plasma levels of BDNF were significantly lower in patients with schizophrenia than in healthy controls and patients with bipolar disorder (F = 37.667, p<0.001); the distribution of the BDNF Val66Met SNP was not different between groups (χ(2) = 5.289, p = 0.507). Nor were plasma BDNF levels significantly different between Met/Met, Met/Val, and Val/Val carriers in each group, which indicated that the BDNF Val66Met SNP did not influence plasma BDNF levels in our participants. Plasma BDNF levels were, however, significantly negatively correlated with depression scores in patients with bipolar disorder and with negative symptoms in patients with schizophrenia. We conclude that plasma BDNF profiles in different mental disorders are not affected by BDNF Val66Met gene variants, but by the process and progression of the illness itself. Copyright © 2014 Elsevier Inc. All rights reserved.

  15. 30. VAL LOOKING DOWN THE LAUNCHER SLAB STAIRS AT THE ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    30. VAL LOOKING DOWN THE LAUNCHER SLAB STAIRS AT THE PROJECTILE LOADING CAR AND LOADING PLATFORM ADJACENT TO THE PROJECTILE LOADING DECK AND LAUNCHER BRIDGE. - Variable Angle Launcher Complex, Variable Angle Launcher, CA State Highway 39 at Morris Reservior, Azusa, Los Angeles County, CA

  16. Her2 Ile655Val polymorphism and its association with breast cancer risk: an updated meta-analysis of case-control studies.

    PubMed

    Krishna, B Madhu; Chaudhary, Sanjib; Panda, Aditya K; Mishra, Dipti Ranjan; Mishra, Sandip K

    2018-05-09

    Breast cancer (BC) is one of the most common types of cancer in women worldwide. Several factors including genetic and environmental have been linked with susceptibility to development of BC. Her2 is a transmembrane protein with tyrosine kinase activity, overexpressed in several cancers including BC. Various studies in different populations have shown association of Her2 variants with susceptibility to BC, however these results were inconsistent, inconclusive and controversial. To obtain a common conclusive finding, we performed meta-analysis of 35 case-control studies reported earlier including 19, 220 cases and 22, 306 controls. We observed significant association of Her2 Ile 655 Val polymorphism with susceptibility to development of breast cancer (Overall allele Val vs Ile: OR = 1.130, 95% CI = 1.051-1.216, p = 0.001; Ile-Val vs Ile-Ile: OR = 1.100, 95% CI = 1.016-1.192, p = 0.019; Val-Val+Ile-Val vs Ile-Ile: OR = 1.127, 95% CI = 1.038-1.223, p = 0.004). Subgroup analysis indicated a significant association with susceptibility to breast cancer in African and Asian populations. However, such association was not observed in other ethnic groups. Our findings suggested that Her2 Ile 655 Val polymorphism is associated with breast cancer risk in overall, Asian and African populations, and can be used as diagnostic marker for BC.

  17. BDNF Val66Met polymorphism moderates the link between child maltreatment and reappraisal ability.

    PubMed

    Miu, A C; Cărnuţă, M; Vulturar, R; Szekely-Copîndean, R D; Bîlc, M I; Chiş, A; Cioară, M; Fernandez, K C; Szentágotai-Tătar, A; Gross, J J

    2017-04-01

    Child maltreatment is associated with increased risk for virtually all common mental disorders, but it is not yet clear why. One possible mechanism is emotion regulation ability. The present study investigated for the first time the influence of a BDNF Val66Met genotype × child maltreatment interaction on emotion regulation, and compared differential susceptibility and diathesis-stress models. A sample of N = 254 healthy volunteers were genotyped for the BDNF Val66Met polymorphism and underwent an experimental assessment of reappraisal ability (i.e. the success of using reappraisal to downregulate negative affect). A self-report instrument previously validated against a clinical interview was used to investigate child maltreatment. There was a significant BDNF Val66Met genotype × child maltreatment interaction (B = -0.31, P < 0.015), with Met carriers showing both the lowest level of reappraisal ability in maltreated participants, and the highest level of reappraisal ability in non-maltreated participants. By assessing alternative models, we found that the best fitting model was in line with strong differential susceptibility. As expected, reappraisal ability was negatively correlated with depressive symptoms. Therefore, the BDNF Val66Met polymorphism moderates the link between child maltreatment and emotion regulation ability. Future studies could investigate whether improving reappraisal in maltreated BDNF Met carriers results in reduced risk for mental disorders. © 2016 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  18. A comparison of the nutritional quality of organic and conventional ready-to-eat breakfast cereals based on NuVal scores.

    PubMed

    Woodbury, Nancy J; George, Valerie A

    2014-07-01

    To identify whether there were differences in nutritional quality between organic and conventional ready-to-eat breakfast cereals of similar types, based on NuVal scores. The current descriptive study analysed NuVal scores for 829 ready-to-eat breakfast cereals and eighteen different cereal types. ANOVA was used to compare the mean NuVal scores of 723 conventional cereals with those of 106 organic cereals. Ready-to-eat breakfast cereals (n 829) with NuVal scores. Not applicable. There was no significant difference in NuVal scores between conventional (mean 28·4 (sd 13·4)) and organic (mean 30·6 (sd 13·2)) cereal types. Consumers who choose the organic version of a ready-to-eat breakfast cereal believing that nutritional quality is superior may not be making a valid assumption. Public health nutrition educators must help consumers understand that organic cereals are not necessarily more nutritious and their consumption could result in excessive intake of undesirable nutrients, such as fat, sugar and sodium.

  19. Is the Val66Met polymorphism of the brain-derived neurotrophic factor gene associated with panic disorder? A meta-analysis.

    PubMed

    Chen, Kaiyuan; Wang, Na; Zhang, Jie; Hong, Xiaohong; Xu, Haiyun; Zhao, Xiaofeng; Huang, Qingjun

    2017-06-01

    Although emerging evidence has suggested an association between the Val66Met (rs6265) polymorphisms in brain-derived neurotrophic factor (BDNF) gene and the panic disorder, the conclusion is inclusive given the mixed results. This meta-analysis reviewed and analyzed the recent studies addressing the potential association between the Val66Met polymorphisms and panic disorder susceptibility. Related case-control studies were retrieved by database searching and selected according to established inclusion criteria. Six articles were identified, which explored the association between the BDNF Val66Met polymorphism and panic disorder. Statistical analyses revealed no association for the allele contrast and the dominant model. However, the recessive model showed a significant association between the BDNF Val66Met polymorphism and panic disorder (odds ratio = 1.26, 95% confidence interval = 1.04-1.52, z = 2.39, P = 0.02). Despite of some limitations, this meta-analysis suggests that the Val66Met polymorphism of BDNF gene is a susceptibility factor for panic disorder. © 2015 Wiley Publishing Asia Pty Ltd.

  20. BDNF Val66Met polymorphism is associated with higher anticipatory cortisol stress response, anxiety, and alcohol consumption in healthy adults.

    PubMed

    Colzato, Lorenza S; Van der Does, A J Willem; Kouwenhoven, Coen; Elzinga, Bernet M; Hommel, Bernhard

    2011-11-01

    The brain-derived neurotrophic factor (BDNF) is a key protein in maintaining neuronal integrity. The BDNF gene is thought to play an important role in the pathophysiology of mood and anxiety disorders. The aim of this study was to investigate, for the first time in a single study, the association between BDNF Val(66)Met polymorphism, anxiety, alcohol consumption, and cortisol stress response. 98 healthy university students (54 females and 44 males), genotyped for the Val(66)Met polymorphism, participated in a physical-stress procedure (cold pressure test, CPT) after having been informed that they would undergo a painful experience. Indices of anxiety and of stress were collected from repeated measurement of salivary cortisol, blood pressure, and heart rate. BDNF Met carriers, were more anxious during the CPT (p<0.001), drank more alcohol per week, (p<0.05), and showed significantly higher anticipatory cortisol response (p<0.05), but not in response to the CPT, than Val/Val homozygotes. The association of BDNF Val(66)Met polymorphism with HPA axis reactivity to stress was not modulated by gender. These results suggest that Met carriers are particularly sensitive in anticipating stressful events, which extends previous findings on the moderating role of the BDNF Val(66)Met polymorphism in the face of stressful life events. Copyright © 2011 Elsevier Ltd. All rights reserved.

  1. The COMT Val/Met polymorphism modulates effects of tDCS on response inhibition.

    PubMed

    Nieratschker, Vanessa; Kiefer, Christoph; Giel, Katrin; Krüger, Rejko; Plewnia, Christian

    2015-01-01

    Transcranial direct current stimulation (tDCS) is increasingly discussed as a new option to support the cognitive rehabilitation in neuropsychiatric disorders. However, the therapeutic impact of tDCS is limited by high inter-individual variability. Genetic factors most likely contribute to this variability by modulating the effects of tDCS. We aimed to investigate the influence of the COMT Val(108/158)Met polymorphism on cathodal tDCS effects on executive functioning. Cathodal tDCS was applied to the left dorsolateral prefrontal cortex (dlPFC) during the performance of a parametric Go/No-Go test. We demonstrate an impairing effect of cathodal tDCS to the dlPFC on response inhibition. This effect was only found in individuals homozygous for the Val-allele of the COMT Val(108/158)Met polymorphism. No effects of stimulation on executive functions in Met-allele carriers were detected. Our data indicate that i) cathodal, excitability reducing tDCS, interferes with inhibitory cognitive control, ii) the left dlPFC is critically involved in the neuronal network underlying the control of response inhibition, and iii) the COMT Val(108/158)Met polymorphism modulates the impact of cathodal tDCS on inhibitory control. Together with our previous finding that anodal tDCS selectively impairs set-shifting abilities in COMT Met/Met homozygous individuals, these results indicate that genetic factors modulate effects of tDCS on cognitive performance. Therefore, future tDCS research should account for genetic variability in the design and analysis of neurocognitive as well as therapeutic applications to reduce the variability of results and facilitate individualized neurostimulation approaches. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. 54. VAL COUNTERWEIGHT CAR DURING CONSTRUCTION SHOWING CAR FRAME, WHEEL ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    54. VAL COUNTERWEIGHT CAR DURING CONSTRUCTION SHOWING CAR FRAME, WHEEL ASSEMBLIES AND METAL REINFORCING, December 19, 1947. (Original photograph in possession of Dave Willis, San Diego, California.) - Variable Angle Launcher Complex, Variable Angle Launcher, CA State Highway 39 at Morris Reservior, Azusa, Los Angeles County, CA

  3. Cerebellar transcranial direct current stimulation interacts with BDNF Val66Met in motor learning.

    PubMed

    van der Vliet, Rick; Jonker, Zeb D; Louwen, Suzanne C; Heuvelman, Marco; de Vreede, Linda; Ribbers, Gerard M; De Zeeuw, Chris I; Donchin, Opher; Selles, Ruud W; van der Geest, Jos N; Frens, Maarten A

    2018-04-11

    Cerebellar transcranial direct current stimulation has been reported to enhance motor associative learning and motor adaptation, holding promise for clinical application in patients with movement disorders. However, behavioral benefits from cerebellar tDCS have been inconsistent. Identifying determinants of treatment success is necessary. BDNF Val66Met is a candidate determinant, because the polymorphism is associated with motor skill learning and BDNF is thought to mediate tDCS effects. We undertook two cerebellar tDCS studies in subjects genotyped for BDNF Val66Met. Subjects performed an eyeblink conditioning task and received sham, anodal or cathodal tDCS (N = 117, between-subjects design) or a vestibulo-ocular reflex adaptation task and received sham and anodal tDCS (N = 51 subjects, within-subjects design). Performance was quantified as a learning parameter from 0 to 100%. We investigated (1) the distribution of the learning parameter with mixture modeling presented as the mean (M), standard deviation (S) and proportion (P) of the groups, and (2) the role of BDNF Val66Met and cerebellar tDCS using linear regression presented as the regression coefficients (B) and odds ratios (OR) with equally-tailed intervals (ETIs). For the eyeblink conditioning task, we found distinct groups of learners (M Learner  = 67.2%; S Learner  = 14.7%; P Learner  = 61.6%) and non-learners (M Non-learner  = 14.2%; S Non-learner  = 8.0%; P Non-learner  = 38.4%). Carriers of the BDNF Val66Met polymorphism were more likely to be learners (OR = 2.7 [1.2 6.2]). Within the group of learners, anodal tDCS supported eyeblink conditioning in BDNF Val66Met non-carriers (B = 11.9% 95%ETI = [0.8 23.0]%), but not in carriers (B = 1.0% 95%ETI = [-10.2 12.1]%). For the vestibulo-ocular reflex adaptation task, we found no effect of BDNF Val66Met (B = -2.0% 95%ETI = [-8.7 4.7]%) or anodal tDCS in either carriers (B = 3.4% 95%ETI = [-3

  4. Mastocytosis in mice expressing human Kit receptor with the activating Asp816Val mutation

    PubMed Central

    Zappulla, Jacques P.; Dubreuil, Patrice; Desbois, Sabine; Létard, Sébastien; Hamouda, Nadine Ben; Daëron, Marc; Delsol, Georges; Arock, Michel; Liblau, Roland S.

    2005-01-01

    Mastocytosis is a rare neoplastic disease characterized by a pathologic accumulation of tissue mast cells (MCs). Mastocytosis is often associated with a somatic point mutation in the Kit protooncogene leading to an Asp/Val substitution at position 816 in the kinase domain of this receptor. The contribution of this mutation to mastocytosis development remains unclear. In addition, the clinical heterogeneity presented by mastocytosis patients carrying the same mutation is unexplained. We report that a disease with striking similarities to human mastocytosis develops spontaneously in transgenic mice expressing the human Asp816Val mutant Kit protooncogene specifically in MCs. This disease is characterized by clinical signs ranging from a localized and indolent MC hyperplasia to an invasive MC tumor. In addition, bone marrow–derived MCs from transgenic animals can be maintained in culture for >24 mo and acquire growth factor independency for proliferation. These results demonstrate a causal link in vivo between the Asp816Val Kit mutation and MC neoplasia and suggest a basis for the clinical heterogeneity of human mastocytosis. PMID:16352739

  5. Enhanced extinction of cocaine seeking in brain-derived neurotrophic factor Val66Met knock-in mice.

    PubMed

    Briand, Lisa A; Lee, Francis S; Blendy, Julie A; Pierce, R Christopher

    2012-03-01

    The Val66Met polymorphism in the brain-derived neurotropic factor (BDNF) gene results in alterations in fear extinction behavior in both human populations and mouse models. However, it is not clear whether this polymorphism plays a similar role in extinction of appetitive behaviors. Therefore, we examined operant learning and extinction of both food and cocaine self-administration behavior in an inbred genetic knock-in mouse strain expressing the variant Bdnf. These mice provide a unique opportunity to relate alterations in aversive and appetitive extinction learning as well as provide insight into how human genetic variation can lead to differences in behavior. BDNF(Met/Met) mice exhibited a severe deficit in operant learning as demonstrated by an inability to learn the food self-administration task. Therefore, extinction experiments were performed comparing wildtype (BDNF(Val/Val) ) animals to mice heterozygous for the Met allele (BDNF(Val/Met) ), which did not differ in food or cocaine self-administration behavior. In contrast to the deficit in fear extinction previously demonstrated in these mice, we found that BDNF(Val/Met) mice exhibited more rapid extinction of cocaine responding compared to wildtype mice. No differences were found between the genotypes in the extinction of food self-administration behavior or the reinstatement of cocaine seeking, indicating that the effect is specific to extinction of cocaine responding. These results suggest that the molecular mechanisms underlying aversive and appetitive extinction are distinct from one another and BDNF may play opposing roles in the two phenomena. © 2012 The Authors. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

  6. 22. VAL, VIEW OF PROJECTILE LOADING DECK LOOKING NORTHEAST TOWARD ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    22. VAL, VIEW OF PROJECTILE LOADING DECK LOOKING NORTHEAST TOWARD TOP OF CONCRETE 'A' FRAME STRUCTURE SHOWING DRIVE CABLES, DRIVE GEAR, BOTTOM OF CAMERA TOWER AND 'CROWS NEST' CONTROL ROOM. - Variable Angle Launcher Complex, Variable Angle Launcher, CA State Highway 39 at Morris Reservior, Azusa, Los Angeles County, CA

  7. Val66Met polymorphism of BDNF alters prodomain structure to induce neuronal growth cone retraction.

    PubMed

    Anastasia, Agustin; Deinhardt, Katrin; Chao, Moses V; Will, Nathan E; Irmady, Krithi; Lee, Francis S; Hempstead, Barbara L; Bracken, Clay

    2013-01-01

    A common single-nucleotide polymorphism (SNP) in the human brain-derived neurotrophic factor (BDNF) gene results in a Val66Met substitution in the BDNF prodomain region. This SNP is associated with alterations in memory and with enhanced risk to develop depression and anxiety disorders in humans. Here we show that the isolated BDNF prodomain is detected in the hippocampus and that it can be secreted from neurons in an activity-dependent manner. Using nuclear magnetic resonance spectroscopy and circular dichroism, we find that the prodomain is intrinsically disordered, and the Val66Met substitution induces structural changes. Surprisingly, application of Met66 (but not Val66) BDNF prodomain induces acute growth cone retraction and a decrease in Rac activity in hippocampal neurons. Expression of p75(NTR) and differential engagement of the Met66 prodomain to the SorCS2 receptor are required for this effect. These results identify the Met66 prodomain as a new active ligand, which modulates neuronal morphology.

  8. Val66Met Polymorphism of BDNF Alters Prodomain Structure to Induce Neuronal Growth Cone Retraction

    PubMed Central

    Anastasia, Agustin; Deinhardt, Katrin; Chao, Moses V.; Will, Nathan E.; Irmady, Krithi; Lee, Francis S.; Hempstead, Barbara L.; Bracken, Clay

    2013-01-01

    A common single-nucleotide polymorphism in the human brain-derived neurotrophic factor (BDNF) gene results in a Val66Met substitution in the BDNF prodomain region. This single-nucleotide polymorphism is associated with alterations in memory and with enhanced risk to develop depression and anxiety disorders in humans. Here we show that the isolated BDNF prodomain is detected in the hippocampus and that it can be secreted from neurons in an activity-dependent manner. Using nuclear magnetic resonance spectroscopy and circular dichroism we find that the prodomain is intrinsically disordered, and the Val66Met substitution induces structural changes. Surprisingly, application of Met66 (but not Val66) BDNF prodomain induces acute growth cone retraction and a decrease in Rac activity in hippocampal neurons. Expression of p75NTR and differential engagement of the Met66 prodomain to the SorCS2 receptor are required for this effect. These results identify the Met66 prodomain as a new active ligand which modulates neuronal morphology. PMID:24048383

  9. Differential Effects of the Catechol-O-Methyltransferase Val158Met Genotype on the Cognitive Function of Schizophrenia Patients and Healthy Japanese Individuals

    PubMed Central

    Tsuchimine, Shoko; Yasui-Furukori, Norio; Kaneda, Ayako; Kaneko, Sunao

    2013-01-01

    Background The functional polymorphism Val158Met in the catechol-O-methyltransferase (COMT) gene has been associated with differences in prefrontal cognitive functions in patients with schizophrenia and healthy individuals. Several studies have indicated that the Met allele is associated with better performance on measures of cognitive function. We investigated whether the COMT Val158Met genotype was associated with cognitive function in 149 healthy controls and 118 patients with schizophrenia. Methods Cognitive function, including verbal memory, working memory, motor speed, attention, executive function and verbal fluency, was assessed by the Brief Assessment of Cognition in Schizophrenia (BACS-J). We employed a one-way analysis of variance (ANOVA) and a multiple regression analysis to determine the associations between the COMT Val158Met genotype and the BACS-J measurements. Results The one-way ANOVA revealed a significant difference in the scores on the Tower of London, a measure of executive function, between the different Val158Met genotypes in the healthy controls (p = 0.023), and a post-hoc analysis showed significant differences between the scores on the Tower of London in the val/val genotype group (18.6 ± 2.4) compared to the other two groups (17.6 ± 2.7 for val/met and 17.1 ± 3.2 for met/met; p = 0.027 and p = 0.024, respectively). Multiple regression analyses revealed that executive function was significantly correlated with the Val158Met genotype (p = 0.003). However, no evidence was found for an effect of the COMT on any cognitive domains of the BACS-J in the patients with schizophrenia. Conclusion These data support the hypothesis that the COMT Val158Met genotype maintains an optimal level of dopamine activity. Further studies should be performed that include a larger sample size and include patients on and off medication, as these patients would help to confirm our findings. PMID:24282499

  10. The BDNF-Val66Met polymorphism modulates parental rearing effects on adult psychiatric symptoms: a community twin-based study.

    PubMed

    Ibarra, P; Alemany, S; Fatjó-Vilas, M; Córdova-Palomera, A; Goldberg, X; Arias, B; González-Ortega, I; González-Pinto, A; Nenadic, I; Fañanás, L

    2014-06-01

    To test whether firstly, different parental rearing components were associated with different dimensions of psychiatric symptoms in adulthood, secondly BDNF-Val66Met polymorphism moderated this association and thirdly, this association was due to genetic confounding. Perceived parental rearing according to Parental Bonding Instrument (PBI), psychiatric symptoms evaluated with the Brief Symptom Inventory (BSI) and the BDNF-Val66Met polymorphism were analyzed in a sample of 232 adult twins from the general population. In the whole sample, paternal care was negatively associated with depression. Maternal overprotection was positively associated with paranoid ideation, obsession-compulsion and somatization. Gene-environment interaction effects were detected between the BDNF-Val66Met polymorphism and maternal care on phobic anxiety, paternal care on hostility, maternal overprotection on somatization and paternal overprotection also in somatization. In the subsample of MZ twins, intrapair differences in maternal care were associated with anxiety, paranoid ideation and somatization. Met carriers were, in general, more sensitive to the effects of parental rearing compared to Val/Val carriers in relation to anxiety and somatization. Contra-intuitively, our findings suggest that high rates of maternal care might be of risk for Met carriers regarding anxiety. Results from analyses controlling for genetic confounding were in line with this finding. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  11. Effects of the BDNF Val66Met polymorphism on neural responses to facial emotion.

    PubMed

    Mukherjee, Prerona; Whalley, Heather C; McKirdy, James W; McIntosh, Andrew M; Johnstone, Eve C; Lawrie, Stephen M; Hall, Jeremy

    2011-03-31

    The brain derived neurotrophic factor (BDNF) Val66Met polymorphism has been associated with affective disorders, but its role in emotion processing has not been fully established. Due to the clinically heterogeneous nature of these disorders, studying the effect of genetic variation in the BDNF gene on a common attribute such as fear processing may elucidate how the BDNF Val66Met polymorphism impacts brain function. Here we use functional magnetic resonance imaging examine the effect of the BDNF Val66Met genotype on neural activity for fear processing. Forty healthy participants performed an implicit fear task during scanning, where subjects made gender judgments from facial images with neutral or fearful emotion. Subjects were tested for facial emotion recognition post-scan. Functional connectivity was investigated using psycho-physiological interactions. Subjects were genotyped for the BDNF Val66Met polymorphism and the measures compared between genotype groups. Met carriers showed overactivation in the anterior cingulate cortex (ACC), brainstem and insula bilaterally for fear processing, along with reduced functional connectivity from the ACC to the left hippocampus, and impaired fear recognition ability. The results show that during fear processing, Met allele carriers show an increased neural response in regions previously implicated in mediating autonomic arousal. Further, the Met carriers show decreased functional connectivity with the hippocampus, which may reflect differential retrieval of emotional associations. Together, these effects show significant differences in the neural substrate for fear processing with genetic variation in BDNF. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  12. Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and post-stroke dementia: a hospital-based study from northern Iran.

    PubMed

    Rezaei, Sajjad; Asgari Mobarake, Karim; Saberi, Alia; Keshavarz, Parvaneh; Leili, Ehsan Kazemnejad

    2016-06-01

    Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is associated with functional and cognitive outcomes of stroke and plays a key role in preventing neuronal death. This study aimed to answer the following question: does BDNF Val66Met polymorphism prognosticate survival status and risk of post-stroke dementia (PSD)? In a retrospective cohort study, 206 patients with ischemic stroke (IS) entered the study. They were consecutively being admitted to the neurology clinic in Poursina Hospital (northern Iran) from 2012 to 2014. The diagnosis of PSD was based on DSM-5 criteria. The current and the premorbid cognitive statuses of the patients were respectively assessed through the third edition of Addenbrooke's Cognitive Examination and the Informant Questionnaire on Cognitive Decline in the Elderly. BDNF Val66Met gene polymorphism was determined by PCR-RFLP. On average, 48 patients (23.3 %) developed PSD 6 months after IS. Log-rank test showed that the survival rate of at least one Val-allele carriers was significantly lower than that of Met/Met homozygotes (P = 0.0005), and the former developed PSD sooner than the latter (375, 492 days, respectively). Cox model showed that heterozygous carriers of Val/Met were at greater risk of PSD over time (HR 2.280, 95 % CI 1.566-4.106, P = 0.006). However, the risk ratio of patients with PSD among different BDNF genotypes decreased after adjusting demographic, clinical, and vascular risk factors, and was no longer statistically significant (AHR 2.434, 95 % CI 0.597-9.926, P = 0.215). Val-allele carriers or Val/Met genotypes were more quickly diagnosed as having dementia after IS. However, this genetic vulnerability became more destructive when it was added to demographic, clinical, and vascular risk factors.

  13. 75. FIRST TEST SHOT OF THE VAL AT THE DEDICATION ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    75. FIRST TEST SHOT OF THE VAL AT THE DEDICATION CEREMONIES AS SEEN FROM A FIXED CAMERA STATION, May 7, 1948. (Original photograph in possession of Dave Willis, San Diego, California.) - Variable Angle Launcher Complex, Variable Angle Launcher, CA State Highway 39 at Morris Reservior, Azusa, Los Angeles County, CA

  14. 63. VIEW LOOKING DOWN VAL LAUNCHING SLAB SHOWING DRIVE GEARS, ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    63. VIEW LOOKING DOWN VAL LAUNCHING SLAB SHOWING DRIVE GEARS, CABLES, LAUNCHER RAILS, PROJECTILE CAR AND SUPPORT CARRIAGE, April 8, 1948. (Original photograph in possession of Dave Willis, San Diego, California.) - Variable Angle Launcher Complex, Variable Angle Launcher, CA State Highway 39 at Morris Reservior, Azusa, Los Angeles County, CA

  15. Analyzing the Boundary Thermal Resistance of Epitaxially Grown Fe2VAl/W Layers by Picosecond Time-Domain Thermoreflectance

    NASA Astrophysics Data System (ADS)

    Hiroi, Satoshi; Choi, Seongho; Nishino, Shunsuke; Seo, Okkyun; Chen, Yanna; Sakata, Osami; Takeuchi, Tsunehiro

    2018-06-01

    To gain deep insight into the mechanism of phonon scattering at grain boundaries, we investigated the boundary thermal resistance by using picosecond pulsed-laser time-domain thermoreflectance for epitaxially grown W/Fe2VAl/W films. By using radio-frequency magnetron sputtering, we prepared a series of the three-layer films whose Fe2VAl thickness ranged from 1 nm to 37 nm. The fine oscillation of reflectivity associated with the top W layer clearly appeared in synchrotron x-ray reflectivity measurements, indicating a less obvious mixture of elements at the boundary. The areal heat diffusion time, obtained from the time-domain thermoreflectance signal in the rear-heating front-detection configuration, reduced rapidly in samples whose Fe2VAl layer was thinner than 15 nm. The ˜ 10% mismatch in lattice constant between Fe2VAl and W naturally produced the randomly distributed lattice stress near the boundary, causing an effective increase of boundary thermal resistance in the thick samples, but the stress became homogeneous in the thinner layers, which reduced the scattering probability of phonons.

  16. 81. VIEW OF VAL LOOKING NORTH AS SEEN FROM THE ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    81. VIEW OF VAL LOOKING NORTH AS SEEN FROM THE RESERVOIR SHOWING TWO LAUNCHING TUBES ON THE LAUNCHER BRIDGE, Date unknown, circa 1952. (Original photograph in possession of Dave Willis, San Diego, California.) - Variable Angle Launcher Complex, Variable Angle Launcher, CA State Highway 39 at Morris Reservior, Azusa, Los Angeles County, CA

  17. Association between Catechol-O-Methyltransferase Val158Met (158G/A) Polymorphism and Suicide Susceptibility: A Meta-analysis.

    PubMed

    Sadeghiyeh, Tahereh; Hosseini Biouki, Fatemeh; Mazaheri, Mahta; Zare-Shehneh, Masoud; Neamatzadeh, Hossein; Poursharif, Zahra

    2017-06-24

    Common functional Val158Met polymorphism in the Catechol-O-methyltransferase (COMT) gene may have an impact on an individual's susceptibility to suicide, but individually published results are inconclusive. Therefore, we performed this meta-analysis to provide a more precise estimation of the association between COMT 158G/A (COMT Val158Met) polymorphism and suicide susceptibility. A cross-sectional study. This systematic review and meta-analysis is a comprehensive literature search of PubMed, Scopus, Web of Science and Google Scholar databases was conducted on case-control studies published up to Mar 2017. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. We identified 14 eligible case-control studies, including 2353 suicide attempters and 2593 controls. The pooled results indicated that COMT 158G/A (COMT Val158Met) polymorphism was not significantly associated with increased overall suicide risk. The same results were revealed based on ethnicity, Hardy-Weinberg equilibrium (HWE) status and genotyping technique. However, there was significant association between COMT Val158Met polymorphism and suicide risk among females under the homozygote (AA vs. GG: OR=1.829, 95% CI=1.158-2.889, P=0.010) and recessive (AA vs. AG +GG: OR = 1.787, 95% CI=1.195, 2.671, P=0.005) models, but not among males. COMT 158G/A (COMT Val158Met) polymorphism was associated with suicide susceptibility only in females.

  18. COMT Val158Met and MTHFR C677T moderate risk of schizophrenia in response to childhood adversity.

    PubMed

    Debost, J-C; Debost, M; Grove, J; Mors, O; Hougaard, D M; Børglum, A D; Mortensen, P B; Petersen, L

    2017-07-01

    Mesolimbic dopamine sensitization has been hypothesized to be a mediating factor of childhood adversity (CA) on schizophrenia risk. Activity of catechol-O-methyltransferase (COMT) Val158Met increases mesolimbic dopamine signaling and may be further regulated by methylenetetrahydrofolate reductase (MTHFR) C677T. This study investigates the three-way interaction between CA, COMT, and MTHFR. We conducted a nested case-control study on individuals born after 1981, linking population-based registers to study the three-way interaction. We included 1699 schizophrenia cases and 1681 controls, and used conditional logistic regression to report incidence rate ratios (IRRs). Childhood adversity was robustly associated with schizophrenia. No main genetic effects were observed. MTHFR C677T increased schizophrenia risk in a dose-dependent manner per MTHFR T allele (P = 0.005) consequent upon CA exposure. After inclusion of the significant (P = 0.03) COMT × MTHFR × CA interaction, the risk was further increased per high-activity COMT Val allele. Hence, exposed COMT Val/Val and MTHFR T/T carriers had an IRR of 2.76 (95% CI, 1.66-4.61). Additional adjustments for ancestry and parental history of mental illness attenuated the results with the interaction being only marginally significant. MTHFR C677T and COMT Val158Met interact with CA to increase risk of schizophrenia. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  19. BDNF val66met modulates the association between childhood trauma, cognitive and brain abnormalities in psychoses.

    PubMed

    Aas, Monica; Haukvik, Unn K; Djurovic, Srdjan; Bergmann, Ørjan; Athanasiu, Lavinia; Tesli, Martin S; Hellvin, Tone; Steen, Nils Eiel; Agartz, Ingrid; Lorentzen, Steinar; Sundet, Kjetil; Andreassen, Ole A; Melle, Ingrid

    2013-10-01

    Brain derived neurotrophic factor (BDNF) is important for brain development and plasticity, and here we tested if the functional BDNF val66met variant modulates the association between high levels of childhood abuse, cognitive function, and brain abnormalities in psychoses. 249 patients with a broad DSM-IV schizophrenia spectrum disorder or bipolar disorder were consecutively recruited to the TOP research study (mean±age: 30.7±10.9; gender: 49% males). History of childhood trauma was obtained using the Childhood Trauma Questionnaire. Cognitive function was assessed through a standardized neuropsychological test battery. BDNF val66met was genotyped using standardized procedures. A sub-sample of n=106 Caucasians with a broad DSM-IV schizophrenia spectrum disorder or bipolar disorder (mean±age: 32.67±10.85; 49% males) had data on sMRI. Carriers of the Methionine (met) allele exposed to high level of childhood abuse demonstrated significantly poorer cognitive functioning compared to homozygotic Valine (val/val) carriers. Taking in consideration multiple testing, using a more conservative p value, this was still shown for physical abuse and emotional abuse, as well as a trend level for sexual abuse. Further, met carriers exposed to high level of childhood sexual abuse showed reduced right hippocampal volume (r(2)=0.43; p=0.008), and larger right and left lateral ventricles (r(2)=0.37; p=0.002, and r(2)=0.27; p=0.009, respectively). Our findings were independent of age, gender, diagnosis and intracranial volume. Our data demonstrate that in patients with psychoses, met carriers of the BDNF val66met with high level of childhood abuse have more cognitive and brain abnormalities than all other groups. © 2013.

  20. Interaction between catechol-O-methyltransferase (COMT) Val158Met genotype and genetic vulnerability to schizophrenia during explicit processing of aversive facial stimuli.

    PubMed

    Lo Bianco, L; Blasi, G; Taurisano, P; Di Giorgio, A; Ferrante, F; Ursini, G; Fazio, L; Gelao, B; Romano, R; Papazacharias, A; Caforio, G; Sinibaldi, L; Popolizio, T; Bellantuono, C; Bertolino, A

    2013-02-01

    Emotion dysregulation is a key feature of schizophrenia, a brain disorder strongly associated with genetic risk and aberrant dopamine signalling. Dopamine is inactivated by catechol-O-methyltransferase (COMT), whose gene contains a functional polymorphism (COMT Val158Met) associated with differential activity of the enzyme and with brain physiology of emotion processing. The aim of the present study was to investigate whether genetic risk for schizophrenia and COMT Val158Met genotype interact on brain activity during implicit and explicit emotion processing. A total of 25 patients with schizophrenia, 23 healthy siblings of patients and 24 comparison subjects genotyped for COMT Val158Met underwent functional magnetic resonance imaging during implicit and explicit processing of facial stimuli with negative emotional valence. We found a main effect of diagnosis in the right amygdala, with decreased activity in patients and siblings compared with control subjects. Furthermore, a genotype × diagnosis interaction was found in the left middle frontal gyrus, such that the effect of genetic risk for schizophrenia was evident in the context of the Val/Val genotype only, i.e. the phenotype of reduced activity was present especially in Val/Val patients and siblings. Finally, a complete inversion of the COMT effect between patients and healthy subjects was found in the left striatum during explicit processing. Overall, these results suggest complex interactions between genetically determined dopamine signalling and risk for schizophrenia on brain activity in the prefrontal cortex during emotion processing. On the other hand, the effects in the striatum may represent state-related epiphenomena of the disorder itself.

  1. Genetic Correlates of Maladaptive Beliefs: COMT VAL(158)MET and Irrational Cognitions Linked Depending on Distress.

    PubMed

    Podina, Ioana; Popp, Radu; Pop, Ioan; David, Daniel

    2015-11-01

    Maladaptive/irrational beliefs are significant cognitive vulnerability mechanisms in psychopathology. They are more likely to be associated with a genetic vulnerability marker under conditions of emotional distress when irrational beliefs are more salient. Therefore, in the current study we investigated the COMT Val(158)Met gene variation in relation to irrational beliefs, assuming this relationship depended on the level of emotional distress. Two hundred and sixty-seven genotyped volunteers were assessed for core/general maladaptive beliefs, as well as trait emotional distress. We focused on context-independent measures of irrational beliefs and emotional distress in the absence of a stressor. As expected, the relationship between COMT Val(158)Met and irrational beliefs depended on the level of emotional distress (f(2)=.314). The COMT Val(158)Met-irrationality association was significant only when individuals fell in the average to above average range of emotional distress. Furthermore, within this range the Met allele seemed to relate to higher irrational beliefs. These results were significant for overall irrational beliefs and its subtypes, but not for rational beliefs, the functional counterpart of irrationality. In light of the study's limitations, the results should be considered as preliminary. If replicable, these findings have potential implications for therapygenetics, changing the view that COMT Val(158)Met might be of greater relevance when treatment modality does not rely on cognitive variables. Copyright © 2015. Published by Elsevier Ltd.

  2. BDNF Val66Met is Associated with Introversion and Interacts with 5-HTTLPR to Influence Neuroticism

    PubMed Central

    Terracciano, Antonio; Tanaka, Toshiko; Sutin, Angelina R; Deiana, Barbara; Balaci, Lenuta; Sanna, Serena; Olla, Nazario; Maschio, Andrea; Uda, Manuela; Ferrucci, Luigi; Schlessinger, David; Costa, Paul T

    2010-01-01

    Brain-derived neurotrophic factor (BDNF) regulates synaptic plasticity and neurotransmission, and has been linked to neuroticism, a major risk factor for psychiatric disorders. A recent genome-wide association (GWA) scan, however, found the BDNF Val66Met polymorphism (rs6265) associated with extraversion but not with neuroticism. In this study, we examine the links between BDNF and personality traits, assessed using the Revised NEO Personality Inventory (NEO-PI-R), in a sample from SardiNIA (n=1560) and the Baltimore Longitudinal Study of Aging (BLSA; n=1131). Consistent with GWA results, we found that BDNF Met carriers were more introverted. By contrast, in both samples and in a meta-analysis inclusive of published data (n=15251), we found no evidence for a main effect of BDNF Val66Met on neuroticism. Finally, on the basis of recent reports of an epistatic effect between BDNF and the serotonin transporter, we explored a Val66Met × 5-HTTLPR interaction in a larger SardiNIA sample (n=2333). We found that 5-HTTLPR LL carriers scored lower on neuroticism in the presence of the BDNF Val variant, but scored higher on neuroticism in the presence of the BDNF Met variant. Our findings support the association between the BDNF Met variant and introversion and suggest that BDNF interacts with the serotonin transporter gene to influence neuroticism. PMID:20042999

  3. BDNF Val66Met in preclinical Alzheimer's disease is associated with short-term changes in episodic memory and hippocampal volume but not serum mBDNF.

    PubMed

    Lim, Yen Ying; Rainey-Smith, Stephanie; Lim, Yoon; Laws, Simon M; Gupta, Veer; Porter, Tenielle; Bourgeat, Pierrick; Ames, David; Fowler, Christopher; Salvado, Olivier; Villemagne, Victor L; Rowe, Christopher C; Masters, Colin L; Zhou, Xin Fu; Martins, Ralph N; Maruff, Paul

    2017-11-01

    The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism Met allele exacerbates amyloid (Aβ) related decline in episodic memory (EM) and hippocampal volume (HV) over 36-54 months in preclinical Alzheimer's disease (AD). However, the extent to which Aβ+ and BDNF Val66Met is related to circulating markers of BDNF (e.g. serum) is unknown. We aimed to determine the effect of Aβ and the BDNF Val66Met polymorphism on levels of serum mBDNF, EM, and HV at baseline and over 18-months. Non-demented older adults (n = 446) underwent Aβ neuroimaging and BDNF Val66Met genotyping. EM and HV were assessed at baseline and 18 months later. Fasted blood samples were obtained from each participant at baseline and at 18-month follow-up. Aβ PET neuroimaging was used to classify participants as Aβ- or Aβ+. At baseline, Aβ+ adults showed worse EM impairment and lower serum mBDNF levels relative to Aβ- adults. BDNF Val66Met polymorphism did not affect serum mBDNF, EM, or HV at baseline. When considered over 18-months, compared to Aβ- Val homozygotes, Aβ+ Val homozygotes showed significant decline in EM and HV but not serum mBDNF. Similarly, compared to Aβ+ Val homozygotes, Aβ+ Met carriers showed significant decline in EM and HV over 18-months but showed no change in serum mBDNF. While allelic variation in BDNF Val66Met may influence Aβ+ related neurodegeneration and memory loss over the short term, this is not related to serum mBDNF. Longer follow-up intervals may be required to further determine any relationships between serum mBDNF, EM, and HV in preclinical AD.

  4. The BDNF Val66Met polymorphism impairs synaptic transmission and plasticity in the infralimbic medial prefrontal cortex

    PubMed Central

    Pattwell, Siobhan S.; Bath, Kevin G.; Perez-Castro, Rosalia; Lee, Francis S.; Chao, Moses V.; Ninan, Ipe

    2012-01-01

    The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is a common human single nucleotide polymorphism (SNP) that affects the regulated release of BDNF, and has been implicated in affective disorders and cognitive dysfunction. A decreased activation of the infralimbic medial prefrontal cortex (IL-mPFC), a brain region critical for the regulation of affective behaviors, has been described in BDNFMet carriers. However, it is unclear whether and how the Val66Met polymorphism affects the IL-mPFC synapses. Here we report that spike timing-dependent plasticity (STDP) was absent in the IL-mPFC pyramidal neurons from BDNFMet/Met mice, a mouse that recapitulates the specific phenotypic properties of the human BDNF Val66Met polymorphism. Also, we observed a decrease in N-methyl-D-aspartic acid (NMDA) and γ-aminobutyric acid (GABA) receptor-mediated synaptic transmission in the pyramidal neurons of BDNFMet/Met mice. While BDNF enhanced non-NMDA receptor transmission and depressed GABA receptor transmission in the wild-type mice, both effects were absent in BDNFMet/Met mice after BDNF treatment. Indeed, exogenous BDNF reversed the deficits in STDP and NMDA receptor transmission in BDNFMet/Met neurons. BDNF-mediated selective reversal of the deficit in plasticity and NMDA receptor transmission, but its lack of effect on GABA and non-NMDA receptor transmission in BDNFMet/Met mice, suggests separate mechanisms of Val66Met polymorphism upon synaptic transmission. The effect of the Val66Met polymorphism on synaptic transmission and plasticity in the IL-mPFC represents a mechanism to account for this SNP's impact on affective disorders and cognitive dysfunction. PMID:22396415

  5. The impact of the Catechol-O-methyltransferase Val158Met polymorphism on survival in the general population – the HUNT study

    PubMed Central

    Hagen, Knut; Stovner, Lars J; Skorpen, Frank; Pettersen, Elin; Zwart, John-Anker

    2007-01-01

    Background The catechol-O-methyltransferase (COMT) gene contains a functional polymorphism, Val158Met which has been related to common diseases like cancer, psychiatric illness and myocardial infarction. Whether the Val158Met polymorphism is associated with survival has not been evaluated in the general population. The aim of this prospective study was to evaluate the impact of codon 158 COMT gene polymorphism on survival in a population-based cohort. Methods The sample comprised 2979 non-diabetic individuals who participated in the Nord-Trøndelag Health Study (HUNT) in the period 1995–97. The subjects were followed up with respect to mortality throughout year 2004. Results 212 men and 183 women died during the follow up. No association between codon 158 COMT gene polymorphism and survival was found. The unadjusted relative risk of death by non-ischemic heart diseases with Met/Met or Met/Val genotypes was 3.27 (95% confidence interval, 1.19–9.00) compared to Val/Val genotype. When we adjusted for age, gender, smoking, coffee intake and body mass index the relative risk decreased to 2.89 (95% confidence interval, 1.04–8.00). Conclusion During 10 year of follow-up, the Val158Met polymorphism had no impact on survival in a general population. Difference in mortality rates from non-ischemic heart diseases may be incidental and should be evaluated in other studies. PMID:17577421

  6. 57. INTERIOR VIEW OF VAL BRIDGE STRUCTURE SHOWING LAUNCHING TUBE, ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    57. INTERIOR VIEW OF VAL BRIDGE STRUCTURE SHOWING LAUNCHING TUBE, STAIRS AND PORTION OF LAUNCHING DECK. NOTE SUPPORT CARRIAGE ASSEMBLY IN DISTANCE. Date unknown, circa March 1948. (Original photograph in possession of Dave Willis, San Diego, California.) - Variable Angle Launcher Complex, Variable Angle Launcher, CA State Highway 39 at Morris Reservior, Azusa, Los Angeles County, CA

  7. COMT Val158Met Polymorphism, Executive Dysfunction, and Sexual Risk Behavior in the Context of HIV Infection and Methamphetamine Dependence

    PubMed Central

    Bousman, C. A.; Cherner, M.; Atkinson, J. H.; Heaton, R. K.; Grant, I.; Everall, I. P.; HNRC Group, The

    2010-01-01

    Catechol-O-methyltransferease (COMT) metabolizes prefrontal cortex dopamine (DA), a neurotransmitter involved in executive behavior; the Val158Met genotype has been linked to executive dysfunction, which might increase sexual risk behaviors favoring HIV transmission. Main and interaction effects of COMT genotype and executive functioning on sexual risk behavior were examined. 192 sexually active nonmonogamous men completed a sexual behavior questionnaire, executive functioning tests, and were genotyped using blood-derived DNA. Main effects for executive dysfunction but not COMT on number of sexual partners were observed. A COMT x executive dysfunction interaction was found for number of sexual partners and insertive anal sex, significant for carriers of the Met/Met and to a lesser extent Val/Met genotypes but not Val/Val carriers. In the context of HIV and methamphetamine dependence, dopaminergic overactivity in prefrontal cortex conferred by the Met/Met genotype appears to result in a liability for executive dysfunction and potentially associated risky sexual behavior. PMID:20069120

  8. Agrometeorological models for forecasting the qualitative attributes of "Valência" oranges

    NASA Astrophysics Data System (ADS)

    Moreto, Victor Brunini; Rolim, Glauco de Souza; Zacarin, Bruno Gustavo; Vanin, Ana Paula; de Souza, Leone Maia; Latado, Rodrigo Rocha

    2017-11-01

    Forecasting is the act of predicting unknown future events using available data. Estimating, in contrast, uses data to simulate an actual condition. Brazil is the world's largest producer of oranges, and the state of São Paulo is the largest producer in Brazil. The "Valência" orange is among the most common cultivars in the state. We analyzed the influence of monthly meteorological variables during the growth cycle of Valência oranges grafted onto "Rangpur" lime rootstocks (VACR) for São Paulo, and developed monthly agrometeorological models for forecasting the qualitative attributes of VACR in mature orchard. For fruits per box for all months, the best accuracy was of 0.84 % and the minimum forecast range of 4 months. For the relation between °brix and juice acidity (RATIO) the best accuracy was of 0.69 % and the minimum forecast range of 5 months. Minimum, mean and maximum air temperatures, and relative evapotranspiration were the most important variables in the models.

  9. The effects of gender and COMT Val158Met polymorphism on fearful facial affect recognition: a fMRI study.

    PubMed

    Kempton, Matthew J; Haldane, Morgan; Jogia, Jigar; Christodoulou, Tessa; Powell, John; Collier, David; Williams, Steven C R; Frangou, Sophia

    2009-04-01

    The functional catechol-O-methyltransferase (COMT Val108/158Met) polymorphism has been shown to have an impact on tasks of executive function, memory and attention and recently, tasks with an affective component. As oestrogen reduces COMT activity, we focused on the interaction between gender and COMT genotype on brain activations during an affective processing task. We used functional MRI (fMRI) to record brain activations from 74 healthy subjects who engaged in a facial affect recognition task; subjects viewed and identified fearful compared to neutral faces. There was no main effect of the COMT polymorphism, gender or genotypexgender interaction on task performance. We found a significant effect of gender on brain activations in the left amygdala and right temporal pole, where females demonstrated increased activations over males. Within these regions, Val/Val carriers showed greater signal magnitude compared to Met/Met carriers, particularly in females. The COMT Val108/158Met polymorphism impacts on gender-related patterns of activation in limbic and paralimbic regions but the functional significance of any oestrogen-related COMT inhibition appears modest.

  10. Effects of BDNF Val66Met polymorphism on brain metabolism in Alzheimer's disease.

    PubMed

    Xu, Cunlu; Wang, Zhenhua; Fan, Ming; Liu, Bing; Song, Ming; Zhen, Xiantong; Jiang, Tianzi

    2010-08-23

    Earlier studies showed that the Val66Met polymorphisms of the brain-derived neurotrophic factor differentially affect gray matter volume and brain region activities. This study used resting positron emission tomography to investigate the relationship between the polymorphisms of Val66Met and the regional cerebral metabolic rate in the brain. We analyzed the positron emission tomography images of 215 patients from the Alzheimer's Disease Neuroimaging Initiative and found significant differences in the parahippocampal gyrus, superior temporal gyrus, prefrontal cortex, and inferior parietal lobule when comparing Met carriers with noncarriers among both the normal controls and those with mild cognitive impairment. For those with Alzheimer's disease, we also found additional differences in the bilateral insula between the carriers and noncarriers.

  11. The COMT Val158Met Polymorphism Is Associated With Response to Add-on Dextromethorphan Treatment in Bipolar Disorder.

    PubMed

    Lee, Sheng-Yu; Chen, Shiou-Lan; Wang, Tzu-Yun; Chang, Yun-Hsuan; Chen, Po See; Huang, San-Yuan; Tzeng, Nian-Sheng; Wang, Liang-Jen; Lee, I Hui; Chen, Kao Ching; Yang, Yen Kuang; Lu, Ru-Band

    2017-02-01

    We previously conducted a randomized, double-blind, controlled, 12-week study evaluating the effect of add-on dextromethorphan (DM), a noncompetitive N-methyl-D-aspartate receptor antagonist, on patients with bipolar disorder (BD) treated using valproate (VPA), which showed negative clinical differences. The genetic variation between each individual may be responsible for interindividual differences. The catechol-O-methyltransferase (COMT) gene has been a candidate gene for BD. In the current study, we investigated whether the COMT Val158Met polymorphism predicts treatment response to VPA + add-on DM and to VPA + placebo. Patients with BD (n = 309) undergoing regular VPA treatments were randomly assigned to groups given either add-on DM (30 mg/d) (n = 102), DM (60 mg/d) (n = 101), or placebo (n = 106) for 12 weeks. The Hamilton Depression Rating Scale and Young Mania Rating Scale were used to evaluate clinical response during weeks 0, 1, 2, 4, 8, and 12. The genotypes of the COMT Val158Met polymorphism were determined using polymerase chain reaction plus restriction fragment length polymorphism analysis. To adjust for within-subject dependence over repeated assessments, multiple linear regression with generalized estimating equation methods was used. When stratified by the COMT Val158Met genotypes, significantly greater decreases in Hamilton Depression Rating Scale scores were found in the VPA + DM (30 mg/d) group in patients with the Val/Met genotype (P = 0.008). We conclude that the COMT Val158Met polymorphism may influence responses to DM (30 mg/d) by decreasing depressive symptoms in BD patients.

  12. Factor XIII Val34Leu polymorphism and the risk of myocardial infarction under the age of 36 years.

    PubMed

    Rallidis, Loukianos S; Politou, Marianna; Komporozos, Christoforos; Panagiotakos, Demosthenes B; Belessi, Chrisoula I; Travlou, Anthi; Lekakis, John; Kremastinos, Dimitrios T

    2008-06-01

    There are limited and controversial data regarding the impact of factor XIII (FXIII) Val34Leu polymorphism in the pathogenesis of premature myocardial infarction (MI). We examined whether FXIII Val34Leu polymorphism is associated with the development of early MI. We recruited 159 consecutive patients who had survived their first acute MI under the age of 36 years (mean age = 32.1 +/- 3.6 years, 138 were men). The control group consisted of 121 healthy individuals matched with cases for age and sex, without a family history of premature coronary heart disease (CHD). FXIII Val34Leu polymorphism was tested with polymerase chain reaction and reverse hybridization. There was a lower prevalence of carriers of the Leu34 allele in patients than in controls (30.2 vs. 47.1%, p = 0.006). FXIII Val34Leu polymorphism was associated with lower risk for acute MI after adjusting for major cardiovascular risk factors (odds ratio [OR] = 0.51, 95% confidence interval [CI] 0.27-0.95, p = 0.03). Subgroup analysis according to angiographic findings ("normal" coronary arteries [n = 29] or significant CHD [n = 130]) showed that only patients with MI and significant CHD had lower prevalence of carriers of the Leu34 allele compared to controls after adjusting for major cardiovascular risk factors (OR = 0.42, 95% CI 0.22-0.83, p = 0.01). Our data indicate that FXIII Val34Leu polymorphism has a protective effect against the development of MI under the age of 36 years, particularly in the setting of significant CHD.

  13. BDNF Val66Met polymorphism, life stress and depression: A meta-analysis of gene-environment interaction.

    PubMed

    Zhao, Mingzhe; Chen, Lu; Yang, Jiarun; Han, Dong; Fang, Deyu; Qiu, Xiaohui; Yang, Xiuxian; Qiao, Zhengxue; Ma, Jingsong; Wang, Lin; Jiang, Shixiang; Song, Xuejia; Zhou, Jiawei; Zhang, Jian; Chen, Mingqi; Qi, Dong; Yang, Yanjie; Pan, Hui

    2018-02-01

    Depression is thought to be multifactorial in etiology, including genetic and environmental components. While a number of gene-environment interaction studies have been carried out, meta-analyses are scarce. The present meta-analysis aimed to quantify evidence on the interaction between brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and stress in depression. Included were 31 peer-reviewed with a pooled total of 21060 participants published before October 2016 and literature searches were conducted using PubMed, Wolters Kluwer, Web of Science, EBSCO, Elsevier Science Direct and Baidu Scholar databases. The results indicated that the Met allele of BDNF Val66Met polymorphism significantly moderated the relationship between stress and depression (Z=2.666, p = 0.003). The results of subgroup analysis concluded that stressful life events and childhood adversity separately interacted with the Met allele of BDNF Val66Met polymorphism in depression (Z = 2.552, p = 0.005; Z = 1.775, p = 0.03). The results could be affected by errors or bias in primary studies which had small sample sizes with relatively lower statistic power. We could not estimate how strong the interaction effect between gene and environment was. We found evidence that supported the hypothesis that BDNF Val66Met polymorphism moderated the relationship between stress and depression, despite the fact that many included individual studies did not show this effect. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. BDNF Val66Met predicts cognitive decline in the Wisconsin Registry for Alzheimer's Prevention

    PubMed Central

    Boots, Elizabeth A.; Schultz, Stephanie A.; Clark, Lindsay R.; Racine, Annie M.; Darst, Burcu F.; Koscik, Rebecca L.; Carlsson, Cynthia M.; Gallagher, Catherine L.; Hogan, Kirk J.; Bendlin, Barbara B.; Asthana, Sanjay; Sager, Mark A.; Hermann, Bruce P.; Christian, Bradley T.; Dubal, Dena B.; Engelman, Corinne D.; Johnson, Sterling C.

    2017-01-01

    Objective: To examine the influence of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism on longitudinal cognitive trajectories in a large, cognitively healthy cohort enriched for Alzheimer disease (AD) risk and to understand whether β-amyloid (Aβ) burden plays a moderating role in this relationship. Methods: One thousand twenty-three adults (baseline age 54.94 ± 6.41 years) enrolled in the Wisconsin Registry for Alzheimer's Prevention underwent BDNF genotyping and cognitive assessment at up to 5 time points (average follow-up 6.92 ± 3.22 years). A subset (n = 140) underwent 11C-Pittsburgh compound B (PiB) scanning. Covariate-adjusted mixed-effects regression models were used to elucidate the effect of BDNF on cognitive trajectories in 4 cognitive domains, including verbal learning and memory, speed and flexibility, working memory, and immediate memory. Secondary mixed-effects regression models were conducted to examine whether Aβ burden, indexed by composite PiB load, modified any observed BDNF-related cognitive trajectories. Results: Compared to BDNF Val/Val homozygotes, Met carriers showed steeper decline in verbal learning and memory (p = 0.002) and speed and flexibility (p = 0.017). In addition, Aβ burden moderated the relationship between BDNF and verbal learning and memory such that Met carriers with greater Aβ burden showed even steeper cognitive decline (p = 0.033). Conclusions: In a middle-aged cohort with AD risk, carriage of the BDNF Met allele was associated with steeper decline in episodic memory and executive function. This decline was exacerbated by greater Aβ burden. These results suggest that the BDNF Val66Met polymorphism may play an important role in cognitive decline and could be considered as a target for novel AD therapeutics. PMID:28468845

  15. BDNF Val66Met predicts cognitive decline in the Wisconsin Registry for Alzheimer's Prevention.

    PubMed

    Boots, Elizabeth A; Schultz, Stephanie A; Clark, Lindsay R; Racine, Annie M; Darst, Burcu F; Koscik, Rebecca L; Carlsson, Cynthia M; Gallagher, Catherine L; Hogan, Kirk J; Bendlin, Barbara B; Asthana, Sanjay; Sager, Mark A; Hermann, Bruce P; Christian, Bradley T; Dubal, Dena B; Engelman, Corinne D; Johnson, Sterling C; Okonkwo, Ozioma C

    2017-05-30

    To examine the influence of the brain-derived neurotrophic factor ( BDNF ) Val66Met polymorphism on longitudinal cognitive trajectories in a large, cognitively healthy cohort enriched for Alzheimer disease (AD) risk and to understand whether β-amyloid (Aβ) burden plays a moderating role in this relationship. One thousand twenty-three adults (baseline age 54.94 ± 6.41 years) enrolled in the Wisconsin Registry for Alzheimer's Prevention underwent BDNF genotyping and cognitive assessment at up to 5 time points (average follow-up 6.92 ± 3.22 years). A subset (n = 140) underwent 11 C-Pittsburgh compound B (PiB) scanning. Covariate-adjusted mixed-effects regression models were used to elucidate the effect of BDNF on cognitive trajectories in 4 cognitive domains, including verbal learning and memory, speed and flexibility, working memory, and immediate memory. Secondary mixed-effects regression models were conducted to examine whether Aβ burden, indexed by composite PiB load, modified any observed BDNF -related cognitive trajectories. Compared to BDNF Val/Val homozygotes, Met carriers showed steeper decline in verbal learning and memory ( p = 0.002) and speed and flexibility ( p = 0.017). In addition, Aβ burden moderated the relationship between BDNF and verbal learning and memory such that Met carriers with greater Aβ burden showed even steeper cognitive decline ( p = 0.033). In a middle-aged cohort with AD risk, carriage of the BDNF Met allele was associated with steeper decline in episodic memory and executive function. This decline was exacerbated by greater Aβ burden. These results suggest that the BDNF Val66Met polymorphism may play an important role in cognitive decline and could be considered as a target for novel AD therapeutics. © 2017 American Academy of Neurology.

  16. Effects of the BDNF Val66Met Polymorphism on Anxiety-Like Behavior Following Nicotine Withdrawal in Mice

    PubMed Central

    Lee, Bridgin G.; Anastasia, Agustin; Hempstead, Barbara L.; Lee, Francis S.

    2015-01-01

    Introduction: Nicotine withdrawal is characterized by both affective and cognitive symptoms. Identifying genetic polymorphisms that could affect the symptoms associated with nicotine withdrawal are important in predicting withdrawal sensitivity and identifying personalized cessation therapies. In the current study we used a mouse model of a non-synonymous single nucleotide polymorphism in the translated region of the brain-derived neurotrophic factor (BDNF) gene that substitutes a valine (Val) for a methionine (Met) amino acid (Val66Met) to examine the relationship between the Val66Met single nucleotide polymorphism and nicotine dependence. Methods: This study measured proBDNF and the BDNF prodomain levels following nicotine and nicotine withdrawal and examined a mouse model of a common polymorphism in this protein (BDNFMet/Met) in three behavioral paradigms: novelty-induced hypophagia, marble burying, and the open-field test. Results: Using the BDNF knock-in mouse containing the BDNF Val66Met polymorphism we found: (1) blunted anxiety-like behavior in BDNFMet/Met mice following withdrawal in three behavioral paradigms: novelty-induced hypophagia, marble burying, and the open-field test; (2) the anxiolytic effects of chronic nicotine are absent in BDNFMet/Met mice; and (3) an increase in BDNF prodomain in BDNFMet/Met mice following nicotine withdrawal. Conclusions: Our study is the first to examine the effect of the BDNF Val66Met polymorphism on the affective symptoms of withdrawal from nicotine in mice. In these mice, a single-nucleotide polymorphism in the translated region of the BDNF gene can result in a blunted withdrawal, as measured by decreased anxiety-like behavior. The significant increase in the BDNF prodomain in BDNFMet/Met mice following nicotine cessation suggests a possible role of this ligand in the circuitry remodeling after withdrawal. PMID:25744957

  17. COMT Val158Met Polymorphism and Symptom Improvement Following a Cognitively-Focused Intervention for Irritable Bowel Syndrome

    PubMed Central

    Han, Claire J.; Kohen, Ruth; Jun, Sangeun; Jarrett, Monica E.; Cain, Kevin C.; Burr, Robert; Heitkemper, Margaret M.

    2016-01-01

    Background Our nurse-delivered Comprehensive Self-Management (CSM) program, a cognitive behavioral therapy intervention, is effective in reducing gastrointestinal and psychological distress symptoms in patients with irritable bowel syndrome (IBS). Findings from non-IBS studies indicate that the catechol-O-methyltransferase (COMT) Val158Met polymorphism may moderate the efficacy of cognitive behavioral therapy. It is unknown whether this COMT polymorphism is associated with symptom improvements in patients with IBS. Objective We tested whether this COMT Val158Met polymorphism influences the efficacy of our two-month CSM intervention. Methods We analyzed data from two published randomized controlled trials of CSM. The combined European-American sample included 149 women and 23 men with IBS (CSM, n =111; Usual Care [UC], n = 61). The primary outcomes were daily reports of abdominal pain, depression, anxiety, and feeling stressed measured three and six months after randomization. Secondary outcomes were additional daily symptoms, retrospective psychological distress, IBS quality of life, and cognitive beliefs about IBS. The interaction between COMT Val158Met polymorphism and treatment group (CSM vs. UC) in a generalized estimating equation model tested the main objective. Results At three months, participants with at least one Val allele benefited more from CSM than did those with the Met/Met genotype (p = .01 for anxiety and feeling stressed, and p < .16 for abdominal pain and depression). The moderating effect of genotype was weaker at six months. Discussion Persons with at least one Val allele may benefit more from CSM than those homozygous for the Met allele. Future studies with larger and more racially diverse samples are needed to confirm these findings. RCT Registration Parent studies were registered at ClinicalTrials.gov (NCT00167635 and NCT00907790). PMID:28252569

  18. COMT Val158Met polymorphism influences the susceptibility to framing in decision-making: OFC-amygdala functional connectivity as a mediator.

    PubMed

    Gao, Xiaoxue; Gong, Pingyuan; Liu, Jinting; Hu, Jie; Li, Yue; Yu, Hongbo; Gong, Xiaoliang; Xiang, Yang; Jiang, Changjun; Zhou, Xiaolin

    2016-05-01

    Individuals tend to avoid risk in a gain frame, in which options are presented in a positive way, but seek risk in a loss frame, in which the same options are presented negatively. Previous studies suggest that emotional responses play a critical role in this "framing effect." Given that the Met allele of COMT Val158Met polymorphism (rs4680) is associated with the negativity bias during emotional processing, this study investigated whether this polymorphism is associated with individual susceptibility to framing and which brain areas mediate this gene-behavior association. Participants were genotyped, scanned in resting state, and completed a monetary gambling task with options (sure vs risky) presented as potential gains or losses. The Met allele carriers showed a greater framing effect than the Val/Val homozygotes as the former gambled more than the latter in the loss frame. Moreover, the gene-behavior association was mediated by resting-state functional connectivity (RSFC) between orbitofrontal cortex (OFC) and bilateral amygdala. Met allele carriers showed decreased RSFC, thereby demonstrating higher susceptibility to framing than Val allele carriers. These findings demonstrate the involvement of COMT Val158Met polymorphism in the framing effect in decision-making and suggest RSFC between OFC and amygdala as a neural mediator underlying this gene-behavior association. Hum Brain Mapp 37:1880-1892, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  19. 11. Photocopy of photograph (original photograph in possession of Val ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    11. Photocopy of photograph (original photograph in possession of Val Brose, General Dynamics Space Systems Division, Vandenberg Air Force Base, California). Photographer unknown, circa July 1961. CREW OF FIRST LAUNCH FROM POINT ARGUELLO LAUNCH COMPLEX 1, PAD 2, (SLC-3E) ON LAUNCH PAD. - Vandenberg Air Force Base, Space Launch Complex 3, Napa & Alden Roads, Lompoc, Santa Barbara County, CA

  20. COMT Val(158)Met genotype and cannabis use in people with an At Risk Mental State for psychosis: Exploring Gene x Environment interactions.

    PubMed

    Nieman, Dorien H; Dragt, Sara; van Duin, Esther D A; Denneman, Nadine; Overbeek, Jozefien M; de Haan, Lieuwe; Rietdijk, Judith; Ising, Helga K; Klaassen, Rianne M C; van Amelsvoort, Thérèse; Wunderink, Lex; van der Gaag, Mark; Linszen, Don H

    2016-07-01

    Epidemiological and retrospective studies suggest a cannabis x catechol-O-methyltransferase (COMT) Val(158)Met interaction effect on development of psychosis. The aim of this study was to examine this interaction and its association with severity of subclinical symptoms in people with an At Risk Mental State (ARMS) for psychosis. Severity of symptoms, cannabis use and genotype were assessed at baseline in 147 help-seeking young adults who met the ARMS criteria and agreed to participate in the Dutch Early Detection and Intervention (EDIE-NL) trial. Cannabis use and COMT Val-allele showed an interaction effect in ARMS subjects. Subjects who were weekly cannabis users at some point prior to entering the study showed more severe positive symptoms. This effect increased if they were carriers of the COMT Val-allele and even more so if they were homozygous for the Val-allele. Our results suggest that the COMT Val(158)Met polymorphism moderates the effect of regular cannabis use on severity of subclinical psychotic symptoms. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. [Social values and addiction: applicability and psychometric properties of VAL-89 questionnaire].

    PubMed

    Pedrero Perez, Eduardo Jose; Rojo Mota, Gloria; Olivar Arroyo, Alvaro

    2008-01-01

    To study the psychometric properties of the VAL-89 questionnaire and its possible use in addict individuals who ask for treatment. Analysis of the psychometric properties of the questionnaire and its factorial structure, applying it to 792 individuals. 365 of them were substance users seeking treatment and 427 were general population. Reliability of the questionnaire is confirmed, although its factorial structure appears to be different from the original. In our study appear 12 factors, instead of the original 10. These factors are named: Power, Stimulation, Submission, Tradition, Spirituality, Self-Sufficience, Hedonism, Sociability, Universality, Convencionalism, Idealism and Self-Realization. These factors are distributed through several dimensions represented by four axis: individual-social, dominance-equality, tradition-pleasure and great values-anomie. The VAL-89 questionnaire seems to be a useful tool to explore which are the more appreciated social values, being of special interest to know which are specially selected by addict individuals.

  2. The BDNF Val66Met Polymorphism Interacts with Maternal Parenting Influencing Adolescent Depressive Symptoms: Evidence of Differential Susceptibility Model.

    PubMed

    Zhang, Leilei; Li, Zhi; Chen, Jie; Li, Xinying; Zhang, Jianxin; Belsky, Jay

    2016-03-01

    Although depressive symptoms are common during adolescence, little research has examined gene-environment interaction on youth depression. This study chose the brain-derived neurotrophic factor (BDNF) gene, tested the interaction between a functional polymorphism resulting amino acid substitution of valine (Val) to methionine (Met) in the proBDNF protein at codon 66 (Val66Met), and maternal parenting on youth depressive symptoms in a sample of 780 community adolescents of Chinese Han ethnicity (aged 11-17, M = 13.6, 51.3 % females). Participants reported their depressive symptoms and perceived maternal parenting. Results indicated the BDNF Val66Met polymorphism significantly moderated the influence of maternal warmth-reasoning, but not harshness-hostility, on youth depressive symptoms. Confirmatory model evaluation indicated that the interaction effect involving warmth-reasoning conformed to the differential-susceptibility rather than diathesis-stress model of person-X-environment interaction. Thus, Val carriers experienced less depressive symptoms than Met homozygotes when mothering was more positive but more symptoms when mothering was less positive. The findings provided evidence in support of the differential susceptibility hypothesis of youth depressive symptoms and shed light on the importance of examining the gene-environment interaction from a developmental perspective.

  3. HSI2/VAL1 Silences AGL15 to Regulate the Developmental Transition from Seed Maturation to Vegetative Growth in Arabidopsis[OPEN

    PubMed Central

    Abdelmageed, Haggag; Kang, Miyoung

    2018-01-01

    Gene expression during seed development in Arabidopsis thaliana is controlled by transcription factors including LEAFY COTYLEDON1 (LEC1) and LEC2, ABA INSENSITIVE3 (ABI3), FUSCA3 (FUS3), known as LAFL proteins, and AGAMOUS-LIKE15 (AGL15). The transition from seed maturation to germination and seedling growth requires the transcriptional silencing of these seed maturation-specific factors leading to downregulation of structural genes including those that encode seed storage proteins, oleosins, and dehydrins. During seed germination and vegetative growth, B3-domain protein HSI2/VAL1 is required for the transcriptional silencing of LAFL genes. Here, we report chromatin immunoprecipitation analysis indicating that HSI2/VAL1 binds to the upstream sequences of the AGL15 gene but not at LEC1, ABI3, FUS3, or LEC2 loci. Functional analysis indicates that the HSI2/VAL1 B3 domain interacts with two RY elements upstream of the AGL15 coding region and at least one of them is required for HSI2/VAL1-dependent AGL15 repression. Expression analysis of the major seed maturation regulatory genes LEC1, ABI3, FUS3, and LEC2 in different genetic backgrounds demonstrates that HSI2/VAL1 is epistatic to AGL15 and represses the seed maturation regulatory program through downregulation of AGL15 by deposition of H3K27me3 at this locus. This hypothesis is further supported by results that show that HSI2/VAL1 physically interacts with the Polycomb Repressive Complex 2 component protein MSI1, which is also enriched at the AGL15 locus. PMID:29475938

  4. Association of single Nucleotide Missence Polymorphism Val109Asp of Omentin-1 gene and coronary artery disease in Pakistani population: Multicenter study

    PubMed Central

    Nazar, Shazia; Zehra, Sitwat; Azhar, Abid

    2017-01-01

    Background & Objective: Coronary artery disease (CAD) is a most important cause of morbidity and mortality worldwide as well as in Pakistan. Recent studies have shown that the combination of obesity, insulin resistance and fluctuation in circulating adipocytokines levels is associated with the pathogenesis of coronary artery disease. Omentin-1 is recently found adipocytokine that is highly expressed in visceral adipose tissue. It has anti- inflammatory properties and is negatively correlated with ischemic heart disease. Therefore, this study was designed to investigate the relationship between omentin-1 Val109Asp polymorphism and CAD in Pakistani population. Methods: A total of 350 subjects were included in the study. Two hundred fifty were diagnosed with coronary artery disease while 100 served as healthy controls. PCR-RFLP was performed at Dr. A Q. Khan Institute of Biotechnology (KIBGE) to analyze Val109Asp polymorphism. In this, case control study SPSS software version 16 (Chicago, IL, USA) was used for data analysis. Continuous variables and categorical variables were presented as mean±SD or in percentage. Independent sample test and chi-square test was performed to compare the differences in means between cases and controls. Genotype distribution was analyzed by chi-square test and results were presented as percentage and frequency. Multivarible regression analysis indicated that Val109Asp SNP might be an independent risk factor for CAD susceptibility after adjustment for some well- known CAD risk factors including age, gender, body mass index, smoking, hypertension, diabetes mellitus and lipid abnormalities. There was estimation of odd ratios (OR) and 95% confidence intervals (CIs) to determine the correlation between genotypes and the risk of CAD. (p> 0.05). Genotype frequencies were compared by Chi-square test. Results: There was prevalence of Omentin-1 Val109Asp polymorphism in both case and control groups. However, Val/Asp (heterozygous mutant) genotype

  5. COMT ValMet moderation of cannabis-induced psychosis: a momentary assessment study of 'switching on' hallucinations in the flow of daily life.

    PubMed

    Henquet, C; Rosa, A; Delespaul, P; Papiol, S; Fananás, L; van Os, J; Myin-Germeys, I

    2009-02-01

    A functional polymorphism in the catechol-o-methyltransferase gene (COMT Val(158)Met) may moderate the psychosis-inducing effects of cannabis. In order to extend this finding to dynamic effects in the flow of daily life, a momentary assessment study of psychotic symptoms in response to cannabis use was conducted. The experience sampling technique was used to collect data on cannabis use and occurrence of symptoms in daily life in patients with a psychotic disorder (n = 31) and healthy controls (n = 25). Carriers of the COMT Val(158)Met Val allele, but not subjects with the Met/Met genotype, showed an increase in hallucinations after cannabis exposure, conditional on prior evidence of psychometric psychosis liability. The findings confirm that in people with psychometric evidence of psychosis liability, COMT Val(158)Met genotype moderates the association between cannabis and psychotic phenomena in the flow of daily life.

  6. Lack of neural compensatory mechanisms of BDNF val66met met carriers and APOE E4 carriers in healthy aging, mild cognitive impairment, and Alzheimer's disease.

    PubMed

    Gomar, Jesus J; Conejero-Goldberg, Concepcion; Huey, Edward D; Davies, Peter; Goldberg, Terry E

    2016-03-01

    Compromises in compensatory neurobiologic mechanisms due to aging and/or genetic factors (i.e., APOE gene) may influence brain-derived neurotrophic factor (BDNF) val66met polymorphism effects on temporal lobe morphometry and memory performance. We studied 2 cohorts from Alzheimer's Disease Neuroimaging Initiative: 175 healthy subjects and 222 with prodromal and established Alzheimer's disease. Yearly structural magnetic resonance imaging and cognitive performance assessments were carried out over 3 years of follow-up. Both cohorts had similar BDNF Val/Val and Met allele carriers' (including both Val/Met and Met/Met individuals) distribution. In healthy subjects, a significant trend for thinner posterior cingulate and precuneus cortices was detected in Met carriers compared to Val homozygotes in APOE E4 carriers, with large and medium effect sizes, respectively. The mild cognitive impairment/Alzheimer's disease cohort showed a longitudinal decline in entorhinal thickness in BDNF Met carriers compared to Val/Val in APOE E4 carriers, with effect sizes ranging from medium to large. In addition, an effect of BDNF genotype was found in APOE E4 carriers for episodic memory (logical memory and ADAS-Cog) and semantic fluency measures, with Met carriers performing worse in all cases. These findings suggest a lack of compensatory mechanisms in BDNF Met carriers and APOE E4 carriers in healthy and pathological aging. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. BDNF Binds Its Pro-Peptide with High Affinity and the Common Val66Met Polymorphism Attenuates the Interaction

    PubMed Central

    Uegaki, Koichi; Kumanogoh, Haruko; Mizui, Toshiyuki; Hirokawa, Takatsugu; Ishikawa, Yasuyuki; Kojima, Masami

    2017-01-01

    Most growth factors are initially synthesized as precursors then cleaved into bioactive mature domains and pro-domains, but the biological roles of pro-domains are poorly understood. In the present study, we investigated the pro-domain (or pro-peptide) of brain-derived neurotrophic factor (BDNF), which promotes neuronal survival, differentiation and synaptic plasticity. The BDNF pro-peptide is a post-processing product of the precursor BDNF. Using surface plasmon resonance and biochemical experiments, we first demonstrated that the BDNF pro-peptide binds to mature BDNF with high affinity, but not other neurotrophins. This interaction was more enhanced at acidic pH than at neutral pH, suggesting that the binding is significant in intracellular compartments such as trafficking vesicles rather than the extracellular space. The common Val66Met BDNF polymorphism results in a valine instead of a methionine in the pro-domain, which affects human brain functions and the activity-dependent secretion of BDNF. We investigated the influence of this variation on the interaction between BDNF and the pro-peptide. Interestingly, the Val66Met polymorphism stabilized the heterodimeric complex of BDNF and its pro-peptide. Furthermore, compared with the Val-containing pro-peptide, the complex with the Met-type pro-peptide was more stable at both acidic and neutral pH, suggesting that the Val66Met BDNF polymorphism forms a more stable complex. A computational modeling provided an interpretation to the role of the Val66Met mutation in the interaction of BDNF and its pro-peptide. Lastly, we performed electrophysiological experiments, which indicated that the BDNF pro-peptide, when pre-incubated with BDNF, attenuated the ability of BDNF to inhibit hippocampal long-term depression (LTD), suggesting a possibility that the BDNF pro-peptide may interact directly with BDNF and thereby inhibit its availability. It was previously reported that the BDNF pro-domain exerts a chaperone-like function

  8. Association between COMT Val158Met and psychiatric disorders: A comprehensive meta-analysis.

    PubMed

    Taylor, Steven

    2018-03-01

    Catechol-O-methyltransferase (COMT) Val158Met is widely regarded as potentially important for understanding the genetic etiology of many different psychiatric disorders. The present study appears to be the first comprehensive meta-analysis of COMT genetic association studies to cover all psychiatric disorders for which there were available data, published in any language, and with an emphasis on investigating disorder subtypes (defined clinically or by demographic or other variables). Studies were included if they reported one or more datasets (i.e., some studies examined more than one clinical group) in which there were sufficient information to compute effect sizes. A total of 363 datasets were included, consisting of 56,998 cases and 74,668 healthy controls from case control studies, and 2,547 trios from family based studies. Fifteen disorders were included. Attention-deficit hyperactivity disorder and panic disorder were associated with the Val allele for Caucasian samples. Substance-use disorder, defined by DSM-IV criteria, was associated with the Val allele for Asian samples. Bipolar disorder was associated with the Met allele in Asian samples. Obsessive-compulsive disorder tended to be associated with the Met allele only for males. There was suggestive evidence that the Met allele is associated with an earlier age of onset of schizophrenia. Results suggest pleiotropy and underscore the importance of examining subgroups-defined by variables such as age of onset, sex, ethnicity, and diagnostic system-rather than examining disorders as monolithic constructs. © 2017 Wiley Periodicals, Inc.

  9. Is SOD2 Ala16Val Polymorphism Associated with Migraine with Aura Phenotype?

    PubMed Central

    Barbanti, Piero; De Marchis, Maria Laura; Egeo, Gabriella; Aurilia, Cinzia; Fofi, Luisa; Ialongo, Cristiano; Valente, Maria Giovanna; Ferroni, Patrizia; Della-Morte, David; Guadagni, Fiorella

    2015-01-01

    Abstract Several studies suggest a role of oxidative stress in the physiopathology of migraine, particularly in the form with aura. In a case-control study, we investigated the association between migraine and superoxide dismutase 1 (SOD1) and superoxide dismutase 2 (SOD2) genes in a cohort of 490 consecutive unrelated Caucasian migraineurs (migraine with aura [MwA], n=107; migraine without aura [MwoA], n=246; chronic migraine [CM], n=137) and 246 healthy controls recruited at our Headache and Pain Unit and stored in the Interinstitutional Multidisciplinary BioBank (BioBIM). Migraine phenotype was carefully detailed using face-to-face interviews. We examined polymorphisms of SOD1 gene (A/C substitution—rs2234694) and SOD2 gene (C/T transition—rs4880—Ala16Val). The rs4880 TT (Val/Val) genotype was associated (p=0.042) with the presence of unilateral cranial autonomic symptoms (UAs) in MwA patients. We also found a mild correlation between SOD2 rs4880 genotype and the type of acute migraine treatment (p=0.048) in MwA patients. Our findings suggest that SOD2 is a disease-modifier gene influencing oxidative mechanisms in MwA. These observations lead to the hypothesis that SOD2 polymorphism may cause a defective control of the oxidative phenomena linked to cortical spreading depression, the neurophysiological hallmark of migraine aura, causing an overstimulation of trigeminal neurons and UAs triggering. Antioxid. Redox Signal. 22, 275–279. PMID:25295643

  10. OCTANOL/WATER PARTITION COEFFICIENTS AND WATER SOLUBILITIES OF PHTHALATE ESTERS

    EPA Science Inventory

    Measurements of the octanol/water partition coefficients (K-ow) and water solubilities of di-n-octyl phthalate (DnOP) and di-n-decyl phthalate (DnDP) by the slow-stirring method are reported. The water solubility was also measured for di-n-hexyl phthalate (DnHP). The log K-ow val...

  11. Low-Temperature Thermoelectric Properties of Fe2VAl with Partial Cobalt Doping

    NASA Astrophysics Data System (ADS)

    Liu, Chang; Morelli, Donald T.

    2012-06-01

    Ternary metallic alloy Fe2VAl with a pseudogap in its energy band structure has received intensive scrutiny for potential thermoelectric applications. Due to the sharp change in the density of states profile near the Fermi level, interesting transport properties can be triggered to render possible enhancement in the overall thermoelectric performance. Previously, this full-Heusler-type alloy was partially doped with cobalt at the iron sites to produce a series of compounds with n-type conductivity. Their thermoelectric properties in the temperature range of 300 K to 850 K were reported. In this research, efforts were made to extend the investigation on (Fe1- x Co x )2VAl to the low-temperature range. Alloy samples were prepared by arc-melting and annealing. Seebeck coefficient, electrical resistivity, and thermal conductivity measurements were performed from 80 K to room temperature. The effects of cobalt doping on the material's electronic and thermal properties are discussed.

  12. Effects of the BDNF Val66Met Polymorphism on Anxiety-Like Behavior Following Nicotine Withdrawal in Mice.

    PubMed

    Lee, Bridgin G; Anastasia, Agustin; Hempstead, Barbara L; Lee, Francis S; Blendy, Julie A

    2015-12-01

    Nicotine withdrawal is characterized by both affective and cognitive symptoms. Identifying genetic polymorphisms that could affect the symptoms associated with nicotine withdrawal are important in predicting withdrawal sensitivity and identifying personalized cessation therapies. In the current study we used a mouse model of a non-synonymous single nucleotide polymorphism in the translated region of the brain-derived neurotrophic factor (BDNF) gene that substitutes a valine (Val) for a methionine (Met) amino acid (Val66Met) to examine the relationship between the Val66Met single nucleotide polymorphism and nicotine dependence. This study measured proBDNF and the BDNF prodomain levels following nicotine and nicotine withdrawal and examined a mouse model of a common polymorphism in this protein (BDNF(Met/Met)) in three behavioral paradigms: novelty-induced hypophagia, marble burying, and the open-field test. Using the BDNF knock-in mouse containing the BDNF Val66Met polymorphism we found: (1) blunted anxiety-like behavior in BDNF(Met/Met) mice following withdrawal in three behavioral paradigms: novelty-induced hypophagia, marble burying, and the open-field test; (2) the anxiolytic effects of chronic nicotine are absent in BDNF(Met/Met) mice; and (3) an increase in BDNF prodomain in BDNF(Met/Met) mice following nicotine withdrawal. Our study is the first to examine the effect of the BDNF Val66Met polymorphism on the affective symptoms of withdrawal from nicotine in mice. In these mice, a single-nucleotide polymorphism in the translated region of the BDNF gene can result in a blunted withdrawal, as measured by decreased anxiety-like behavior. The significant increase in the BDNF prodomain in BDNF(Met/Met) mice following nicotine cessation suggests a possible role of this ligand in the circuitry remodeling after withdrawal. © The Author 2015. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For

  13. BDNF Val66Met moderates memory impairment, hippocampal function and tau in preclinical autosomal dominant Alzheimer's disease.

    PubMed

    Lim, Yen Ying; Hassenstab, Jason; Cruchaga, Carlos; Goate, Alison; Fagan, Anne M; Benzinger, Tammie L S; Maruff, Paul; Snyder, Peter J; Masters, Colin L; Allegri, Ricardo; Chhatwal, Jasmeer; Farlow, Martin R; Graff-Radford, Neill R; Laske, Christoph; Levin, Johannes; McDade, Eric; Ringman, John M; Rossor, Martin; Salloway, Stephen; Schofield, Peter R; Holtzman, David M; Morris, John C; Bateman, Randall J

    2016-10-01

    SEE ROGAEVA AND SCHMITT-ULMS DOI101093/AWW201 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is implicated in synaptic excitation and neuronal integrity, and has previously been shown to moderate amyloid-β-related memory decline and hippocampal atrophy in preclinical sporadic Alzheimer's disease. However, the effect of BDNF in autosomal dominant Alzheimer's disease is unknown. We aimed to determine the effect of BDNF Val66Met on cognitive function, hippocampal function, tau and amyloid-β in preclinical autosomal dominant Alzheimer's disease. We explored effects of apolipoprotein E (APOE) ε4 on these relationships. The Dominantly Inherited Alzheimer Network conducted clinical, neuropsychological, genetic, biomarker and neuroimaging measures at baseline in 131 mutation non-carriers and 143 preclinical autosomal dominant Alzheimer's disease mutation carriers on average 12 years before clinical symptom onset. BDNF genotype data were obtained for mutation carriers (95 Val 66 homozygotes, 48 Met 66 carriers). Among preclinical mutation carriers, Met 66 carriers had worse memory performance, lower hippocampal glucose metabolism and increased levels of cerebrospinal fluid tau and phosphorylated tau (p-tau) than Val 66 homozygotes. Cortical amyloid-β and cerebrospinal fluid amyloid-β 42 levels were significantly different from non-carriers but did not differ between preclinical mutation carrier Val 66 homozygotes and Met 66 carriers. There was an effect of APOE on amyloid-β levels, but not cognitive function, glucose metabolism or tau. As in sporadic Alzheimer's disease, the deleterious effects of amyloid-β on memory, hippocampal function, and tau in preclinical autosomal dominant Alzheimer's disease mutation carriers are greater in Met 66 carriers. To date, this is the only genetic factor found to moderate downstream effects of amyloid-β in autosomal dominant Alzheimer's disease. © The Author (2016

  14. The divergent impact of catechol-O-methyltransferase (COMT) Val158Met genetic polymorphisms on executive function in adolescents with discrete patterns of childhood adversity.

    PubMed

    Zhang, Huihui; Li, Jie; Yang, Bei; Ji, Tao; Long, Zhouting; Xing, Qiquan; Shao, Di; Bai, Huayu; Sun, Jiwei; Cao, Fenglin

    2018-02-01

    Catechol-O-methyltransferase (COMT) Val 158 Met functional polymorphisms play a crucial role in the development of executive function (EF), but their effect may be moderated by environmental factors such as childhood adversity. The present study aimed at testing the divergent impact of the COMT Val 158 Met genotype on EF in non-clinical adolescents with discrete patterns of childhood adversity. A total of 341 participants completed the Childhood Trauma Questionnaire, the self-reported version of the Behavior Rating Inventory of Executive Function, and self-administered questionnaires on familial function. The participants' COMT Val 158 Met genotype was determined. Associations among the variables were explored using latent class analysis and general linear models. We found that Val/Val homozygotes showed significantly worse performance on behavioral shift, relative to Met allele carriers (F=5.921, p=0.015, Partial η 2 =0.018). Moreover, three typical patterns of childhood adversity, namely, low childhood adversity (23.5%), childhood neglect (59.8%), and high childhood adversity (16.7%), were found. Both childhood neglect and high childhood adversity had a negative impact on each aspect of EF and on global EF performance. Importantly, these results provided evidence for significant interaction effects, as adolescents with the Val/Val genotype showed inferior behavioral shift performance than Met carriers (F=6.647, p=0.010, Partial η 2 =0.020) in the presence of high childhood adversity. Furthermore, there were no differences between the genotypes for childhood neglect and low childhood adversity. Overall, this is the first study to show that an interaction between the COMT genotype and childhood adversity affects EF in non-clinical adolescents. These results suggest that the COMT genotype may operate as a susceptibility gene vulnerable to an adverse environment. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. The impact of brain-derived neurotrophic factor Val66Met polymorphism on cognition and functional brain networks in patients with intractable partial epilepsy.

    PubMed

    Sidhu, Meneka K; Thompson, Pamela J; Wandschneider, Britta; Foulkes, Alexandra; de Tisi, Jane; Stretton, Jason; Perona, Marina; Thom, Maria; Bonelli, Silvia B; Burdett, Jane; Williams, Elaine; Duncan, John S; Matarin, Mar

    2018-06-27

    Medial temporal lobe epilepsy (mTLE) is the most common refractory focal epilepsy in adults. Around 30%-40% of patients have prominent memory impairment and experience significant postoperative memory and language decline after surgical treatment. BDNF Val66Met polymorphism has also been associated with cognition and variability in structural and functional hippocampal indices in healthy controls and some patient groups. We examined whether BDNF Val66Met variation was associated with cognitive impairment in mTLE. In this study, we investigated the association of Val66Met polymorphism with cognitive performance (n = 276), postoperative cognitive change (n = 126) and fMRI activation patterns during memory encoding and language paradigms in 2 groups of patients with mTLE (n = 37 and 34). mTLE patients carrying the Met allele performed more poorly on memory tasks and showed reduced medial temporal lobe activation and reduced task-related deactivations within the default mode networks in both the fMRI memory and language tasks than Val/Val patients. Although cognitive impairment in epilepsy is the result of a complex interaction of factors, our results suggest a role of genetic factors on cognitive impairment in mTLE. © 2018 John Wiley & Sons Ltd.

  16. Performance characteristics of NuVal and the Overall Nutritional Quality Index (ONQI).

    PubMed

    Katz, David L; Njike, Valentine Y; Rhee, Lauren Q; Reingold, Arthur; Ayoob, Keith T

    2010-04-01

    Improving diets has considerable potential to improve health, but progress in this area has been limited, and advice to increase fruit and vegetable intake has largely gone unheeded. Our objective was to test the performance characteristics of the Overall Nutritional Quality Index (ONQI), a tool designed to help improve dietary patterns one well-informed choice at a time. The ONQI was developed by a multidisciplinary group of nutrition and public health scientists independent of food industry interests and is the basis for the NuVal Nutritional Guidance System. Dietary guidelines, existing nutritional scoring systems, and other pertinent scientific literature were reviewed. An algorithm incorporating >30 entries that represent both micro- and macronutrient properties of foods, as well as weighting coefficients representing epidemiologic associations between nutrients and health outcomes, was developed and subjected to consumer research and testing of performance characteristics. ONQI and expert panel rankings correlated highly (R = 0.92, P < 0.001). In consumer testing, approximately 80% of >800 study participants indicated that the ONQI would influence their purchase intent. ONQI scoring distinguished the more-healthful DASH (Dietary Approaches to Stop Hypertension) diet (mean score: 46) from the typical American diet according to the National Health and Nutrition Examination Survey (NHANES) 2003-2006 (mean score: 26.5; P < 0.01). In linear regression analysis of the NHANES 2003-2006 populations (n = 15,900), the NuVal system was significantly associated with the Healthy Eating Index 2005 (P < 0.0001). Recently generated data from ongoing studies indicate favorable effects on purchase patterns and significant correlation with health outcomes in large cohorts of men and women followed for decades. NuVal offers universally applicable nutrition guidance that is independent of food industry interests and is supported by consumer research and scientific evaluation of

  17. Social Support in Older Individuals: The Role of the BDNF Val66Met Polymorphism

    PubMed Central

    Taylor, Warren D.; Züchner, Stephan; McQuoid, Douglas R.; Steffens, David C.; Blazer, Dan G.; Krishnan, K. Ranga R.

    2008-01-01

    Although often viewed as a purely environmental construct, perception of social support may be influenced by genetic factors. This study examined the relationship between the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and social support measures in older subjects. The sample consisted of 243 depressed and 115 nondepressed older subjects, age 60 years or older; 233 were Val66 allele homozygotes, while 125 were Met66 allele carriers. All subjects completed clinical assessments, including a self-report questionnaire assessing four social support domains, and provided blood for genotyping. Statistical models examined the relationship between scale scores of social support and BDNF Val66Met genotype, while controlling for presence or absence of major depressive disorder and other demographic factors significantly associated with social support. As social support measures were not normally distributed, log-transformed scores were examined. After controlling for diagnosis and education level, the Met66 allele was associated with lower levels of subjective social support (F1, 357 = 5.33, p = 0.0216) and a trend for fewer social interactions (F1, 357 = 3.66, p = 0.0567). To our knowledge, this is the first report associating a measure of social support with a genetic polymorphism. This supports previous work that genetic factors may influence social support perception. Further work is needed to determine the generalizability of this finding to the broader population, as well as its significance for clinical outcomes. PMID:18384075

  18. Age-Dependent Effects of Catechol-O-Methyltransferase (COMT) Gene Val158Met Polymorphism on Language Function in Developing Children.

    PubMed

    Sugiura, Lisa; Toyota, Tomoko; Matsuba-Kurita, Hiroko; Iwayama, Yoshimi; Mazuka, Reiko; Yoshikawa, Takeo; Hagiwara, Hiroko

    2017-01-01

    The genetic basis controlling language development remains elusive. Previous studies of the catechol-O-methyltransferase (COMT) Val158Met genotype and cognition have focused on prefrontally guided executive functions involving dopamine. However, COMT may further influence posterior cortical regions implicated in language perception. We investigated whether COMT influences language ability and cortical language processing involving the posterior language regions in 246 children aged 6-10 years. We assessed language ability using a language test and cortical responses recorded during language processing using a word repetition task and functional near-infrared spectroscopy. The COMT genotype had significant effects on language performance and processing. Importantly, Met carriers outperformed Val homozygotes in language ability during the early elementary school years (6-8 years), whereas Val homozygotes exhibited significant language development during the later elementary school years. Both genotype groups exhibited equal language performance at approximately 10 years of age. Val homozygotes exhibited significantly less cortical activation compared with Met carriers during word processing, particularly at older ages. These findings regarding dopamine transmission efficacy may be explained by a hypothetical inverted U-shaped curve. Our findings indicate that the effects of the COMT genotype on language ability and cortical language processing may change in a narrow age window of 6-10 years. © The Author 2016. Published by Oxford University Press.

  19. Role of Superoxide Dismutase 2 Gene Ala16Val Polymorphism and Total Antioxidant Capacity in Diabetes and its Complications

    PubMed Central

    Pourvali, Katayoun; Abbasi, Mehrnaz; Mottaghi, Azadeh

    2016-01-01

    Diabetes Mellitus (DM) is a chronic heterogeneous disorder and oxidative stress is a key participant in the development and progression of it and its complications. Anti-oxidant status can affect vulnerability to oxidative damage, onset and progression of diabetes and diabetes complications. Superoxide dismutase 2 (SOD2) is one of the major antioxidant defense systems against free radicals. SOD2 is encoded by the nuclear SOD2 gene located on the human chromosome 6q25 and the Ala16Val polymorphism has been identified in exon 2 of the human SOD2 gene. Ala16Val (rs4880) is the most commonly studied SOD2 single nucleotide polymorphism (SNP) in SOD2 gene. This SNP changes the amino acid at position 16 from valine (Val) to alanine (Ala), which has been shown to cause a conformational change in the target sequence of manganese superoxide dismutase (MnSOD) and also affects MnSOD activity in mitochondria. Ala16Val SNP and changes in the activity of the SOD2 antioxidant enzyme have been associated with altered progression and risk of different diseases. Association of this SNP with diabetes and some of its complications have been studied in numerous studies. This review evaluated how rs4880, oxidative stress and antioxidant status are associated with diabetes and its complications although some aspects of this line still remain unclear. PMID:27141263

  20. Modulating effect of COMT Val(158)Met polymorphism on interference resolution during a working memory task.

    PubMed

    Jaspar, Mathieu; Dideberg, Vinciane; Bours, Vincent; Maquet, Pierre; Collette, Fabienne

    2015-04-01

    Genetic variability related to the catechol-O-methyltransferase (COMT) gene has received increasing attention in the last 15years, in particular as a potential modulator of the neural substrates underlying inhibitory processes and updating in working memory (WM). In an event-related functional magnetic resonance imaging (fMRI) study, we administered a modified version of the Sternberg probe recency task (Sternberg, 1966) to 43 young healthy volunteers, varying the level of interference across successive items. The task was divided into two parts (high vs. low interference) to induce either proactive or reactive control processes. The participants were separated into three groups according to their COMT Val(158)Met genotype [Val/Val (VV); Val/Met (VM); Met/Met (MM)]. The general aim of the study was to determine whether COMT polymorphism has a modulating effect on the neural substrates of interference resolution during WM processing. Results indicate that interfering trials were associated with greater involvement of frontal cortices (bilateral medial frontal gyrus, left precentral and superior frontal gyri, right inferior frontal gyrus) in VV homozygous subjects (by comparison to Met allele carriers) only in the proactive condition of the task. In addition, analysis of peristimulus haemodynamic responses (PSTH) revealed that the genotype-related difference observed in the left SFG was specifically driven by a larger increase in activity from the storage to the recognition phase of the interfering trials in VV homozygous subjects. These results confirm the impact of COMT genotype on inhibitory processes during a WM task, with an advantage for Met allele carriers. Interestingly, this impact on frontal areas is present only when the level of interference is high, and especially during the transition from storage to recognition in the left superior frontal gyrus. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. Catechol-O-methyltransferase Val(158)Met association with parahippocampal physiology during memory encoding in schizophrenia.

    PubMed

    Di Giorgio, A; Caforio, G; Blasi, G; Taurisano, P; Fazio, L; Romano, R; Ursini, G; Gelao, B; Bianco, L Lo; Papazacharias, A; Sinibaldi, L; Popolizio, T; Bellomo, A; Bertolino, A

    2011-08-01

    Catechol-O-methyltransferase (COMT) Val158Met has been associated with activity of the mesial temporal lobe during episodic memory and it may weakly increase risk for schizophrenia. However, how this variant affects parahippocampal and hippocampal physiology when dopamine transmission is perturbed is unclear. The aim of the present study was to compare the effects of the COMT Val158Met genotype on parahippocampal and hippocampal physiology during encoding of recognition memory in patients with schizophrenia and in healthy subjects. Using blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI), we studied 28 patients with schizophrenia and 33 healthy subjects matched for a series of sociodemographic and genetic variables while they performed a recognition memory task. We found that healthy subjects had greater parahippocampal and hippocampal activity during memory encoding compared to patients with schizophrenia. We also found different activity of the parahippocampal region between healthy subjects and patients with schizophrenia as a function of the COMT genotype, in that the predicted COMT Met allele dose effect had an opposite direction in controls and patients. Our results demonstrate a COMT Val158Met genotype by diagnosis interaction in parahippocampal activity during memory encoding and may suggest that modulation of dopamine signaling interacts with other disease-related processes in determining the phenotype of parahippocampal physiology in schizophrenia. © Cambridge University Press 2010

  2. ALA16VAL-MnSOD gene polymorphism and stroke: Association with dyslipidemia and glucose levels.

    PubMed

    Flores, Ariane Ethur; Pascotini, Eduardo Tanuri; Kegler, Aline; Gabbi, Patricia; Bochi, Guilherme Vargas; Barbisan, Fernanda; Duarte, Thiago; Prado, Ana Lucia Cervi; Duarte, Marta M M F; da Cruz, Ivana B M; Moresco, Rafael Noal; Santos, Adair Roberto Soares; Bresciani, Guilherme; Royes, Luiz Fernando Freire; Fighera, Michele Rechia

    2017-09-05

    Stroke risk has been associated to the progression of carotid plaques due to high glucose levels and lipid accumulation, which are greatly associated to cerebral injury, brain oxidative stress, and apoptosis. The ALA16VAL-MnSOD gene single nucleotide polymorphism (SNP) has shown to modulate risk factors of several metabolic and vascular diseases, such as blood glucose (GLU) and lipid levels. However, the association of these factors in stroke patients has not been studied to date. Thus, we evaluated the influence of the Ala16Val-MnSOD SNP on lipid profile, GLU levels, oxidative and DNA damage of 44 patients in a late phase of stroke (>6months). The statistical analysis showed a greater proportion of VV carries in stroke patients. The results also indicated that stroke patients had higher cholesterol (CHO) and GLU levels when compared to healthy counterparts. Interestingly, V allele carriers with stroke showed higher levels of CHO and GLU when compared to AA stroke and healthy counterparts. Our findings suggest that oxidative stress markers are still increased even after 6 months of cerebral injury. Furthermore, we propose that the Ala16Val-MnSOD SNPs may contribute to hypercholesterolemia and higher GLU levels, increasing the risk to neurovascular events that may lead to stroke. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Brain-derived neurotrophic factor Val66met polymorphism and plasma levels in road traffic accident survivors.

    PubMed

    van den Heuvel, Leigh; Suliman, Sharain; Malan-Müller, Stefanie; Hemmings, Sian; Seedat, Soraya

    2016-11-01

    Alterations in brain-derived neurotrophic factor (BDNF) expression and release may play a role in the pathogenesis of post-traumatic stress disorder (PTSD). This study evaluated road traffic accident (RTA) survivors to determine whether PTSD and trauma-related factors were associated with plasma BDNF levels and BDNF Val66Met carrier status following RTA exposure. One hundred and twenty-three RTA survivors (mean age 33.2 years, SD = 10.6 years; 56.9% male) were assessed 10 (SD = 4.9) days after RTA exposure. Acute stress disorder (ASD), as assessed with the Acute Stress Disorder Scale, was present in 50 (42.0%) of the participants. Plasma BDNF levels were measured with enzyme-linked immunosorbent assay and BDNF Val66Met genotyping was performed. PTSD, as assessed with the Clinician-Administered PTSD Scale, was present in 10 (10.8%) participants at 6 months follow-up. Neither BDNF Val66Met genotype nor plasma BDNF was significantly associated with the presence or severity of ASD or PTSD. Plasma BDNF levels were, however, significantly correlated with the lifetime number of trauma exposures. In RTA survivors, plasma BDNF levels increased with increasing number of prior trauma exposures. Plasma BDNF may, therefore, be a marker of trauma load.

  4. [Anxiety and polymorphism Val66Met of BDNF gene--predictors of depression severity in ischemic heart disease].

    PubMed

    Golimbet, V E; Volel', B A; Kopylov, F Iu; Dolzhikov, A V; Korovaitseva, G I; Kasparov, S V; Isaeva, M I

    2015-01-01

    In a framework of search for early predictors of depression in patients with ischemic heart disease (IHD) we studied effect of molecular-genetic factors (polymorphism of brain-derived neirotrophic factor--BDNF), personality traits (anxiety, neuroticism), IHD severity, and psychosocial stressors on manifestations of depression in men with verified diagnosis of IHD. Severity of depression was assessed by Hamilton Depression Rating Scale 21-item (HAMD 21), anxiety and neuroticism were evaluated by the Spielberger State-Trait Anxiety Inventory and "Big Five" questionnaire, respectively. It wa shown that personal anxiety and ValVal genotype of BDNF gene appeared to be predictors of moderate and severe depression.

  5. The role of brain-derived neurotrophic factor (BDNF) Val66Met genetic polymorphism in bipolar disorder: a case-control study, comorbidities, and meta-analysis of 16,786 subjects.

    PubMed

    González-Castro, Thelma Beatriz; Nicolini, Humberto; Lanzagorta, Nuria; López-Narváez, Lilia; Genis, Alma; Pool García, Sherezada; Tovilla-Zárate, Carlos Alfonso

    2015-02-01

    The aim of this study was to evaluate the association of Val66Met brain-derived neurotrophic factor (BDNF) polymorphism with bipolar disorder in (i) a meta-analysis and (ii) a case-control study in a Mexican population. We also investigated the possible association of this polymorphism with clinical features. We performed a keyword search of the PubMed and Web of Science databases. A total of 22 studies that have investigated the association of Val66Met (rs6265) with bipolar disorder were selected for inclusion and combined with random effects meta-analysis, using allelic, additive, dominant, and recessive models. Finally, the single nucleotide polymorphism (rs6265) Val66Met in the BDNF gene was genotyped and compared between 139 patients with bipolar disorder and 141 healthy volunteers in a Mexican population. The pooled results from the meta-analysis (9,349 cases and 7,437 controls) did not show a significant association in any of the models. The same results were obtained in our case-control study when analyzing the distribution of the genotypic frequencies of the Val66Met polymorphism in patients with bipolar disorder. However, when we analyzed the association between rs6265 and lifetime history of suicidal behavior, we found an association between genotype Val-Val and suicide attempt (p = 0.02). Although the present study has some limitations, the results indicate a lack of association between the Val66Met polymorphism and bipolar disorder. However, in our case-control study in a Mexican population, the Val66Met polymorphism was associated with suicidal behavior in patients with bipolar disorder. Nevertheless, it is important to consider potential interactions of the BDNF gene, the environment, and different inheritance patterns, when carrying out future genetic studies with larger samples. © 2014 The Authors. Bipolar Disorders Published by John Wiley & Sons Ltd.

  6. The rare DAT coding variant Val559 perturbs DA neuron function, changes behavior, and alters in vivo responses to psychostimulants.

    PubMed

    Mergy, Marc A; Gowrishankar, Raajaram; Gresch, Paul J; Gantz, Stephanie C; Williams, John; Davis, Gwynne L; Wheeler, C Austin; Stanwood, Gregg D; Hahn, Maureen K; Blakely, Randy D

    2014-11-04

    Despite the critical role of the presynaptic dopamine (DA) transporter (DAT, SLC6A3) in DA clearance and psychostimulant responses, evidence that DAT dysfunction supports risk for mental illness is indirect. Recently, we identified a rare, nonsynonymous Slc6a3 variant that produces the DAT substitution Ala559Val in two male siblings who share a diagnosis of attention-deficit hyperactivity disorder (ADHD), with other studies identifying the variant in subjects with bipolar disorder (BPD) and autism spectrum disorder (ASD). Previously, using transfected cell studies, we observed that although DAT Val559 displays normal total and surface DAT protein levels, and normal DA recognition and uptake, the variant transporter exhibits anomalous DA efflux (ADE) and lacks capacity for amphetamine (AMPH)-stimulated DA release. To pursue the significance of these findings in vivo, we engineered DAT Val559 knock-in mice, and here we demonstrate in this model the presence of elevated extracellular DA levels, altered somatodendritic and presynaptic D2 DA receptor (D2R) function, a blunted ability of DA terminals to support depolarization and AMPH-evoked DA release, and disruptions in basal and psychostimulant-evoked locomotor behavior. Together, our studies demonstrate an in vivo functional impact of the DAT Val559 variant, providing support for the ability of DAT dysfunction to impact risk for mental illness.

  7. The rare DAT coding variant Val559 perturbs DA neuron function, changes behavior, and alters in vivo responses to psychostimulants

    PubMed Central

    Mergy, Marc A.; Gowrishankar, Raajaram; Gresch, Paul J.; Gantz, Stephanie C.; Williams, John; Davis, Gwynne L.; Wheeler, C. Austin; Stanwood, Gregg D.; Hahn, Maureen K.; Blakely, Randy D.

    2014-01-01

    Despite the critical role of the presynaptic dopamine (DA) transporter (DAT, SLC6A3) in DA clearance and psychostimulant responses, evidence that DAT dysfunction supports risk for mental illness is indirect. Recently, we identified a rare, nonsynonymous Slc6a3 variant that produces the DAT substitution Ala559Val in two male siblings who share a diagnosis of attention-deficit hyperactivity disorder (ADHD), with other studies identifying the variant in subjects with bipolar disorder (BPD) and autism spectrum disorder (ASD). Previously, using transfected cell studies, we observed that although DAT Val559 displays normal total and surface DAT protein levels, and normal DA recognition and uptake, the variant transporter exhibits anomalous DA efflux (ADE) and lacks capacity for amphetamine (AMPH)-stimulated DA release. To pursue the significance of these findings in vivo, we engineered DAT Val559 knock-in mice, and here we demonstrate in this model the presence of elevated extracellular DA levels, altered somatodendritic and presynaptic D2 DA receptor (D2R) function, a blunted ability of DA terminals to support depolarization and AMPH-evoked DA release, and disruptions in basal and psychostimulant-evoked locomotor behavior. Together, our studies demonstrate an in vivo functional impact of the DAT Val559 variant, providing support for the ability of DAT dysfunction to impact risk for mental illness. PMID:25331903

  8. Brain-derived neurotrophic factor Val66Met genotype modulates amygdala habituation.

    PubMed

    Perez-Rodriguez, M Mercedes; New, Antonia S; Goldstein, Kim E; Rosell, Daniel; Yuan, Qiaoping; Zhou, Zhifeng; Hodgkinson, Colin; Goldman, David; Siever, Larry J; Hazlett, Erin A

    2017-05-30

    A deficit in amygdala habituation to repeated emotional stimuli may be an endophenotype of disorders characterized by emotion dysregulation, such as borderline personality disorder (BPD). Amygdala reactivity to emotional stimuli is genetically modulated by brain-derived neurotrophic factor (BDNF) variants. Whether amygdala habituation itself is also modulated by BDNF genotypes remains unknown. We used imaging-genetics to examine the effect of BDNF Val66Met genotypes on amygdala habituation to repeated emotional stimuli. We used functional magnetic resonance imaging (fMRI) in 57 subjects (19 BPD patients, 18 patients with schizotypal personality disorder [SPD] and 20 healthy controls [HC]) during a task involving viewing of unpleasant, neutral, and pleasant pictures, each presented twice to measure habituation. Amygdala responses across genotypes (Val66Met SNP Met allele-carriers vs. Non-Met carriers) and diagnoses (HC, BPD, SPD) were examined with ANOVA. The BDNF 66Met allele was significantly associated with a deficit in amygdala habituation, particularly for emotional pictures. The association of the 66Met allele with a deficit in habituation to unpleasant emotional pictures remained significant in the subsample of BPD patients. Using imaging-genetics, we found preliminary evidence that deficient amygdala habituation may be modulated by BDNF genotype. Copyright © 2017. Published by Elsevier B.V.

  9. Calculation of Half-Metal, Debye and Curie Temperatures of Co2VAl Compound: First Principles Study

    NASA Astrophysics Data System (ADS)

    Arash, Boochani; Heidar, Khosravi; Jabbar, Khodadadi; Shahram, Solaymani; Masoud Majidiyan, Sarmazdeh; Rohollah Taghavi, Mendi; Sayed, Mohammad Elahi

    2015-05-01

    By FP-LAPW calculations, the structural, elastic, Debye and Curie temperatures, electronic and magnetic properties of Co2 VAl are investigated. The results indicate that Ferromagnetic (FM) phase is more stable than Anti-Ferromagnetic (AFM) and Non-magnetic (NM) ones. In addition, C11-C12 > 0, C44 > 0, and B > 0 so Co2VAl is an elastically stable material with high Debye temperature. Also, the B/G ratio exhibits a ductility behavior. The relatively high Curie temperature provides it as a favorable material for spintronic application. It's electronic and magnetic properties are studied by GGA+U approach leading to a 100% spin polarization at Fermi level. Supported by the simulation of Nano Physics Lab center of Kermanshah Branch, Islamic Azad University

  10. Brain-Derived Neurotrophic Factor Val66Met Polymorphism Affects the Relationship Between an Anxiety-Related Personality Trait and Resting Regional Cerebral Blood Flow.

    PubMed

    Wei, Shau-Ming; Eisenberg, Daniel P; Nabel, Katherine G; Kohn, Philip D; Kippenhan, J Shane; Dickinson, Dwight; Kolachana, Bhaskar; Berman, Karen F

    2017-03-01

    Brain-derived neurotrophic factor (BDNF) is an important modulator of constitutive stress responses mediated by limbic frontotemporal circuits, and its gene contains a functional polymorphism (Val66Met) that may influence trait stress sensitivity. Reports of an association of this polymorphism with anxiety-related personality traits have been controversial and without clear neurophysiological support. We, therefore, determined the relationship between resting regional cerebral blood flow (rCBF) and a well-validated measure of anxiety-related personality, the TPQ Harm Avoidance (HA) scale, as a function of BDNF Val66Met genotype. Sixty-four healthy participants of European ancestry underwent resting H215O positron emission tomography scans. For each genotype group separately, we first determined the relationship between participants' HA scores and their resting rCBF values in each voxel across the entire brain, and then directly compared these HA-rCBF relationships between Val66Met genotype groups. HA-rCBF relationships differed between Val homozygotes and Met carriers in several regions relevant to stress regulation: subgenual cingulate, orbital frontal cortex, and the hippocampal/parahippocampal region. In each of these areas, the relationship was positive in Val homozygotes and negative in Met carriers. These data demonstrate a coupling between trait anxiety and basal resting blood flow in frontolimbic neurocircuitry that may be determined in part by genetically mediated BDNF signaling. Published by Oxford University Press 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.

  11. Genotypes do not confer risk for delinquency but rather alter susceptibility to positive and negative environmental factors: gene-environmentinteractions of BDNF Val66Met, 5-HTTLPR, and MAOA-uVNTR [corrected].

    PubMed

    Nilsson, Kent W; Comasco, Erika; Hodgins, Sheilagh; Oreland, Lars; Åslund, Cecilia

    2014-12-10

    Previous evidence of gene-by-environment interactions associated with emotional and behavioral disorders is contradictory. Differences in findings may result from variation in valence and dose of the environmental factor, and/or failure to take account of gene-by-gene interactions. The present study investigated interactions between the brain-derived neurotrophic factor gene (BDNF Val66Met), the serotonin transporter gene-linked polymorphic region (5-HTTLPR), the monoamine oxidase A (MAOA-uVNTR) polymorphisms, family conflict, sexual abuse, the quality of the child-parent relationship, and teenage delinquency. In 2006, as part of the Survey of Adolescent Life in Västmanland, Sweden, 1 337 high-school students, aged 17-18 years, anonymously completed questionnaires and provided saliva samples for DNA analyses. Teenage delinquency was associated with two-, three-, and four-way interactions of each of the genotypes and the three environmental factors. Significant four-way interactions were found for BDNF Val66Met × 5-HTTLPR×MAOA-uVNTR × family conflicts and for BDNF Val66Met × 5-HTTLPR×MAOA-uVNTR × sexual abuse. Further, the two genotype combinations that differed the most in expression levels (BDNF Val66Met Val, 5-HTTLPR LL, MAOA-uVNTR LL [girls] and L [boys] vs BDNF Val66Met Val/Met, 5-HTTLPR S/LS, MAOA-uVNTR S/SS/LS) in interaction with family conflict and sexual abuse were associated with the highest delinquency scores. The genetic variants previously shown to confer vulnerability for delinquency (BDNF Val66Met Val/Met × 5-HTTLPR S × MAOA-uVNTR S) were associated with the lowest delinquency scores in interaction with a positive child-parent relationship. Functional variants of the MAOA-uVNTR, 5-HTTLPR, and BDNF Val66Met, either alone or in interaction with each other, may be best conceptualized as modifying sensitivity to environmental factors that confer either risk or protection for teenage delinquency. © The Author 2015. Published by Oxford University

  12. Genotypes Do Not Confer Risk For Delinquency ut Rather Alter Susceptibility to Positive and Negative Environmental Factors: Gene-Environment Interactions of BDNF Val66Met, 5-HTTLPR, and MAOA-uVNTR

    PubMed Central

    Comasco, Erika; Hodgins, Sheilagh; Oreland, Lars; Åslund, Cecilia

    2015-01-01

    Background: Previous evidence of gene-by-environment interactions associated with emotional and behavioral disorders is contradictory. Differences in findings may result from variation in valence and dose of the environmental factor, and/or failure to take account of gene-by-gene interactions. The present study investigated interactions between the brain-derived neurotrophic factor gene (BDNF Val66Met), the serotonin transporter gene-linked polymorphic region (5-HTTLPR), the monoamine oxidase A (MAOA-uVNTR) polymorphisms, family conflict, sexual abuse, the quality of the child-parent relationship, and teenage delinquency. Methods: In 2006, as part of the Survey of Adolescent Life in Västmanland, Sweden, 1 337 high-school students, aged 17–18 years, anonymously completed questionnaires and provided saliva samples for DNA analyses. Results: Teenage delinquency was associated with two-, three-, and four-way interactions of each of the genotypes and the three environmental factors. Significant four-way interactions were found for BDNF Val66Met × 5-HTTLPR×MAOA-uVNTR × family conflicts and for BDNF Val66Met × 5-HTTLPR×MAOA-uVNTR × sexual abuse. Further, the two genotype combinations that differed the most in expression levels (BDNF Val66Met Val, 5-HTTLPR LL, MAOA-uVNTR LL [girls] and L [boys] vs BDNF Val66Met Val/Met, 5-HTTLPR S/LS, MAOA-uVNTR S/SS/LS) in interaction with family conflict and sexual abuse were associated with the highest delinquency scores. The genetic variants previously shown to confer vulnerability for delinquency (BDNF Val66Met Val/Met × 5-HTTLPR S × MAOA-uVNTR S) were associated with the lowest delinquency scores in interaction with a positive child-parent relationship. Conclusions: Functional variants of the MAOA-uVNTR, 5-HTTLPR, and BDNF Val66Met, either alone or in interaction with each other, may be best conceptualized as modifying sensitivity to environmental factors that confer either risk or protection for teenage delinquency. PMID

  13. ValWorkBench: an open source Java library for cluster validation, with applications to microarray data analysis.

    PubMed

    Giancarlo, R; Scaturro, D; Utro, F

    2015-02-01

    The prediction of the number of clusters in a dataset, in particular microarrays, is a fundamental task in biological data analysis, usually performed via validation measures. Unfortunately, it has received very little attention and in fact there is a growing need for software tools/libraries dedicated to it. Here we present ValWorkBench, a software library consisting of eleven well known validation measures, together with novel heuristic approximations for some of them. The main objective of this paper is to provide the interested researcher with the full software documentation of an open source cluster validation platform having the main features of being easily extendible in a homogeneous way and of offering software components that can be readily re-used. Consequently, the focus of the presentation is on the architecture of the library, since it provides an essential map that can be used to access the full software documentation, which is available at the supplementary material website [1]. The mentioned main features of ValWorkBench are also discussed and exemplified, with emphasis on software abstraction design and re-usability. A comparison with existing cluster validation software libraries, mainly in terms of the mentioned features, is also offered. It suggests that ValWorkBench is a much needed contribution to the microarray software development/algorithm engineering community. For completeness, it is important to mention that previous accurate algorithmic experimental analysis of the relative merits of each of the implemented measures [19,23,25], carried out specifically on microarray data, gives useful insights on the effectiveness of ValWorkBench for cluster validation to researchers in the microarray community interested in its use for the mentioned task. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  14. The VALS: A new tool to measure people's general valued attributes of landscapes.

    PubMed

    Kendal, Dave; Ford, Rebecca M; Anderson, Nerida M; Farrar, Alison

    2015-11-01

    Research on values for natural areas has largely focussed on theoretical concerns such as distinguishing different kinds of values held by people. However practice, policymaking, planning and management is typically focused on more tangible valued attributes of the landscape such as biodiversity and recreation infrastructure that can be manipulated by management actions. There is a need for valid psychometric measures of such values that are suited to informing land management policies. A Valued Attributes of Landscape Scale (VALS) was developed, derived from a document analysis of values expressed in public land policy documents. The validity of the VALS was tested in an online survey comparing values across one of three randomly presented landscape contexts in Victoria, Australia: all publicly managed natural land, coastal areas, and large urban parks. A purposive snowball sample was used to recruit participants with a range of views and professional experience with land management, including members of the urban public. Factor analysis of responses (n = 646) separated concepts relating to natural attributes, social functions, the experience of being in natural areas, cultural attributes and productive uses. Relative importance of valued attribute factors was similar across all landscape contexts, although there were small but significant differences in the way people valued social functions (higher in urban parks) and productive uses (lower in urban parks). We conclude that the concept of valued attributes is useful for linking theoretical understandings of people's environmental values to the way values are considered by land managers, and that these attributes can be measured using the VALS instrument to produce data that should be useful for the policy and planning of natural resources. Copyright © 2015 Elsevier Ltd. All rights reserved.

  15. The Effects of a BDNF Val66Met Polymorphism on Posttraumatic Stress Disorder: A Meta-Analysis.

    PubMed

    Bountress, Kaitlin E; Bacanu, Silviu-Alin; Tomko, Rachel L; Korte, Kristina J; Hicks, Terrell; Sheerin, Christina; Lind, Mackenzie J; Marraccini, Marisa; Nugent, Nicole; Amstadter, Ananda B

    2018-06-06

    Given evidence that posttraumatic stress disorder (PTSD) is moderately heritable, a number of studies utilizing candidate gene approaches have attempted to examine the potential contributions of theoretically relevant genetic variation. Some of these studies have found sup port for a brain-derived neurotrophic factor (BDNF) variant, Val66Met, in the risk of developing PTSD, while others have failed to find this link. This study sought to reconcile these conflicting findings using a meta-analysis framework. Analyses were also used to determine whether there is significant heterogeneity in the link between this variant and PTSD. We conducted a systematic review of the literature on BDNF and PTSD from the PsycINFO and PubMed databases. A total of 11 studies were included in the analysis. Findings indicate a marginally significant effect of the BDNF Val66Met variant on PTSD (p < 0.1). However, of the 11 studies included, only 2 suggested an effect with a non-zero confidence interval, one of which showed a z score of 3.31. We did not find any evidence for heterogeneity. Findings from this meta-analytic investigation of the published literature provide little support for the Val66Met variant of BDNF as a predictor of PTSD. Future well-powered agnostic genome-wide association studies with more refined phenotyping are needed to clarify genetic influences on PTSD. © 2018 S. Karger AG, Basel.

  16. Construction of a New Phage Integration Vector pFIV-Val for Use in Different Francisella Species

    PubMed Central

    Tlapák, Hana; Köppen, Kristin; Rydzewski, Kerstin; Grunow, Roland; Heuner, Klaus

    2018-01-01

    We recently identified and described a putative prophage on the genomic island FhaGI-1 located within the genome of Francisella hispaniensis AS02-814 (F. tularensis subsp. novicida-like 3523). In this study, we constructed two variants of a Francisella phage integration vector, called pFIV1-Val and pFIV2-Val (Francisella Integration Vector-tRNAVal-specific), using the attL/R-sites and the site-specific integrase (FN3523_1033) of FhaGI-1, a chloramphenicol resistance cassette and a sacB gene for counter selection of transformants against the vector backbone. We inserted the respective sites and genes into vector pUC57-Kana to allow for propagation in Escherichia coli. The constructs generated a circular episomal form in E. coli which could be used to transform Francisella spp. where FIV-Val stably integrated site specifically into the tRNAVal gene of the genome, whereas pUC57-Kana is lost due to counter selection. Functionality of the new vector was demonstrated by the successfully complementation of a Francisella mutant strain. The vectors were stable in vitro and during host-cell infection without selective pressure. Thus, the vectors can be applied as a further genetic tool in Francisella research, expanding the present genetic tools by an integrative element. This new element is suitable to perform long-term experiments with different Francisella species. PMID:29594068

  17. Plasma BDNF Concentration, Val66Met Genetic Variant, and Depression-Related Personality Traits

    PubMed Central

    Terracciano, Antonio; Martin, Bronwen; Ansari, David; Tanaka, Toshiko; Ferrucci, Luigi; Maudsley, Stuart; Mattson, Mark P.; Costa, Paul T.

    2010-01-01

    Brain derived neurotrophic factor (BDNF) regulates synaptic plasticity and neurogenesis, and BDNF plasma and serum levels have been associated with depression, Alzheimer's disease, and other psychiatric and neurodegenerative disorders. In a relatively large community sample, drawn from the Baltimore Longitudinal Study of Aging (BLSA), we examine whether BDNF plasma concentration is associated with the Val66Met functional polymorphism of the BDNF gene (n = 335) and with depression-related personality traits assessed with the NEO-PI-R (n = 391). Plasma concentration of BDNF was not associated with the Val66Met variant in either men or women. However, in men, but not in women, BDNF plasma level was associated with personality traits linked to depression. Contrary to the notion that low BDNF is associated with negative outcomes, we found lower plasma levels in men who score lower on depression and vulnerability to stress (two facets of Neuroticism) and higher on Conscientiousness and Extraversion. These findings challenge the prevailing hypothesis that lower peripheral levels of BDNF are a marker of depression. PMID:20345896

  18. Association of the Catechol-O-Methyltransferase (COMT) Val158Met Polymorphism and Anxiety-Related Traits: A Meta-Analysis

    PubMed Central

    Lee, Lewina O.; Prescott, Carol A.

    2014-01-01

    Objectives The main goals of this study were: (i) to examine genotypic association of the COMT val158met polymorphism with anxiety-related traits via a meta-analysis; (ii) to examine sex and ethnicity as moderators of the association, and (iii) to evaluate whether the association differed by particular anxiety traits. Methods Association studies of the COMT val18met polymorphism and anxiety traits were identified from the PubMed or PsycInfo databases, conference abstracts and listserv postings. Exclusion criteria were: (a) pediatric samples, (b) exclusively clinical samples, and (c) samples selected for a non-anxiety phenotype. Standardized mean differences in anxiety between genotypes were aggregated to produce mean effect sizes across all available samples, and for subgroups stratified by sex and ethnicity (Caucasians vs. Asians). Construct-specific analysis was conducted to evaluate the association of COMT with neuroticism, harm avoidance, and behavioral inhibition. Results Twenty seven eligible studies (N=15,979) with available data were identified. Overall findings indicate sex-specific and ethnic-specific effects: Val homozygotes had higher neuroticism than Met homozygotes in studies of Caucasian males ( ES¯=0.13, 95%CI: 0.02 – 0.25, p = 0.03), and higher harm avoidance in studies of Asian males ( ES¯=0.43, 95%CI: 0.14 – 0.72, p = 0.004). No significant associations were found in women and effect sizes were diminished when studies were aggregated across ethnicity or anxiety traits. Conclusions: This meta-analysis provides evidence for sex and ethnicity differences in the association of the COMT val158met polymorphism with anxiety traits. Our findings contribute to current knowledge on the relation between prefrontal dopaminergic transmission and anxiety. PMID:24300663

  19. MTHFR 677C --> T genotype disrupts prefrontal function in schizophrenia through an interaction with COMT 158Val --> Met.

    PubMed

    Roffman, Joshua L; Gollub, Randy L; Calhoun, Vince D; Wassink, Thomas H; Weiss, Anthony P; Ho, Beng C; White, Tonya; Clark, Vincent P; Fries, Jill; Andreasen, Nancy C; Goff, Donald C; Manoach, Dara S

    2008-11-11

    Understanding how risk genes cumulatively impair brain function in schizophrenia could provide critical insights into its pathophysiology. Working memory impairment in schizophrenia has been associated with abnormal dopamine signaling in the prefrontal cortex, which is likely under complex genetic control. The catechol-O-methyltransferase (COMT) 158Val --> Met polymorphism (rs4680), which affects the availability of prefrontal dopamine signaling, consistently stratifies prefrontal activation during working memory performance. However, the low-dopamine COMT 158Val allele does not confer increased risk for schizophrenia, and its effects on prefrontal function are not specific to the disorder. In the setting of other genetic variants influencing prefrontal dopamine signaling, COMT 158Val --> Met genotype may exert disease-specific effects. A second polymorphism, methylenetetrahydrofolate reductase (MTHFR) 677C --> T (rs1801133), has been associated with overall schizophrenia risk and executive function impairment in patients, and may influence dopamine signaling through mechanisms upstream of COMT effects. We found that the hypofunctional 677T variant was associated with decreased working memory load-dependent activation in the prefrontal and insular cortices in 79 schizophrenia patients, but not in 75 demographically matched healthy controls. Further, significant MTHFR x COMT genotype interactions were observed, which differed by diagnostic group: Reduced prefrontal activation was associated with the 677T and 158Val alleles in patients, but with 677C/C and 158Met/Met genotype in controls. These findings are consistent with epistatic effects of the COMT and MTHFR polymorphisms on prefrontal dopamine signaling, and suggest that in schizophrenia patients, the MTHFR 677T allele exacerbates prefrontal dopamine deficiency. The findings also suggest the importance of weighing COMT effects on prefrontal function within the context of MTHFR genotype.

  20. BDNF Val66Met polymorphism and plasma levels in Chinese Han population with obsessive-compulsive disorder and generalized anxiety disorder.

    PubMed

    Wang, Yuan; Zhang, Haiyin; Li, Ying; Wang, Zhen; Fan, Qing; Yu, Shunying; Lin, Zhiguang; Xiao, Zeping

    2015-11-01

    Anxiety disorders are a category of mental disorders characterized by feelings of anxiety and fear, which include generalized anxiety disorder (GAD). Obsessive-Compulsive Disorder (OCD) used to be categorized as anxiety disorder in DSM-IV. However OCD was no longer included in anxiety disorders and came into its own category titled as Obsessive-Compulsive and Related Disorders (OCRD) in DSM-5. It will be interesting to explore is there any different biological characteristics between OCD and anxiety disorders. Brain-derived neurotrophic factor (BDNF) was a potential candidate gene in both OCD and GAD. The results of genetic association studies between BDNF and OCD have been inconsistent. BDNF plasma/serum levels in OCD have been found lower than those in healthy controls. However the heritable reason of the lowered BDNF levels was not well elucidated. The amount of studies about BDNF and GAD were relatively small. The aims of this study were to determine whether single nucleotide polymorphism Val66Met of BDNF was associated with OCD and GAD, to examine BDNF plasma levels in OCD and GAD, and to explore whether Val66Met variation influences BDNF plasma levels. We genotyped Val66Met variation in 148 OCD patients, 108 GAD patients and 99 healthy controls. Within the same sample, BDNF plasma levels were determined in 113 OCD patients, 102 GAD patients and 63 healthy controls. Val66Met variation was not associated with OCD or GAD. BDNF plasma levels in OCD and GAD patients were significant lower than those in healthy controls. Val66Met variation had no influence on BDNF plasma levels. No difference was found between OCD and GAD. Results do not change no matter taking OCD and GAD as one group or separated two. First, the sample size for genotyping was relatively small, which leaded to a low statistical power of the genetic part in this study. Second, we genotyped just one SNP in BDNF gene. Third, parts of the participants did not be assayed for BDNF plasma levels. Our

  1. BDNF Val66Met polymorphism and stressful life events in melancholic childhood-onset depression.

    PubMed

    Rimay, Timea; Benak, Istvan; Kiss, Eniko; Baji, Ildiko; Feher, Agnes; Juhasz, Anna; Strauss, John; Kennedy, James; Barr, Cathy; Kovacs, Maria; Vetro, Agnes; Kapornai, Krisztina

    2015-12-01

    Brain-derived neurotrophic factor (BDNF) polymorphisms have been examined for their contribution toward depression with equivocal results. More homogeneous phenotypes might be used to improve our understanding of genetic liability to depression. The aim of our study was to (a) test for an association between the BDNF Val66Met polymorphism and childhood-onset melancholic depression and (b) to examine the interactive effects of stressful life events (SLE) and the Val66Met polymorphism on the risk of childhood-onset melancholic depression. A total of 583 depressed probands were involved in this study (162 of the melancholic subtype). Diagnoses were derived through the Interview Schedule for Children and Adolescents - Diagnostic Version and life event data were collected using an Intake General Information Sheet. Overall, 27.8% of the participants fulfilled the criteria for melancholy. In the melancholic group, the proportion of females was higher (53.1%), although there were more males in the overall depressed sample. We detected no significant differences in genotype or allele frequency between the melancholic and the nonmelancholic depressed group. The BDNF Val66Met polymorphism and SLE interaction was not significantly associated with the melancholy outcome. In our study, females were more prone to developing the early-onset melancholic phenotype. To our knowledge, this is the first study to investigate the differentiating effect of the genotype and the G×E interaction on the melancholic phenotype in a large sample of depressed young patients. We did not find an association between the melancholic subtype of major depression and the BDNF genotype and SLE interaction in this sample, which is representative of the Hungarian clinic-referred population of depressed youths.

  2. Hematopoietic prostaglandin D synthase (HPGDS): a high stability, Val187Ile isoenzyme common among African Americans and its relationship to risk for colorectal cancer

    PubMed Central

    Tippin, Brigette L.; Levine, A. Joan; Materi, Alicia M.; Song, Wen-Liang; Keku, Temitope O.; Goodman, Julie E.; Sansbury, Leah B.; Das, Sudipto; Dai, Aihua; Kwong, Alan M.; Lin, Amy M.; Lin, John M.; Park, Jae Man; Patterson, Ruth E.; Chlebowski, Rowan T.; Garavito, R. Michael; Inoue, Tsuyoshi; Cho, Wonhwa; Lawson, John A.; Kapoor, Shiv; Kolonel, Laurence N.; Marchand, Loïc Le; Haile, Robert W.; Sandler, Robert S.; Lin, Henry J.

    2011-01-01

    Intestinal tumors in ApcMin/+ mice are suppressed by over-production of HPGDS, which is a glutathione transferase that forms prostaglandin D2 (PGD2). We characterized naturally occurring HPGDS isoenzymes, to see if HPGDS variation is associated with human colorectal cancer risk. We used DNA heteroduplex analysis and sequencing to identify HPGDS variants among healthy individuals. HPGDS isoenzymes were produced in bacteria, and their catalytic activities were tested. To determine in vivo effects, we conducted pooled case-control analyses to assess whether there is an association of the isoenzyme with colorectal cancer. Roughly 8% of African Americans and 2% of Caucasians had a highly stable Val187lle isoenzyme (with isoleucine instead of valine at position 187). At 37 °C, the wild-type enzyme lost 15% of its activity in one hour, whereas the Val187Ile form remained >95% active. At 50 °C, the half life of native HPGDS was 9 minutes, compared to 42 minutes for Val187Ile. The odds ratio for colorectal cancer among African Americans with Val187Ile was 1.10 (95% CI, 0.75–1.62; 533 cases, 795 controls). Thus, the Val187Ile HPGDS isoenzyme common among African Americans is not associated with colorectal cancer risk. Other approaches will be needed to establish a role for HPGDS in occurrence of human intestinal tumors, as indicated by a mouse model. PMID:21821144

  3. Toluidine blue-O is a Nissl bright-field counterstain for lipophilic fluorescent tracers Di-ASP, DiI and DiO.

    PubMed

    Chelvanayagam, D K; Beazley, L D

    1997-03-01

    The stain toluidine blue-O (tol blue), applied to sections of neural tissue, is shown to be compatible with the vivid fluorescent lipophilic neural tracers 4-(4-dihexadecylaminostyryl)-N-methylpyridinium iodide (Di-ASP), 3,3'-dioctadecyloxacarbocyanine perchlorate (DiO) and 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI). As with other Nissl stains, toluidine blue-O fluoresces in the red end of the spectrum but such fluorescence quenches upon binding with tissue. Moreover, progressive staining occurs at concentrations low enough to minimise any background fluorescence attributable to non-specific residence of the stain. The bright yellow Di-ASP and vivid green DiO signals are spectrally removed from the red fluorescence of toluidine blue-O. With toluidine blue-O counterstaining, Di-ASP generally offers contrast superior to that with DiI, however, the latter is improved by viewing in a polarised green bright field. Visible Di-ASP emission, although broad, peaks at a more film-sensitive region of the spectrum than that for DiI, thus reducing the photographic exposure required.

  4. Interaction between COMT Val(158)Met polymorphism and childhood adversity affects reward processing in adulthood.

    PubMed

    Boecker-Schlier, Regina; Holz, Nathalie E; Buchmann, Arlette F; Blomeyer, Dorothea; Plichta, Michael M; Jennen-Steinmetz, Christine; Wolf, Isabella; Baumeister, Sarah; Treutlein, Jens; Rietschel, Marcella; Meyer-Lindenberg, Andreas; Banaschewski, Tobias; Brandeis, Daniel; Laucht, Manfred

    2016-05-15

    Accumulating evidence suggests that altered dopamine transmission may increase the risk of mental disorders such as ADHD, schizophrenia or depression, possibly mediated by reward system dysfunction. This study aimed to clarify the impact of the COMT Val(158)Met polymorphism in interaction with environmental variation (G×E) on neuronal activity during reward processing. 168 healthy young adults from a prospective study conducted over 25years participated in a monetary incentive delay task measured with simultaneous EEG-fMRI. DNA was genotyped for COMT, and childhood family adversity (CFA) up to age 11 was assessed by a standardized parent interview. At reward delivery, a G×E revealed that fMRI activation for win vs. no-win trials in reward-related regions increased with the level of CFA in Met homozygotes as compared to Val/Met heterozygotes and Val homozygotes, who showed no significant effect. During the anticipation of monetary vs. verbal rewards, activation decreased with the level of CFA, which was also observed for EEG, in which the CNV declined with the level of CFA. These results identify convergent genetic and environmental effects on reward processing in a prospective study. Moreover, G×E effects during reward delivery suggest that stress during childhood is associated with higher reward sensitivity and reduced efficiency in processing rewarding stimuli in genetically at-risk individuals. Together with previous evidence, these results begin to define a specific system mediating interacting effects of early environmental and genetic risk factors, which may be targeted by early intervention and prevention. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Genetic susceptibility to family environment: BDNF Val66met and 5-HTTLPR influence depressive symptoms.

    PubMed

    Dalton, Elizabeth D; Hammen, Constance L; Najman, Jake M; Brennan, Patricia A

    2014-12-01

    Functional genetic polymorphisms associated with Brain-Derived Neurotrophic Factor (BDNF) and serotonin (5-HTTLPR) have demonstrated associations with depression in interaction with environmental stressors. In light of evidence for biological connections between BDNF and serotonin, it is prudent to consider genetic epistasis between variants in these genes in the development of depressive symptoms. The current study examined the effects of val66met, 5-HTTLPR, and family environment quality on youth depressive symptoms in adolescence and young adulthood in a longitudinal sample oversampled for maternal depression history. A differential susceptibility model was tested, comparing the effects of family environment on depression scores across different levels of a cumulative plasticity genotype, defined as presence of both, either, or neither plasticity alleles (defined here as val66met Met and 5-HTTLPR 'S'). Cumulative plasticity genotype interacted with family environment quality to predict depression among males and females at age 15. After age 15, however, the interaction of cumulative plasticity genotype and early family environment quality was only predictive of depression among females. Results supported a differential susceptibility model at age 15, such that plasticity allele presence was associated with more or less depressive symptoms depending on valence of the family environment, and a diathesis-stress model of gene-environment interaction after age 15. These findings, although preliminary because of the small sample size, support prior results indicating interactive effects of 5-HTTLPR, val66met, and environmental stress, and suggest that family environment may have a stronger influence on genetically susceptible women than men.

  6. Insights on the structural perturbations in human MTHFR Ala222Val mutant by protein modeling and molecular dynamics.

    PubMed

    Abhinand, P A; Shaikh, Faraz; Bhakat, Soumendranath; Radadiya, Ashish; Bhaskar, L V K S; Shah, Anamik; Ragunath, P K

    2016-01-01

    Methylenetetrahydrofolate reductase (MTHFR) protein catalyzes the only biochemical reaction which produces methyltetrahydrofolate, the active form of folic acid essential for several molecular functions. The Ala222Val polymorphism of human MTHFR encodes a thermolabile protein associated with increased risk of neural tube defects and cardiovascular disease. Experimental studies have shown that the mutation does not affect the kinetic properties of MTHFR, but inactivates the protein by increasing flavin adenine dinucleotide (FAD) loss. The lack of completely solved crystal structure of MTHFR is an impediment in understanding the structural perturbations caused by the Ala222Val mutation; computational modeling provides a suitable alternative. The three-dimensional structure of human MTHFR protein was obtained through homology modeling, by taking the MTHFR structures from Escherichia coli and Thermus thermophilus as templates. Subsequently, the modeled structure was docked with FAD using Glide, which revealed a very good binding affinity, authenticated by a Glide XP score of -10.3983 (kcal mol(-1)). The MTHFR was mutated by changing Alanine 222 to Valine. The wild-type MTHFR-FAD complex and the Ala222Val mutant MTHFR-FAD complex were subjected to molecular dynamics simulation over 50 ns period. The average difference in backbone root mean square deviation (RMSD) between wild and mutant variant was found to be ~.11 Å. The greater degree of fluctuations in the mutant protein translates to increased conformational stability as a result of mutation. The FAD-binding ability of the mutant MTHFR was also found to be significantly lowered as a result of decreased protein grip caused by increased conformational flexibility. The study provides insights into the Ala222Val mutation of human MTHFR that induces major conformational changes in the tertiary structure, causing a significant reduction in the FAD-binding affinity.

  7. Assessment of tight-gas resources in Canyon sandstones of the Val Verde Basin, Texas, 2016

    USGS Publications Warehouse

    Schenk, Christopher J.; Tennyson, Marilyn E.; Klett, Timothy R.; Mercier, Tracey J.; Brownfield, Michael E.; Gaswirth, Stephanie B.; Hawkins, Sarah J.; Leathers-Miller, Heidi M.; Marra, Kristen R.; Finn, Thomas M.; Pitman, Janet K.

    2016-07-08

    Using a geology-based assessment methodology, the U.S. Geological Survey assessed mean resources of 5 trillion cubic feet of gas and 187 million barrels of natural gas liquids in tight-gas assessment units in the Canyon sandstones of the Val Verde Basin, Texas.

  8. Genetic Modulation of Training and Transfer in Older Adults: BDNF Val66Met Polymorphism is Associated with Wider Useful Field of View

    PubMed Central

    Colzato, Lorenza S.; van Muijden, Jesse; Band, Guido P. H.; Hommel, Bernhard

    2011-01-01

    Western society has an increasing proportion of older adults. Increasing age is associated with a general decrease in the control over task-relevant mental processes. In the present study we investigated the possibility that successful transfer of game-based cognitive improvements to untrained tasks in elderly people is modulated by preexisting neuro-developmental factors as genetic variability related to levels of the brain-derived neurotrophic factor (BDNF), an important neuromodulator underlying cognitive processes. We trained participants, genotyped for the BDNF Val66Met polymorphism, on cognitive tasks developed to improve dynamic attention. Pre-training (baseline) and post-training measures of attentional processes (divided and selective attention) were acquired by means of the useful field of view task. As expected, Val/Val homozygous individuals showed larger beneficial transfer effects than Met/-carriers. Our findings support the idea that genetic predisposition modulates transfer effects. PMID:21909331

  9. Val66Met BDNF polymorphism as a vulnerability factor for inflammation-associated depressive symptoms in women with breast cancer

    PubMed Central

    Dooley, Larissa N.; Ganz, Patricia A.; Cole, Steve W.; Crespi, Catherine M.; Bower, Julienne E.

    2016-01-01

    Background Inflammation contributes to the development of depression in a subset of individuals, but risk factors that render certain individuals vulnerable to inflammation-associated depression are undetermined. Drawing from animal studies showing that reduced neuroplasticity mediates effects of inflammation on depression, we hypothesized that individuals genetically predisposed to lower levels of neuroplasticity would be more susceptible to inflammation-associated depression. The current study examined whether the Met allele of the BDNF Val66met polymorphism, which predisposes individuals to reduced levels of brain-derived neurotrophic factor (BDNF), a protein vital for neuroplasticity, moderates the association between inflammation and depressive symptoms. Methods Our sample was 112 women with early-stage breast cancer who had recently completed cancer treatment, which can activate inflammation. Participants provided blood for genotyping and assessment of circulating inflammatory markers, and completed a questionnaire assessing depressive symptoms, including somatic, affective, and cognitive dimensions. Results There was a significant interaction between C-reactive protein (CRP) and the BDNF Val66met polymorphism in predicting cognitive depressive symptoms (p=.004), such that higher CRP was related to more cognitive depressive symptoms among Met allele carriers, but not among Val/Val homozygotes. Post-hoc longitudinal analyses suggested that, for Met carriers, higher CRP at baseline predicted higher cognitive depressive symptoms across a one-year follow-up period (p<.001). Conclusion The BDNF Met allele may be a risk factor for inflammation-associated cognitive depressive symptoms among breast cancer survivors. Women with breast cancer who carry this genotype may benefit from early identification and treatment. Limitation BDNF genotype is an indirect measure of BDNF protein levels. PMID:26967918

  10. Facial emotion recognition in schizophrenia: An exploratory study on the role of comorbid alcohol and substance use disorders and COMT Val158Met.

    PubMed

    Carrà, Giuseppe; Nicolini, Gabriella; Lax, Annamaria; Bartoli, Francesco; Castellano, Filippo; Chiorazzi, Alessia; Gamba, Giulia; Bava, Mattia; Crocamo, Cristina; Papagno, Costanza

    2017-11-01

    To explore whether facial emotion recognition (FER), impaired in both schizophrenia and alcohol and substance use disorders (AUDs/SUDs), is additionally compromised among comorbid subjects, also considering the role of catechol-O-methyltransferase (COMT) Val158Met. We conducted a cross-sectional study, randomly recruiting 67 subjects with a DSM-IV-TR diagnosis of schizophrenia, and rigorously assessing AUDs/SUDs and COMT Val158Met polymorphism. FER was assessed using the Ekman 60 Faces Test- EK-60F. As a whole, the sample scored significantly lower than normative data on EK-60F. However, subjects with comorbid AUDs/SUDs did not perform worse on EK-60F than those without, who had a better performance on EK-60F if they carried the COMT Val/Met variant. This study is the first to date examining the impact of AUDs/SUDs and COMT variants on FER in an epidemiologically representative sample of subjects with schizophrenia. Our findings do not suggest an additional impairment from comorbid AUDs/SUDs on FER among subjects with schizophrenia, whilst COMT Val158Met, though based on a limited sample, might have a role just among those without AUDs/SUDs. Based on our results, additional research is needed also exploring differential roles of various substances. Copyright © 2017 John Wiley & Sons, Ltd.

  11. Does adult ADHD interact with COMT val (158) met genotype to influence working memory performance?

    PubMed

    Biehl, Stefanie C; Gschwendtner, Kathrin M; Guhn, Anne; Müller, Laura D; Reichert, Susanne; Heupel, Julia; Reif, Andreas; Deckert, Jürgen; Herrmann, Martin J; Jacob, Christian P

    2015-03-01

    Both attention-deficit/hyperactivity disorder (ADHD) and catechol-O-methyltransferase (COMT) genotype have been linked to altered dopaminergic transmission and possible impairment in frontal lobe functioning. This study offers an investigation of a possible interaction between ADHD diagnosis and COMT genotype on measures of working memory and executive function. Thirty-five adults with ADHD, who were recruited from the ADHD outpatient clinic at the Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, and thirty-five matched healthy controls completed the Digit Span test and the Stroop Color Word Test. While there were no main effects of ADHD or COMT, the two factors interacted on both Digit Span subtests with the two groups' met/met carriers showing significantly different performance on the Digit Span Forward subtest and the val/val carriers showing significantly different performance on the Digit Span Backward subtest. Findings provide preliminary support for a differential impact of COMT genotype on working memory measures in adult patients with ADHD compared to healthy controls.

  12. Interaction of motor training and intermittent theta burst stimulation in modulating motor cortical plasticity: influence of BDNF Val66Met polymorphism.

    PubMed

    Lee, Mina; Kim, Song E; Kim, Won Sup; Lee, Jungyeun; Yoo, Hye Kyung; Park, Kee-Duk; Choi, Kyoung-Gyu; Jeong, Seon-Yong; Kim, Byung Gon; Lee, Hyang Woon

    2013-01-01

    Cortical physiology in human motor cortex is influenced by behavioral motor training (MT) as well as repetitive transcranial magnetic stimulation protocol such as intermittent theta burst stimulation (iTBS). This study aimed to test whether MT and iTBS can interact with each other to produce additive changes in motor cortical physiology. We hypothesized that potential interaction between MT and iTBS would be dependent on BDNF Val66Met polymorphism, which is known to affect neuroplasticity in the human motor cortex. Eighty two healthy volunteers were genotyped for BDNF polymorphism. Thirty subjects were assigned for MT alone, 23 for iTBS alone, and 29 for MT + iTBS paradigms. TMS indices for cortical excitability and motor map areas were measured prior to and after each paradigm. MT alone significantly increased the motor cortical excitability and expanded the motor map areas. The iTBS alone paradigm also enhanced excitability and increased the motor map areas to a slightly greater extent than MT alone. A combination of MT and iTBS resulted in the largest increases in the cortical excitability, and the representational motor map expansion of MT + iTBS was significantly greater than MT or iTBS alone only in Val/Val genotype. As a result, the additive interaction between MT and iTBS was highly dependent on BDNF Val66Met polymorphism. Our results may have clinical relevance in designing rehabilitative strategies that combine therapeutic cortical stimulation and physical exercise for patients with motor disabilities.

  13. Leu432Val polymorphism in CYP1B1 as a susceptible factor towards predisposition to primary open-angle glaucoma

    PubMed Central

    Banerjee, Deblina; Mookherjee, Suddhasil; Banerjee, Antara; Sen, Abhijit; Variation Consortium, the Indian Genome

    2008-01-01

    Purpose Defects in cytochrome P450 1B1 (CYP1B1) cause primary congenital glaucoma. However, defects in the gene have also been reported in primary open-angle glaucoma (POAG). Since POAG is primarily a complex disease, we examined the potential of coding single nucleotide polymorphisms (cSNPs) in the gene for association with the disease. Methods Five coding SNPs – c.514 C>G (Arg48Gly), c.727 G>T (Ala119Ser), c.1666 C>G (Leu432Val), c.1719 C>T (Asp449Asp), and c.1730 A>G (Asn453Ser) – were genotyped in 264 unrelated POAG patients and 95 controls. In addition, 542 normal individuals selected from various ethnic groups representing the Indian population were also genotyped for these cSNPs. The patterns of linkage disequilibrium between the SNPs and haplotype variations for comparison between POAG patients and controls as well as different ethnic groups of the Indian population were determined using Haploview. Allelic variants of Leu432Val were cloned by site-directed mutagenesis of normal CYP1B1 cDNA, which were used for transfection of retinal pigment epithelium (RPE) cells. The generation of reactive oxygen species (ROS) was quantified by measuring fluorescence emission by degradation of CM-H2DCFDA using a fluoremeter. Results The c.1666G allele of the Leu432Val in CYP1B1 showed a statistically significant higher representation among POAG patients compared to controls (p=0.0001; Odds ratio=6.027; 95% CI: 3.863–9.401) suggesting it to be a potential risk allele toward disease predisposition. Analysis of genotype frequencies of the polymorphism between the two groups demonstrated GG as a potential risk genotype (p=0.0001; Odds ratio=15.505; 95% CI: 5.529–43.474) for the disease. CYP1B1 Val432 was estimated to generate higher ROS in RPE cells compared to its allelic variant (Leu432; p=0.0245 for 15 min and p=0.0197 for 30 min). Comparison of haplotype diversities revealed CGGTA as the risk haplotype for the disease (p=0.0001, by Fisher’s exact test

  14. First Lady of the World: Eleanor Roosevelt at Val-Kill. Teaching with Historic Places.

    ERIC Educational Resources Information Center

    Stoeberl, Todd

    This lesson traces the use of Eleanor Roosevelt's retreat, Val-Kill, a "shack" (actually a stone cottage) built in 1925 on the grounds of the Roosevelt family estate at Hyde Park (New York), and how it nurtured her spirit, personal style, and humanitarian efforts. The lesson explains that Eleanor and her women friends later expanded the…

  15. COMT Val158Met polymorphism moderates the association between PTSD symptom severity and hippocampal volume.

    PubMed

    Hayes, Jasmeet P; Logue, Mark W; Reagan, Andrew; Salat, David; Wolf, Erika J; Sadeh, Naomi; Spielberg, Jeffrey M; Sperbeck, Emily; Hayes, Scott M; McGlinchey, Regina E; Milberg, William P; Verfaellie, Mieke; Stone, Annjanette; Schichman, Steven A; Miller, Mark W

    2017-03-01

    Memory-based alterations are among the hallmark symptoms of posttraumatic stress disorder (PTSD) and may be associated with the integrity of the hippocampus. However, neuroimaging studies of hippocampal volume in individuals with PTSD have yielded inconsistent results, raising the possibility that various moderators, such as genetic factors, may influence this association. We examined whether the catechol-O-methyltransferase (COMT) Val158Met polymorphism, which has previously been shown to be associated with hippocampal volume in healthy individuals, moderates the association between PTSD and hippocampal volume. Recent war veterans underwent structural MRI on a 3 T scanner. We extracted volumes of the right and left hippocampus using FreeSurfer and adjusted them for individual differences in intracranial volume. We assessed PTSD severity using the Clinician-Administered PTSD Scale. Hierarchical linear regression was used to model the genotype (Val158Met polymorphism) × PTSD severity interaction and its association with hippocampal volume. We included 146 white, non-Hispanic recent war veterans (90% male, 53% with diagnosed PTSD) in our analyses. A significant genotype × PTSD symptom severity interaction emerged such that individuals with greater current PTSD symptom severity who were homozygous for the Val allele showed significant reductions in left hippocampal volume. The direction of proposed effects is unknown, thus precluding definitive assessment of whether differences in hippocampal volume reflect a consequence of PTSD, a pre-existing characteristic, or both. Our findings suggest that the COMT polymorphism moderates the association between PTSD and hippocampal volume. These results highlight the role that the dopaminergic system has in brain structure and suggest a possible mechanism for memory disturbance in individuals with PTSD.

  16. COMT Val158Met polymorphism moderates the association between PTSD symptom severity and hippocampal volume

    PubMed Central

    Hayes, Jasmeet P.; Logue, Mark W.; Reagan, Andrew; Salat, David; Wolf, Erika J.; Sadeh, Naomi; Spielberg, Jeffrey M.; Sperbeck, Emily; Hayes, Scott M.; McGlinchey, Regina E.; Milberg, William P.; Verfaellie, Mieke; Stone, Annjanette; Schichman, Steven A.; Miller, Mark W.

    2017-01-01

    Background Memory-based alterations are among the hallmark symptoms of posttraumatic stress disorder (PTSD) and may be associated with the integrity of the hippocampus. However, neuroimaging studies of hippocampal volume in individuals with PTSD have yielded inconsistent results, raising the possibility that various moderators, such as genetic factors, may influence this association. We examined whether the catechol-O-methyltransferase (COMT) Val158Met polymorphism, which has previously been shown to be associated with hippocampal volume in healthy individuals, moderates the association between PTSD and hippocampal volume. Methods Recent war veterans underwent structural MRI on a 3 T scanner. We extracted volumes of the right and left hippocampus using FreeSurfer and adjusted them for individual differences in intracranial volume. We assessed PTSD severity using the Clinician-Administered PTSD Scale. Hierarchical linear regression was used to model the genotype (Val158Met polymorphism) × PTSD severity interaction and its association with hippocampal volume. Results We included 146 white, non-Hispanic recent war veterans (90% male, 53% with diagnosed PTSD) in our analyses. A significant genotype × PTSD symptom severity interaction emerged such that individuals with greater current PTSD symptom severity who were homozygous for the Val allele showed significant reductions in left hippocampal volume. Limitations The direction of proposed effects is unknown, thus precluding definitive assessment of whether differences in hippocampal volume reflect a consequence of PTSD, a pre-existing characteristic, or both. Conclusion Our findings suggest that the COMT polymorphism moderates the association between PTSD and hippocampal volume. These results highlight the role that the dopaminergic system has in brain structure and suggest a possible mechanism for memory disturbance in individuals with PTSD. PMID:28234210

  17. Geodiversity and Geoheritage of the Sesia-Val Grande Unesco Geopark (NW-Italy)

    NASA Astrophysics Data System (ADS)

    Giardino, Marco; Palomba, Mauro; Selvaggio, Ilaria; Ghiraldi, Luca; Giordano, Enrico

    2015-04-01

    The Sesia-Valgrande Geopark has been founded in September 2013. It is located in the northern sector of Piemonte region covering an area of almost 214000 hectares. In the northern side the Geopark includes the entire territory of the Val Grande National Park, a small portion of the Ossola Valley and the Cannobina valley, while in the south covers most of the mountain range of the Sesia Valley and portions of neighbouring territories such as Valsessera, Prealpi Biellesi, Val Strona and Alte Colline Novaresi. The present morphology of the whole area is characterized by landforms shaped by different geomorphological processes: glacial, hydrological, gravitational and in the south parts also by karstic phenomena. From the geological point of view the Sesia-Val Grande Geopark "rides" the Canavese segment of the Insubric Line, a major tectonic boundary of the Alps. North- and Westward of the Insubric Line, the Austro-Alpine domain consists of piles of nappes, which were assembled and affected by a polymetamorphic event during the Alpine orogeny. South- and Eastward of the Insubric Line, South-Alpine Rock units were not affected by this metamorphic event: they preserve an older history, despite experiencing substantial Alpine tectonic deformation. These are the original rocks of the northern margin of the Adriatic plate, an exceptional record of metamorphic and igneous events preserved with a virtually intact section of the pre-Alpine crust. Beyond geological heritage this territory is one of the most appealing natural environments of the Western Alps, including several different protected areas, important Walser settlement (13th century) and Palaeolithic human traces in the Monte Fenera caves, religious and artistic attraction dominated by the Ghiffa and Varallo Sacred Mount and eventually sport activities such as rafting, hiking, mountaineering and climbing. In order to promote cultural and geological heritage of the area, several scientific institution have been

  18. MELAS syndrome associated with a new mitochondrial tRNA-Val gene mutation (m.1616A>G).

    PubMed

    Toyoshima, Yuka; Tanaka, Yuji; Satomi, Kazuo

    2017-09-11

    We describe the case of a 40-year-old-man with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome, with cardiomyopathy and severe heart failure. He had a mitochondrial transfer RNA (tRNA) mutation (m.1616A>G) of the (tRNA-Val) gene, and it was not found in MELAS syndrome ever before. The presence of this newly observed tRNA-Val mutation (m.1616A>G) may induce multiple respiratory chain enzyme deficiencies and contribute to MELAS syndrome symptoms that are associated with mitochondrial DNA (mtDNA) mutations. We report that the pathognomonic symptom in MELAS syndrome caused by this newly observed mtDNA mutation may be rapid progression of cardiomyopathy and severe heart failure. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  19. Time constraints for post-LGM landscape response to deglaciation in Val Viola, Central Italian Alps

    NASA Astrophysics Data System (ADS)

    Scotti, Riccardo; Brardinoni, Francesco; Crosta, Giovanni Battista; Cola, Giuseppe; Mair, Volkmar

    2017-12-01

    Across the northern European Alps, a long tradition of Quaternary studies has constrained post-LGM (Last Glacial Maximum) landscape history. The same picture remains largely unknown for the southern portion of the orogen. In this work, starting from existing 10Be exposure dating of three boulders in Val Viola, Central Italian Alps, we present the first detailed, post-LGM reconstruction of landscape (i.e., glacial, periglacial and paraglacial) response south of the Alpine divide. We pursue this task through Schmidt-hammer exposure-age dating (SHD) at 34 sites including moraines, rock glaciers, protalus ramparts, rock avalanche deposits and talus cones. In addition, based on the mapping of preserved moraines and on the numerical SHD ages, we reconstruct the glacier extent of four different stadials, including Egesen I (13.1 ± 1.1 ka), Egesen II (12.3 ± 0.6 ka), Kartell (11.0 ± 1.4 ka) and Kromer (9.7 ± 1.4 ka), whose chronologies agree with available counterparts from north of the Alpine divide. Results show that Equilibrium Line Altitude depressions (ΔELAs) associated to Younger Dryas and Early Holocene stadials are smaller than documented at most available sites in the northern Alps. These findings not only support the hypothesis of a dominant north westerly atmospheric circulation during the Younger Dryas, but also suggest that this pattern could have lasted until the Early Holocene. SHD ages on rock glaciers and protalus ramparts indicate that favourable conditions to periglacial landform development occurred during the Younger Dryas (12.7 ± 1.1 ka), on the valley slopes above the glacier, as well as in newly de-glaciated areas, during the Early Holocene (10.7 ± 1.3 and 8.8 ± 1.8 ka). The currently active rock glacier started to develop before 3.7 ± 0.8 ka and can be associated to the Löbben oscillation. Four of the five rock avalanches dated in Val Viola cluster within the Early Holocene, in correspondence of an atmospheric warming phase. By contrast

  20. Role of BDNF val66met polymorphism on the association between physical activity and incident dementia.

    PubMed

    Kim, Jae-Min; Stewart, Robert; Bae, Kyung-Yeol; Kim, Sung-Wan; Yang, Su-Jin; Park, Kee-Hyung; Shin, Il-Seon; Yoon, Jin-Sang

    2011-03-01

    Increased physical activity may have beneficial effects on cognitive outcomes; a role of brain-derived neurotrophic factor (BDNF) has been suggested in animal models but not yet tested in humans. This study investigated modification by BDNF val66met polymorphism of the association between physical activity, incident dementia and other cognitive outcomes. Of 732 community elders, 107 had dementia at baseline, and 518 (83%) of the remainder were followed over 2.4 years. Cognitive impairment and decline were defined from Mini-Mental State Examination scores. Self-reported level of physical activity was recorded on a 4-point scale. BDNF val66met and apolipoprotein E genotypes were ascertained. Covariates included age, sex, education, depression, vascular risk factors, and instrumental activities of daily living. Baseline lower physical activity was significantly associated with incident dementia as well as with baseline dementia and cognitive impairment and incident cognitive decline. BDNF val66met polymorphism itself was not associated with any cognitive outcome. However, the strength of association between lower activity and all cognitive outcomes increased incrementally with the number of met alleles, and was strongest in those with the met/met genotype. BDNF×activity interaction terms were stronger for prospective outcomes (incident dementia, cognitive decline) compared to cross-sectional outcomes (prevalent dementia, cognitive impairment no dementia). This study supports a previously suggested neurobiological basis for the effects of physical activity on dementia involving the BDNF system since the met allele is recognised to be associated with lower activity-dependent secretion of BDNF. Copyright © 2010. Published by Elsevier Inc.

  1. The BDNF Val66Met polymorphism does not moderate the effect of self-reported physical activity on depressive symptoms in midlife

    PubMed Central

    Gujral, Swathi; Manuck, Stephen B.; Ferrell, Robert E.; Flory, Janine D.; Erickson, Kirk I.

    2014-01-01

    Background The brain-derived neurotrophic factor (BDNF) Val66Met single nucleotide polymorphism may be associated with clinical and subsyndromal depression, but physical activity improves mood and increases BDNF expression. Aims To examine whether the BDNF polymorphism moderates an effect of physical activity on depressive symptoms. Methods BDNF genotype, physical activity measured by the Paffenbarger Questionnaire, and depressive symptoms using the Center for Epidemiology Depression Scale (CES-D) were collected on 1072 participants (Mean Age=44). Multiple linear regression was used to examine the association between BDNF genotype, physical activity, and depressive symptoms. Results After adjusting for family income, age, and education, depressive symptoms were higher in Met carriers compared to Val homozygotes (p=0.03), but this was only significant in men. Physical activity was associated with fewer depressive symptoms, but only in women (p=0.01). BDNF genotype did not moderate the effect of physical activity on depressive symptoms (p= 0.94). Conclusions In midlife, the BDNF Val66Met polymorphism neither attenuates nor magnifies the effect of physical activity on depressive symptoms. PMID:24745471

  2. Clinical correlates of the presence of the Asp816Val c-kit mutation in the peripheral blood mononuclear cells of patients with mastocytosis.

    PubMed

    Worobec, A S; Semere, T; Nagata, H; Metcalfe, D D

    1998-11-15

    The Asp816Val mutation in the catalytic domain of the c-kit receptor has been identified in patients with systemic mastocytosis. To determine whether this mutation is associated with identifiable clinical patterns of disease and prognosis, a total of 65 patients with mastocytosis were screened for the presence of the Asp816Val mutation in peripheral blood mononuclear cells (PBMCs). By analysis of HinfI digestion products, the authors found that the overall prevalence of this mutation in the current patient series was 25%. The presence of the Asp816Val mutation in PBMCs was observed in 15 adults (of 16 Asp816Val mutation positive patients) and 1 infant, but not in any children with mastocytosis. Patients whose PBMCs were positive for this mutation (category II and a subset of category Ib mastocytosis patients) manifested a more severe disease pattern, with clinical features ranging in severity from early to advanced myelodysplastic or myeloproliferative syndromes. These patients more commonly had osteosclerotic bone involvement (a clinical feature primarily observed in mastocytosis patients with an associated hematologic disorder) as well as immunoglobulin dysregulation and peripheral blood abnormalities. Furthermore, pedigree analysis of three families provided evidence that the mutation was somatic. Twenty-five percent of all patients with mastocytosis had the Asp816Val mutation in PBMCs; 56% of these patients had evidence of a myelodysplastic or myeloproliferative syndrome, and 44% had been clinically placed in the indolent mastocytosis category, suggesting that the current classification scheme used to assign prognosis may be inadequate. Therefore, determination of the presence or absence of this mutation in PBMCs of mastocytosis patients offers a useful adjunct in determining the extent of workup and assigning prognosis in this complex and heterogeneous disease.

  3. Association of the brain-derived neurotrophic factor Val66Met polymorphism with negative symptoms severity, but not cognitive function, in first-episode schizophrenia spectrum disorders.

    PubMed

    Mezquida, G; Penadés, R; Cabrera, B; Savulich, G; Lobo, A; González-Pinto, A; Penzol, M J; Corripio, I; Fernandez-Egea, E; Gassó, P; Cuesta, M J; Bernardo, M

    2016-10-01

    A functional polymorphism of the brain-derived neurotrophic factor gene (BDNF) Val66Met has been associated with cognitive function and symptom severity in patients with schizophrenia. It has been suggested that the Val66Met polymorphism has a role as a modulator in a range of clinical features of the illness, including symptoms severity, therapeutic responsiveness, age of onset, brain morphology and cognitive function. However, little work has been done in first-episode schizophrenia (FES) spectrum disorders. The objective of this study is to investigate the association of the BDNF Val66Met polymorphism on cognitive function and clinical symptomatology in FES patients. Using a cross-sectional design in a cohort of 204 patients with FES or a schizophrenia spectrum disorder and 204 healthy matched controls, we performed BDNF Val66Met genotyping and tested its relationship with cognitive testing (attention, working memory, learning/verbal memory and reasoning/problem-solving) and assessment of clinical symptom severity. There was no significant influence of the BDNF allele frequency on cognitive factor scores in either patients or controls. An augmented severity of negative symptoms was found in FES patients that carried the Met allele. The results of this study suggest that in patients with a first-episode of schizophrenia or a schizophrenia spectrum disorder, the BDNF Val66Met polymorphism does not exert an influence on cognitive functioning, but is associated with negative symptoms severity. BDNF may serve as suitable marker of negative symptomatology severity in FES patients within the schizophrenia spectrum. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  4. Sub-Cellular Localization and Complex Formation by Aminoacyl-tRNA Synthetases in Cyanobacteria: Evidence for Interaction of Membrane-Anchored ValRS with ATP Synthase.

    PubMed

    Santamaría-Gómez, Javier; Ochoa de Alda, Jesús A G; Olmedo-Verd, Elvira; Bru-Martínez, Roque; Luque, Ignacio

    2016-01-01

    tRNAs are charged with cognate amino acids by aminoacyl-tRNA synthetases (aaRSs) and subsequently delivered to the ribosome to be used as substrates for gene translation. Whether aminoacyl-tRNAs are channeled to the ribosome by transit within translational complexes that avoid their diffusion in the cytoplasm is a matter of intense investigation in organisms of the three domains of life. In the cyanobacterium Anabaena sp. PCC 7120, the valyl-tRNA synthetase (ValRS) is anchored to thylakoid membranes by means of the CAAD domain. We have investigated whether in this organism ValRS could act as a hub for the nucleation of a translational complex by attracting other aaRSs to the membranes. Out of the 20 aaRSs, only ValRS was found to localize in thylakoid membranes whereas the other enzymes occupied the soluble portion of the cytoplasm. To investigate the basis for this asymmetric distribution of aaRSs, a global search for proteins interacting with the 20 aaRSs was conducted. The interaction between ValRS and the FoF1 ATP synthase complex here reported is of utmost interest and suggests a functional link between elements of the gene translation and energy production machineries.

  5. No evidence for a role of Ile587Val polymorphism of EIF2B5 gene in multiple sclerosis in Kashmir Valley of India.

    PubMed

    Zahoor, Insha; Asimi, Ravouf; Haq, Ehtishamul

    2015-12-15

    Multiple sclerosis (MS) is an inflammatory neurodegenerative disease of the nervous system with a profound genetic element. It is already known that alterations in Eukaryotic Translation Initiation Factor 2B (EIF2B) gene encoding the five subunits of eIF2B complex cause Vanishing White Matter (VWM) disease of the brain and emerging evidences have advocated certain resemblances between MS and VWM in terms of clinical and epidemiological characteristics, thus validating the association study between EIF2B and MS. Moreover, a recent study has implicated EIF2B5 Ile587Val (rs843358) polymorphism as a susceptibility factor for MS. In order to investigate the association of EIF2B5 Ile587Val polymorphism with MS susceptibility in Kashmir region in India, we screened EIF2B5 Exon 13 in 30 MS patients and 65 controls (a total of 95 participants). During the present course of study, we could not find statistically significant difference in the frequency of Ile587Val between MS patients and controls, thus indicating that such alteration does not appear to influence MS development in Kashmiri population. Our results provide evidence against a major role for Ile587Val polymorphism in MS susceptibility. Copyright © 2015 Elsevier B.V. All rights reserved.

  6. The modulatory influence of the functional COMT Val158Met polymorphism on lexical decisions and semantic priming.

    PubMed

    Reuter, Martin; Montag, Christian; Peters, Kristina; Kocher, Anne; Kiefer, Markus

    2009-01-01

    The role of the prefrontal Cortex (PFC) in higher cognitive functions - including working memory, conflict resolution, set shifting and semantic processing - has been demonstrated unequivocally. Despite the great heterogeneity among tasks measuring these phenotypes, due in part to the different cognitive sub-processes implied and the specificity of the stimulus material used, there is agreement that all of these tasks recruit an executive control system located in the PFC. On a biochemical level it is known that the dopaminergic system plays an important role in executive control functions. Evidence comes from molecular genetics relating the functional COMT Val158Met polymorphism to working memory and set shifting. In order determine whether this pattern of findings generalises to linguistic and semantic processing, we investigated the effects of the COMT Val158Met polymorphism in lexical decision making using masked and unmasked versions of the semantic priming paradigm on N = 104 healthy subjects. Although we observed strong priming effects in all conditions (masked priming, unmasked priming with short/long stimulus asynchronies (SOAs), direct and indirect priming), COMT was not significantly related to priming, suggesting no reliable influence on semantic processing. However, COMT Val158Met was strongly associated with lexical decision latencies in all priming conditions if considered separately, explaining between 9 and 14.5% of the variance. Therefore, the findings indicate that COMT mainly influences more general executive control functions in the PFC supporting the speed of lexical decisions.

  7. An experimental study of catechol-o-methyltransferase Val158Met moderation of delta-9-tetrahydrocannabinol-induced effects on psychosis and cognition.

    PubMed

    Henquet, Cécile; Rosa, Araceli; Krabbendam, Lydia; Papiol, Sergi; Fananás, Lourdes; Drukker, Marjan; Ramaekers, Johannes G; van Os, Jim

    2006-12-01

    Observational studies have suggested that psychometric psychosis liability and a functional polymorphism in the catechol-O-methyltransferase (COMT Val(158)Met) gene moderate the psychosis-inducing effect of cannabis. To replicate and extend this finding, a double-blind, placebo-controlled cross-over design was used in which patients with a psychotic disorder (n=30), relatives of patients with a psychotic disorder (n=12), and healthy controls (n=32) were exposed to Delta-9-tetrahydrocannabinol (Delta-9-THC, the principal component of cannabis) or placebo, followed by cognitive assessment and assessment of current psychotic experiences. Previous expression of psychometric psychosis liability was also assessed. Models of current psychotic experiences and cognition were examined with multilevel random regression analyses to assess (i) main effects of genotype and condition, (ii) interactions between condition and genotype, and (iii) three-way interactions between condition, genotype, and psychometric psychosis liability. Carriers of the Val allele were most sensitive to Delta-9-THC-induced psychotic experiences, but this was conditional on prior evidence of psychometric psychosis liability. Delta-9-THC impacted negatively on cognitive measures. Carriers of the Val allele were also more sensitive to Delta-9-THC-induced memory and attention impairments compared to carriers of the Met allele. Experimental effects of Delta-9-THC on cognition and psychosis are moderated by COMT Val(158)Met genotype, but the effects may in part be conditional on the additional presence of pre-existing psychosis liability. The association between cannabis and psychosis may represent higher order gene-environment and gene-gene interactions.

  8. Interaction of Motor Training and Intermittent Theta Burst Stimulation in Modulating Motor Cortical Plasticity: Influence of BDNF Val66Met Polymorphism

    PubMed Central

    Lee, Mina; Kim, Song E.; Kim, Won Sup; Lee, Jungyeun; Yoo, Hye Kyung; Park, Kee-Duk; Choi, Kyoung-Gyu; Jeong, Seon-Yong; Kim, Byung Gon; Lee, Hyang Woon

    2013-01-01

    Cortical physiology in human motor cortex is influenced by behavioral motor training (MT) as well as repetitive transcranial magnetic stimulation protocol such as intermittent theta burst stimulation (iTBS). This study aimed to test whether MT and iTBS can interact with each other to produce additive changes in motor cortical physiology. We hypothesized that potential interaction between MT and iTBS would be dependent on BDNF Val66Met polymorphism, which is known to affect neuroplasticity in the human motor cortex. Eighty two healthy volunteers were genotyped for BDNF polymorphism. Thirty subjects were assigned for MT alone, 23 for iTBS alone, and 29 for MT + iTBS paradigms. TMS indices for cortical excitability and motor map areas were measured prior to and after each paradigm. MT alone significantly increased the motor cortical excitability and expanded the motor map areas. The iTBS alone paradigm also enhanced excitability and increased the motor map areas to a slightly greater extent than MT alone. A combination of MT and iTBS resulted in the largest increases in the cortical excitability, and the representational motor map expansion of MT + iTBS was significantly greater than MT or iTBS alone only in Val/Val genotype. As a result, the additive interaction between MT and iTBS was highly dependent on BDNF Val66Met polymorphism. Our results may have clinical relevance in designing rehabilitative strategies that combine therapeutic cortical stimulation and physical exercise for patients with motor disabilities. PMID:23451258

  9. Investigating the role of the brain-derived neurotrophic factor (BDNF) val66met variant in obsessive-compulsive disorder (OCD).

    PubMed

    Hemmings, Sîan M J; Kinnear, Craig J; Van der Merwe, Lize; Lochner, Christine; Corfield, Valerie A; Moolman-Smook, Johanna C; Stein, Dan J

    2008-01-01

    Although evidence from family studies suggest that genetic factors play an important role in mediating obsessive-compulsive disorder (OCD), results from genetic case-control association analyses have been inconsistent. Discrepant findings may be attributed to the lack of phenotypic resolution, and population stratification. The aim of the present study was to investigate the role that the val66met variant within the gene encoding brain-derived neurotrophic factor (BDNF) may play in mediating the development of selected OCD subtypes accounting for the aforementioned confounding factors. One hundred and twelve OCD subjects and 140 controls were selected from the South African Afrikaner population. A significant association was observed in the male subgroup, with the met66 allele implicated as the risk allele in the development of OCD. This allele was also found to be associated with an earlier age at onset of OCD in males. On the other hand, the val66val genotype was associated with more severe OCD in the female population. No evidence of population stratification was observed in Afrikaner control subjects. These preliminary results point towards genetically distinct characteristics of OCD mediated by dysfunctions in BDNF. The present investigation forms part of ongoing research to elucidate the genetic components involved in the aetiology of OCD and OCD-related characteristics.

  10. Creating an open access cal/val repository via the LACO-Wiki online validation platform

    NASA Astrophysics Data System (ADS)

    Perger, Christoph; See, Linda; Dresel, Christopher; Weichselbaum, Juergen; Fritz, Steffen

    2017-04-01

    There is a major gap in the amount of in-situ data available on land cover and land use, either as field-based ground truth information or from image interpretation, both of which are used for the calibration and validation (cal/val) of products derived from Earth Observation. Although map producers generally publish their confusion matrices and the accuracy measures associated with their land cover and land use products, the cal/val data (also referred to as reference data) are rarely shared in an open manner. Although there have been efforts in compiling existing reference datasets and making them openly available, e.g. through the GOFC/GOLD (Global Observation for Forest Cover and Land Dynamics) portal or the European Commission's Copernicus Reference Data Access (CORDA), this represents a tiny fraction of the reference data collected and stored locally around the world. Moreover, the validation of land cover and land use maps is usually undertaken with tools and procedures specific to a particular institute or organization due to the lack of standardized validation procedures; thus, there are currently no incentives to share the reference data more broadly with the land cover and land use community. In an effort to provide a set of standardized, online validation tools and to build an open repository of cal/val data, the LACO-Wiki online validation portal has been developed, which will be presented in this paper. The portal contains transparent, documented and reproducible validation procedures that can be applied to local as well as global products. LACO-Wiki was developed through a user consultation process that resulted in a 4-step wizard-based workflow, which supports the user from uploading the map product for validation, through to the sampling process and the validation of these samples, until the results are processed and a final report is created that includes a range of commonly reported accuracy measures. One of the design goals of LACO-Wiki has been

  11. The Flexible Mind Is Associated with the Catechol-O-Methyltransferase (COMT) Val[superscript 158]Met Polymorphism: Evidence for a Role of Dopamine in the Control of Task-Switching

    ERIC Educational Resources Information Center

    Colzato, Lorenza S.; Waszak, Florian; Nieuwenhuis, Sander; Posthuma, Danielle; Hommel, Bernhard

    2010-01-01

    Genetic variability related to the catechol-O-methyltransferase (COMT) gene Val[superscript 128]Met polymorphism) has received increasing attention as a possible modulator of cognitive control functions. Recent evidence suggests that the Val[superscript 128]Met genotype may differentially affect cognitive stability and flexibility, in such a way…

  12. UHV AFM based colloidal probe studies of adhesive properties of VAlN hard coatings

    NASA Astrophysics Data System (ADS)

    Wiesing, M.; de los Arcos, T.; Grundmeier, G.

    2018-01-01

    The adhesion of polystyrene (PS) on V0.27Al0.29N0.44 and the related influence of the oxidation states of both surfaces was investigated using X-Ray Photoelectron Spectroscopy (XPS) and Colloidal Force Spectroscopy (CFS) in Ultra-High Vacuum (UHV). Complementary, the intimate relation between the adhesion force, the chemical structure and surface polarizability was investigated by XPS valence band spectroscopy and the calculation of non-retarded Hamaker coefficients using Lifshitz theory based on optical data as derived from Reflection Electron Energy Loss Spectroscopy (REELS) spectra. The combined electron and force spectroscopic analysis of the interaction forces disclosed quantitatively the separation of the adhesion force in van der Waals and Lewis acid-base contributions. Further, the surface polarizability of VAlN was shown to be unaffected by oxygen incorporation due to the formation of an only gradually oxidized surface comprising a range of vanadium oxidation states. In contrast, the adhesion force analysis revealed additional Lewis acid-base interactions between the oxidized and non-oxidized VAlN surfaces and carboxyl groups present in the surface of PS after an oxidative oxygen beam treatment.

  13. The Effects of BDNF Val66Met Gene Polymorphism on Serum BDNF and Cognitive Function in Methamphetamine-Dependent Patients and Normal Controls: A Case-Control Study.

    PubMed

    Su, Hang; Tao, Jingyan; Zhang, Jie; Xie, Ying; Wang, Yue; Zhang, Yu; Han, Bin; Lu, Yuling; Sun, Haiwei; Wei, Youdan; Zou, Shengzhen; Wu, Wenxiu; Zhang, Jiajia; Xu, Ke; Zhang, Xiangyang; He, Jincai

    2015-10-01

    Studies suggest that a functional polymorphism of the brain-derived neurotrophic factor gene (BDNF Val66Met) may contribute to methamphetamine dependence. We hypothesized that this polymorphism had a role in cognitive deficits in methamphetamine-dependent patients and in the relationship of serum BDNF with cognitive impairments. We conducted a case-control study by assessing 194 methamphetamine-dependent patients and 378 healthy volunteers without history of drug use on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the presence of the BDNF Val66Met polymorphism and serum BDNF levels. We showed no significant differences in genotype and allele distributions between the methamphetamine-dependent patients and controls. Some aspects of cognitive function significantly differed in the 2 groups. The serum BDNF levels in methamphetamine-dependent patients were significantly higher than those of the healthy controls. In the patients, partial correlation analysis showed a significant positive correlation between serum BDNF and the delayed memory index score. The RBANS scores showed statistically significant BDNF level × genotype interaction. Further regression analyses showed a significant positive association between BDNF levels and the RBANS total score, immediate memory or attention index among Val homozygote patients, whereas a significant negative association of BDNF levels with the RBANS total score, visuospatial/constructional, or language index was found among Met/Val heterozygous patients. We demonstrated significant impairment on some aspects of cognitive function and increased BDNF levels in methamphetamine-dependent patients as well as genotypic differences in the relationships between BDNF levels and RBANS scores on the BDNF Val66Met polymorphism only in these patients.

  14. IceVal DatAssistant: An Interactive, Automated Icing Data Management System

    NASA Technical Reports Server (NTRS)

    Levinson, Laurie H.; Wright, William B.

    2008-01-01

    As with any scientific endeavor, the foundation of icing research at the NASA Glenn Research Center (GRC) is the data acquired during experimental testing. In the case of the GRC Icing Branch, an important part of this data consists of ice tracings taken following tests carried out in the GRC Icing Research Tunnel (IRT), as well as the associated operational and environmental conditions documented during these tests. Over the years, the large number of experimental runs completed has served to emphasize the need for a consistent strategy for managing this data. To address the situation, the Icing Branch has recently elected to implement the IceVal DatAssistant automated data management system. With the release of this system, all publicly available IRT-generated experimental ice shapes with complete and verifiable conditions have now been compiled into one electronically-searchable database. Simulation software results for the equivalent conditions, generated using the latest version of the LEWICE ice shape prediction code, are likewise included and are linked to the corresponding experimental runs. In addition to this comprehensive database, the IceVal system also includes a graphically-oriented database access utility, which provides reliable and easy access to all data contained in the database. In this paper, the issues surrounding historical icing data management practices are discussed, as well as the anticipated benefits to be achieved as a result of migrating to the new system. A detailed description of the software system features and database content is also provided; and, finally, known issues and plans for future work are presented.

  15. IceVal DatAssistant: An Interactive, Automated Icing Data Management System

    NASA Technical Reports Server (NTRS)

    Levinson, Laurie H.; Wright, William B.

    2008-01-01

    As with any scientific endeavor, the foundation of icing research at the NASA Glenn Research Center (GRC) is the data acquired during experimental testing. In the case of the GRC Icing Branch, an important part of this data consists of ice tracings taken following tests carried out in the GRC Icing Research Tunnel (IRT), as well as the associated operational and environmental conditions during those tests. Over the years, the large number of experimental runs completed has served to emphasize the need for a consistent strategy to manage the resulting data. To address this situation, the Icing Branch has recently elected to implement the IceVal DatAssistant automated data management system. With the release of this system, all publicly available IRT-generated experimental ice shapes with complete and verifiable conditions have now been compiled into one electronically-searchable database; and simulation software results for the equivalent conditions, generated using the latest version of the LEWICE ice shape prediction code, are likewise included and linked to the corresponding experimental runs. In addition to this comprehensive database, the IceVal system also includes a graphically-oriented database access utility, which provides reliable and easy access to all data contained in the database. In this paper, the issues surrounding historical icing data management practices are discussed, as well as the anticipated benefits to be achieved as a result of migrating to the new system. A detailed description of the software system features and database content is also provided; and, finally, known issues and plans for future work are presented.

  16. Hb Beograd [beta121(GH4)Glu-->Val, GAA-->GTA] in the Turkish population.

    PubMed

    Atalay, Ayfer; Koyuncu, Hasan; Köseler, Aylin; Ozkan, Anzel; Atalay, Erol O

    2007-01-01

    Hb Beograd [beta121(GH4)Glu-->Val, GAA-->GTA] is a rare variant first reported in Yugoslavia and then in Turkey, Australia and New Zealand. We report two further unrelated cases from Turkey. The importance of identifying Hb Beograd at the molecular level, especially in regions where Hb D-Los Angeles [beta121(GH4)Glu-->Gln, GAA-->CAA] is prevalent, is emphasized.

  17. Variant BDNF (Val66Met) polymorphism contributes to developmental and estrous-stage-specific expression of anxiety-like behavior in female mice

    PubMed Central

    Bath, Kevin G.; Chuang, Jocelyn; Spencer-Segal, Joanna L.; Amso, Dima; Altemus, Margaret; McEwen, Bruce S.; Lee, Francis S.

    2012-01-01

    Background Most anxiety and depressive disorders are twice as common in women compared to men and the sex difference in prevalence typically emerges during adolescence. Hormonal changes across the menstrual cycle and during the postpartum and peri-menopausal periods are associated with increased risk for anxiety and depression symptoms. In humans and animals, reduced brain derived neurotrophic factor (BDNF) has been associated with increased expression of affective pathology. Recently, a single nucleotide polymorphism (SNP) in the BDNF gene (BDNF Val66Met), which reduces BDNF bioavailability, has been identified in humans and associated with a variety of neuropsychiatric disorders. Although BDNF expression can be directly influenced by estrogen and progesterone, the potential impact of the BDNF Val66Met SNP on sensitivity to reproductive hormone changes remains an open question. Approach As a predictive model, we used female mice in which the human SNP (BDNF Val66Met) was inserted into the mouse BDNF gene. Using standard behavioral paradigms, we tested the impact of this SNP on age and estrous-cycle specific expression of anxiety-like behaviors. Results Mice homozygous for the BDNF Val66Met SNP begin to exhibit increased anxiety-like behaviors over prepubertal and early adult development, show significant fluctuations in anxiety-like behaviors over the estrous cycle, and as adults differ from wild-type mice by showing significant fluctuations in anxiety-like behaviors over the estrous cycle, specifically more anxiety-like behaviors during the estrus phase. Conclusions These findings have implications regarding the potential role of this SNP in contributing to developmental and reproductive hormone-dependent changes in affective disorders in humans. PMID:22552045

  18. Val158Met polymorphism in the COMT gene is associated with hypersomnia and mental health-related quality of life in a Colombian sample.

    PubMed

    Jiménez, Karen M; Pereira-Morales, Angela J; Forero, Diego A

    2017-03-22

    The identification of genes that are risk factors for major depressive disorder remains a main task for global psychiatric research. The Catechol-O-methyltransferase (COMT) gene has been an important candidate risk factor for several psychiatric disorders. Previous studies have shown that a functional polymorphism (Val158Met) in this gene has an effect on several brain circuits and endophenotypes of psychiatric relevance. The aim of this study was to explore the association of a functional polymorphism in the COMT gene with psychological distress, sleep problems and health-related quality of life. Two hundred seventy young Colombian subjects (mean age: 21.3 years; range: 18-57 years) completed the Patient Health Questionnaire-9, the Perceived Stress Scale, the Oviedo Sleep Questionnaire and the 12-Item Short-Form Health Survey and were genotyped for the Val158Met polymorphism (rs4680) in the COMT gene. A linear regression analysis, adjusting for potential confounding factors, was carried out. Subjects that were Met carriers (Val/Met and Met/Met genotypes) showed higher scores for hypersomnia (p=0.001) and lower scores for mental health-related quality of life (p=0.007), these associations remained significant after correcting for multiple testing. These findings support the hypothesis of a broad effect of the Val158Met polymorphism in the COMT gene on several dimensions of behavior and neuropsychiatric symptoms. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. COMT Val158Met and 5-HT1A-R -1019 C/G polymorphisms: effects on the negative symptom response to clozapine.

    PubMed

    Bosia, Marta; Lorenzi, Cristina; Pirovano, Adele; Guglielmino, Carmelo; Cocchi, Federica; Spangaro, Marco; Bramanti, Placido; Smeraldi, Enrico; Cavallaro, Roberto

    2015-01-01

    Clozapine is still considered the gold standard for treatment-resistant schizophrenia patients; however, up to 40% of patients do not respond adequately. Identifying potential predictors of clinical response to this last-line antipsychotic could represent an important goal for treatment. Among these, functional polymorphisms involved in dopamine system modulation, known to be disrupted in schizophrenia, may play a role. We examined the COMT Val158Met polymorphism, which plays a key role in dopamine regulation at the prefrontal level, and the 5-HT1A-R -1019 C/G polymorphism, a target of clozapine activity involved in the interaction between the serotonin and dopamine systems. 107 neuroleptic-refractory, biologically unrelated Italian patients (70 males and 37 females) with a DSM-IV diagnosis of schizophrenia who were being treated with clozapine were recruited. Psychopathology was assessed by the Positive and Negative Symptoms Scale (PANSS) at the beginning of treatment, and at weeks 8 and 12. Genomic DNA was extracted from venous blood samples. COMT rs4680 (Val158Met) and 5-HT1A-R rs6295 (-1019 C/G) polymorphisms were analyzed by PCR-based restriction fragment length and direct sequencing, respectively. We found a significant effect of COMT and 5-HT1A-R on the PANSS Negative Subscale variation, with greater improvement among COMT Val/Val and 5-HT1A-R G/G subjects. The findings support the hypothesis that COMT rs4680 and 5-HT1A-R rs6295 polymorphisms could influence the negative symptom response to clozapine, probably through modulation of the dopaminergic system.

  20. Glutathione S-transferase P1 Ile105Val Polymorphism and Male Infertility Risk: An Updated Meta-analysis

    PubMed Central

    Huang, Xue-Kun; Huang, Yong-Han; Huang, Juan-Hua; Liang, Jing-Yao

    2017-01-01

    Background: Several studies concerning the association between glutathione S-transferase P1 (GSTP1) Ile105Val polymorphism and male infertility risk have reported controversial findings. The present study was aimed to explore this association using a meta-analysis. Methods: The PubMed, EMBASE, China National Knowledge Infrastructure (CNKI), and Wanfang databases were searched. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to estimate the strength of the association. Results: A total of 3282 cases and 3268 controls in nine case-control studies were included. There was no significant association between GSTP1 Ile105Val polymorphism and male infertility in the overall population, but significant associations were found under the dominant (OR = 1.23, 95% CI = 1.04–1.46, I2 = 32.2%) and heterozygote (OR = 1.29, 95% CI = 1.08–1.53, I2 = 26.8%) models after excluding studies for which the data did not satisfy Hardy-Weinberg equilibrium (HWE). Similarly, subgroup analyses revealed no significant association in Asians or Chinese population although a significant association was apparent among Chinese population in studies with HWE under the heterozygote model (OR = 1.25, 95% CI = 1.03–1.52, I2 = 44.1%). Significant heterogeneity could be observed in some genetic models, but this heterogeneity was not significant when stratified by HWE. No evidence for publication bias was found. Conclusions: The GSTP1 Ile105Val polymorphism might not be associated with male infertility risk, and thus additional well-designed studies with larger sample size are warranted. PMID:28397729

  1. Lack of an association of BDNF Val66Met polymorphism and plasma BDNF with hippocampal volume and memory

    PubMed Central

    Kim, Ana; Fagan, Anne M; Goate, Alison M; Benzinger, Tammie LS; Morris, John C; Head, Denise

    2015-01-01

    Brain-derived neurotrophic factor (BDNF) has been shown to be important for neuronal survival and synaptic plasticity in the hippocampus in non-human animals. The Val66Met polymorphism in the BDNF gene, involving a valine (Val) to methionine (Met) substitution at codon 66, has been associated with lower BDNF secretion in vitro. However, there have been mixed results regarding associations between either circulating BDNF or the BDNF Val66Met polymorphism with hippocampal volume and memory in humans. The current study examined the association of BDNF genotype and plasma BDNF with hippocampal volume and memory in two large independent cohorts of middle-aged and older adults (both cognitively normal and early-stage dementia). Sample sizes ranged from 123 to 649. Measures of the BDNF genotype, plasma BDNF, MRI-based hippocampal volume and memory performance were obtained from the Knight Alzheimer Disease Research Center (ADRC) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). There were no significant differences between BDNF Met+ and Met- groups on either hippocampal volume or memory in either cohort. In addition, plasma BDNF was not significantly associated with either hippocampal volume or memory in either cohort. Neither age, cognitive status nor gender moderated any of the relationships. Overall, current findings suggest that BDNF genotype and plasma BDNF may not be robust predictors for variance in hippocampal volume and memory in middle age and older adult cohorts. PMID:25784293

  2. Sviluppi di Ricevitori E di Componentistica Per Banda 3 mm Ad INAF-OA Cagliari

    NASA Astrophysics Data System (ADS)

    Navarrini, Alessandro

    2017-11-01

    L'INAF-OA Cagliari (OACa) sta sviluppando un ricevitore criogenico a basso rumore basato su un mixer SSB (Single Side Band) a superconduttore SIS (Superconductor-Insulator-Superconductor) per la banda 3 mm. Il ricevitore, acquistato da IRAM, è stato fortemente modificato per essere adattato al fuoco Gregoriano di SRT (Sardinia Radio Telescope). Lo strumento è caratterizzato da una nuova criogenia a ciclo chiuso 4 K (per evitare l'uso di elio liquido in antenna), da un nuovo oscillatore locale (di tipo ALMA Banda 3) e da un nuovo sistema di controllo e di monitoraggio basato su schede Raspberry ed Arduino sviluppato ad OACa. Verranno presentati i recenti sviluppi sul ricevitore, inclusi i risultati preliminari della misura della temperatura di rumore, che raggiunge un valore pari a Trec=66 K alla frequenza di 86 GHz, nonostante la criogenia non sia ancora ottimizzata. L'INAF-OACa è coinvolto nel progetto AETHRA (Advanced European Technologies for Heterodyne Receivers for Astronomy) nel quadro del programma Radionet/Horizon2020 per il quale sta contribuendo al WP1 (Work Package 1). Lo scopo del WP1 è di sviluppare e costruire un dimostratore di un array di ricevitori a doppia polarizzazione per la banda 3 mm basato su amplificatori criogenici a basso rumore (LNA) in tecnologia a semiconduttore MMIC. Nell'ambito del WP1 l'OACa ha in carico il progetto di un OrthomodeTransducer (OMT) in guida d'onda o in tecnologia planare per la banda 72-116 GHz che sia integrabile con amplificatori MMICs ed adatto all'integrazione in un array da installare nel piano focale di un radiotelescopio. Verranno presentati i design preliminari degli OMT per AETHRA, che sono basati su prototipi sviluppati in passato da OACa.

  3. Hb L'Aquila [beta106(G8)Leu-->Val, CTG-->GTG]: a novel thalassemic hemoglobin variant.

    PubMed

    Amato, Antonio; Cappabianca, Maria Pia; Ponzini, Donatella; Rinaldi, Silvana; Biagio, Paola Di; Foglietta, Enrica; Grisanti, Paola; Mastropietro, Fabrizio

    2007-01-01

    A new beta-globin variant at codon 106 (CTG-->GTG), and which we named Hb L'Aquila [beta106(G8)Leu-->Val], was detected by DNA analysis. The proband and her father presented with the features of a mild beta(+)-thalassemia (thal), confirmed by their alpha/beta-globin chain biosynthesis ratios.

  4. Cervical Mullerian adenosarcoma with heterologous sarcomatous overgrowth: a fourth case and review of literature.

    PubMed

    Patrelli, Tito Silvio; Gizzo, Salvatore; Di Gangi, Stefania; Guidi, Giorgia; Rondinelli, Mario; Nardelli, Giovanni Battista

    2011-06-11

    Uterine sarcomas are relatively rare tumors that account for approximately 1-3% of female genital tract malignancies and between 4-9% of uterine cancers. Less than 8% of all cases are Mullerian adenosarcoma, a distinctive uterine neoplasm characterized by a benign, but occasionally atypical, epithelial and a malignant, usually low-grade, stromal component, both of which should be integral and neoplastic constituents of the tumor. Mullerian adenosarcoma with sarcomatous overgrowth (MASO) is a very aggressive variant, associated with post-operative recurrence, metastases, even when diagnosed in early stage. We present a fourth MASO case derived from uterine cervix in a 72-year-old woman with metrorrhagia and a polypoid mass protruding through the cervical ostium. Total abdominal hysterectomy, bilateral salpingo-oophorectomy, systematic pelvic lymph node dissection, omental biopsy and appendectomy were performed. Surgery treatment was associated with adjuvant whole-pelvis radiation (45 Gy) and adjuvant chemotherapy (cisplatin/ifosfamide). After nine months of follow up, the patient was free of tumor. The rarity of MASO of the cervix involves a management difficult. Most authors recommend total abdominal hysterectomy, usually accompanied by bilateral salpingo-oophorectomy. There is no common agreement on staging by lymphadenectomy during primary surgery and adjuvant chemo-radio therapy.

  5. Interaction Between 5-HTTLPR and BDNF Val66Met Polymorphisms on HPA Axis Reactivity in Preschoolers

    PubMed Central

    Dougherty, Lea R.; Klein, Daniel N.; Congdon, Eliza; Canli, Turhan; Hayden, Elizabeth P.

    2009-01-01

    This study examined whether the interaction between the serotonin transporter promoter region (5-HTTLPR) and brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms was associated with hypothalamic-pituitary-adrenal (HPA) axis reactivity to stress. A community sample of 144 preschool-aged children was genotyped and exposed to stress-inducing laboratory tasks. Salivary cortisol was obtained at four time points during a standardized laboratory assessment before and after stressors involving separation from a parent and frustrating tasks. Children homozygous for the short-5-HTTLPR allele and carrying the Met-BDNF allele evidenced a significantly lower initial level of cortisol, followed by a positive increase in cortisol in response to the laboratory stressors. In contrast, children who were homozygous for the short-5-HTTLPR and the Val-BDNF alleles evidenced a greater decline in cortisol in response to the laboratory stressors. Findings indicated that the BDNF gene moderated the association between 5-HTTLPR and children’s biological stress responses, suggesting that epistatic effects play a role in individual differences in stress regulation, and possibly genetic vulnerability to stress-related disorders. PMID:19914329

  6. The effect of COMT Val158 Met genotype on decision-making and preliminary findings on its interaction with the 5-HTTLPR in healthy females.

    PubMed

    van den Bos, Ruud; Homberg, Judith; Gijsbers, Ellen; den Heijer, Esther; Cuppen, Edwin

    2009-02-01

    Poor decision-making is inherent to several psychiatric conditions for which a genetic basis may exist. We previously showed that healthy female volunteers homozygous for the short allele (s/s) of the serotonin transporter length polymorphic region (5-HTTLPR) chose more often cards from disadvantageous decks in the Iowa Gambling Task (IGT), which measures decision-making, than long (l) allele carriers. The 5-HTTLPR and catechol-O-methyltransferase (COMT) Val(158) Met polymorphism affect the same set of neuronal structures. Therefore, we explored the effect of the (COMT) Val(158) Met polymorphism on IGT performance and its interaction with the 5-HTTLPR in the same subjects in this study. We observed that subjects homozygous for methionine (Met/Met) chose more disadvantageously than subjects homozygous for valine (Val/Val). s/s-Met/Met-subjects appeared to show the poorest IGT performance of all possible combinations of 5-HTTLPR and COMT allelic variants. Using the Expectancy-Valence model, no differences were found for the three different 5-HTTLPR or COMT genotypes regarding (i) attention to wins versus losses, (ii) updating rate, or (iii) response consistency. However, subjects with at least one Met-allele were paying more attention to wins than subjects with no Met-alleles. We discuss whether a common neuronal mechanism relates to s- and Met-allele-related deficits in updating and/or processing of choice outcome to guide subsequent choices in this gamble-based test.

  7. No association between catechol-o-methyltransferase Val108/158Met polymorphism and schizophrenia or its clinical symptomatology in a Mexican population.

    PubMed

    Tovilla-Zárate, Carlos; Medellín, Beatriz Camarena; Fresán, Ana; López-Narváez, Lilia; Castro, Thelma Beatriz Gonzalez; Juárez Rojop, Isela; Ramírez-Bello, Julián; Genis, Alma; Nicolini, Humberto

    2013-02-01

    The gene coding for catecol-o-methyltransferase (COMT), participant in the metabolism of catecholamines, has long been implicated as a candidate gene for schizophrenia. We determined the relation of the COMT Val108/158Met polymorphism with schizophrenia or its symptomatology (negative, disorganized and psychotic dimension). We conducted a case-control study comprising 186 patients with schizophrenia and 247 controls. The diagnosis of schizophrenia was established using the DSM-IV criteria for this illness. The clinical symptomatology was assessed through the Scale for the Assessment of Negative Symptoms and the Scale for the Assessment of Positive Symptoms. No significant differences were found in the distribution of alleles (χ2 = 0.01, df = 1, p = 0.90) or genotypes (χ2 = 1.66, df = 2, p = 0.43) between schizophrenic patients and the control group. Multivariate analysis showed that the COMT Val108/158Met polymorphism has no influence in the clinical symptomatology of schizophrenia. Our results showed no association between COMT Val108/158Met and schizophrenia or evidence for an association between COMT and the clinical symptomatology of this illness. This suggests that the COMT gene may not contribute to the risk for schizophrenia among the Mexican population.

  8. BDNF Val66Met Polymorphism Interacts with Sleep Consolidation to Predict Ability to Create New Declarative Memories.

    PubMed

    Gosselin, Nadia; De Beaumont, Louis; Gagnon, Katia; Baril, Andrée-Ann; Mongrain, Valérie; Blais, Hélène; Montplaisir, Jacques; Gagnon, Jean-François; Pelleieux, Sandra; Poirier, Judes; Carrier, Julie

    2016-08-10

    It is hypothesized that a fundamental function of sleep is to restore an individual's day-to-day ability to learn and to constantly adapt to a changing environment through brain plasticity. Brain-derived neurotrophic factor (BDNF) is among the key regulators that shape brain plasticity. However, advancing age and carrying the BDNF Met allele were both identified as factors that potentially reduce BDNF secretion, brain plasticity, and memory. Here, we investigated the moderating role of BDNF polymorphism on sleep and next-morning learning ability in 107 nondemented individuals who were between 55 and 84 years of age. All subjects were tested with 1 night of in-laboratory polysomnography followed by a cognitive evaluation the next morning. We found that in subjects carrying the BDNF Val66Val polymorphism, consolidated sleep was associated with significantly better performance on hippocampus-dependent episodic memory tasks the next morning (β-values from 0.290 to 0.434, p ≤ 0.01). In subjects carrying at least one copy of the BDNF Met allele, a more consolidated sleep was not associated with better memory performance in most memory tests (β-values from -0.309 to -0.392, p values from 0.06 to 0.15). Strikingly, increased sleep consolidation was associated with poorer performance in learning a short story presented verbally in Met allele carriers (β = -0.585, p = 0.005). This study provides new evidence regarding the interacting roles of consolidated sleep and BDNF polymorphism in the ability to learn and stresses the importance of considering BDNF polymorphism when studying how sleep affects cognition. Individuals with the BDNF Val/Val (valine allele) polymorphism showed better memory performance after a night of consolidated sleep. However, we observed that middle-aged and older individuals who are carriers of the BDNF Met allele displayed no positive association between sleep quality and their ability to learn the next morning. This interaction between sleep and

  9. Effect of BDNF Val66Met on Memory Decline and Hippocampal Atrophy in Prodromal Alzheimer’s Disease: A Preliminary Study

    PubMed Central

    Lim, Yen Ying; Villemagne, Victor L.; Laws, Simon M.; Ames, David; Pietrzak, Robert H.; Ellis, Kathryn A.; Harrington, Karra; Bourgeat, Pierrick; Bush, Ashley I.; Martins, Ralph N.; Masters, Colin L.; Rowe, Christopher C.; Maruff, Paul

    2014-01-01

    Objective Cross-sectional genetic association studies have reported equivocal results on the relationship between the brain-derived neurotrophic factor (BDNF) Val66Met and risk of Alzheimer’s disease (AD). As AD is a neurodegenerative disease, genetic influences may become clearer from prospective study. We aimed to determine whether BDNF Val66Met polymorphism influences changes in memory performance, hippocampal volume, and Aβ accumulation in adults with amnestic mild cognitive impairment (aMCI) and high Aβ. Methods Thirty-four adults with aMCI were recruited from the Australian, Imaging, Biomarkers and Lifestyle (AIBL) Study. Participants underwent PiB-PET and structural MRI neuroimaging, neuropsychological assessments and BDNF genotyping at baseline, 18 month, and 36 month assessments. Results In individuals with aMCI and high Aβ, Met carriers showed significant and large decline in episodic memory (d = 0.90, p = .020) and hippocampal volume (d = 0.98, p = .035). BDNF Val66Met was unrelated to the rate of Aβ accumulation (d = −0.35, p = .401). Conclusions Although preliminary due to the small sample size, results of this study suggest that high Aβ levels and Met carriage may be useful prognostic markers of accelerated decline in episodic memory, and reductions in hippocampal volume in individuals in the prodromal or MCI stage of AD. PMID:24475133

  10. Effect of GSTM1, GSTT1, and GSTP1 IIe105Val polymorphisms on susceptiblity to gestational diabetes mellitus.

    PubMed

    Qiu, Y H; Xu, Y L; Zhang, W H

    2016-06-03

    We investigate the role of the GSTM1, GSTT1, and GSTP1 IIe105Val genetic polymorphisms in the susceptibility to gestational diabetes mellitus. A total of 223 pregnant women with gestational diabetes mellitus and 265 healthy pregnant women were examined at The Second Affiliated Hospital of Shaanxi University of Chinese Medicine from May 2013 to November 2013. Genotyping for detection of GSTM1, GSTT1, and GSTP1 IIe105Val polymorphisms was conducted using the restriction fragment length polymorphism-polymerase chain reaction. There were statistically significant differences between patients with gestational diabetes mellitus and control subjects in terms of age (χ(2) = 6.68, P = 0.01) and BMI (t = 7.56, P < 0.001) levels of HDL-C (t = 2.62, P = 0.005) and LDL-C (t = 3.98, P < 0.001). By the chi-square test, we found significant differences between the present and null genotype distributions of GSTM1 (χ(2) = 10.95, P = 0.0009). Null genotype of GSTM1 could influence the susceptibility to gestational diabetes mellitus compared to the present genotype [adjusted OR (95%CI) = 1.85 (1.26-2.72)]. However, the unconditional logistic analysis revealed that GSTT1 and GSTP1 IIe105Val polymorphisms could not influence the risk of gestational diabetes mellitus in a Chinese population. In summary, we suggest that the GSTM1 gene polymorphism could influence the susceptibility to gestational diabetes mellitus in a Chinese population.

  11. Nicholas DiOrio | NREL

    Science.gov Websites

    Engineering Intern, NREL, Golden, CO, 2013 Featured Publications N. DiOrio, A. Dobos, S. Janzou, A. Nelson and Renewable Energy Laboratory, Golden, CO. N. DiOrio, A. Dobos and S. Janzou. 2015. "Economic Analysis . C. Christensen, J. Maguire, J. Burch, N. DiOrio. "Simplified Solar Water Heater Simulation

  12. Association between glutathione S-transferase P1 Ile (105) Val gene polymorphism and chronic obstructive pulmonary disease: A meta-analysis based on seventeen case-control studies.

    PubMed

    Yang, Lingjing; Li, Xixia; Tong, Xiang; Fan, Hong

    2015-12-01

    Previous studies have shown that glutathione S-transferase P1 (GSTP1) was associated with chronic obstructive pulmonary disease (COPD). However, the association between GSTP1 Ile (105) Val gene polymorphism and COPD remains controversial. To drive a more precise estimation, we performed a meta-analysis based on published case-control studies. An electronic search of PubMed, EMBASE, Cochrane library, Web of Science and China Knowledge Resource Integrated (CNKI) Database for papers on GSTP1 Ile (105) Val gene polymorphism and COPD risk was performed. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association in the homozygote model, heterozygote model, dominant model, recessive model and an additive mode. Statistical heterogeneity, test of publication bias and sensitivity analysis was performed. The software STATA (Version 13.0) was used data analysis. Overall, seventeen studies with 1892 cases and 2012 controls were included in this meta-analysis. The GSTP1 Ile (105) Val polymorphism showed pooled odds ratios for the homozygote comparison (OR = 1.501, 95%CI [0.862, 2.614]), heterozygote comparison (OR = 0.924, 95%CI [0.733, 1.165]), dominant model (OR = 1.003, 95%CI [0.756, 1.331]), recessive model (OR = 1.510, 95%CI [0.934, 2.439]), and an additive model (OR = 1.072, 95%CI [0.822, 1.398]). In conclusion, the current meta-analysis, based on the most updated information, showed no significant association between GSTP1 Ile (105) Val gene polymorphism and COPD risk in any genetic models. The results of subgroup analysis also showed no significant association between GSTP1 Ile (105) Val gene polymorphism and COPD risk in Asian population and Caucasian population. Further studies involving large populations and careful control with age, sex, ethnicity, and cigarette smoking are greatly needed.

  13. Association between glutathione S-transferase P1 Ile (105) Val gene polymorphism and chronic obstructive pulmonary disease: A meta-analysis based on seventeen case–control studies

    PubMed Central

    Yang, Lingjing; Li, Xixia; Tong, Xiang; Fan, Hong

    2015-01-01

    Introduction Previous studies have shown that glutathione S-transferase P1 (GSTP1) was associated with chronic obstructive pulmonary disease (COPD). However, the association between GSTP1 Ile (105) Val gene polymorphism and COPD remains controversial. To drive a more precise estimation, we performed a meta-analysis based on published case–control studies. Methods An electronic search of PubMed, EMBASE, Cochrane library, Web of Science and China Knowledge Resource Integrated (CNKI) Database for papers on GSTP1 Ile (105) Val gene polymorphism and COPD risk was performed. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association in the homozygote model, heterozygote model, dominant model, recessive model and an additive mode. Statistical heterogeneity, test of publication bias and sensitivity analysis was performed. The software STATA (Version 13.0) was used data analysis. Results Overall, seventeen studies with 1892 cases and 2012 controls were included in this meta-analysis. The GSTP1 Ile (105) Val polymorphism showed pooled odds ratios for the homozygote comparison (OR = 1.501, 95%CI [0.862, 2.614]), heterozygote comparison (OR = 0.924, 95%CI [0.733, 1.165]), dominant model (OR = 1.003, 95%CI [0.756, 1.331]), recessive model (OR = 1.510, 95%CI [0.934, 2.439]), and an additive model (OR = 1.072, 95%CI [0.822, 1.398]). Conclusions In conclusion, the current meta-analysis, based on the most updated information, showed no significant association between GSTP1 Ile (105) Val gene polymorphism and COPD risk in any genetic models. The results of subgroup analysis also showed no significant association between GSTP1 Ile (105) Val gene polymorphism and COPD risk in Asian population and Caucasian population. Further studies involving large populations and careful control with age, sex, ethnicity, and cigarette smoking are greatly needed. PMID:26504746

  14. [Trattamento del disturbo da uso di alcol da un punto di vista psicologico].

    PubMed

    Coriale, Giovanna; Fiorentino, Daniela; De Rosa, Francesca; Solombrino, Simona; Scalese, Bruna; Ciccarelli, Rosaria; Attilia, Fabio; Vitali, Mario; Musetti, Alessia; Fiore, Marco; Ceccanti, Mauro

    2018-01-01

    RIASSUNTO. L'elaborazione del piano di trattamento rappresenta un momento molto delicato e complesso del processo terapeutico del disturbo da abuso di alcol (DUA). È la fase in cui le informazioni raccolte da un'équipe di professionisti (medici, psicologi e assistenti sociali) (modello bio-psico-sociale del DUA) vengono messe insieme per decidere il percorso terapeutico più adatto. Per quanto riguarda la parte psicologica, è di notevole importanza scegliere un trattamento clinico in grado di ridurre al minimo la mancata adesione al trattamento e, per i soggetti che rimangono in trattamento, di garantirne l'efficacia. Se da una parte, le tecniche psicoanalitiche e comportamentali hanno fornito le basi della terapia psicologica dell'alcolismo, dall'altra, gli approcci basati sull'evidenza scientifica sono stati elaborati a partire dai principi del colloquio motivazionale e della terapia cognitivo-comportamentale. In questo articolo viene fornita una panoramica dei trattamenti che sono risultati più efficaci nel trattare il DUA e delle modalità temporali più adeguate per monitorare l'efficacia del trattamento.

  15. Trasforiiazioni Termoelastiche Finite di Solidi Incomprimibili

    NASA Astrophysics Data System (ADS)

    Signorini, A.

    Queste lezlioni hanno come direttiva una sintesi di quanto si trova sistematicamente sviluppato in una mia Memoria sulle trasformazioni termoelastiche finite di solidi incomprimibili, in corso di stampa negli Annali di Matematica pura e applicata t. XXXIX ( 1955) pp. 147-201 , Verranno anche esposti, come necessaria premessa, alcuni d ei risultati di due precedenti Memorie degli stessi Annali. Invece, per motivo di brevità, non potrò dare neppure un cenno delle ulteriori ricerche svilup pate dal prof. T. Manacorda in tre recentissimi suoi lavori:

  16. Heteroplasmic mutation in the anticodon-stem of mitochondrial tRNA(Val) causing MNGIE-like gastrointestinal dysmotility and cachexia.

    PubMed

    Horváth, Rita; Bender, Andreas; Abicht, Angela; Holinski-Feder, Elke; Czermin, Birgit; Trips, Tobias; Schneiderat, Peter; Lochmüller, Hanns; Klopstock, Thomas

    2009-05-01

    While mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is typically associated with mutations in the nuclear gene encoding for thymidine phosphorylase (ECGF1, TYMP), a similar clinical phenotype was described in patients carrying mutations in the nuclear-encoded polymerase gamma (POLG1) as well as a few mitochondrial tRNA genes. Here we report a novel mutation in the mitochondrial tRNA(Val) (MTTV) gene in a girl presenting with clinical symptoms of MNGIE-like gastrointestinal dysmotility and cachexia. Clinical, histological, biochemical and single cell investigations were performed. The heteroplasmic m.1630A>G mutation was detected in the mitochondrial tRNA(Val) (MTTV) gene in the patient's muscle, blood leukocytes and myoblasts, as well as in blood DNA of the unaffected mother. We provide clinical, biochemical, histological, and molecular genetic evidence on the single cell level for the pathogenicity of this mutation. Our finding adds to the genetic heterogeneity of MNGIE-like gastrointestinal symptoms and highlights the importance of a thorough genetic workup in case of suspected mitochondrial disease.

  17. Optogenetic Manipulation of Cyclic Di-GMP (c-di-GMP) Levels Reveals the Role of c-di-GMP in Regulating Aerotaxis Receptor Activity in Azospirillum brasilense.

    PubMed

    O'Neal, Lindsey; Ryu, Min-Hyung; Gomelsky, Mark; Alexandre, Gladys

    2017-09-15

    Bacterial chemotaxis receptors provide the sensory inputs that inform the direction of navigation in changing environments. Recently, we described the bacterial second messenger cyclic di-GMP (c-di-GMP) as a novel regulator of a subclass of chemotaxis receptors. In Azospirillum brasilense , c-di-GMP binds to a chemotaxis receptor, Tlp1, and modulates its signaling function during aerotaxis. Here, we further characterize the role of c-di-GMP in aerotaxis using a novel dichromatic optogenetic system engineered for manipulating intracellular c-di-GMP levels in real time. This system comprises a red/near-infrared-light-regulated diguanylate cyclase and a blue-light-regulated c-di-GMP phosphodiesterase. It allows the generation of transient changes in intracellular c-di-GMP concentrations within seconds of irradiation with appropriate light, which is compatible with the time scale of chemotaxis signaling. We provide experimental evidence that binding of c-di-GMP to the Tlp1 receptor activates its signaling function during aerotaxis, which supports the role of transient changes in c-di-GMP levels as a means of adjusting the response of A. brasilense to oxygen gradients. We also show that intracellular c-di-GMP levels in A. brasilense change with carbon metabolism. Our data support a model whereby c-di-GMP functions to imprint chemotaxis receptors with a record of recent metabolic experience, to adjust their contribution to the signaling output, thus allowing the cells to continually fine-tune chemotaxis sensory perception to their metabolic state. IMPORTANCE Motile bacteria use chemotaxis to change swimming direction in response to changes in environmental conditions. Chemotaxis receptors sense environmental signals and relay sensory information to the chemotaxis machinery, which ultimately controls the swimming pattern of cells. In bacteria studied to date, differential methylation has been known as a mechanism to control the activity of chemotaxis receptors and

  18. Optogenetic Manipulation of Cyclic Di-GMP (c-di-GMP) Levels Reveals the Role of c-di-GMP in Regulating Aerotaxis Receptor Activity in Azospirillum brasilense

    PubMed Central

    O'Neal, Lindsey; Ryu, Min-Hyung; Gomelsky, Mark

    2017-01-01

    ABSTRACT Bacterial chemotaxis receptors provide the sensory inputs that inform the direction of navigation in changing environments. Recently, we described the bacterial second messenger cyclic di-GMP (c-di-GMP) as a novel regulator of a subclass of chemotaxis receptors. In Azospirillum brasilense, c-di-GMP binds to a chemotaxis receptor, Tlp1, and modulates its signaling function during aerotaxis. Here, we further characterize the role of c-di-GMP in aerotaxis using a novel dichromatic optogenetic system engineered for manipulating intracellular c-di-GMP levels in real time. This system comprises a red/near-infrared-light-regulated diguanylate cyclase and a blue-light-regulated c-di-GMP phosphodiesterase. It allows the generation of transient changes in intracellular c-di-GMP concentrations within seconds of irradiation with appropriate light, which is compatible with the time scale of chemotaxis signaling. We provide experimental evidence that binding of c-di-GMP to the Tlp1 receptor activates its signaling function during aerotaxis, which supports the role of transient changes in c-di-GMP levels as a means of adjusting the response of A. brasilense to oxygen gradients. We also show that intracellular c-di-GMP levels in A. brasilense change with carbon metabolism. Our data support a model whereby c-di-GMP functions to imprint chemotaxis receptors with a record of recent metabolic experience, to adjust their contribution to the signaling output, thus allowing the cells to continually fine-tune chemotaxis sensory perception to their metabolic state. IMPORTANCE Motile bacteria use chemotaxis to change swimming direction in response to changes in environmental conditions. Chemotaxis receptors sense environmental signals and relay sensory information to the chemotaxis machinery, which ultimately controls the swimming pattern of cells. In bacteria studied to date, differential methylation has been known as a mechanism to control the activity of chemotaxis receptors and

  19. Effects of the glucagon-like polypeptide-1 analogue (Val8)GLP-1 on learning, progenitor cell proliferation and neurogenesis in the C57B/16 mouse brain.

    PubMed

    McGovern, Stephen F J; Hunter, Kerry; Hölscher, Christian

    2012-09-14

    Type 2 diabetes (T2DM) has been identified as a risk factor for Alzheimer's disease. Here, we tested the properties of the glucagon-like polypetide-1 (GLP-1) analogue (Val8)GLP-1, a drug originally developed as a treatment for T2DM at a range of doses (2.5 nmol; 25 nmol; 100 nmol; or 250 nmol/kg bw ip.) in an acute memory study in wild type C57B/l6 mice. We also tested (Val8)GLP-1 and the GLP-1 receptor antagonist exendin (9-39) in a chronic study (3 weeks at 25 nmol/kg bw ip. once-daily). We found that (Val8)GLP-1 crossed the blood brain barrier readily and that peripheral injection increased levels in the brain 30 min post-injection ip. but not 2h post-injection in rats. In the acute study, the low dose of 2.5 nmol/kg ip. enhanced motor activity in the open field task, while total distance travelled, exploratory behaviour and anxiety was not affected at any dose. Learning an object recognition task was not affected either. In the chronic study, no effect was observed in the open field assessment. The antagonist exendin (9-39) impaired object recognition learning and spatial learning in a water maze task, demonstrating the importance of GLP-1 signalling in memory formation. Locomotor activity was also affected in some cases. Blood sugar levels and insulin sensitivity was not affected in chronically treated mice. Neuronal stem cells and neurogenesis was enhanced by (Val8)GLP-1 in the dentate gyrus of wild type mice. The results demonstrate that (Val8)GLP-1 is safe in a range of doses, crosses the BBB and has potentially beneficial effects in the CNS by enhancing neurogenesis. Copyright © 2012 Elsevier B.V. All rights reserved.

  20. Interaction between 5-HTTLPR and BDNF Val66Met polymorphisms on HPA axis reactivity in preschoolers.

    PubMed

    Dougherty, Lea R; Klein, Daniel N; Congdon, Eliza; Canli, Turhan; Hayden, Elizabeth P

    2010-02-01

    This study examined whether the interaction between the serotonin transporter promoter region (5-HTTLPR) and brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms was associated with hypothalamic-pituitary-adrenal (HPA) axis reactivity to stress. A community sample of 144 preschool-aged children was genotyped and exposed to stress-inducing laboratory tasks. Salivary cortisol was obtained at four time points during a standardized laboratory assessment before and after stressors involving separation from a parent and frustrating tasks. Children homozygous for the short-5-HTTLPR allele and carrying the Met-BDNF allele evidenced a significantly lower initial level of cortisol, followed by a positive increase in cortisol in response to the laboratory stressors. In contrast, children who were homozygous for the short-5-HTTLPR and the Val-BDNF alleles evidenced a greater decline in cortisol in response to the laboratory stressors. Findings indicated that the BDNF gene moderated the association between 5-HTTLPR and children's biological stress responses, suggesting that epistatic effects play a role in individual differences in stress regulation, and possibly genetic vulnerability to stress-related disorders. Copyright 2009 Elsevier B.V. All rights reserved.

  1. Monitoring the Restart of a High-Rate Wastewater Disposal Well in the Val d'Agri Oilfield (Italy)

    NASA Astrophysics Data System (ADS)

    De Gori, P.; Improta, L.; Moretti, M.; Colasanti, G.; Criscuoli, F.

    2015-12-01

    The Val d'Agri Quaternary basin in the Southern Apennine range of Italy hosts the largest inland oil field in Europe. Wastewater coming from the oil exploitation is re-injected by a high-rate disposal well into strongly fractured limestones of the hydrocarbon carbonate reservoir. Disposal activity has induced micro-seismicity since the beginning of injection in June 2006. Around 220 small magnitude events (ML < 2.3) were recorded between 2006 and 2013 by the trigger-mode monitoring local network managed by the oil company and by the National Seismic Network of Istituto Nazionale di Geofisica e Vulcanologia. The induced micro-seismicity illuminated a pre-existing high-angle fault located 1 km below the well. Since June 2006, wastewater has been re-injected with only short interruptions due acid stimulations. In January 2015 disposal activity was halted due to technical operations in the oil refinery and wastewater injection restarted after two weeks. We installed 5 short-period stations within 10 km of the disposal well to carefully monitor the re-start phase and the subsequent 3 months of disposal activity. This temporary network was complemented by stations of the National Seismic Network giving this final configuration:9 stations within 10 km of the well with the closest station 2 km apart, 13 stations within 20 km. Here we report on the preliminary analysis of the local earthquake recorded during the survey focusing on the events occurred in the injection area. The seismicity rate is compared with injection data.In spite of the dense network, we found that the rate of induced seismicity (both the number and energy of events) is very low when compared to the seismicity recorded during the first 5 years of injection activity carried out with comparable rate and pressure.

  2. Activation of a synapse weakening pathway by human Val66 but not Met66 pro-brain-derived neurotrophic factor (proBDNF)

    PubMed Central

    Kailainathan, Sumangali; Piers, Thomas M.; Yi, Jee Hyun; Choi, Seongmin; Fahey, Mark S.; Borger, Eva; Gunn-Moore, Frank J.; O’Neill, Laurie; Lever, Michael; Whitcomb, Daniel J.; Cho, Kwangwook; Allen, Shelley J.

    2016-01-01

    This study describes a fundamental functional difference between the two main polymorphisms of the pro-form of brain-derived neurotrophic factor (proBDNF), providing an explanation as to why these forms have such different age-related neurological outcomes. Healthy young carriers of the Met66 form (present in ∼30% Caucasians) have reduced hippocampal volume and impaired hippocampal-dependent memory function, yet the same polymorphic population shows enhanced cognitive recovery after traumatic brain injury, delayed cognitive dysfunction during aging, and lower risk of late-onset Alzheimer’s disease (AD) compared to those with the more common Val66 polymorphism. To examine the differences between the protein polymorphisms in structure, kinetics of binding to proBDNF receptors and in vitro function, we generated purified cleavage-resistant human variants. Intriguingly, we found no statistical differences in those characteristics. As anticipated, exogenous application of proBDNF Val66 to rat hippocampal slices dysregulated synaptic plasticity, inhibiting long-term potentiation (LTP) and facilitating long-term depression (LTD). We subsequently observed that this occurred via the glycogen synthase kinase 3β (GSK3β) activation pathway. However, surprisingly, we found that Met66 had no such effects on either LTP or LTD. These novel findings suggest that, unlike Val66, the Met66 variant does not facilitate synapse weakening signaling, perhaps accounting for its protective effects with aging. PMID:26687096

  3. Perceived Stress in Adults Aged 65 to 90: Relations to Facets of Time Perspective and COMT Val158Met Polymorphism

    PubMed Central

    Rönnlund, Michael; Åström, Elisabeth; Adolfsson, Rolf; Carelli, Maria G.

    2018-01-01

    This study examined the relation between perceived stress and time perspective (views of past, present, future) in a population-based sample of older adults (65–90 years, N = 340). The Perceived Questionnaire (PSQ index) was used to measure stress and the Swedish version of the Zimbardo Time Perspective Inventory (S-ZTPI) was used to operationalize time perspective. Unlike the original inventory, S-ZTPI separates positive and negative aspects of a future time perspective and we hypothesized that the Future Negative (FN) scale would be important to account for variations in stress. Additionally, associations with Catechol-O-methyltransferase (COMT) Val158Met polymorphism were examined, motivated by prior associations of this single nucleotide polymorphism (SNP) with stress (or “anxiety”) related personality traits. In line with the hypotheses, FN was the strongest predictor of PSQ index scores in multiple regression analyses. In a related vein, the dichotomization of the unitary Future scale increased the association between PSQ scores and a measure of deviations from a balanced time perspective, i.e., the difference between a proposed optimal and observed ZTPI profile. Finally, higher levels of stress as well as higher scores on FN were observed in COMT Val/Val carriers, at least among men. This suggests a shared dopaminergic genetic influence on these variables. Collectively, the results demonstrate that perceived stress is closely linked to time perspective and highlight the need to take negative aspects of a future temporal orientation into account to understand this relation. PMID:29623060

  4. Perceived Stress in Adults Aged 65 to 90: Relations to Facets of Time Perspective and COMT Val158Met Polymorphism.

    PubMed

    Rönnlund, Michael; Åström, Elisabeth; Adolfsson, Rolf; Carelli, Maria G

    2018-01-01

    This study examined the relation between perceived stress and time perspective (views of past, present, future) in a population-based sample of older adults (65-90 years, N = 340). The Perceived Questionnaire (PSQ index) was used to measure stress and the Swedish version of the Zimbardo Time Perspective Inventory (S-ZTPI) was used to operationalize time perspective. Unlike the original inventory, S-ZTPI separates positive and negative aspects of a future time perspective and we hypothesized that the Future Negative (FN) scale would be important to account for variations in stress. Additionally, associations with Catechol-O-methyltransferase ( COMT ) Val 158 Met polymorphism were examined, motivated by prior associations of this single nucleotide polymorphism (SNP) with stress (or "anxiety") related personality traits. In line with the hypotheses, FN was the strongest predictor of PSQ index scores in multiple regression analyses. In a related vein, the dichotomization of the unitary Future scale increased the association between PSQ scores and a measure of deviations from a balanced time perspective, i.e., the difference between a proposed optimal and observed ZTPI profile. Finally, higher levels of stress as well as higher scores on FN were observed in COMT Val/Val carriers, at least among men. This suggests a shared dopaminergic genetic influence on these variables. Collectively, the results demonstrate that perceived stress is closely linked to time perspective and highlight the need to take negative aspects of a future temporal orientation into account to understand this relation.

  5. Modification of Depression by COMT val[superscript 158]Met Polymorphism in Children Exposed to Early Severe Psychosocial Deprivation

    ERIC Educational Resources Information Center

    Drury, Stacy S.; Theall, Katherine P.; Smyke, Anna T.; Keats, Bronya J. B.; Egger, Helen L.; Nelson, Charles A.; Fox, Nathan A.; Marshall, Peter J.; Zeanah, Charles H.

    2010-01-01

    Objective: To examine the impact of the catechol-O-methyltransferase (COMT) val[superscript 158]met allele on depressive symptoms in young children exposed to early severe social deprivation as a result of being raised in institutions. Methods: One hundred thirty six children from the Bucharest Early Intervention Project (BEIP) were randomized…

  6. EEG alpha power as an intermediate measure between brain-derived neurotrophic factor Val66Met and depression severity in patients with major depressive disorder.

    PubMed

    Zoon, Harriët F A; Veth, C P M; Arns, Martijn; Drinkenburg, W H I M; Talloen, Willem; Peeters, Pieter J; Kenemans, J L

    2013-06-01

    Major depressive disorder has a large impact on patients and society and is projected to be the second greatest global burden of disease by 2020. The brain-derived neurotrophic factor (BDNF) gene is considered to be one of the important factors in the etiology of major depressive disorder. In a recent study, alpha power was found to mediate between BDNF Met and subclinical depressed mood. The current study looked at a population of patients with major depressive disorder (N = 107) to examine the association between the BDNF Val66Met polymorphism, resting state EEG alpha power, and depression severity. For this purpose, repeated-measures analysis of variance, partial correlation, and multiple linear models were used. Results indicated a negative association between parietal-occipital alpha power in the eyes open resting state and depression severity. In addition, Met/Met patients showed lower global absolute alpha power in the eyes closed condition compared with Val-carriers. These findings are in accordance with the previously uncovered pathway between BDNF Val66Met, resting state EEG alpha power, and depression severity. Additional research is needed for the clarification of this tentative pathway and its implication in personalized treatment of major depressive disorder.

  7. Compound-Specific Effects of Mutations at Val787 in DII-S6 of Nav1.4 Sodium Channels on the Action of Sodium Channel Inhibitor Insecticides

    PubMed Central

    von Stein, Richard T.; Soderlund, David M.

    2012-01-01

    Sodium channel inhibitor (SCI) insecticides are hypothesized to inhibit voltage-gated sodium channels by binding selectively to the slow-inactivated state. Replacement of valine at position 787 in the S6 segment of homology domain II of the rat Nav1.4 sodium channel by lysine (V787K) enchances slow inactivation of this channel whereas replacement by alanine or cysteine (V787A, V787C) inhibits slow inactivation. To test the hypothesis that SCI insecticides bind selectively to the slow-inactivated state, we constructed mutated Nav1.4/V787A, Nav1.4/V787C, and Nav1.4/V787K cDNAs, expressed wildtype and mutated channels with the auxiliary β1 subunit in Xenopus oocytes, and used the two-electrode voltage clamp technique to examine the effects of these mutations on channel inhibition by four SCI insecticides (indoxacarb, its bioactivated metabolite DCJW, metaflumizone, and RH3421). Mutations at Val787 affected SCI insecticide sensitivity in a manner that was independent of mutation-induced changes in slow inactivation gating. Sensitivity to inhibition by 10 μM indoxacarb was significantly increased in all three mutated channels, whereas sensitivity to inhibition by 10 μM metaflumizone was significantly reduced in Nav1.4/V787A channels and completely abolished in Nav1.4/V787K channels. The effects of Val787 mutations on metaflumizone were correlated with the hydrophobicity of the substituted amino acid rather than the extent of slow inactivation. None of the mutations at Val787 significantly affected the sensitivity to inhibition by DCJW or RH3421. These results demonstrate that the impact of mutations at Val787 on sodium channel inhibition by SCI insecticides depends on the specific insecticide examined and is independent of mutation-induced changes in slow inactivation gating. We propose that Val787 may be a unique determinant of metaflumizone binding. PMID:22983119

  8. Gray Matter Volume in Adolescent Anxiety: An Impact of the Brain-Derived Neurotrophic Factor Val[superscript 66]Met Polymorphism?

    ERIC Educational Resources Information Center

    Mueller, Sven C.; Aouidad, Aveline; Gorodetsky, Elena; Goldman, David; Pine, Daniel S.; Ernst, Monique

    2013-01-01

    Objective: Minimal research links anxiety disorders in adolescents to regional gray matter volume (GMV) abnormalities and their modulation by genetic factors. Prior research suggests that a brain-derived neurotrophic factor (BNDF) Val[superscript 66]Met polymorphism may modulate such brain morphometry profiles. Method: Using voxel-based…

  9. Structural insight into the role of VAL1 B3 domain for targeting to FLC locus in Arabidopsis thaliana.

    PubMed

    Wu, Baixing; Zhang, Mengmeng; Su, Shichen; Liu, Hehua; Gan, Jianhua; Ma, Jinbiao

    2018-06-22

    Vernalization is a pivotal stage for some plants involving many epigenetic changes during cold exposure. In Arabidopsis, an essential step in vernalization for further flowering is successful silence the potent floral repressor Flowering Locus C (FLC) by repressing histone mark. AtVal1 is a multi-function protein containing five domains that participate into many recognition processes and is validated to recruit the repress histone modifier PHD-PRC2 complex and interact with components of the ASAP complex target to the FLC nucleation region through recognizing a cis element known as CME (cold memory element) by its plant-specific B3 domain. Here, we determine the crystal structure of the B3 domain in complex with Sph/RY motif in CME. Our structural analysis reveals the specific DNA recognition by B3 domain, combined with our in vitro experiments, we provide the structural insight into the important implication of AtVAL1-B3 domain in flowering process. Copyright © 2018 Elsevier Inc. All rights reserved.

  10. A Val85Met Mutation in Melanocortin-1 Receptor Is Associated with Reductions in Eumelanic Pigmentation and Cell Surface Expression in Domestic Rock Pigeons (Columba livia)

    PubMed Central

    Guernsey, Michael W.; Ritscher, Lars; Miller, Matthew A.; Smith, Daniel A.; Schöneberg, Torsten; Shapiro, Michael D.

    2013-01-01

    Variation in the melanocortin-1 receptor (Mc1r) is associated with pigmentation diversity in wild and domesticated populations of vertebrates, including several species of birds. Among domestic bird species, pigmentation variation in the rock pigeon ( Columba livia ) is particularly diverse. To determine the potential contribution of Mc1r variants to pigment diversity in pigeons, we sequenced Mc1r in a wide range of pigeon breeds and identified several single nucleotide polymorphisms, including a variant that codes for an amino acid substitution (Val85Met). In contrast to the association between Val85Met and eumelanism in other avian species, this change was associated with pheomelanism in pigeons. In vitro cAMP accumulation and protein expression assays revealed that Val85Met leads to decreased receptor function and reduced cell surface expression of the mutant protein. The reduced in vitro function is consistent with the observed association with reduced eumelanic pigmentation. Comparative genetic and cellular studies provide important insights about the range of mechanisms underlying diversity among vertebrates, including different phenotypic associations with similar mutations in different species. PMID:23977400

  11. A Critique of "Research Strategies in Comparative Education" by Val D. Rust, Aminata Soumare, Octavio Pescador, and Megumi Shibuya

    ERIC Educational Resources Information Center

    Comp, David

    2006-01-01

    Val Rust, Aminata Soumare, Octavio Pescador, and Megumi Shibuya's article, "Research Strategies in Comparative Education" is a very important piece of scholarship in the field of comparative and international education. Historically, there has been much scholarly debate regarding the theoretical approaches found in the field and, on a smaller…

  12. [La diagnosi del disturbo da uso di alcol dal punto di vista psicologico].

    PubMed

    Coriale, Giovanna; Fiorentino, Daniela; Porrari, Raffaella; Battagliese, Gemma; Capriglione, Ida; Cereatti, Federica; Iannuzzi, Silvia; Mauri, Benilde; Galli, Domenica; Fiore, Marco; Attilia, Maria Luisa; Ceccanti, Mauro

    2018-01-01

    RIASSUNTO. Il disturbo da uso di alcol (DUA) è uno dei disturbi psichiatrici più comuni nella popolazione generale. Il DUA è caratterizzato da un pattern di bere eccessivo, che si mantiene nonostante gli effetti negativi che l'alcol ha sul funzionamento lavorativo, sulla salute, sulle problematiche legali, sull'educazione e sulla vita sociale. Attualmente, il modello bio-psico-sociale è quello che spiega meglio il DUA. Infatti, molte ricerche hanno fornito evidenze su come il DUA sia una patologia multidimensionale. Variabili biologiche, psicologiche e socio-culturali entrano in gioco nell'eziologia, nella natura, nel mantenimento e nel cambiamento nel tempo del disturbo. La fase diagnostica è un momento importante del processo di cura, perché il successo del trattamento dipende in larga misura dall'esattezza e dall'adeguatezza della diagnosi. La diagnosi clinica si basa su una valutazione globale del funzionamento del paziente e utilizza il colloquio e gli strumenti psicometrici come mezzo di raccolta di informazioni. Questo articolo fornirà una panoramica delle dimensioni psicologiche più importanti da valutare e sui migliori strumenti psicometrici da usare per una diagnosi adeguata.

  13. The COMT Val/Met polymorphism is associated with reading related skills and consistent patterns of functional neural activation

    PubMed Central

    Landi, Nicole; Frost, Stephen J.; Mencl, W. Einar; Preston, Jonathan L.; Jacobsen, Leslie K.; Lee, Maria; Yrigollen, Carolyn; Pugh, Kenneth R.; Grigorenko, Elena L.

    2013-01-01

    In both children and adults there is large variability in reading skill, with approximately 5–10% of individuals characterized as having reading disability; these individuals struggle to learn to read despite adequate intelligence and opportunity. Although it is well established that a substantial portion of this variability is attributed to the genetic differences between individuals, specifics of the connections between reading and the genome are not understood. This article presents data that suggest that variation in the COMT gene, which has previously been associated with variation in higher-order cognition, is associated with reading and reading-related skills, both at the level of brain and behavior. In particular, we found that the COMT Val/Met polymorphism at rs4680, which results in the substitution of the ancestral Valine (Val) by Methionine (Met), was associated with better performance on a number of critical reading measures and with patterns of functional neural activation that have been linked to better readers. We argue that this polymorphism, known for its broad effects on cognition, may modulate (likely through frontal lobe function) reading skill. PMID:23278923

  14. [The Val606Met mutation of human beta myosin heavy chain in a Chinese familial hypertrophic cardiomyopathy family].

    PubMed

    Yuan, Jian-song; Qiao, Shu-bin; Wang, Shu-xia; Teng, Si-yong; You, Shi-jie; Yang, Wei-xian; Gao, Run-lin; Chen, Ji-lin; Yang, Yue-jin

    2008-04-01

    To explore the disease-causing gene mutation in Chinese families with hypertrophic cardiomyopathy (HCM) and to analyze the correlation between the genotype and phenotype. Samples of peripheral blood were collected from three Chinese families with HCM (at least two HCM patients existed/family). The exons in the functional regions of the beta myosin heavy chain gene (MYH7) were amplified with PCR and the products were sequenced. A Val606Met missen mutation was identified in the exon 16 of MYH7 gene in a Chinese family and this mutation was identified in all HCM patients (n = 4) and there was also a 15-years-old young mutation carrier who was not HCM patient now (penetrance of 80%). This mutation was not identified in other healthy family members in this family, in other 2 Chinese familiar HCM families and in 120 non-HCM control patients. The Val606Met missen mutation is closely associated with familiar HCM in a Chinese family which is associated with clinical phenotype with a penetrance of 80%.

  15. Stress aligned cracks in the upper crust of the Val d'Agri region as revealed by shear wave splitting

    NASA Astrophysics Data System (ADS)

    Pastori, M.; Piccinini, D.; Margheriti, L.; Improta, L.; Valoroso, L.; Chiaraluce, L.; Chiarabba, C.

    2009-10-01

    Shear wave splitting is measured at 19 seismic stations of a temporary network deployed in the Val d'Agri area to record low-magnitude seismic activity. The splitting results suggest the presence of an anisotropic layer between the surface and 15 km depth (i.e. above the hypocentres). The dominant fast polarization direction strikes NW-SE parallel to the Apennines orogen and is approximately parallel to the maximum horizontal stress in the region, as well as to major normal faults bordering the Val d'Agri basin. The size of the normalized delay times in the study region is about 0.01 s km-1, suggesting 4.5 percent shear wave velocity anisotropy (SWVA). On the south-western flank of the basin, where most of the seismicity occurs, we found larger values of normalized delay times, between 0.017 and 0.02 s km-1. These high values suggest a 10 percent of SWVA. These parameters agree with an interpretation of seismic anisotropy in terms of the Extensive-Dilatancy Anisotropy (EDA) model that considers the rock volume pervaded by fluid-saturated microcracks aligned by the active stress field. Anisotropic parameters are consistent with borehole image logs from deep exploration wells in the Val d'Agri oil field that detect pervasive fluid saturated microcracks striking NW-SE parallel to the maximum horizontal stress in the carbonatic reservoir. However, we cannot rule out the contribution of aligned macroscopic fractures because the main Quaternary normal faults are parallel to the maximum horizontal stress. The strong anisotropy and the seismicity concentration testify for active deformation along the SW flank of the basin.

  16. Association of GSTM1, GSTT1, GSTP1-ILE105VAL and ACE I/D polymorphisms with ankylosing spondylitis.

    PubMed

    İnal, Esra Erkol; Görükmez, Orhan; Eroğlu, Selma; Görükmez, Özlem; Solak, Özlem; Topak, Ali; Yakut, Tahsin

    2016-01-01

    Ankylosing spondylitis (AS) is a chronic inflammatory disease of unknown origin. The aim of this study is to clarify the relationships between susceptibility and severity of AS and GST-mu1 (GSTM1), GST-theta1 (GSTT1), GST-pi1 (GSTP1)-Ile105Val and angiotensin-converting enzyme (ACE) I/D polymorphisms in AS patients. One hundred thirty-eight AS patients and seventy-one healthy controls were enrolled in this study. Erythrocyte sedimentation rate and C-reactive protein (CRP) levels of the AS patients were recorded. The scores of the numeric rating scale (NRS) pain, the Bath Ankylosing Spondylitis Activity Index, the Bath Ankylosing Spondylitis Metrology Index and the Bath Ankylosing Spondylitis Functional Index were calculated. The genotypes distributions and allele frequencies of GSTM1, GSTT1, GSTP1-Ile105Val and ACE I/D polymorphisms were compared between patients and healthy controls. The Multiplex polymerase chain reaction (PCR) and the PCR-restriction fragment length polymorphism methods were used to detect the polymorphisms of ACE I/D, the GSTT1 and GSTM1 genes and the GSTP1-Ile105Val polymorphism, respectively. There were significantly higher levels of the GSTT1 null and the ACE II genotypes in AS patients compared to those in healthy controls (p = 0.002 and 0.005, respectively). We found significantly higher levels of CRP and the NRS pain scores in the patients with ACE ID or DD genotypes compared to those in the patients with ACE II genotypes (p = 0.005 and 0.035, respectively). The present results showed that genes involved in protection from oxidative stress and ACE gene may influence disease development and course in AS.

  17. Crystal structures of isomeric 3,5-di-chloro-N-(2,3-di-methyl-phen-yl)benzene-sulfonamide, 3,5-di-chloro-N-(2,6-di-methyl-phen-yl)benzene-sulfonamide and 3,5-di-chloro-N-(3,5-di-methyl-phen-yl)benzene-sulfonamide.

    PubMed

    Shakuntala, K; Naveen, S; Lokanath, N K; Suchetan, P A

    2017-05-01

    The crystal structures of three isomeric compounds of formula C 14 H 13 Cl 2 NO 2 S, namely 3,5-di-chloro- N -(2,3-di-methyl-phen-yl)-benzene-sulfonamide (I), 3,5-di-chloro- N -(2,6-di-methyl-phen-yl)benzene-sulfonamide (II) and 3,5-di-chloro- N -(3,5-di-methyl-phen-yl)benzene-sulfonamide (III) are described. The mol-ecules of all the three compounds are U-shaped with the two aromatic rings inclined at 41.3 (6)° in (I), 42.1 (2)° in (II) and 54.4 (3)° in (III). The mol-ecular conformation of (II) is stabilized by intra-molecular C-H⋯O hydrogen bonds and C-H⋯π inter-actions. The crystal structure of (I) features N-H⋯O hydrogen-bonded R 2 2 (8) loops inter-connected via C (7) chains of C-H⋯O inter-actions, forming a three-dimensional architecture. The structure also features π-π inter-actions [ Cg ⋯ Cg = 3.6970 (14) Å]. In (II), N-H⋯O hydrogen-bonded R 2 2 (8) loops are inter-connected via π-π inter-actions [inter-centroid distance = 3.606 (3) Å] to form a one-dimensional architecture running parallel to the a axis. In (III), adjacent C (4) chains of N-H⋯O hydrogen-bonded mol-ecules running parallel to [010] are connected via C-H⋯π inter-actions, forming sheets parallel to the ab plane. Neighbouring sheets are linked via offset π-π inter-actions [inter-centroid distance = 3.8303 (16) Å] to form a three-dimensional architecture.

  18. 40 CFR 721.10325 - Cyclosilazanes, di-Me, Me hydrogen, polymers with di-Me, Me hydrogen silazanes, reaction products...

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Cyclosilazanes, di-Me, Me hydrogen, polymers with di-Me, Me hydrogen silazanes, reaction products with 3-(triethoxysilyl)-1-propanamine. 721... Substances § 721.10325 Cyclosilazanes, di-Me, Me hydrogen, polymers with di-Me, Me hydrogen silazanes...

  19. 40 CFR 721.10325 - Cyclosilazanes, di-Me, Me hydrogen, polymers with di-Me, Me hydrogen silazanes, reaction products...

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Cyclosilazanes, di-Me, Me hydrogen, polymers with di-Me, Me hydrogen silazanes, reaction products with 3-(triethoxysilyl)-1-propanamine. 721... Substances § 721.10325 Cyclosilazanes, di-Me, Me hydrogen, polymers with di-Me, Me hydrogen silazanes...

  20. 40 CFR 721.10325 - Cyclosilazanes, di-Me, Me hydrogen, polymers with di-Me, Me hydrogen silazanes, reaction products...

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Cyclosilazanes, di-Me, Me hydrogen, polymers with di-Me, Me hydrogen silazanes, reaction products with 3-(triethoxysilyl)-1-propanamine. 721... Substances § 721.10325 Cyclosilazanes, di-Me, Me hydrogen, polymers with di-Me, Me hydrogen silazanes...

  1. The role of the BDNF Val66Met polymorphism in individual differences in long-term memory capacity.

    PubMed

    Montag, Christian; Felten, Andrea; Markett, Sebastian; Fischer, Luise; Winkel, Katja; Cooper, Andrew; Reuter, Martin

    2014-12-01

    The protein brain-derived neurotrophic factor (BDNF) plays an important role in diverse memory processes and is strongly expressed in the hippocampus. The hippocampus itself is a key structure involved in the processing of information from short-term to long-term memory. Due to the putative role of BDNF in memory consolidation, a prominent single nucleotide polymorphism (SNP) on the BDNF gene (BDNF Val66Met) was investigated in the context of long-term memory performance. N=138 students were presented with 40 words from 10 categories, each consisting of eight words such as 'fruits' or 'vehicles' in a memory recognition task (specifically the Deese-Roediger-McDermott Paradigm). Recognition performance was analyzed 25 min after the initial presentation of the word list and subsequently 1 week after the initial presentation. Overall, individual long-term memory performance immediately after learning the word list (T1) and performance 1 week later (T2) did not differ on the basis of the BDNF SNP, but an interaction effect of BDNF Val66Met by time-of-recall was found: Carriers of the Met66+ variant showed the strongest decline in hit rate performance over time.

  2. Effect of BDNF val(66)met polymorphism on declarative memory and its neural substrate: a meta-analysis.

    PubMed

    Kambeitz, Joseph P; Bhattacharyya, Sagnik; Kambeitz-Ilankovic, Lana M; Valli, Isabel; Collier, David A; McGuire, Philip

    2012-10-01

    Brain derived neurotrophic factor (BDNF) is a critical component of the molecular mechanism of memory formation. Variation in the BDNF gene, particularly the rs6265 (val(66)met) single nucleotide polymorphism (SNP), has been linked to variability in human memory performance and to both the structure and physiological response of the hippocampus, which plays a central role in memory processing. However, these effects have not been consistently reported, which may reflect the modest size of the samples studied to date. Employing a meta-analytic approach, we examined the effect of the BDNF val(66)met polymorphism on human memory (5922 subjects) and hippocampal structure (2985 subjects) and physiology (362 subjects). Our results suggest that variations in the rs6265 SNP of the BDNF gene have a significant effect on memory performance, and on both the structure and physiology of the hippocampus, with carriers of the met allele being adversely affected. These results underscore the role of BDNF in moderating variability between individuals in human memory performance and in mediating some of the neurocognitive impairments underlying neuropsychiatric disorders. Copyright © 2012 Elsevier Ltd. All rights reserved.

  3. Harsh parenting and serotonin transporter and BDNF Val66Met polymorphisms as predictors of adolescent depressive symptoms

    PubMed Central

    Koss, Kalsea J.; Cummings, E. Mark; Davies, Patrick T.; Hetzel, Susan; Cicchetti, Dante

    2016-01-01

    Objective Depressive symptoms are prevalent and rise during adolescence. The present study is a prospective investigation of environmental and genetic factors that contribute to the growth in depressive symptoms and the frequency of heightened symptoms during adolescence. Method Participants included 206 mother-father-adolescent triads (M age at T1 = 13.06 years, SD = .51, 52% female). Harsh parenting was observationally assessed during a family conflict paradigm. DNA was extracted from saliva samples and genotyped for the 5-HTTLPR and BDNF Val66Met polymorphisms. Adolescents provide self-reports of depressive symptoms annually across early adolescence. Results The results reveal gene-by-environment (GxE) interactions as predictors of adolescent depressive symptom trajectories in the context of harsh parenting as an environmental risk factor. A BDNF Val66Met x harsh parenting interaction predicted the rise in depressive symptoms across a three-year period while a 5-HTTLPR x harsh parenting interaction predicted greater frequency in elevated depressive symptoms. Conclusions The findings highlight the importance of unique genetic and environmental influences in the development and course of heightened depressive symptoms during adolescence. PMID:27736236

  4. Val8-glucagon-like peptide-1 protects against Aβ1-40-induced impairment of hippocampal late-phase long-term potentiation and spatial learning in rats.

    PubMed

    Wang, X H; Li, L; Hölscher, C; Pan, Y F; Chen, X R; Qi, J S

    2010-11-10

    Amyloid β protein (Aβ) is considered to be partly responsible for the impairment of learning and memory in Alzheimer disease (AD). In addition, it has been found recently that type 2 diabetes mellitus (T2DM) is a risk factor for developing AD. One promising treatment for AD is using analogues for the insulin-release facilitating gut hormone glucagon-like peptide-1 (GLP-1) that has been developed as a T2DM therapy. GLP-1 has been shown to have neuroprotective properties. However, if GLP-1 can protect the late phase-long term potentiation (L-LTP) and related cognitive function against Aβ-induced impairment it is still an open question. To further characterize the neuroprotective function of GLP-1 in the brain, we investigated the effects of i.c.v. injected Val(8)-GLP-1(7-36) on the Aβ fragment-induced impairment of in vivo hippocampal L-LTP and spatial learning and memory in rats. The results showed that (1) Aβ1-40 (5 nmol) injection did not affect the baseline field excitatory postsynaptic potentials (fEPSPs), but significantly suppressed multiple high frequency stimulation (HFS)-induced L-LTP in hippocampal CA1 region; (2) Val(8)-GLP-1(7-36) (0.05 pmol) administration alone did not affect the baseline synaptic transmission and the maintenance of L-LTP; (3) pretreatment with Val(8)-GLP-1(7-36) (0.05 pmol) effectively prevented Aβ1-40-induced deficit of L-LTP; (4) i.c.v. injection of 5 nmol Aβ1-40 resulted in a significant decline learning a spatial Morris water maze (MWM) test; (5) Val(8)-GLP-1(7-36) (0.05 pmol) administration alone did not affect spatial learning in this task, while pretreatment with Val(8)-GLP-1(7-36) effectively reversed the impairment of spatial learning and memory induced by Aβ1-40. At the same time, the swim speeds and escape latencies of rats among all groups in the visible platform tests did not show any difference. These results suggest that increase of GLP-1 signalling in the brain may be a promising strategy to ameliorate the

  5. The interaction of BDNF Val66Met, PTSD, and child abuse on psychophysiological reactivity and HPA axis function in a sample of Gulf War Veterans.

    PubMed

    Young, Dmitri A; Neylan, Thomas C; O'Donovan, Aoife; Metzler, Thomas; Richards, Anne; Ross, Jessica A; Inslicht, Sabra S

    2018-08-01

    While the BDNF Val66Met polymorphism has been linked to various psychological disorders, limited focus has been on its relationship to posttraumatic stress disorder (PTSD) and early traumas such as child abuse. Therefore, we assessed whether Val66Met was associated with fear potentiated psychophysiological response and HPA axis dysfunction and whether PTSD status or child abuse history moderated these outcomes in a sample of Veterans. 226 and 173 participants engaged in a fear potentiated acoustic startle paradigm and a dexamethasone suppression test (DST) respectively. Fear conditions included no, ambiguous, and high threat conditions. Psychophysiological response measures included electromyogram (EMG), skin conductance response (SCR), and heart rate. The Clinician Administered PTSD Scale (CAPS) and the Trauma History Questionnaire (THQ) were used to assess PTSD status and child abuse history respectively. Met allele carriers exhibited greater SCR magnitudes in the no and ambiguous threat conditions (p < 0.01 and p < 0.05 respectively). Met carriers with PTSD exhibited greater physiological response magnitudes in the ambiguous (SCR, p < 0.001) and high threat conditions (SCR and heart rate, both p ≤ 0.005). Met carrier survivors of child abuse exhibited blunted heart rate magnitudes in the high threat condition (p < 0.01). Met allele carries with PTSD also exhibited greater percent cortisol suppression (p < 0.005). Limitations included small sample size and the cross-sectional nature of the data. The Val66met may impact PTSD susceptibility differentially via enhanced threat sensitivity and HPA axis dysregulation. Child abuse may moderate Val66Met's impact on threat reactivity. Future research should explore how neuronal mechanisms might mediate this risk. Published by Elsevier B.V.

  6. Catechol-O-Methyltransferase "Val[superscript 158]Met" Genotype, Parenting Practices and Adolescent Alcohol Use: Testing the Differential Susceptibility Hypothesis

    ERIC Educational Resources Information Center

    Laucht, Manfred; Blomeyer, Dorothea; Buchmann, Arlette F.; Treutlein, Jens; Schmidt, Martin H.; Esser, Gunter; Jennen-Steinmetz, Christine; Rietschel, Marcella; Zimmermann, Ulrich S.; Banaschewski, Tobias

    2012-01-01

    Background: Recently, first evidence has been reported for a gene-parenting interaction (G x E) with regard to adolescent alcohol use. The present investigation set out to extend this research using the catechol-O-methyltransferase ("COMT") "Val[superscript 158]Met" polymorphism as a genetic susceptibility factor. Moreover, the current study…

  7. Evaluation of oxidative stress biomarkers in Zosterisessor ophiocephalus from the Venice Lagoon, Italy.

    PubMed

    Pascoli, Francesco; Negrato, Elena; Di Giancamillo, Alessia; Bertotto, Daniela; Domeneghini, Cinzia; Simontacchi, Claudia; Mutinelli, Franco; Radaelli, Giuseppe

    2011-02-01

    Several studies carried out in the last years have demonstrated the presence of a wide range of contaminants in some areas of the Venice Lagoon. Many of these contaminants are able to drive free radical reactions, which lead to oxidative stress and can potentially affect fish health. In the present study, oxidative stress biomarkers were examined in three different sites (Porto Marghera, Val di Brenta and Caroman) of the Venice Lagoon and their levels monitored in Zosterisessor ophiocephalus, one of the most common fish species present in the lagoon. Schmorl's staining revealed the presence of melanomacrophage centres in spleen and head kidney, and the highest number of melanomacrophage centres was observed in the animals sampled at the Porto Marghera (Porto Marghera vs Val di brenta and Caroman: p<0.01). The cellular localization of HNE and NT, investigated through an immunohistochemical approach, showed that immunopositivity was mainly localized in melanomacrophage centres of spleen and kidney. It is relevant that the animals of the detoxified control group did not exhibit any immunoreactivity. By Western blot, the antibodies against HNE and NT recognized in the liver polypeptides damaged by oxidative stress with molecular weights under 66kDa. Comparing the relative densities, animals from the Val di Brenta site exhibited the lowest levels of HNE adducts (p<0.05), whereas animals from the Porto Marghera site exhibited the highest levels of NT adducts (p<0.05). MDA levels, measured spectrophotometrically by TBARS assay did not exhibit any statistical difference among sites. Copyright © 2010 Elsevier B.V. All rights reserved.

  8. GNSS Radio Occultation Excess Phase Processing with Integrated Uncertainty Estimation for Thermodynamic Cal/Val of Passive Atmospheric Sounders and Climate Science

    NASA Astrophysics Data System (ADS)

    Innerkofler, J.; Pock, C.; Kirchengast, G.; Schwaerz, M.; Jaeggi, A.; Andres, Y.; Marquardt, C.; Hunt, D.; Schreiner, W. S.; Schwarz, J.

    2017-12-01

    Global Navigation Satellite System (GNSS) radio occultation (RO) is a highly valuable satellite remote sensing technique for atmospheric and climate sciences, including calibration and validation (cal/val) of passive sounding instruments such as radiometers. It is providing accurate and precise measurements in the troposphere and stratosphere regions with global coverage, long-term stability, and virtually all-weather capability since 2001. For fully exploiting the potential of RO data as a cal/val reference and climate data record, uncertainties attributed to the data need to be assessed. Here we focus on the atmospheric excess phase data, based on the raw occultation tracking and orbit data, and its integrated uncertainty estimation within the new Reference Occultation Processing System (rOPS) developed at the WEGC. These excess phases correspond to integrated refractivity, proportional to pressure/temperature and water vapor, and are therefore highly valuable reference data for thermodynamic cal/val of passive (radiometric) sounder data. In order to enable high accuracy of the excess phase profiles, accurate orbit positions and velocities as well as clock estimates of the GNSS transmitter satellites and RO receiver satellites are determined using the Bernese and Napeos orbit determination software packages. We find orbit uncertainty estimates of about 5 cm (position) / 0.05 mm/s (velocity) for daily orbits for the MetOp, GRACE, and CHAMP RO missions, and decreased uncertainty estimates near 20 cm (position) / 0.2 mm/s (velocity) for the COSMIC RO mission. The strict evaluation and quality control of the position, velocity, and clock accuracies of the daily LEO and GNSS orbits assure smallest achievable uncertainties in the excess phase data. We compared the excess phase profiles from WEGC against profiles from EUMETSAT and UCAR. Results show good agreement in line with the estimated uncertainties, with millimetric differences in the upper stratosphere and

  9. A Porphyromonas gingivalis Periplasmic Novel Exopeptidase, Acylpeptidyl Oligopeptidase, Releases N-Acylated Di- and Tripeptides from Oligopeptides*

    PubMed Central

    Nemoto, Takayuki K.; Ohara-Nemoto, Yuko; Bezerra, Gustavo Arruda; Shimoyama, Yu; Kimura, Shigenobu

    2016-01-01

    Exopeptidases, including dipeptidyl- and tripeptidylpeptidase, are crucial for the growth of Porphyromonas gingivalis, a periodontopathic asaccharolytic bacterium that incorporates amino acids mainly as di- and tripeptides. In this study, we identified a novel exopeptidase, designated acylpeptidyl oligopeptidase (AOP), composed of 759 amino acid residues with active Ser615 and encoded by PGN_1349 in P. gingivalis ATCC 33277. AOP is currently listed as an unassigned S9 family peptidase or prolyl oligopeptidase. Recombinant AOP did not hydrolyze a Pro-Xaa bond. In addition, although sequence similarities to human and archaea-type acylaminoacyl peptidase sequences were observed, its enzymatic properties were apparently distinct from those, because AOP scarcely released an N-acyl-amino acid as compared with di- and tripeptides, especially with N-terminal modification. The kcat/Km value against benzyloxycarbonyl-Val-Lys-Met-4-methycoumaryl-7-amide, the most potent substrate, was 123.3 ± 17.3 μm−1 s−1, optimal pH was 7–8.5, and the activity was decreased with increased NaCl concentrations. AOP existed predominantly in the periplasmic fraction as a monomer, whereas equilibrium between monomers and oligomers was observed with a recombinant molecule, suggesting a tendency of oligomerization mediated by the N-terminal region (Met16–Glu101). Three-dimensional modeling revealed the three domain structures (residues Met16–Ala126, which has no similar homologue with known structure; residues Leu127–Met495 (β-propeller domain); and residues Ala496–Phe736 (α/β-hydrolase domain)) and further indicated the hydrophobic S1 site of AOP in accord with its hydrophobic P1 preference. AOP orthologues are widely distributed in bacteria, archaea, and eukaryotes, suggesting its importance for processing of nutritional and/or bioactive oligopeptides. PMID:26733202

  10. The BDNF polymorphism Val66Met may be predictive of swallowing improvement post pharyngeal electrical stimulation in dysphagic stroke patients.

    PubMed

    Essa, H; Vasant, D H; Raginis-Zborowska, A; Payton, A; Michou, E; Hamdy, S

    2017-08-01

    The aim of this study was to explore the effect of brain-derived neurotrophic factor (BDNF) polymorphism rs6265 (Val66Met) in both "natural" and treatment induced recovery of swallowing after dysphagic stroke. Sixteen dysphagic stroke patients that completed a single-blind randomized sham controlled trial of pharyngeal electrical stimulation (PES) within 6 weeks of their stroke (N=38), were genotyped for the BDNF SNP Val66Met (rs6265) from saliva samples. These patients received active or sham PES according to randomized allocation. PES was delivered at a set frequency (5 Hz), intensity (75% of maximal tolerated), and duration (10 minutes) once a day for three consecutive days. Clinical measurements were taken from patients at baseline, 2 weeks and 3 months post entering the study. Changes in swallowing ability based on the dysphagia severity rating scale (DSRS) were compared between active and sham groups and associated with BDNF SNP status. In the active stimulation group, patients with the Met BDNF allele demonstrated significantly greater improvements in DSRS at 3 months compared to patients homozygous for the Val allele (P=.009). By comparison, there were no significant associations at the 2 week stage in either the active or sham group, or at 3 month in the sham group. Functional scores including the Barthel Index and modified Rankin scale were also unaffected by BDNF status. Our findings suggest an association between BDNF and stimulation induced swallowing recovery. Further work will be required to validate these observations and demonstrate clinical utility in patients. © 2017 John Wiley & Sons Ltd.

  11. The COMT Val/Met polymorphism is associated with reading-related skills and consistent patterns of functional neural activation.

    PubMed

    Landi, Nicole; Frost, Stephen J; Mencl, W Einar; Preston, Jonathan L; Jacobsen, Leslie K; Lee, Maria; Yrigollen, Carolyn; Pugh, Kenneth R; Grigorenko, Elena L

    2013-01-01

    In both children and adults there is large variability in reading skill, with approximately 5-10% of individuals characterized as having reading disability; these individuals struggle to learn to read despite adequate intelligence and opportunity. Although it is well established that a substantial portion of this variability is attributed to the genetic differences between individuals, specifics of the connections between reading and the genome are not understood. This article presents data that suggest that variation in the COMT gene, which has previously been associated with variation in higher-order cognition, is associated with reading and reading-related skills, at the level of both brain and behavior. In particular, we found that the COMT Val/Met polymorphism at rs4680, which results in the substitution of the ancestral Valine (Val) by Methionine (Met), was associated with better performance on a number of critical reading measures and with patterns of functional neural activation that have been linked to better readers. We argue that this polymorphism, known for its broad effects on cognition, may modulate (likely through frontal lobe function) reading skill. © 2012 Blackwell Publishing Ltd.

  12. Effects of the BDNF Val66Met polymorphism and met allele load on declarative memory related neural networks.

    PubMed

    Dodds, Chris M; Henson, Richard N; Suckling, John; Miskowiak, Kamilla W; Ooi, Cinly; Tait, Roger; Soltesz, Fruzsina; Lawrence, Phil; Bentley, Graham; Maltby, Kay; Skeggs, Andrew; Miller, Sam R; McHugh, Simon; Bullmore, Edward T; Nathan, Pradeep J

    2013-01-01

    It has been suggested that the BDNF Val66Met polymorphism modulates episodic memory performance via effects on hippocampal neural circuitry. However, fMRI studies have yielded inconsistent results in this respect. Moreover, very few studies have examined the effect of met allele load on activation of memory circuitry. In the present study, we carried out a comprehensive analysis of the effects of the BDNF polymorphism on brain responses during episodic memory encoding and retrieval, including an investigation of the effect of met allele load on memory related activation in the medial temporal lobe. In contrast to previous studies, we found no evidence for an effect of BDNF genotype or met load during episodic memory encoding. Met allele carriers showed increased activation during successful retrieval in right hippocampus but this was contrast-specific and unaffected by met allele load. These results suggest that the BDNF Val66Met polymorphism does not, as previously claimed, exert an observable effect on neural systems underlying encoding of new information into episodic memory but may exert a subtle effect on the efficiency with which such information can be retrieved.

  13. Analysis of the surface expression of c-kit and occurrence of the c-kit Asp816Val activating mutation in T cells, B cells, and myelomonocytic cells in patients with mastocytosis.

    PubMed

    Akin, C; Kirshenbaum, A S; Semere, T; Worobec, A S; Scott, L M; Metcalfe, D D

    2000-02-01

    The Asp816Val c-kit activating mutation is detectable in the peripheral blood cells of some patients with mastocytosis and in lesional skin biopsies obtained from adult patients with urticaria pigmentosa. These observations led to the conclusion that this mutation is present in mast cells and mast cell precursors that express c-kit. However, the distribution of the Asp816Val mutation among hematopoietic lineages is unknown. To determine the distribution of the Asp816Val mutation among hematopoietic lineages and to explore its relationship to clinical disease, we examined cells bearing differentiation markers for myelomonocytic cells as well as T and B lymphocytes, in both peripheral blood and bone marrow obtained from patients with mastocytosis. The presence of Asp816Val c-kit mutation in cells magnetically sorted from peripheral blood or bone marrow according to surface differentiation markers was studied by reverse transcriptase polymerase chain reaction (RT-PCR) restriction fragment length polymorphism (RFLP) analysis. The surface expression of c-kit was determined by flow cytometry. The mutation was detectable by RT-PCR in at least one cell lineage in the bone marrow in 7 of 7 patients examined and in the peripheral blood of 11 of 11 adult patients with urticaria pigmentosa and indolent disease. The mutation was identified most frequently in B cells and myeloid cells. Flow cytometric analysis demonstrated that the differentiated cells expressing mutated c-kit were negative for surface KIT. These results are consistent with the conclusion that the c-kit Asp816Val mutation occurs in an early progenitor cell and is carried by myelomonocytic cells, T cells, and B cells in addition to mast cells. However, unlike mast cells, these myelomonocytic cells, T cells, and B cells do not concomitantly express surface c-kit and thus may be less susceptible to the effects of this mutation.

  14. Predictive value of GSTP1 Ile105Val polymorphism in clinical outcomes of chemotherapy in gastric and colorectal cancers: a systematic review and meta-analysis.

    PubMed

    Shen, Xiaobing; Wang, Jia; Yan, Xiaoluan; Ren, Xiaofeng; Wang, Fan; Chen, Xiaowei; Xu, Yuchao

    2016-06-01

    Gastric and colorectal cancers remain the major causes of cancer-related death with a bad prognosis. Up to now, platinum combined with fluoropyrimidines has been most commonly used in chemotherapy regimens of gastric and colorectal cancers. Recently, a series of studies have been conducted to investigate the associations of biomarkers, such as GSTP1 Ile105Val polymorphism, with the chemotherapy efficacy in gastric and colorectal cancers; however, the results were not consistent and inconclusive. Here, we performed a systematic review and meta-analysis to summarize the associations of GSTP1 Ile105Val polymorphism with the chemotherapy efficacy in gastric and colorectal cancers. A systematic review was conducted to search relevant studies in English databases (PubMed, ISI Web of Science, and EMBASE) up to November 30, 2015. The pooling ORs or HRs were used to assess the strength of the associations of GSTP1 Ile105Val polymorphism with clinical outcomes such as tumor response, toxicity, progression-free survival (PFS), and overall survival (OS). Forty-one papers containing 8169 cases were finally included in the present meta-analysis study. Of which, 28 articles were performed in colorectal cancers, one in gastrointestinal carcinoma (gastric and colon cancer), 11 in gastric cancers, and one in colorectal and gastroesophageal cancers. After pooling all the eligible studies, we identified significant associations of GSTP1 Ile105Val polymorphism with chemotherapy-related tumor response (G vs. A: OR 1.697, 95 % CI 1.191-2.418; GG vs. AA: OR 2.804, 95 % CI 1.414-5.560; AG vs. AA: OR 1.540, 95 % CI 1.011-2.347; GG vs. AAAG: OR 2.139, 95 % CI 1.256-3.641), PFS (GG vs. AA, HR 0.640, 95 % CI 0.455-0.900; AGGG vs. AA: HR 0.718, 95 % CI 0.562-0.919), and OS (AG vs. AA: HR 0.857, 95 % CI 0.746-0.986; GG vs. AA: HR 0.679, 95 % CI 0.523-0.882; AGGG vs. AA: HR 0.663, 95 % CI 0.542-0.812) in gastric and colorectal cancers and no significant association was found

  15. The British Interplanetary Society - Val Cleaver and Wernher von Braun

    NASA Astrophysics Data System (ADS)

    Willhite, I. P.

    This article is concerned with the early relationship between Wernher von Braun and the British Interplanetary Society (BIS). The BIS/Wernher von Braun/Val Cleaver correspondence files located here at the US Space & Rocket Center in Huntsville, Alabama are unparalleled. As one reads the stimulating comments between Cleaver and von Braun, the need to share their thoughts prevails. Following is an excerpt from one letter that whets ones appetite for more. 10 June 1951 Cleaver writes, “I'm so glad you enjoyed my last letter, and look forward to your promised further contribution to our discussion of the ethics of science in general and astronautics in particu- lar. As regards the one particular point on which you found yourself unable to hold your fire, I should say there are really two distinct issues at stake:. . .” This article attempts to represent the best of the letters as they goad each other on scientific principles, means to prevent wars, and other philosophic ideas.

  16. The Convergent and Divergent Validity of the Vanderbilt Assessment of Leadership in Education (VAL-ED): Instructional Leadership and Emotional Intelligence

    ERIC Educational Resources Information Center

    Goldring, Ellen; Cravens, Xiu; Porter, Andrew; Murphy, Joseph; Elliott, Steve

    2015-01-01

    Purpose: The purpose of this paper is to contribute to the ongoing dialog of whether and how instructional leadership is distinguished conceptually from general leadership notions, such as charisma, and to continue the ongoing psychometric research on the The Vanderbilt Assessment of Leadership in Education (VAL-ED) by examining its convergent and…

  17. [La combinazione di gemcitabina e oxaliplatino (GEMOX) nel trattamento del carcinoma pancreatico in fase avanzata di malattia: le notizie sulla mia morte sono state esagerate?

    PubMed

    Giuliani, Jacopo; Bonetti, Andrea

    2017-12-01

    Riassunto. L'analisi è stata condotta al fine di valutare l'effetto sia sulla sopravvivenza globale (OS) sia sulla sopravvivenza libera da progressione di malattia (PFS) della chemioterapia di combinazione in prima linea per il carcinoma pancreatico in fase avanzata di malattia. La presente analisi è limitata agli studi randomizzati controllati (RCT) di fase III. Successivamente è stata applicata la European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) agli RCT di fase III analizzati per ricavare uno score relativo all'entità del beneficio clinico ottenuto per ciascun RCT. Sono state calcolate inoltre le differenze in termini di PFS tra i diversi bracci di trattamento rapportandole con i costi dei farmaci necessari per ottenere il beneficio di PFS. La nostra analisi ha valutato 11 RCT di fase III, per un totale di 4572 pazienti. Combinando i costi della terapia con la misura dell'efficacia espressa dalla PFS, è stato ottenuto un costo di 74,12 euro (€) per mese di vita guadagnato in termini di PFS con la combinazione di 5-fluorouracil, leucovorin, irinotecan e oxaliplatino (FOLFIRINOX), 90,14 € per la combinazione di gemcitabina e oxaliplatino (GEMOX) e 4708,7 € per la combinazione di nab-paclitaxel e gemcitabina. Da questo punto di vista riteniamo che l'utilizzo delle "vecche chemioterapie di combinazione" (per es., GEMOX) non dovrebbe essere completamente abbandonato, ma valutato sul singolo paziente, sulla base di diversi fattori (età, ECOG PS, comorbilità, carico di malattia), al fine di ottenere una reale "tailored therapy".

  18. The impact of the Val158Met catechol-O-methyltransferase genotype on neural correlates of sad facial affect processing in patients with bipolar disorder and their relatives.

    PubMed

    Lelli-Chiesa, G; Kempton, M J; Jogia, J; Tatarelli, R; Girardi, P; Powell, J; Collier, D A; Frangou, S

    2011-04-01

    The Met allele of the catechol-O-methyltransferase (COMT) valine-to-methionine (Val158Met) polymorphism is known to affect dopamine-dependent affective regulation within amygdala-prefrontal cortical (PFC) networks. It is also thought to increase the risk of a number of disorders characterized by affective morbidity including bipolar disorder (BD), major depressive disorder (MDD) and anxiety disorders. The disease risk conferred is small, suggesting that this polymorphism represents a modifier locus. Therefore our aim was to investigate how the COMT Val158Met may contribute to phenotypic variation in clinical diagnosis using sad facial affect processing as a probe for its neural action. We employed functional magnetic resonance imaging to measure activation in the amygdala, ventromedial PFC (vmPFC) and ventrolateral PFC (vlPFC) during sad facial affect processing in family members with BD (n=40), MDD and anxiety disorders (n=22) or no psychiatric diagnosis (n=25) and 50 healthy controls. Irrespective of clinical phenotype, the Val158 allele was associated with greater amygdala activation and the Met158 allele with greater signal change in the vmPFC and vlPFC. Signal changes in the amygdala and vmPFC were not associated with disease expression. However, in the right vlPFC the Met158 allele was associated with greater activation in all family members with affective morbidity compared with relatives without a psychiatric diagnosis and healthy controls. Our results suggest that the COMT Val158Met polymorphism has a pleiotropic effect within the neural networks subserving emotional processing. Furthermore the Met158 allele further reduces cortical efficiency in the vlPFC in individuals with affective morbidity.

  19. The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is associated with increased body mass index and insulin resistance measures in bipolar disorder and schizophrenia.

    PubMed

    Bonaccorso, Stefania; Sodhi, Monsheel; Li, Jiang; Bobo, William V; Chen, Yuejin; Tumuklu, Mevhibe; Theleritis, Christos; Jayathilake, Karuna; Meltzer, Herbert Y

    2015-08-01

    We tested the hypothesis that a common functional variant in brain-derived neurotrophic factor (BDNF), Val66Met, which has been shown to be associated with increased body mass index (BMI) in schizophrenia (SCZ) and schizoaffective disorder (SAD), is also associated with antipsychotic-induced weight gain in bipolar disorder (BPD). Association of Val66Met with other metabolic measures, including high- and low-density cholesterol, triglycerides, total cholesterol, fasting blood glucose, and hemoglobin A1c, was also tested. This was a 12-month, prospective, randomized trial of two atypical antipsychotic drugs (APDs) with moderate (risperidone) or high (olanzapine) risk to cause weight gain. Subjects were diagnosed as having BPD (n = 90) and SCZ or SAD (n = 76). BMI was significantly greater in all diagnoses for Met66 allele carriers at six months (p = 0.01). Met66 carriers with BPD showed a greater increase in the triglycerides/high-density (HDL) cholesterol ratio (p = 0.01), a key marker for metabolic syndrome related to insulin resistance, and log-triglycerides (p = 0.04), after three or six months of treatment. Met66 carriers had the greatest increase in log-triglycerides (p = 0.03) and triglycerides/HDL cholesterol ratio after three months of treatment with risperidone (p = 0.003), and the highest BMI at six months (p = 0.01). The positive association of BNDF Val66Met with high BMI values replicates previous findings in patients with SCZ and indicates the BDNF Val66Met genotype as a potential risk factor for obesity and insulin resistance measures in patients with BPD receiving antipsychotics as well. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  20. The Val/Met functional polymorphism in COMT confers susceptibility to bipolar disorder: evidence from an association study and a meta-analysis.

    PubMed

    Zhang, Zhao; Lindpaintner, Klaus; Che, Ronglin; He, Zangdong; Wang, Peng; Yang, Ping; Feng, Guoyin; He, Lin; Shi, Yongyong

    2009-10-01

    The COMT gene is considered as one of the prominent candidate genes for susceptibility to BP, and most studies focused a functional polymorphism in the gene: the Val/Met polymorphism (rs4680). However, results from these studies are sometimes contradictory, due to small sample size or heterogeneity. In this study, we first investigate the possible association between the Val/Met polymorphism in COMT and bipolar disorder in the Han population, which has never been done before. Then a systematic meta-analysis was conducted to determine if the low-activity allele (Met) increases the risk of BP in different ethnic groups. A total of 478 BP patients and 469 healthy subjects were recruited in our case/control study. MIX software package was employed to perform the meta-analysis on 19 studies after careful search and selection. We observed statistically-significant differences in allele (p = 0.00060) and genotype (p = 0.00203) frequencies between patients and controls in our samples. The meta-analysis also provided a significant pooled OR for association of the Met allele in rs4680 with BP in the total population (p = 0.0223) and in the Asian population (p = 0.0232). Although a significant pooled OR was also found for the Caucasian population (p = 0.0409) after one of the studies as discussed below was removed, the role for Val/Met polymorphism in BP in Caucasian ethnicity was not yet to be confirmed. In conclusion, the low-activity allele (Met) of rs4680 in COMT gene possibly confers risk for bipolar disorder in the Han population, while it needs further evidence for concluding its association with BP in the Caucasian population.

  1. DOE Office of Scientific and Technical Information (OSTI.GOV)

    Colantonio, Patrizia; Leboffe, Loris; Bolli, Alessandro

    Caspase-3 is responsible for the cleavage of several proteins including the nuclear enzyme poly(ADP-ribose) polymerase (PARP). Designed on the cleavage site of PARP, Ac-Asp-Glu-Val-Asp-H has been reported as a highly specific inhibitor. To overcome the susceptibility to proteolysis, the intrinsic instability, and the scarce membrane permeability of tetra-peptidyl aldehydes, di- and tri-peptidyl caspase-3 inhibitors have been synthesized. Here, the synthesis and the inhibition properties of peptidyl aldehydes Z-tLeu-Asp-H, Z-tLeu-Val-Asp-H, and Z-Val-tLeu-Asp-H are reported. Z-tLeu-Asp-H, Z-tLeu-Val-Asp-H, and Z-Val-tLeu-Asp-H inhibit competitively human caspase-3 activity in vitro with K{sub i}{sup 0} = 3.6 nM, 18.2 nM, and 109 nM, respectively (pH 7.4 andmore » 25 deg. C). Moreover, Z-tLeu-Asp-H impairs apoptosis in human DLD-1 colon adenocarcinoma cells without affecting caspase-8. Therefore, Ac-Asp-Glu-Val-Asp-H can be truncated to Z-tLeu-Asp-H retaining nanomolar inhibitory activity in vitro and displaying action in whole cells, these properties reflect the unprecedented introduction of the bulky and lipophilic tLeu residue at the P{sub 2} position.« less

  2. A novel presenilin 1 mutation (Ala275Val) as cause of early-onset familial Alzheimer disease.

    PubMed

    Luedecke, Daniel; Becktepe, Jos S; Lehmbeck, Jan T; Finckh, Ulrich; Yamamoto, Raina; Jahn, Holger; Boelmans, Kai

    2014-04-30

    Mutations in the presenilin 1 (PS1) gene (PSEN1) are associated with familial Alzheimer disease (FAD). Here, we report on a 50-year-old patient presenting with progressive deterioration of his short-term memory and a family history of early-onset dementia. Diagnostic workup included a neuropsychological examination, structural magnetic resonance (MR) imaging, cerebrospinal fluid (CSF) biomarkers including total tau, phosphorylated tau, and Aβ42 levels, as well as sequencing relevant fragments of the genes PSEN1, PSEN2, and APP. Additionally, we were able to obtain archival paraffin-embedded cerebellar tissue from the patient's father for cosegregation analysis. Clinical, neuropsychological and MR imaging data were indicative of early-onset Alzheimer disease. Furthermore, CSF biomarkers showed a typical pattern for Alzheimer disease. DNA sequencing revealed a heterozygous nucleotide transition (c.824C>T) in exon 8 of PSEN1, leading to an amino acid change from alanine to valine at codon 275 (Ala275Val). The same mutation was found in an archival brain specimen of the patient's demented father, but not in a blood sample of the non-demented mother. This mutation alters a conserved residue in the large hydrophilic loop of PS1, suggesting pathogenic relevance. Cosegregegation analysis and the structural as well as the presumed functional role of the mutated and highly conserved residue suggest FAD causing characteristics of the novel PSEN1 mutation Ala275Val. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  3. Manganese superoxide dismutase Ala-9Val polymorphism and risk of breast cancer in a population-based case–control study of African Americans and whites

    PubMed Central

    Millikan, Robert C; Player, Jon; de Cotret, Allan René; Moorman, Patricia; Pittman, Gary; Vannappagari, Vani; Tse, Chiu-Kit J; Keku, Temitope

    2004-01-01

    Introduction A polymorphism in the manganese superoxide dismutase (MnSOD) gene, Ala-9Val, has been examined in association with breast cancer risk in several epidemiologic studies. Results suggest that the Ala allele increases the risk of breast cancer and modifies the effects of environmental exposures that produce oxidative damage to DNA. Methods We examined the role of the MnSOD Ala-9Val polymorphism in a population-based case–control study of invasive and in situ breast cancer in North Carolina. Genotypes were evaluated for 2025 cases (760 African Americans and 1265 whites) and for 1812 controls (677 African Americans and 1135 whites). Results The odds ratio for MnSOD Ala/Ala versus any MnSOD Val genotypes was not elevated in African Americans (odds ratio = 0.9, 95% confidence interval = 0.7–1.2) or in whites (odds ratio = 1.0, 95% confidence interval = 0.8–1.2). Greater than additive joint effects were observed for the Ala/Ala genotype and smoking, radiation to the chest, and occupational exposure to ionizing radiation. Antagonism was observed between the Ala/Ala genotype and the use of nonsteroidal anti-inflammatory drugs. Conclusions The MnSOD genotype may contribute to an increased risk of breast cancer in the presence of specific environmental exposures. These results provide further evidence for the importance of reactive oxygen species and of oxidative DNA damage in the etiology of breast cancer. PMID:15217492

  4. Translation Sociology and Social Capital in Rural Development Initiatives. A Case Study from the Italian Alps

    ERIC Educational Resources Information Center

    Magnani, Natalia; Struffi, Lauro

    2009-01-01

    This article analyses the results of a European "research and demonstration" project promoting multifunctional and sustainable agriculture in Alpine regions through a participatory approach. It focuses in particular on initiatives undertaken by a local farmers group in the Italian Alpine area of Val di Sole, the purpose being to draw…

  5. Diversity of Cyclic Di-GMP-Binding Proteins and Mechanisms

    PubMed Central

    2015-01-01

    ABSTRACT Cyclic di-GMP (c-di-GMP) synthetases and hydrolases (GGDEF, EAL, and HD-GYP domains) can be readily identified in bacterial genome sequences by using standard bioinformatic tools. In contrast, identification of c-di-GMP receptors remains a difficult task, and the current list of experimentally characterized c-di-GMP-binding proteins is likely incomplete. Several classes of c-di-GMP-binding proteins have been structurally characterized; for some others, the binding sites have been identified; and for several potential c-di-GMP receptors, the binding sites remain to be determined. We present here a comparative structural analysis of c-di-GMP-protein complexes that aims to discern the common themes in the binding mechanisms that allow c-di-GMP receptors to bind it with (sub)micromolar affinities despite the 1,000-fold excess of GTP. The available structures show that most receptors use their Arg and Asp/Glu residues to bind c-di-GMP monomers, dimers, or tetramers with stacked guanine bases. The only exception is the EAL domains that bind c-di-GMP monomers in an extended conformation. We show that in c-di-GMP-binding signature motifs, Arg residues bind to the O-6 and N-7 atoms at the Hoogsteen edge of the guanine base, while Asp/Glu residues bind the N-1 and N-2 atoms at its Watson-Crick edge. In addition, Arg residues participate in stacking interactions with the guanine bases of c-di-GMP and the aromatic rings of Tyr and Phe residues. This may account for the presence of Arg residues in the active sites of every receptor protein that binds stacked c-di-GMP. We also discuss the implications of these structural data for the improved understanding of the c-di-GMP signaling mechanisms. PMID:26055114

  6. Association of GSTM1, GSTT1 and GSTP1 Ile105Val polymorphisms with clinical response to imatinib mesylate treatment among Malaysian chronic myeloid leukaemia patients.

    PubMed

    Makhtar, Siti Maziras; Husin, Azlan; Baba, Abdul Aziz; Ankathil, Ravindran

    2017-09-01

    The detoxifying activity of glutathione S-transferases (GST) enzymes not only protect cells from the adverse effects of xenobiotics, but also alters the effectiveness of drugs in cancer cells, resulting in toxicity or drug resistance. In this study, we aimed to evaluate the association of GSTM1, GSTT1 and GSTP1 Ile105Val polymorphisms with treatment response among Malaysian chronic myeloid leukaemia (CML) patients who everyday undergo 400 mg of imatinib mesylate (IM) therapy. Multiplex polymerase chain reaction (multiplex-PCR) was performed to detect GSTM1 and GSTT1 polymorphisms simultaneously and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis was conducted to detect the GSTP1 Ile195Val polymorphism. On evaluating the association of the variant genotype with treatment outcome, heterozygous variant (AG) and homozygous variant (GG) of GSTP1 Ile105Val showed significantly a higher risk for the development of resistance to IM with OR: 1.951 (95% CI: 1.186-3.209, P = 0.009) and OR: 3.540 (95% CI: 1.305-9.606, P = 0.013), respectively. Likewise, GSTT1 null genotype was also associated with a significantly higher risk for the development of resistance to IM with OR = 1.664 (95% CI: 1.011-2.739, P = 0.045). Our results indicate the potential usefulness of GST polymorphism genotyping in predicting the IM treatment response among CML patients.

  7. Benzyloxycarbonyl-Val-Ala-Asp (OMe) fluoromethylketone (Z-VAD.FMK) inhibits apoptosis by blocking the processing of CPP32.

    PubMed Central

    Slee, E A; Zhu, H; Chow, S C; MacFarlane, M; Nicholson, D W; Cohen, G M

    1996-01-01

    Interleukin-1 beta converting enzyme (ICE)-like proteases, which are synthesized as inactive precursors, play a key role in the induction of apoptosis. We now demonstrate that benzyloxycarbonyl-Val-Ala-Asp (OMe) fluoromethylketone (Z-VAD.FMK), an ICE-like protease inhibitor, inhibits apoptosis by preventing the processing of CPP32 to its active form. These results suggest that novel inhibitors of apoptosis can be developed which prevent processing of proforms of ICE-like proteases. PMID:8670109

  8. Di(hydroxyphenyl)- benzimidazole monomers

    NASA Technical Reports Server (NTRS)

    Connell, John W. (Inventor); Hergenrother, Paul M. (Inventor); Smith, Joseph G. (Inventor)

    1993-01-01

    Di(hydroxyphenyl)benzimidazole monomers were prepared from phenyl-hydroxybenzoate and aromatic bis(o-diamine)s. These monomers were used in the synthesis of soluble polybenzimidazoles. The reaction involved the aromatic nucleophilic displacement of various di(hydroxyphenyl)benzimidazole monomers with activated aromatic dihalides or activated aromatic dinitro compounds in the presence of an alkali metal base. These polymers exhibited lower glass transition temperatures, improved solubility, and better compression moldability over their commercial counterparts.

  9. The relationship between MnSOD Val16Ala gene polymorphism and the level of serum total antioxidant capacity with the risk of chronic kidney disease in type 2 diabetic patients: a nested case-control study in the Tehran lipid glucose study.

    PubMed

    Abbasi, Mehrnaz; Daneshpour, Maryam S; Hedayati, Mehdi; Mottaghi, Azadeh; Pourvali, Katayoun; Azizi, Fereidoun

    2018-01-01

    Several studies have shown significant associations between manganese superoxide dismutase (MnSOD) Val16Ala polymorphism and diabetic complications, but this association has not been explored in relation with chronic kidney disease (CKD) in Type 2 diabetes mellitus (T2DM) patients. Total antioxidant capacity (TAC) level changes in diabetic condition and may play important role in onset or progression of the disease and its complications. The present study investigated the association of MnSOD Val16Ala polymorphism and serum TAC with the risk of CKD in T2DM patients. This nested case-control study included 280 type 2 diabetic patients with CKD and 280 age, sex and diabetes duration-matched control subjects selected from the participants of the Tehran Lipid and Glucose Study. MnSOD val16Ala (rs4880) SNP was genotyped by the Tetra-Primer ARMS-polymerase chain reaction analysis. Serum TAC was measured using ferric-reducing antioxidant power assay. Statistical analysis was performed using STATA statistical package v.12.0 or SPSS (Version 22.0). The Ala allele of the MnSOD Val16Ala polymorphism was associated with a lower risk of CKD (odds ratio (OR), 0.55; 95% confidence interval (CI), 0.36-0.84; P  = 0.006). Median serum TAC in CKD group was 920 μmol/L and was significantly lower ( p  < 0.001) compared to the control group (1045 μmol/L). Using an adjusted conditional logistic regression, we didn't observe any significant interaction between MnSOD Val16Ala SNP with quartiles of serum TAC in relation to CKD. A significant association was found between the MnSOD Val16Ala polymorphism and CKD, but this association is not affected by serum TAC level in T2DM patients.

  10. Meningococco B: controllo di due focolai epidemici mediante vaccinazione

    PubMed Central

    2014-01-01

    Riassunto La problematica di un efficace approccio vaccinale nei confronti del Meningococco B (MenB) è stata superata identificando con la metodica della "reverse vaccinology" alcuni antigeni capaci di indurre una risposta verso la maggior parte dei ceppi di MenB circolanti nel mondo. Il nuovo vaccino MenB a 4 componenti (4CMenB) è stato autorizzato in Europa, Australia e Canada, ed è entrato nei calendari di immunizzazione pediatrica internazionali: Australia, Canada, UK. In Italia, le prime regioni che hanno raccomandato la vaccinazione contro il MenB sono state Basilicata e Puglia. La gestione di epidemie/focolai epidemici richiede la messa in atto di una risposta rapida da parte delle autorità sanitarie nei confronti di una emergenza sanitaria ad elevato impatto, anche emotivo, sulla popolazione, come recentemente dimostrato in due università americane. Alla dichiarazione di focolaio epidemico in atto, in entrambi i contesti si è attivata una procedura per l'uso del vaccino 4CMenB non ancora autorizzato negli USA. È stato così possibile organizzare gli interventi di profilassi attiva nei due campus universitari, adottando il primo impiego su larga scala del nuovo vaccino 4CMenB e conseguendo, in tempi relativamente brevi, elevati tassi di copertura vaccinale. A fronte di circa 14000 studenti immunizzati con almeno una dose, non è stata segnalata alcuna problematica di eventi avversi conseguenti all'immunizzazione; ad oggi non si sono verificati casi nei soggetti che hanno ricevuto il vaccino. Come conseguenza dei due focolai descritti, è oggi in corso la valutazione da parte dell'FDA per l'estensione dell'uso del vaccino 4CMenB negli Stati Uniti negli adolescenti e giovani adulti. PMID:25916017

  11. Allele related mutation specific-polymerase chain reaction for rapid diagnosis of Hb New York (beta 113 (G15) Val-->Glu, beta(CD113 GTG-->GAG)).

    PubMed

    Viprakasit, Vip; Tachavanich, Kalaya; Suwantol, Lerlugsn; Pung-Amritt, Parichat; Chinchang, Worawut; Tanphaichitr, Voravarn S

    2002-08-01

    Hemoglobin New York (beta 113 (G15) Val-->Glu), a beta-globin variant, was first reported in a Chinese family living in New York. Subsequently, this abnormal hemoglobin was reported in many Chinese descendants from several groups and it was also known as Hb Kaohsiung. The subtle change in alpha1beta1 contact region apart from the heme group connecting area by Val-->Glu substitution has minor changes in both the electrophoretic mobility and stability making this hemoglobin variant difficult to distinguish from Hb A using routine hemoglobin analysis. The authors described a case of heterozygosity of Hb New York diagnosed by a molecular technique and revealed a mutation in beta(CD113 GTG-->GAG). A novel Allele Related Mutation Specific-Polymerase Chain Reaction (ARMS-PCR) for rapid diagnosis of this mutation has been proposed.

  12. The psychology of psychiatric genetics: evidence that positive emotions in females moderate genetic sensitivity to social stress associated with the BDNF Val-sup-6-sup-6Met polymorphism.

    PubMed

    Wichers, Marieke; Kenis, Gunter; Jacobs, Nele; Myin-Germeys, Inez; Schruers, Koen; Mengelers, Ron; Delespaul, Philippe; Derom, Catherine; Vlietinck, Robert; van Os, Jim

    2008-08-01

    Previous work indicated protective effects of positive emotions on genetically influenced stress sensitivity. Given the fact that expression of brain-derived-neurotrophic-factor (BDNF) is associated with stress-induced behavioral changes, it was hypothesized that the BDNF Val-sup-6-sup-6Met genotype may mediate genetic effects on stress sensitivity, conditional on the level of concurrent positive emotions. Subjects (n=446) participated in a momentary assessment study, collecting appraisals of stress and affect in the flow of daily life. Multilevel regression analyses examined moderation of daily life stress-induced negative affect (NA) by BDNF genotype, and to what degree this was conditional on concurrent positive emotions. Results showed that heterozygous BDNF "Met" carriers exhibited an increased NA response to social stress compared with "Val/Val" subjects. Positive emotions at the time of the stressor decreased BDNF genetic moderation of the NA response to social stress in a dose-response fashion. This effect was most pronounced in BDNF Met carriers. Thus, the impact of BDNF genotype on stress sensitivity is conditional on the experience of positive emotions. Interdisciplinary research in psychology and psychiatric genetics may lead to the improvement of treatment choices in stress-related disorders. Copyright (c) 2008 APA, all rights reserved.

  13. The Val30Met familial amyloid polyneuropathy specific Rasch-built overall disability scale (FAP-RODS(©) ).

    PubMed

    Pruppers, Mariëlle H J; Merkies, Ingemar S J; Faber, Catharina G; Da Silva, Ana M; Costa, Vanessa; Coelho, Teresa

    2015-09-01

    Familial amyloid polyneuropathy (FAP) is a chronic debilitating multi-organic disorder, mainly assessed using ordinal-based impairment measures. To date, no outcome measure at the activity and participation level has been constructed in FAP. The current study aimed to design an interval activity/participation scale for FAP through Rasch methodology. A preliminary FAP Rasch-built overall disability scale (pre-FAP-RODS) containing 146 activity/participation items was assessed twice (interval: 2-4 week; test-retest reliability) in 248 patients with Val30Met FAP examined in Porto, Portugal, of which 65.7% have received liver transplantation. An ordinal-based 24-item FAP-symptoms inventory questionnaire (FAP-SIQ) was also assessed (validity purposes). The pre-FAP-RODS and FAP-SIQ data were subjected to Rasch analyses. The pre-FAP-RODS did not meet model's expectations. On the basis of requirements such as misfit statistics, differential item functioning, and local dependency, items were systematically removed until a final 34-item FAP-RODS(©) was constructed fulfilling all Rasch requirements. Acceptable reliability/validity scores were demonstrated. In conclusion, the 34-item FAP-RODS(©) is a disease-specific interval measure suitable for detecting activity and participation restrictions in patients with FAP. The use of the FAP-RODS(©) is recommended for future international clinical trials in patients with Val30Met FAP determining its responsiveness and its cross-cultural validation. Its expansion to other forms of FAP should also be focus of future clinical studies. © 2015 Peripheral Nerve Society.

  14. Telemedicine in Primary Care for Patients With Chronic Conditions: The ValCrònic Quasi-Experimental Study.

    PubMed

    Orozco-Beltran, Domingo; Sánchez-Molla, Manuel; Sanchez, Julio Jesus; Mira, José Joaquin

    2017-12-15

    The increase of chronic diseases prevalence has created the need to adapt care models and to provide greater home supervision. The objective of our study was to evaluate the impact of telemonitoring on patients with long-term conditions at high risk for rehospitalization or an emergency department visit, in terms of target disease control (diabetes, hypertension, heart failure, and chronic obstructive pulmonary disease). We conducted a quasi-experimental study with a before-and-after analysis to assess the effectiveness of the ValCrònic program after 1 year of primary care monitoring. The study included high-risk patients with 1 or more of the following conditions: diabetes, high blood pressure, heart failure, and chronic obstructive pulmonary disease. We assessed risk according to the Community Assessment Risk Screen. Participants used an electronic device (tablet) to self-report relevant health information, which was then automatically entered into their eHealth record for consultation. The total sample size was 521 patients. Compared with the preintervention year, there were significant reductions in weight (82.3 kg before vs 80.1 kg after; P=.001) and in the proportion of people with high systolic (≥140 mmHg; 190, 36.5% vs 170, 32.6%; P=.001) and diastolic (≥90 mmHg; 72, 13.8% vs 40, 7.7%; P=.01) blood pressures, and hemoglobin A 1c ≥8% (186, 35.7% vs 104, 20.0%; P=.001). There was also a decrease in the proportion of participants who used emergency services in primary care (68, 13.1% vs 33, 6.3%; P<.001) and in hospital (98, 18.8% vs 67, 12.8%; P<.001). Likewise, fewer participants required hospital admission due to an emergency (105, 20.2% vs 71, 13.6%; P<.001) or disease exacerbation (55, 10.5% vs 42, 8.1%; P<.001). The ValCrònic telemonitoring program in patients at high risk for rehospitalization or an emergency department visit appears to be useful to improve target disease control and to reduce the use of resources. ©Domingo Orozco

  15. Development of a Δ9-Tetrahydrocannabinol Amino Acid-Dicarboxylate Prodrug With Improved Ocular Bioavailability

    PubMed Central

    Adelli, Goutham R.; Bhagav, Prakash; Taskar, Pranjal; Hingorani, Tushar; Pettaway, Sara; Gul, Waseem; ElSohly, Mahmoud A.; Repka, Michael A.; Majumdar, Soumyajit

    2017-01-01

    Purpose The aim of the present study was to evaluate the utility of the relatively hydrophilic Δ9-tetrahydrocannabinol (THC) prodrugs, mono and di-valine esters (THC-Val and THC-Val-Val) and the amino acid (valine)-dicarboxylic acid (hemisuccinate) ester (THC-Val-HS), with respect to ocular penetration and intraocular pressure (IOP) lowering activity. THC, timolol, and pilocarpine eye drops were used as controls. Methods THC-Val, THC-Val-Val, and THC-Val-HS were synthesized and chemically characterized. Aqueous solubility and in vitro transcorneal permeability of THC and the prodrugs, in the presence of various surfactants and cyclodextrins, were determined. Two formulations were evaluated for therapeutic activity in the α-chymotrypsin induced rabbit glaucoma model, and the results were compared against controls comprising of THC emulsion and marketed timolol maleate and pilocarpine eye drops. Results THC-Val-HS demonstrated markedly improved solubility (96-fold) and in vitro permeability compared to THC. Selected formulations containing THC-Val-HS effectively delivered THC to the anterior segment ocular tissues in the anesthetized rabbits: 62.1 ng/100 μL of aqueous humor (AH) and 51.4 ng/50 mg of iris ciliary bodies (IC) (total THC). The duration and extent of IOP lowering induced by THC-Val-HS was 1 hour longer and 10% greater, respectively, than that obtained with THC and was comparable with the pilocarpine eye drops. Timolol ophthalmic drops, however, exhibited a longer duration of activity. Both THC and THC-Val-HS were detected in the ocular tissues following multiple dosing of THC-Val-HS in conscious animals. The concentration of THC in the iris-ciliary bodies at the 60- and 120-minute time points (53 and 57.4 ng/50 mg) were significantly greater than that of THC-Val-HS (24.2 and 11.3 ng/50 mg). Moreover, at the two time points studied, the concentration of THC was observed to increase or stay relatively constant, whereas THC-Val-HS concentration decreased

  16. A whole mitochondrial genome screening in a MELAS patient: A novel mitochondrial tRNA{sup Val} mutation

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Mezghani, Najla; Mnif, Mouna; Kacem, Maha

    2011-04-22

    Highlights: {yields} We report a young Tunisian patient with clinical features of MELAS syndrome. {yields} Reported mitochondrial mutations were absent after a mutational screening of the whole mtDNA. {yields} We described a novel m.1640A>G mutation in the tRNA{sup Val} gene which was absent in 150 controls. {yields} Mitochondrial deletions and POLG1 gene mutations were absent. {yields} The m.1640A>G mutation could be associated to MELAS syndrome. -- Abstract: Mitochondrial encephalopathy, lactic acidosis and strokelike episodes (MELAS) syndrome is a mitochondrial disorder characterized by a wide variety of clinical presentations and a multisystemic organ involvement. In this study, we report a Tunisianmore » girl with clinical features of MELAS syndrome who was negative for the common m.3243A>G mutation, but also for the reported mitochondrial DNA (mtDNA) mutations and deletions. Screening of the entire mtDNA genome showed several known mitochondrial variants besides to a novel transition m.1640A>G affecting a wobble adenine in the anticodon stem region of the tRNA{sup Val}. This nucleotide was conserved and it was absent in 150 controls suggesting its pathogenicity. In addition, no mutations were found in the nuclear polymerase gamma-1 gene (POLG1). These results suggest further investigation nuclear genes encoding proteins responsible for stability and structural components of the mtDNA or to the oxidative phosphorylation machinery to explain the phenotypic variability in the studied family.« less

  17. URINARY BIOMARKERS OF DI-ISONONYL PHTHALATE IN RATS

    EPA Science Inventory

    Commercial di-isononyl phthalate (DiNP) is a mixture of various branched-chain dialkyl phthalates mainly containing ninecarbon alkyl isomers. At high doses in rodents, DiNP is a carcinogen, and a developmental toxicant. After exposure, the diester isomers are de-esterified to for...

  18. A decade of passive seismic monitoring experiments with local networks in four Italian regions

    NASA Astrophysics Data System (ADS)

    Chiaraluce, L.; Valoroso, L.; Anselmi, M.; Bagh, S.; Chiarabba, C.

    2009-10-01

    We report on four seismic monitoring experiments that in the past ten years we carried out with dense local networks in seismically active Italian areas where for at least a year, tens of three component seismic stations were set up to record microseismicity. The areas observed are Alpago-Cansiglio, located in the Venetian Alps, Città di Castello in the Northern Apennines, Marsica in the Central Apennines and Val d'Agri located in the Southern Apennines. We produced homogeneous catalogues regarding earthquake locations and local magnitudes to investigate seismicity patterns during an inter-seismic period. The four regions are characterised by different kinematics, strain rates and historical/recent seismicity. We investigate earthquake distribution in space, time and size obtaining reference seismic rates and parameters of the Gutenberg and Richter law. We declustered the catalogues to look for coherent signs in the background seismic activity. Despite a difference in the catalogues magnitudes of completeness due both to the diverse detection threshold of the local networks and different seismic release, we detect and observe two common main behaviours: a) The Alpago-Cansiglio and Marsica regions are characterised by a relatively lower rate of seismic release associated to the episodic occurrence of seismic sequences with the largest event being 3 < ML < 4. In these areas the seismicity is not localised around the main faults. b) The Città di Castello and Val d'Agri regions have a relatively high rate of seismicity release almost continuously with time, and the increase in earthquake production is not clearly related to seismic sequences. In these areas the seismicity nucleates around defined fault systems and is usually lower than ML < 3. We suggest that the presence of over-pressured fluids in the Città di Castello and Val d'Agri uppermost crustal volume may favour and mould the higher rate of microseismic release.

  19. DI: An interactive debugging interpreter for applicative languages

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Skedzielewski, S.K.; Yates, R.K.; Oldehoeft, R.R.

    1987-03-12

    The DI interpreter is both a debugger and interpreter of SISLAL programs. Its use as a program interpreter is only a small part of its role; it is designed to be a tool for studying compilation techniques for applicative languages. DI interprets dataflow graphs expressed in the IF1 and IF2 languages, and is heavily instrumented to report the activity of dynamic storage activity, reference counting, copying and updating of structured data values. It also aids the SISAL language evaluation by providing an interim execution vehicle for SISAL programs. DI provides determinate, sequential interpretation of graph nodes for sequential and parallelmore » operations in a canonical order. As a debugging aid, DI allows tracing, breakpointing, and interactive display of program data values. DI handles creation of SISAL and IF1 error values for each data type and propagates them according to a well-defined algebra. We have begun to implement IF1 optimizers and have measured the improvements with DI.« less

  20. Numerical investigation of the triggering mechanisms of the Piz Dora sackung system (Val Mustair, Switzerland)

    NASA Astrophysics Data System (ADS)

    Riva, Federico; Agliardi, Federico; Crosta, Giovanni B.; Zanchi, Andrea

    2015-04-01

    Deep-Seated Gravitational Slope Deformations (DSGSD) are widespread phenomena in alpine environments, where they affect entire high-relief valley flanks involving huge rock volumes. Slope scale inherited structures related to ductile and brittle tectonic deformation can control the onset and development of DSGSD and the localization of strain in deep gravitational shear zones. Slope unloading, rock mass damage and hydrological perturbations related to deglaciation are considered important triggers of these phenomena in formerly glaciated areas. Furthermore, earthquake shaking and the long-term effects of seismicity in active tectonic areas might provide an additional triggering component. Nevertheless, the role played by these different processes and their interplay is not obvious, especially in geological context less typically favourable to DSGSD and in low-magnitude seismicity settings as the axial European Alps. We analysed the Piz Dora sackung system (Val Mustair, Switzerland), which affects conglomerates, meta-conglomerates and phyllites of the Austroalpine S-Charl nappe, involved in a slope-scale, WNW trending closed anticline fold. The area is actively uplifting, seismically active (maximum Mw>5) and experienced extensive glaciation during the LGM. The slope is affected by sharp gravitational morphostructures associated to the deep-seated sliding of 1.85 km3 of rock along a basal shear zone up to 300 m deep (Agliardi et al., 2014; Barbarano et al., 2015). We investigated the controlling role of inherited tectonic features and the relative influence of different candidate triggering processes (post-glacial debuttressing, related changes in slope hydrology, seismicity) through a series of 2D Distinct Element (DEM) numerical models set up using the code UDEC (ItascaTM). Based on field structural and geomechanical data, we discretized the slope into an ensemble of discontinuum domains, accounting for the slope-scale folded structure and characterised by unique

  1. Effect of Early-Life Fluoxetine on Anxiety-Like Behaviors in BDNF Val66Met Mice.

    PubMed

    Dincheva, Iva; Yang, Jianmin; Li, Anfei; Marinic, Tina; Freilingsdorf, Helena; Huang, Chienchun; Casey, B J; Hempstead, Barbara; Glatt, Charles E; Lee, Francis S; Bath, Kevin G; Jing, Deqiang

    2017-12-01

    Adolescence is a developmental stage in which the incidence of psychiatric disorders, such as anxiety disorders, peaks. Selective serotonin reuptake inhibitors (SSRIs) are the main class of agents used to treat anxiety disorders. However, the impact of SSRIs on the developing brain during adolescence remains unknown. The authors assessed the impact of developmentally timed SSRI administration in a genetic mouse model displaying elevated anxiety-like behaviors. Knock-in mice containing a common human single-nucleotide polymorphism (Val66Met; rs6265) in brain-derived neurotrophic factor (BDNF), a growth factor implicated in the mechanism of action of SSRIs, were studied based on their established phenotype of increased anxiety-like behavior. Timed administration of fluoxetine was delivered during one of three developmental periods (postnatal days 21-42, 40-61, or 60-81), spanning the transition from childhood to adulthood. Neurochemical and anxiety-like behavioral analyses were performed. We identified a "sensitive period" during periadolescence (postnatal days 21-42) in which developmentally timed fluoxetine administration rescued anxiety-like phenotypes in BDNF Val66Met mice in adulthood. Compared with littermate controls, BDNF Met/Met mice exhibited diminished maturation of serotonergic fibers projecting particularly to the prefrontal cortex, as well as decreased expression of the serotonergic trophic factor S100B in the dorsal raphe. Interestingly, deficient serotonergic innervation, as well as S100B levels, were rescued with fluoxetine administration during periadolescence. These findings suggest that SSRI administration during a "sensitive period" during periadolescence leads to long-lasting anxiolytic effects in a genetic mouse model of elevated anxiety-like behaviors. These persistent effects highlight the role of BDNF in the maturation of the serotonin system and the capacity to enhance its development through a pharmacological intervention.

  2. Enzymatic Production of c-di-GMP Using a Thermophilic Diguanylate Cyclase.

    PubMed

    Venkataramani, Prabhadevi; Liang, Zhao-Xun

    2017-01-01

    C-di-GMP has emerged as a prevalent bacterial messenger that controls a multitude of bacterial behaviors. Having access to milligram or gram quantities of c-di-GMP is essential for the biochemical and structural characterization of enzymes and effectors involved in c-di-GMP signaling. Although c-di-GMP can be synthesized using chemical methods, diguanylate cyclases (DGC)-based enzymatic synthesis is the most efficient method of preparing c-di-GMP today. Many DGCs are not suitable for c-di-GMP production because of poor protein stability and the presence of a c-di-GMP-binding inhibitory site (I-site) in most DGCs. We have identified and engineered a thermophilic DGC for efficient production of c-di-GMP for characterizing c-di-GMP signaling proteins and riboswitches. Importantly, residue replacement in the inhibitory I-site of the thermophilic DGC drastically relieved product inhibition to enable the production of hundreds of milligrams of c-di-GMP using 5-10 mg of this robust biocatalyst.

  3. Elevated Serum Brain-Derived Neurotrophic Factor (BDNF) but not BDNF Gene Val66Met Polymorphism Is Associated with Autism Spectrum Disorders.

    PubMed

    Meng, Wei-Dong; Sun, Shao-Jun; Yang, Jie; Chu, Rui-Xue; Tu, Wenjun; Liu, Qiang

    2017-03-01

    The aim of our study was to illuminate the potential role of brain-derived neurotrophic factor (BDNF) in autism spectrum disorder (ASD). We measured the circulating levels of BDNF in serum and BDNF gene (Val66Met) polymorphisms, in which two indicators were then compared between ASD and normal controls. A total of 82 drug-naïve ASD children and 82 age- and gender-matched normal controls were enrolled in the study. Their serum BDNF levels were detected by the ELISA. BDNF Val66Met polymorphism genotyping was conducted as according to the laboratory's standard protocol in laboratory. The ASD severity assessment was mainly determined by the score of the Childhood Autism Rating Scale (CARS). ELISA assay showed that the mean serum BDNF level of children with ASD was significantly (P < 0.0001) higher than that of the control cases (17.75 ± 5.43 vs. 11.49 ± 2.85 ng/ml; t = 9.236). Besides, the serum BDNF levels and CARS scores (P < 0.0001) were positively related. And, the BDNF genotyping results showed that there was no difference between the ASD cases and the control. Among the children with ASD, the mean serum BDNF level of Met/Met group was lower than other groups. According to the ROC curve generated from our clinical data, the optimal cutoff value of serum BDNF levels, an indicator for diagnosis of ASD, was projected to be 12.50 ng/ml. Thus, it yielded a corresponding sensitivity of 81.7 % and the specificity of 66.9 %. Accordingly, area value under the curve was 0.836 (95 % CI, 0.774-0.897); the positive predictive value (PPV) and the negative predictive value (NPV) were 70.1 and 79.1 %, respectively. These results suggested that rather than Val66Met polymorphism, BDNF was more possible to impact the pathogenesis of ASD.

  4. Characterization of a Novel BCHE “Silent” Allele: Point Mutation (p.Val204Asp) Causes Loss of Activity and Prolonged Apnea with Suxamethonium

    PubMed Central

    Delacour, Herve; Lushchekina, Sofya; Mabboux, Isabelle; Bousquet, Aurore; Ceppa, Franck; Schopfer, Lawrence M.; Lockridge, Oksana; Masson, Patrick

    2014-01-01

    Butyrylcholinesterase deficiency is characterized by prolonged apnea after the use of muscle relaxants (suxamethonium or mivacurium) in patients who have mutations in the BCHE gene. Here, we report a case of prolonged neuromuscular block after administration of suxamethonium leading to the discovery of a novel BCHE variant (c.695T>A, p.Val204Asp). Inhibition studies, kinetic analysis and molecular dynamics were undertaken to understand how this mutation disrupts the catalytic triad and determines a “silent” phenotype. Low activity of patient plasma butyrylcholinesterase with butyrylthiocholine (BTC) and benzoylcholine, and values of dibucaine and fluoride numbers fit with heterozygous atypical silent genotype. Electrophoretic analysis of plasma BChE of the proband and his mother showed that patient has a reduced amount of tetrameric enzyme in plasma and that minor fast-moving BChE components: monomer, dimer, and monomer-albumin conjugate are missing. Kinetic analysis showed that the p.Val204Asp/p.Asp70Gly-p.Ala539Thr BChE displays a pure Michaelian behavior with BTC as the substrate. Both catalytic parameters Km = 265 µM for BTC, two times higher than that of the atypical enzyme, and a low Vmax are consistent with the absence of activity against suxamethonium. Molecular dynamic (MD) simulations showed that the overall effect of the mutation p.Val204Asp is disruption of hydrogen bonding between Gln223 and Glu441, leading Ser198 and His438 to move away from each other with subsequent disruption of the catalytic triad functionality regardless of the type of substrate. MD also showed that the enzyme volume is increased, suggesting a pre-denaturation state. This fits with the reduced concentration of p.Ala204Asp/p.Asp70Gly-p.Ala539Thr tetrameric enzyme in the plasma and non-detectable fast moving-bands on electrophoresis gels. PMID:25054547

  5. Effects of valsartan on circulating brain natriuretic peptide and norepinephrine in symptomatic chronic heart failure: the Valsartan Heart Failure Trial (Val-HeFT).

    PubMed

    Latini, Roberto; Masson, Serge; Anand, Inder; Judd, Dianne; Maggioni, Aldo P; Chiang, Yann-Tong; Bevilacqua, Maurizio; Salio, Monica; Cardano, Paola; Dunselman, Peter H J M; Holwerda, Nicolaas J; Tognoni, Gianni; Cohn, Jay N

    2002-11-05

    Brain natriuretic peptide (BNP) and norepinephrine (NE) are strongly related to severity of and are independent predictors of outcome in heart failure. The long-term effects of angiotensin receptor blockers on BNP and NE in heart failure patients are not known. Both BNP and NE were measured in 4284 patients randomized to valsartan or placebo in the Valsartan Heart Failure Trial (Val-HeFT) at baseline and 4, 12, and 24 months after randomization. The effects of valsartan were tested by ANCOVA, controlling for baseline values and concomitant ACE inhibitors and/or beta-blockers. BNP and NE concentrations were similar at baseline in the 2 groups and were decreased by valsartan starting at 4 months and up to 24 months. BNP increased over time in the placebo group. At the end point, least-squares mean (+/-SEM) BNP increased from baseline by 23+/-5 pg/mL in the placebo group (n=1979) but decreased by 21+/-5 pg/mL (n=1940) in the valsartan group (P<0.0001). NE increased by 41+/-6 pg/mL (n=1979) and 12+/-6 pg/mL (n=1941) for placebo and valsartan, respectively (P=0.0003). Concomitant therapy with both ACE inhibitors and beta-blockers significantly reduced the effect of valsartan on BNP but not on NE (P for interaction=0.0223 and 0.2289, respectively). In Val-HeFT, the largest neurohormone study in patients with symptomatic chronic heart failure, BNP and NE rose over time in the placebo group. Valsartan caused sustained reduction in BNP and attenuated the increase in NE over the course of the study. These neurohormone effects of valsartan are consistent with the clinical benefits reported in Val-HeFT.

  6. DiGeorge syndrome and unilateral symbrachydactyly.

    PubMed

    Devriendt, K; De Smet, L; De Boeck, K; Fryns, J P

    1997-01-01

    We describe a child with DiGeorge syndrome due to a del22(q11) and a symbrachydactyly of the left hand. The underlying cardiovascular malformations in DiGeorge syndrome may lead to an increased susceptibility to vascular disruptions, giving further support to the subclavian-artery-disruption-sequence theory.

  7. Fumigant and Repellent Activity of Limonene Enantiomers Against Tribolium confusum du Val.

    PubMed

    Malacrinò, A; Campolo, O; Laudani, F; Palmeri, V

    2016-10-01

    The use of pesticides, as carried out in the last 50 years, caused several negative environmental and human health consequences, leading to the development of alternative techniques to control pests, such as the use of compounds of plant origin. In this study, we assessed the fumigant and repellent activity of both the enantiomers of limonene, a monoterpene usually found in many plant species, against Tribolium confusum du Val. We tested both molecules at different doses, air temperatures, and in absence and presence of flour. R-(+)-limonene resulted more effective than S-(-)-limonene; indeed, it was able to reach 100% of efficacy at a concentration of 85 mg/L air when tested at different temperatures without flour. Data showed a positive relationship between efficacy and temperature, and a negative effect of the presence of debris on the bioactivity of limonene. Furthermore, repellency trials reported a higher activity of R-(+)-limonene compared to the other enantiomer.

  8. Retinal phenotypic characterization of patients with ABCA4 retinopathydue to the homozygous p.Ala1773Val mutation

    PubMed Central

    López-Rubio, Salvador; Chacon-Camacho, Oscar F.; Matsui, Rodrigo; Guadarrama-Vallejo, Dalia; Astiazarán, Mirena C.

    2018-01-01

    Purpose To describe the retinal clinical features of a group of Mexican patients with Stargardt disease carrying the uncommon p.Ala1773Val founder mutation in ABCA4. Methods Ten patients carrying the p.Ala1773Val mutation, nine of them homozygously, were included. Visual function studies included best-corrected visual acuity, electroretinography, Goldmann kinetic visual fields, and full-field electroretinography (ERG). In addition, imaging studies, such as optical coherence tomography (OCT), short-wave autofluorescence imaging, and quantitative analyses of hypofluorescence, were performed in each patient. Results Best-corrected visual acuities ranged from 20/200 to 4/200. The median age of the patients at diagnosis was 23.3 years. The majority of the patients had photophobia and nyctalopia, and were classified as Fishman stage 4 (widespread choriocapillaris atrophy, resorption of flecks, and greatly reduced ERG amplitudes). An atypical retinal pigmentation pattern was observed in the patients, and the majority showed cone-rod dystrophy on full-field ERG. In vivo retinal microstructure assessment with OCT demonstrated central retinal thinning, variable loss of photoreceptors, and three different patterns of structural retinal degeneration. Two dissimilar patterns of abnormal autofluorescence were observed. No apparent age-related differences in the pattern of retinal degeneration were observed. Conclusions The results indicate that this particular mutation in ABCA4 is associated with a severe retinal phenotype and thus, could be classified as null. Careful phenotyping of patients carrying specific mutations in ABCA4 is essential to enhance our understanding of disease expression linked to particular mutations and the resulting genotype–phenotype correlations. PMID:29422768

  9. The Val192Leu mutation in the alpha-subunit of beta-hexosaminidase A is not associated with the B1-variant form of Tay-Sachs disease.

    PubMed

    Hou, Y; Vavougios, G; Hinek, A; Wu, K K; Hechtman, P; Kaplan, F; Mahuran, D J

    1996-07-01

    Substitution mutations adversely affecting the alpha-subunit of beta-hexosaminidase A (alphabeta) (EC 3.2.1.52) result in Tay-Sachs disease. The majority affect the initial folding of the pro-alpha chain in the endoplasmic reticulum, resulting in its retention and degradation. A much less common occurrence is a mutation that specifically affects an "active-site" residue necessary for substrate binding and/or catalysis. In this case, hexosaminidase A is present in the lysosome, but it lacks all alpha-specific activity. This biochemical phenotype is referred to as the "B1-variant form" of Tay-Sachs disease. Kinetic analysis of suspected B1-variant mutations is complex because hexosaminidase A is heterodimeric and both subunits possess similar active sites. In this report, we examine a previously identified B1-variant mutation, alpha-Val192Leu. Chinese hamster ovary cells were permanently cotransfected with an alpha-cDNA-construct encoding the substitution and a mutant beta-cDNA (beta-Arg211Lys), encoding a beta-subunit that is inactive but normal in all other respects. We were surprised to find that the Val192Leu substitution, produced a pro-alpha chain that did not form alpha-beta dimers and was not transported to the lysosome. Finally, we reexamined the hexosaminidase activity and protein levels in the fibroblasts from the original patient. These data were also not consistent with the biochemical phenotype of the B1 variant of Tay-Sachs disease previously reported to be present. Thus, we conclude that the Val192Leu substitution does not specifically affect the alpha-active site.

  10. Catechol-o-methyl transferase (COMT) val158met polymorphism and adolescent cortical development in patients with childhood-onset schizophrenia, their non-psychotic siblings, and healthy controls

    PubMed Central

    Raznahan, Armin; Greenstein, Deanna; Lee, Yohan; Long, Robert; Clasen, Liv; Gochman, Pete; Addington, Anjene; Giedd, Jay N.; Rapoport, Judith L.; Gogtay, Nitin

    2012-01-01

    Non-psychotic individuals at increased risk for schizophrenia show alterations in fronto-striatal dopamine signaling and cortical gray matter maturation reminiscent of those seen in schizophrenia. It remains unclear however if variations in dopamine signaling influence rates of structural cortical maturation in typically developing individuals, and whether such influences are disrupted in patients with schizophrenia and their non-psychotic siblings. We sought to address these issues by relating a functional Val→Met polymorphism within the gene encoding catechol-o-methyltransferase (COMT)—a key enzymatic regulator of cortical dopamine levels—to longitudinal structural neuroimaging measures of cortical gray matter thickness. We included a total of 792 magnetic resonance imaging brain scans, acquired between ages 9 and 22 years from patients with childhood-onset schizophrenia (COS), their non-psychotic full siblings, and matched healthy controls. Whereas greater Val allele dose (which confers enhanced dopamine catabolism and is proposed to aggravate cortical deficits in schizophrenia) accelerated adolescent cortical thinning in both schizophrenia probands and their siblings, it attenuated cortical thinning in healthy controls. This similarity between COS patients and their siblings was accompanied by differences between the two groups in the timing and spatial distribution of disrupted COMT influences on cortical maturation. Consequently, whereas greater Val “dose” conferred persistent dorsolateral prefrontal cortical deficits amongst affected probands by adulthood, cortical thickness differences associated with varying Val dose in non-psychotic siblings resolved over the age-range studied. These findings suggest that cortical abnormalities in pedigrees affected by schizophrenia may be contributed to by a disruption of dopaminergic infleunces on cortical maturation. PMID:21620981

  11. Structural Perturbations in the Ala → Val Polymorphism of Methylenetetrahydrofolate Reductase: How Binding of Folates May Protect against Inactivation†‡

    PubMed Central

    Pejchal, Robert; Campbell, Elizabeth; Guenther, Brian D.; Lennon, Brett W.; Matthews, Rowena G.; Ludwig, Martha L.

    2006-01-01

    In human methylenetetrahydrofolate reductase (MTHFR) the Ala222Val (677C → T) polymorphism encodes a heat-labile gene product that is associated with elevated levels of homocysteine and possibly with risk for cardiovascular disease. Generation of the equivalent Ala to Val mutation in Escherichia coli MTHFR, which is 30% identical to the catalytic domain of the human enzyme, creates a protein with enhanced thermolability. In both human and E. coli MTHFR, the A → V mutation increases the rate of dissociation of FAD, and in both enzymes, loss of FAD is linked to changes in quaternary structure [Yamada, K., Chen, Z., Rozen, R., and Matthews, R. G. (2001) Proc. Natl. Acad. Sci. U.S.A. 98, 14853–14858; Guenther, B. D., Sheppard, C. A., Tran, P., Rozen, R., Matthews, R. G., and Ludwig, M. L. (1999) Nat. Struct. Biol. 6, 359–365]. Folates have been shown to protect both human and bacterial enzymes from loss of FAD. Despite its effect on affinity for FAD, the A → V mutation is located at the bottom of the (βα)8 barrel of the catalytic domain in a position that does not contact the bound FAD prosthetic group. Here we report the structures of the Ala177Val mutant of E. coli MTHFR and of its complex with the 5,10-dideazafolate analogue, LY309887, and suggest mechanisms by which the mutation may perturb FAD binding. Helix α5, which immediately precedes the loop bearing the mutation, carries several residues that interact with FAD, including Asn168, Arg171, and Lys172. In the structures of the mutant enzyme this helix is displaced, perturbing protein–FAD interactions. In the complex with LY309887, the pterin-like ring of the analogue stacks against the si face of the flavin and is secured by hydrogen bonds to residues Gln183 and Asp120 that adjoin this face. The direct interactions of bound folate with the cofactor provide one mechanism for linkage between binding of FAD and folate binding that could account in part for the protective action of folates

  12. Di-codon Usage for Gene Classification

    NASA Astrophysics Data System (ADS)

    Nguyen, Minh N.; Ma, Jianmin; Fogel, Gary B.; Rajapakse, Jagath C.

    Classification of genes into biologically related groups facilitates inference of their functions. Codon usage bias has been described previously as a potential feature for gene classification. In this paper, we demonstrate that di-codon usage can further improve classification of genes. By using both codon and di-codon features, we achieve near perfect accuracies for the classification of HLA molecules into major classes and sub-classes. The method is illustrated on 1,841 HLA sequences which are classified into two major classes, HLA-I and HLA-II. Major classes are further classified into sub-groups. A binary SVM using di-codon usage patterns achieved 99.95% accuracy in the classification of HLA genes into major HLA classes; and multi-class SVM achieved accuracy rates of 99.82% and 99.03% for sub-class classification of HLA-I and HLA-II genes, respectively. Furthermore, by combining codon and di-codon usages, the prediction accuracies reached 100%, 99.82%, and 99.84% for HLA major class classification, and for sub-class classification of HLA-I and HLA-II genes, respectively.

  13. Di-hadron production at Jefferson Lab

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Anefalos Pereira, Sergio; et. al.,

    Semi-inclusive deep inelastic scattering (SIDIS) has been used extensively in recent years as an important testing ground for QCD. Studies so far have concentrated on better determination of parton distribution functions, distinguishing between the quark and antiquark contributions, and understanding the fragmentation of quarks into hadrons. Hadron pair (di-hadron) SIDIS provides information on the nucleon structure and hadronization dynamics that complement single hadron SIDIS. Di-hadrons allow the study of low- and high-twist distribution functions and Dihadron Fragmentation Functions (DiFF). Together with the twist-2 PDFs ( f1, g1, h1), the Higher Twist (HT) e and hL functions are very interesting becausemore » they offer insights into the physics of the largely unexplored quark-gluon correlations, which provide access into the dynamics inside hadrons. The CLAS spectrometer, installed in Hall-B at Jefferson Lab, has collected data using the CEBAF 6 GeV longitudinally polarized electron beam on longitudinally polarized solid NH3 targets. Preliminary results on di-hadron beam-, target- and double-spin asymmetries will be presented.« less

  14. Val-407 and Ile-408 in the β5′-Loop of Pancreatic Lipase Mediate Lipase-Colipase Interactions in the Presence of Bile Salt Micelles*

    PubMed Central

    Freie, Angela Bourbon; Ferrato, Francine; Carrière, Frédéric; Lowe, Mark E.

    2013-01-01

    In a previous study, we demonstrated that the β5′-loop in the C-terminal domain of human pancreatic triglyceride lipase (hPTL) makes a major contribution in the function of hPTL (Chahinian et al. (2002) Biochemistry 41, 13725–13735). In the present study, we characterized the contribution of three residues in the β5′-loop, Val-407, Ile-408, and Leu-412, to the function of hPTL. By substituting charged residues, aspartate or lysine, in these positions, we altered the hydrophilic to lipophilic ratio of the β5′-loop. Each of the mutants was expressed, purified, and characterized for activity and binding with both monolayers and emulsions and for binding to colipase. Experiments with monolayers and with emulsions suggested that the interaction of hPTL with a phospholipid monolayer differs from the interaction of the hPTL-colipase complex with a dicaprin monolayer or a triglyceride emulsion (i.e. neutral lipids). Val-407, Ile-408, and Leu-412 make major contributions to interactions with monolayers, whereas only Val-407 and Ile-408 appear essential for activity on triglyceride emulsions in the presence of bile salt micelles. In solutions of taurodeoxycholate at micellar concentrations, a major effect of the β5′-loop mutations is to change the interaction between hPTL and colipase. These observations support a major contribution of residues in the β5′-loop in the function of hPTL and suggest that a third partner, bile salt micelles or the lipid interface or both, influence the binding of colipase and hPTL through interactions with the β5′-loop. PMID:16431912

  15. COMT Val158Met Genotype Selectively Alters Prefrontal [18F]Fallypride Displacement and Subjective Feelings of Stress in Response to a Psychosocial Stress Challenge

    PubMed Central

    Lataster, Johan; Ceccarini, Jenny; Kenis, Gunther; Booij, Linda; Pruessner, Jens; Van Laere, Koen; van Winkel, Ruud; van Os, Jim; Myin-Germeys, Inez

    2013-01-01

    Catechol-O-methyltransferase (COMT) plays an essential role in degradation of extracellular dopamine in prefrontal regions of the brain. Although a polymorphism in this gene, COMT Val158Met, affects human behavior in response to stress little is known about its effect on dopaminergic activity associated with the human stress response, which may be of interest for stress-related psychiatric disorders such as psychosis. We aimed to investigate the effect of variations in COMT genotype on in vivo measures of stress-induced prefrontal cortex (PFC) dopaminergic processing and subjective stress responses. A combined sample of healthy controls and healthy first-degree relatives of psychosis patients (n = 26) were subjected to an [18F]fallypride Positron Emission Tomography scan. Psychosocial stress during the scan was induced using the Montreal Imaging Stress Task and subjective stress was assessed every 12 minutes. Parametric t-maps, generated using the linear extension of the simplified reference region model, revealed an effect of COMT genotype on the spatial extent of [18F]fallypride displacement. Detected effects of exposure to psychosocial stress were unilateral and remained restricted to the left superior and right inferior frontal gyrus, with Met-hetero- and homozygotes showing less [18F]fallypride displacement than Val-homozygotes. Additionally, Met-hetero- and homozygotes experienced larger subjective stress responses than Val-homozygotes. The direction of the effects remained the same when the data was analyzed separately for controls and first-degree relatives. The human stress response may be mediated in part by COMT-dependent dopaminergic PFC activity, providing speculation for the neurobiology underlying COMT-dependent differences in human behaviour following stress. Implications of these results for stress-related psychopathology and models of dopaminergic functioning are discussed. PMID:23799032

  16. COMT Val158Met genotype selectively alters prefrontal [18F]fallypride displacement and subjective feelings of stress in response to a psychosocial stress challenge.

    PubMed

    Hernaus, Dennis; Collip, Dina; Lataster, Johan; Ceccarini, Jenny; Kenis, Gunther; Booij, Linda; Pruessner, Jens; Van Laere, Koen; van Winkel, Ruud; van Os, Jim; Myin-Germeys, Inez

    2013-01-01

    Catechol-O-methyltransferase (COMT) plays an essential role in degradation of extracellular dopamine in prefrontal regions of the brain. Although a polymorphism in this gene, COMT Val(158)Met, affects human behavior in response to stress little is known about its effect on dopaminergic activity associated with the human stress response, which may be of interest for stress-related psychiatric disorders such as psychosis. We aimed to investigate the effect of variations in COMT genotype on in vivo measures of stress-induced prefrontal cortex (PFC) dopaminergic processing and subjective stress responses. A combined sample of healthy controls and healthy first-degree relatives of psychosis patients (n = 26) were subjected to an [(18)F]fallypride Positron Emission Tomography scan. Psychosocial stress during the scan was induced using the Montreal Imaging Stress Task and subjective stress was assessed every 12 minutes. Parametric t-maps, generated using the linear extension of the simplified reference region model, revealed an effect of COMT genotype on the spatial extent of [(18)F]fallypride displacement. Detected effects of exposure to psychosocial stress were unilateral and remained restricted to the left superior and right inferior frontal gyrus, with Met-hetero- and homozygotes showing less [(18)F]fallypride displacement than Val-homozygotes. Additionally, Met-hetero- and homozygotes experienced larger subjective stress responses than Val-homozygotes. The direction of the effects remained the same when the data was analyzed separately for controls and first-degree relatives. The human stress response may be mediated in part by COMT-dependent dopaminergic PFC activity, providing speculation for the neurobiology underlying COMT-dependent differences in human behaviour following stress. Implications of these results for stress-related psychopathology and models of dopaminergic functioning are discussed.

  17. [Trattamento della dipendenza da alcol. Alcol e giovani: punto di vista sociale].

    PubMed

    Alessandrini, Giovanni; Ciccarelli, Rosaria; Battagliese, Gemma; Lombardo, Giuseppe; De Rosa, Francesca; Messina, Marisa Patrizia; Vitali, Mario; Pisciotta, Fabiola; Nanut, Miriana; Attilia, Maria Luisa; Ceccanti, Mauro

    2018-01-01

    RIASSUNTO. Gli adolescenti rappresentano la fascia di età più vulnerabile ai danni causati dall'abuso di alcol, in quanto iniziare a bere in giovane età è associato a un aumento del rischio di dipendenza da alcolici in età adulta. I giovani tendono a bere grandi quantità di alcolici al fine di ricercare forti emozioni e nel tentativo di raggiungere il divertimento a ogni costo, tramite le proprietà psicotrope degli alcolici. Le cause che li inducono ad assumere questi comportamenti sono da ricercare nella non conoscenza degli effetti dannosi dell'alcol, nel rito di convivialità sociale (evenienza per la quale si attribuisce all'alcol la funzione di facilitatore dell'aggregazione tra giovani), nella mancanza di interessi personali, nella scarsità dei controlli e nelle abitudini familiari. Le azioni da intraprendere per limitare o arrestare il consumo nocivo di alcol nei giovani si devono basare su interventi finalizzati a ritardare l'età del primo contatto con le bevande alcoliche, mediante la realizzazione di campagne educazionali rivolte ai giovani stessi, ai loro familiari e alla società intera.

  18. Structural Basis of Ligand Binding by a C-di-GMP Riboswitch

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Smith, K.; Lipchock, S; Ames, T

    2009-01-01

    The second messenger signaling molecule bis-(3{prime}-5{prime})-cyclic dimeric guanosine monophosphate (c-di-GMP) regulates many processes in bacteria, including motility, pathogenesis and biofilm formation. c-di-GMP-binding riboswitches are important downstream targets in this signaling pathway. Here we report the crystal structure, at 2.7 {angstrom} resolution, of a c-di-GMP riboswitch aptamer from Vibrio cholerae bound to c-di-GMP, showing that the ligand binds within a three-helix junction that involves base-pairing and extensive base-stacking. The symmetric c-di-GMP is recognized asymmetrically with respect to both the bases and the backbone. A mutant aptamer was engineered that preferentially binds the candidate signaling molecule c-di-AMP over c-di-GMP. Kinetic and structuralmore » data suggest that genetic regulation by the c-di-GMP riboswitch is kinetically controlled and that gene expression is modulated through the stabilization of a previously unidentified P1 helix, illustrating a direct mechanism for c-di-GMP signaling.« less

  19. An experiment of formation of charmoni states in annihilation P-Pbarra. Un esperimento di formazione di stati del charmonio in annichilazione P-Pbarra (in Italian)

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Pallavicini, Marco

    1995-01-01

    Oggetto di questa tesi e la misura di alcune caratteristiche fisiche (massa, larghezza, e larghezza parziale in p -more » $$\\bar{p}$$) degli stati 3P 1 e 3P 2 del charmonio, -ovvero del sistema legato di un quark "charm" e del suo antiquark-, nell'amito dell'esperimento E-760, installato nell'accumulatore di antiprotoni del Fermilab.« less

  20. Misura della sezione d'urto totale e Dello scattering elastico all'energia Nel centro di massa di $$\\sqrt{s}=1.8$$ TeV (in Italian)

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Paoletti, Riccardo

    La produzione di eventi elastici è stata misurata al Collider Tevatron del Fermi National Accelerator Laboratory (Batavia. 11.~ U .S.A.) alla energia nel centro di massa. di √s = 1800 GeV, nell'intervallo 0.06 < I t I< 0.24. Sono forniti dettagli sull'esperimento CDF che ha compiuto la misura e sui criteri di selezione degli eventi.

  1. Cyclic Di-GMP modulates the disease progression of Erwinia amylovora.

    PubMed

    Edmunds, Adam C; Castiblanco, Luisa F; Sundin, George W; Waters, Christopher M

    2013-05-01

    The second messenger cyclic di-GMP (c-di-GMP) is a nearly ubiquitous intracellular signal molecule known to regulate various cellular processes, including biofilm formation, motility, and virulence. The intracellular concentration of c-di-GMP is inversely governed by diguanylate cyclase (DGC) enzymes and phosphodiesterase (PDE) enzymes, which synthesize and degrade c-di-GMP, respectively. The role of c-di-GMP in the plant pathogen and causal agent of fire blight disease Erwinia amylovora has not been studied previously. Here we demonstrate that three of the five predicted DGC genes in E. amylovora (edc genes, for Erwinia diguanylate cyclase), edcA, edcC, and edcE, are active diguanylate cyclases. We show that c-di-GMP positively regulates the secretion of the main exopolysaccharide in E. amylovora, amylovoran, leading to increased biofilm formation, and negatively regulates flagellar swimming motility. Although amylovoran secretion and biofilm formation are important for the colonization of plant xylem tissues and the development of systemic infections, deletion of the two biofilm-promoting DGCs increased tissue necrosis in an immature-pear infection assay and an apple shoot infection model, suggesting that c-di-GMP negatively regulates virulence. In addition, c-di-GMP inhibited the expression of hrpA, a gene encoding the major structural component of the type III secretion pilus. Our results are the first to describe a role for c-di-GMP in E. amylovora and suggest that downregulation of motility and type III secretion by c-di-GMP during infection plays a key role in the coordination of pathogenesis.

  2. Cyclic Di-GMP Modulates the Disease Progression of Erwinia amylovora

    PubMed Central

    Edmunds, Adam C.; Castiblanco, Luisa F.; Sundin, George W.

    2013-01-01

    The second messenger cyclic di-GMP (c-di-GMP) is a nearly ubiquitous intracellular signal molecule known to regulate various cellular processes, including biofilm formation, motility, and virulence. The intracellular concentration of c-di-GMP is inversely governed by diguanylate cyclase (DGC) enzymes and phosphodiesterase (PDE) enzymes, which synthesize and degrade c-di-GMP, respectively. The role of c-di-GMP in the plant pathogen and causal agent of fire blight disease Erwinia amylovora has not been studied previously. Here we demonstrate that three of the five predicted DGC genes in E. amylovora (edc genes, for Erwinia diguanylate cyclase), edcA, edcC, and edcE, are active diguanylate cyclases. We show that c-di-GMP positively regulates the secretion of the main exopolysaccharide in E. amylovora, amylovoran, leading to increased biofilm formation, and negatively regulates flagellar swimming motility. Although amylovoran secretion and biofilm formation are important for the colonization of plant xylem tissues and the development of systemic infections, deletion of the two biofilm-promoting DGCs increased tissue necrosis in an immature-pear infection assay and an apple shoot infection model, suggesting that c-di-GMP negatively regulates virulence. In addition, c-di-GMP inhibited the expression of hrpA, a gene encoding the major structural component of the type III secretion pilus. Our results are the first to describe a role for c-di-GMP in E. amylovora and suggest that downregulation of motility and type III secretion by c-di-GMP during infection plays a key role in the coordination of pathogenesis. PMID:23475975

  3. Enhanced healing of full-thickness burn wounds using di-rhamnolipid

    PubMed Central

    Stipcevic, Tamara; Piljac, Ante; Piljac, Goran

    2006-01-01

    The aim of this study was to investigate the properties of di-rhamnolipid [α-L-rhamnopyranosyl-(1–2)-α-L-rhamnopyranosyl-3-hydroxydecanoyl-3-hydroxydecanoic acid, also referred to as di-rhamnolipid BAC-3] relating to the process of cutaneous wound healing. Di-rhamnolipid was prepared in a eucerin ointment and applied topically on full-thickness burn wounds in normal Sprague–Dawley rats covering 5% of the total body surface area. The rate of wound closure was measured over the period of 45 days. The collagen content was evaluated microscopically, by performing densitometric analysis on Verhoeff’s stained histopathological slides of wound biopsies taken at the end of 45th day of di-rhamnolipid treatment. Di-rhamnolipid toxicity was assessed with the subcutaneous multi-dose study in Swiss–Webster mice. The treatment of full-thickness-burn wounds with topical 0.1% di-rhamnolipid accelerated the closure of wounds on day 21 of the treatment by 32% compared to the control ( p < 0.05). On day 35, the wounds closed in all animals-treated with 0.1% di-rhamnolipid ointment while some rats in the control group had open wounds on days 35 and even 45. Histologic comparisons have shown that di-rhamnolipid significantly decreased collagen content in burn wounds (47.5%, p < 0.05) as compared to the vehicle-treated (control) wounds. Di-rhamnolipid was well-tolerated. The results of this study raise the possibility of potential efficacy of di-rhamnolipid in accelerating normal wound healing and perhaps in overcoming defects associated with healing failure in chronic wounds. PMID:16380213

  4. Association of BDNF Val66Met Polymorphism and Brain BDNF Levels with Major Depression and Suicide.

    PubMed

    Youssef, Mariam M; Underwood, Mark D; Huang, Yung-Yu; Hsiung, Shu-Chi; Liu, Yan; Simpson, Norman R; Bakalian, Mihran J; Rosoklija, Gorazd B; Dwork, Andrew J; Arango, Victoria; Mann, J John

    2018-06-01

    Brain-derived neurotrophic factor is implicated in the pathophysiology of major depressive disorder and suicide. Both are partly caused by early life adversity, which reduces brain-derived neurotrophic factor protein levels. This study examines the association of brain-derived neurotrophic factor Val66Met polymorphism and brain brain-derived neurotrophic factor levels with depression and suicide. We hypothesized that both major depressive disorder and early life adversity would be associated with the Met allele and lower brain brain-derived neurotrophic factor levels. Such an association would be consistent with low brain-derived neurotrophic factor mediating the effect of early life adversity on adulthood suicide and major depressive disorder. Brain-derived neurotrophic factor Val66Met polymorphism was genotyped in postmortem brains of 37 suicide decedents and 53 nonsuicides. Additionally, brain-derived neurotrophic factor protein levels were determined by Western blot in dorsolateral prefrontal cortex (Brodmann area 9), anterior cingulate cortex (Brodmann area 24), caudal brainstem, and rostral brainstem. The relationships between these measures and major depressive disorder, death by suicide, and reported early life adversity were examined. Subjects with the Met allele had an increased risk for depression. Depressed patients also have lower brain-derived neurotrophic factor levels in anterior cingulate cortex and caudal brainstem compared with nondepressed subjects. No effect of history of suicide death or early life adversity was observed with genotype, but lower brain-derived neurotrophic factor levels in the anterior cingulate cortex were found in subjects who had been exposed to early life adversity and/or died by suicide compared with nonsuicide decedents and no reported early life adversity. This study provides further evidence implicating low brain brain-derived neurotrophic factor and the brain-derived neurotrophic factor Met allele in major depression

  5. The brain-derived neurotrophic factor Val66Met polymorphism is associated with reduced functional magnetic resonance imaging activity in the hippocampus and increased use of caudate nucleus-dependent strategies in a human virtual navigation task

    PubMed Central

    Banner, Harrison; Bhat, Venkataramana; Etchamendy, Nicole; Joober, Ridha; Bohbot, Véronique D

    2011-01-01

    Multiple memory systems are involved in parallel processing of spatial information during navigation. A series of studies have distinguished between hippocampus-dependent ‘spatial’ navigation, which relies on knowledge of the relationship between landmarks in one’s environment to build a cognitive map, and habit-based ‘response’ learning, which requires the memorization of a series of actions and is mediated by the caudate nucleus. Studies have demonstrated that people spontaneously use one of these two alternative navigational strategies with almost equal frequency to solve a given navigation task, and that strategy correlates with functional magnetic resonance imaging (fMRI) activity and grey matter density. Although there is evidence for experience modulating grey matter in the hippocampus, genetic contributions may also play an important role in the hippocampus and caudate nucleus. Recently, the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene has emerged as a possible inhibitor of hippocampal function. We have investigated the role of the BDNF Val66Met polymorphism on virtual navigation behaviour and brain activation during an fMRI navigation task. Our results demonstrate a genetic contribution to spontaneous strategies, where ‘Met’ carriers use a response strategy more frequently than individuals homozygous for the ‘Val’ allele. Additionally, we found increased hippocampal activation in the Val group relative to the Met group during performance of a virtual navigation task. Our results support the idea that the BDNF gene with the Val66Met polymorphism is a novel candidate gene involved in determining spontaneous strategies during navigation behaviour. PMID:21255124

  6. 40 CFR 721.10261 - Oxime, di-Me silane (generic).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Oxime, di-Me silane (generic). 721... Substances § 721.10261 Oxime, di-Me silane (generic). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as oxime, di-Me silane (PMN P-09-589...

  7. 40 CFR 721.10261 - Oxime, di-Me silane (generic).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Oxime, di-Me silane (generic). 721... Substances § 721.10261 Oxime, di-Me silane (generic). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as oxime, di-Me silane (PMN P-09-589...

  8. Environmental monitoring of the area surrounding oil wells in Val d'Agri (Italy): element accumulation in bovine and ovine organs.

    PubMed

    Miedico, Oto; Iammarino, Marco; Paglia, Giuseppe; Tarallo, Marina; Mangiacotti, Michele; Chiaravalle, A Eugenio

    2016-06-01

    In this work, environmental heavy metal contamination in the Val d'Agri area of Southern Italy was monitored, measuring the accumulation of 18 heavy metals (U, Hg, Pb, Cd, As, Sr, Sn, V, Ni, Cr, Mo, Co, Cu, Zn, Ca, Mn, Fe, and Al) in the organs of animals raised in the surrounding area (kidney, lung, and liver of bovine and ovine species). Val d'Agri features various oil processing centers which are potentially a significant source of environmental pollution, making it essential to perform studies that will outline the state of the art on which any recovery plans and interventions may be developed. The analysis was carried out using official and accredited analytical methods based on inductively coupled plasma mass spectrometry, and the measurements were statistically processed in order to give a contribution to risk assessment. Even though five samples showed Pb and Cd concentrations above the limits defined in the European Commission Regulation (EC) No 1881/2006, the mean concentrations of most elements suggest that contamination in this area is low. Consequently, these results also suggest that there is no particular risk for human exposure to toxic trace elements. Nevertheless, the findings of this work confirm that element accumulation in ovine species is correlated with geographical livestock area. Therefore, ovine-specific organs might be used as bioindicators for monitoring contamination by specific toxic elements in exposed areas.

  9. BDNF Val66Met Polymorphism Interacts with Sleep Consolidation to Predict Ability to Create New Declarative Memories

    PubMed Central

    Gosselin, Nadia; De Beaumont, Louis; Gagnon, Katia; Baril, Andrée-Ann; Mongrain, Valérie; Blais, Hélène; Montplaisir, Jacques; Gagnon, Jean-François; Pelleieux, Sandra; Poirier, Judes; Carrier, Julie

    2016-01-01

    It is hypothesized that a fundamental function of sleep is to restore an individual’s day-to-day ability to learn and to constantly adapt to a changing environment through brain plasticity. Brain-derived neurotrophic factor (BDNF) is among the key regulators that shape brain plasticity. However, advancing age and carrying the BDNF Met allele were both identified as factors that potentially reduce BDNF secretion, brain plasticity, and memory. Here, we investigated the moderating role of BDNF polymorphism on sleep and next-morning learning ability in 107 nondemented individuals who were between 55 and 84 years of age. All subjects were tested with 1 night of in-laboratory polysomnography followed by a cognitive evaluation the next morning. We found that in subjects carrying the BDNF Val66Val polymorphism, consolidated sleep was associated with significantly better performance on hippocampus-dependent episodic memory tasks the next morning (β-values from 0.290 to 0.434, p ≤ 0.01). In subjects carrying at least one copy of the BDNF Met allele, a more consolidated sleep was not associated with better memory performance in most memory tests (β-values from −0.309 to −0.392, p values from 0.06 to 0.15). Strikingly, increased sleep consolidation was associated with poorer performance in learning a short story presented verbally in Met allele carriers (β = −0.585, p = 0.005). This study provides new evidence regarding the interacting roles of consolidated sleep and BDNF polymorphism in the ability to learn and stresses the importance of considering BDNF polymorphism when studying how sleep affects cognition. PMID:27511011

  10. Isolation and identification of curcumin and bisacurone from rhizome extract of temu glenyeh (Curcuma soloensis. Val)

    NASA Astrophysics Data System (ADS)

    Vitasari, Rista A.; Wibowo, Fajar R.; Marliyana, Soerya D.; Widyo Wartono, M.

    2016-02-01

    Temu glenyeh (Curcuma soloensis. Val) is one of the medicinal plants that grow in Surakarta. This plant is similar with C. longa and C. Xanthoriza. Chemical constituents from an extract of the plant have never been studied. In this paper, we report the isolation of a terpenoid and curcumin from the rhizome of C. soloensis. The isolation was employed by soxhlet apparatus using acetone as solvent. The fractionation and purification of the compound from the acetone extracts were undertaken by vacuum liquid chromatography and flash chromatography. Identification of compounds used spectroscopy methods, such as FTIR, NMR (1H NMR, 13C NMR, COSY, HSQC and HMBC) and GC-MS. Isolated compounds were identified as curcumin (1) and bisacurone (2).

  11. Lattice stability and thermal properties of Fe2VAl and Fe2TiSn Heusler compounds

    NASA Astrophysics Data System (ADS)

    Shastri, Shivprasad S.; Pandey, Sudhir K.

    2018-04-01

    Fe2VAl and Fe2TiSn are two full-Heusler compounds with non-magnetic ground states. They have application as potential thermoelectric materials. Along with first-principles electronic structure calculations, phonon calculation is one of the important tools in condensed matter physics and material science. Phonon calculations are important in understanding mechanical properties, thermal properties and phase transitions of periodic solids. A combination of electronic structure code and phonon calculation code - phonopy is employed in this work. The vibrational spectra, phonon DOS and thermal properties are studied for these two Heusler compounds. Two compounds are found to be dynamically stable with absence of negative frequencies (energy) in the phonon band structure.

  12. Rendering justice in witch trials: the case of the val de Lièpvre.

    PubMed

    Simon, Maryse

    2011-01-01

    The borderland of the val de Lièpvre, with lands in Alsace and in the Duchy of Lorraine, and divided by religion and language, offers a rich collection of sources for the history of witchcraft persecution. The territory sharply reveals what was undoubtedly characteristic of witchcraft trials more widely. The crime of witchcraft was considered abominable before the Christian community and God, and its prosecution justified abandoning many of the safeguards and constraints in legal procedure, whether restrictions on the use of torture, the reliance on dubious testimony or even denial of advocacy to the witches. The action of the judges was nonetheless, as they understood it, the rendering of true justice, by punishing the culprits with a harshness that would expiate their crimes before the community and preserve them from damnation in the face of God's judgment.

  13. Associations between glutathione S-transferase pi Ile105Val and glyoxylate aminotransferase Pro11Leu and Ile340Met polymorphisms and early-onset oxaliplatin-induced neuropathy.

    PubMed

    Kanai, Masashi; Yoshioka, Akira; Tanaka, Shiro; Nagayama, Satoshi; Matsumoto, Shigemi; Nishimura, Takafumi; Niimi, Miyuki; Teramukai, Satoshi; Takahashi, Ryo; Mori, Yukiko; Kitano, Toshiyuki; Ishiguro, Hiroshi; Yanagihara, Kazuhiro; Chiba, Tsutomu; Fukushima, Masanori; Matsuda, Fumihiko

    2010-04-01

    Although the risk of oxaliplatin-induced neuropathy depends on cumulative oxaliplatin dose, susceptibility to this adverse event differs greatly among patients. In this study, we investigated the associations between oxaliplatin-induced neuropathy and the following polymorphisms: glutathione S-transferase pi (GSTP1) Ile(105)Val, and glyoxylate aminotransferase (AGXT) Pro(11)Leu and AGXT Ile(340)Met. Eighty-two Japanese patients with histologically confirmed colorectal cancer who received at least six cycles of the modified FOLFOX6 (m-FOLFOX6) regimen were enrolled. To minimize differences in cumulative oxaliplatin dose between patients, oxaliplatin-induced neuropathy was evaluated using an oxaliplatin-specific scale during the 2-week period after completion of the sixth cycle of treatment. Forty-four patients developed grade 2/3 oxaliplatin-induced neuropathy. There were more patients carrying at least one GSTP1(105)Val allele among the group with grade 2/3 neuropathy (18/44, 41%) than among the group with grade 1 neuropathy (9/38, 24%), although the difference was not statistically significant (P=0.098). There were similar numbers of patients carrying at least one AGXT(105)Met allele in the grade 2/3 neuropathy (7/44, 16%) and grade 1 neuropathy groups (5/38, 13%; P=0.725). The AGXT(11)Leu allele was not found in any of our patients or controls. We found no significant association between oxaliplatin-induced neuropathy and the GSTP1 Ile(105)Val and AGXT Ile(340)Met polymorphisms. Given that no AGXT(11)Leu allele was found among our study population (n=177), evaluating this polymorphism in Japanese patients in future studies is likely to be uninformative.

  14. The Val192Leu mutation in the alpha-subunit of beta-hexosaminidase A is not associated with the B1-variant form of Tay-Sachs disease.

    PubMed Central

    Hou, Y.; Vavougios, G.; Hinek, A.; Wu, K. K.; Hechtman, P.; Kaplan, F.; Mahuran, D. J.

    1996-01-01

    Substitution mutations adversely affecting the alpha-subunit of beta-hexosaminidase A (alphabeta) (EC 3.2.1.52) result in Tay-Sachs disease. The majority affect the initial folding of the pro-alpha chain in the endoplasmic reticulum, resulting in its retention and degradation. A much less common occurrence is a mutation that specifically affects an "active-site" residue necessary for substrate binding and/or catalysis. In this case, hexosaminidase A is present in the lysosome, but it lacks all alpha-specific activity. This biochemical phenotype is referred to as the "B1-variant form" of Tay-Sachs disease. Kinetic analysis of suspected B1-variant mutations is complex because hexosaminidase A is heterodimeric and both subunits possess similar active sites. In this report, we examine a previously identified B1-variant mutation, alpha-Val192Leu. Chinese hamster ovary cells were permanently cotransfected with an alpha-cDNA-construct encoding the substitution and a mutant beta-cDNA (beta-Arg211Lys), encoding a beta-subunit that is inactive but normal in all other respects. We were surprised to find that the Val192Leu substitution, produced a pro-alpha chain that did not form alpha-beta dimers and was not transported to the lysosome. Finally, we reexamined the hexosaminidase activity and protein levels in the fibroblasts from the original patient. These data were also not consistent with the biochemical phenotype of the B1 variant of Tay-Sachs disease previously reported to be present. Thus, we conclude that the Val192Leu substitution does not specifically affect the alpha-active site. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:8659543

  15. BDNF Val66Met but not transcranial direct current stimulation affects motor learning after stroke.

    PubMed

    van der Vliet, Rick; Ribbers, Gerard M; Vandermeeren, Yves; Frens, Maarten A; Selles, Ruud W

    tDCS is a non-invasive neuromodulation technique that has been reported to improve motor skill learning after stroke. However, the contribution of tDCS to motor skill learning has only been investigated in a small number of studies. In addition, it is unclear if tDCS effects are mediated by activity-dependent BDNF release and dependent on timing of tDCS relative to training. Investigate the role of activity-dependent BDNF release and timing of tDCS relative to training in motor skill learning. Double-blind, between-subjects randomized controlled trial of circuit tracing task improvement (ΔMotor skill) in 80 chronic stroke patients who underwent tDCS and were genotyped for BDNF Val66Met. Patients received either short-lasting tDCS (20 min) during training (short-lasting online group), long-lasting tDCS (10 min-25 min break - 10 min) one day before training (long-lasting offline group), short-lasting tDCS one day before training (short-lasting offline group), or sham tDCS. ΔMotor skill was defined as the skill difference on the circuit tracing task between day one and day nine of the study. Having at least one BDNF Met allele was found to diminish ΔMotor skill (β BDNF,Met  = -0.217 95%HDI = [-0.431 -0.0116]), indicating activity-dependent BDNF release is important for motor skill learning after stroke. However, none of the tDCS protocols affected ΔMotor skill (β Short-lasting,online  = 0.0908 95%HDI = [-0.227 0.403]; β Long-lasting,offline  = 0.0242 95%HDI = [-0.292 0.349]; β Short-lasting,offline  = -0.108 95%HDI = [-0.433 0.210]). BDNF Val66Met is a determinant of motor skill learning after stroke and could be important for prognostic models. tDCS does not modulate motor skill learning in our study and might be less effective than previously assumed. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. [Trattamento farmacologico del disturbo da uso di alcol. Evidenze scientifiche].

    PubMed

    Attilia, Fabio; Perciballi, Roberta; Rotondo, Claudia; Capriglione, Ida; Iannuzzi, Silvia; Attilia, Maria Luisa; Vitali, Mario; Alessandrini, Giovanni; Scamporrino, Maria Concetta Marcella; Fiore, Marco; Ceccanti, Mauro

    2018-01-01

    RIASSUNTO. La terapia farmacologica nei pazienti con disturbo da uso di alcol riveste un ruolo centrale nel progetto terapeutico, altamente contestualizzato in un approccio multidisciplinare. Sebbene i trattamenti non farmacologici per la dipendenza da alcol risultino ben strutturati e in continua evoluzione, dal punto di vista medico le possibilità di intervento sono realmente ristrette, con poche molecole a disposizione approvate per il disturbo da uso di alcol: nello specifico, l'acamprostato, il naltrexone e, più recentemente, il nalmefene tra gli anticraving; il disulfiram tra gli avversivanti. Nuovi approcci sperimentali stanno cercando di ampliare tale gamma attraverso l'utilizzo di farmaci off-label. Evidenze scientifiche devono supportare l'indicazione terapeutica, quest'ultima deve dimostrarsi "cucita" sulle esigenze del paziente e sulle comorbilità presenti tenendo conto del profilo bio-psico-sociale individuale. Fondamentale risulta il follow-up per valutare la ritenzione in trattamento e il monitoraggio degli outcome alcologici.

  17. Identification of a G‐Protein Subunit‐α11 Gain‐of‐Function Mutation, Val340Met, in a Family With Autosomal Dominant Hypocalcemia Type 2 (ADH2)

    PubMed Central

    Piret, Sian E; Gorvin, Caroline M; Pagnamenta, Alistair T; Howles, Sarah A; Cranston, Treena; Rust, Nigel; Nesbit, M Andrew; Glaser, Ben; Taylor, Jenny C; Buchs, Andreas E; Hannan, Fadil M

    2016-01-01

    ABSTRACT Autosomal dominant hypocalcemia (ADH) is characterized by hypocalcemia, inappropriately low serum parathyroid hormone concentrations and hypercalciuria. ADH is genetically heterogeneous with ADH type 1 (ADH1), the predominant form, being caused by germline gain‐of‐function mutations of the G‐protein coupled calcium‐sensing receptor (CaSR), and ADH2 caused by germline gain‐of‐function mutations of G‐protein subunit α‐11 (Gα11). To date Gα11 mutations causing ADH2 have been reported in only five probands. We investigated a multigenerational nonconsanguineous family, from Iran, with ADH and keratoconus which are not known to be associated, for causative mutations by whole‐exome sequencing in two individuals with hypoparathyroidism, of whom one also had keratoconus, followed by cosegregation analysis of variants. This identified a novel heterozygous germline Val340Met Gα11 mutation in both individuals, and this was also present in the other two relatives with hypocalcemia that were tested. Three‐dimensional modeling revealed the Val340Met mutation to likely alter the conformation of the C‐terminal α5 helix, which may affect G‐protein coupled receptor binding and G‐protein activation. In vitro functional expression of wild‐type (Val340) and mutant (Met340) Gα11 proteins in HEK293 cells stably expressing the CaSR, demonstrated that the intracellular calcium responses following stimulation with extracellular calcium, of the mutant Met340 Gα11 led to a leftward shift of the concentration‐response curve with a significantly (p < 0.0001) reduced mean half‐maximal concentration (EC50) value of 2.44 mM (95% CI, 2.31 to 2.77 mM) when compared to the wild‐type EC50 of 3.14 mM (95% CI, 3.03 to 3.26 mM), consistent with a gain‐of‐function mutation. A novel His403Gln variant in transforming growth factor, beta‐induced (TGFBI), that may be causing keratoconus was also identified, indicating likely digenic

  18. Screening of soy protein-derived hypotriglyceridemic di-peptides in vitro and in vivo

    PubMed Central

    2011-01-01

    Background Soy protein and soy peptides have attracted considerable attention because of their potentially beneficial biological properties, including antihypertensive, anticarcinogenic, and hypolipidemic effects. Although soy protein isolate contains several bioactive peptides that have distinct physiological activities in lipid metabolism, it is not clear which peptide sequences are responsible for the triglyceride (TG)-lowering effects. In the present study, we investigated the effects of soy protein-derived peptides on lipid metabolism, especially TG metabolism, in HepG2 cells and obese Otsuka Long-Evans Tokushima fatty (OLETF) rats. Results In the first experiment, we found that soy crude peptide (SCP)-LD3, which was prepared by hydrolyze of soy protein isolate with endo-type protease, showed hypolipidemic effects in HepG2 cells and OLETF rats. In the second experiment, we found that hydrophilic fraction, separated from SCP-LD3 with hydrophobic synthetic absorbent, revealed lipid-lowering effects in HepG2 cells and OLETF rats. In the third experiment, we found that Fraction-C (Frc-C) peptides, fractionated from hydrophilic peptides by gel permeation chromatography-high performance liquid chromatography, significantly reduced TG synthesis and apolipoprotein B (apoB) secretion in HepG2 cells. In the fourth experiment, we found that the fraction with 0.1% trifluoroacetic acid, isolated from Frc-C peptides by octadecylsilyl column chromatography, showed hypolipidemic effects in HepG2 cells. In the final experiment, we found that 3 di-peptides, Lys-Ala, Val-Lys, and Ser-Tyr, reduced TG synthesis, and Ser-Tyr additionally reduced apoB secretion in HepG2 cells. Conclusion Novel active peptides with TG-lowering effects from soy protein have been isolated. PMID:21600040

  19. RATE CONSTANTS FOR THE REACTIONS OF OH RADICALS AND CL ATOMS WITH DI-N-PROPYL ETHER AND DI-N-BUTYL ETHER AND THEIR DEUTERATED ANALOGS. (R825252)

    EPA Science Inventory

    Using relative rate methods, rate constants for the gas-phase reactions of OH radicals and Cl atoms with di-n-propyl ether, di-n-propyl ether-d14, di-n-butyl ether and di-n-butyl ether-d18 have been measured at 296 ? 2 K and atmos...

  20. Recommendations from the European Working Group for Value Assessment and Funding Processes in Rare Diseases (ORPH-VAL).

    PubMed

    Annemans, Lieven; Aymé, Ségolène; Le Cam, Yann; Facey, Karen; Gunther, Penilla; Nicod, Elena; Reni, Michele; Roux, Jean-Louis; Schlander, Michael; Taylor, David; Tomino, Carlo; Torrent-Farnell, Josep; Upadhyaya, Sheela; Hutchings, Adam; Le Dez, Lugdivine

    2017-03-10

    Rare diseases are an important public health issue with high unmet need. The introduction of the EU Regulation on orphan medicinal products (OMP) has been successful in stimulating investment in the research and development of OMPs. Despite this advancement, patients do not have universal access to these new medicines. There are many factors that affect OMP uptake, but one of the most important is the difficulty of making pricing and reimbursement (P&R) decisions in rare diseases. Until now, there has been little consensus on the most appropriate assessment criteria, perspective or appraisal process. This paper proposes nine principles to help improve the consistency of OMP P&R assessment in Europe and ensure that value assessment, pricing and funding processes reflect the specificities of rare diseases and contribute to both the sustainability of healthcare systems and the sustainability of innovation in this field. These recommendations are the output of the European Working Group for Value Assessment and Funding Processes in Rare Diseases (ORPH-VAL), a collaboration between rare disease experts, patient representatives, academics, health technology assessment (HTA) practitioners, politicians and industry representatives. ORPH-VAL reached its recommendations through careful consideration of existing OMP P&R literature and through a wide consultation with expert stakeholders, including payers, regulators and patients. The principles cover four areas: OMP decision criteria, OMP decision process, OMP sustainable funding systems and European co-ordination. This paper also presents a guide to the core elements of value relevant to OMPs that should be consistently considered in all OMP appraisals. The principles outlined in this paper may be helpful in drawing together an emerging consensus on this topic and identifying areas where consistency in payer approach could be achievable and beneficial. All stakeholders have an obligation to work together to ensure

  1. Conditional transgenesis using Dimerizable Cre (DiCre).

    PubMed

    Jullien, Nicolas; Goddard, Isabelle; Selmi-Ruby, Samia; Fina, Jean-Luc; Cremer, Harold; Herman, Jean-Paul

    2007-12-26

    Cre recombinase is extensively used to engineer the genome of experimental animals. However, its usefulness is still limited by the lack of an efficient temporal control over its activity. We have recently developed a conceptually new approach to regulate Cre recombinase, that we have called Dimerizable Cre or DiCre. It is based on splitting Cre into two inactive moieties and fusing them to FKBP12 (FK506-binding protein) and FRB (binding domain of the FKBP12-rapamycin associated protein), respectively. These latter can be efficiently hetero-dimerized by rapamycin, leading to the reinstatement of Cre activity. We have been able to show, using in vitro approaches, that this ligand-induced dimerization is an efficient way to regulate Cre activity, and presents a low background activity together with a high efficiency of recombination following dimerization. To test the in vivo performance of this system, we have, in the present work, knocked-in DiCre into the Rosa26 locus of mice. To evaluate the performance of the DiCre system, mice have been mated with indicator mice (Z/EG or R26R) and Cre-induced recombination was examined following activation of DiCre by rapamycin during embryonic development or after birth of progenies. No recombination could be observed in the absence of treatment of the animals, indicating a lack of background activity of DiCre in the absence of rapamycin. Postnatal rapamycin treatment (one to five daily injection, 10 mg/kg i.p) induced recombination in a number of different tissues of progenies such as liver, heart, kidney, muscle, etc. On the other hand, recombination was at a very low level following in utero treatment of DiCrexR26R mice. In conclusion, DiCre has indeed the potentiality to be used to establish conditional Cre-deleter mice. An added advantage of this system is that, contrary to other modulatable Cre systems, it offers the possibility of obtaining regulated recombination in a combinatorial manner, i.e. induce recombination at

  2. Riboswitches in eubacteria sense the second messenger c-di-AMP

    PubMed Central

    Nelson, James W.; Sudarsan, Narasimhan; Furukawa, Kazuhiro; Weinberg, Zasha; Wang, Joy X.; Breaker, Ronald R.

    2013-01-01

    Cyclic di-adenosine monophosphate (c-di-AMP) is a recently discovered bacterial second messenger implicated in the control of cell wall metabolism, osmotic stress responses, and sporulation. However, the mechanisms by which c-di-AMP triggers these physiological responses have remained largely unknown. Intriguingly, a candidate riboswitch class called ydaO associates with numerous genes involved in these same processes. Although a representative ydaO motif RNA recently was reported to weakly bind ATP, we report that numerous members of this noncoding RNA class selectively respond to c-di-AMP with sub-nanomolar affinity. Our findings resolve the mystery regarding the primary ligand for this extremely common riboswitch class and expose a major portion of the super-regulon of genes that are controlled by the widespread bacterial second messenger c-di-AMP. PMID:24141192

  3. Cyclic di-adenosine monophosphate (c-di-AMP) is required for osmotic regulation in Staphylococcus aureus but dispensable for viability in anaerobic conditions.

    PubMed

    Zeden, Merve S; Schuster, Christopher F; Bowman, Lisa; Zhong, Qiyun; Williams, Huw D; Gründling, Angelika

    2018-03-02

    Cyclic di-adenosine monophosphate (c-di-AMP) is a recently discovered signaling molecule important for the survival of Firmicutes, a large bacterial group that includes notable pathogens such as Staphylococcus aureus However, the exact role of this molecule has not been identified. dacA , the S. aureus gene encoding the diadenylate cyclase enzyme required for c-di-AMP production, cannot be deleted when bacterial cells are grown in rich medium, indicating that c-di-AMP is required for growth in this condition. Here, we report that an S. aureus dacA mutant can be generated in chemically defined medium. Consistent with previous findings, this mutant had a severe growth defect when cultured in rich medium. Using this growth defect in rich medium, we selected for suppressor strains with improved growth to identify c-di-AMP-requiring pathways. Mutations bypassing the essentiality of dacA were identified in alsT and opuD, encoding a predicted amino acid and osmolyte transporter, the latter of which we show here to be the main glycine betaine-uptake system in S. aureus. Inactivation of these transporters likely prevents the excessive osmolyte and amino acid accumulation in the cell, providing further evidence for a key role of c-di-AMP in osmotic regulation. Suppressor mutations were also obtained in hepS, hemB, ctaA, and qoxB, coding proteins required for respiration. Furthermore, we show that dacA is dispensable for growth in anaerobic conditions. Together, these findings reveal an essential role for the c-di-AMP signaling network in aerobic, but not anaerobic, respiration in S. aureus . © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

  4. A novel missense substitution (Val1483Ile) in the fatty acid synthase gene (FAS) is associated with percentage of body fat and substrate oxidation rates in nondiabetic Pima Indians.

    PubMed

    Kovacs, Peter; Harper, Inge; Hanson, Robert L; Infante, Aniello M; Bogardus, Clifton; Tataranni, P Antonio; Baier, Leslie J

    2004-07-01

    Inhibition of fatty acid synthase (FAS) induces a rapid decline in fat stores in mice, suggesting a role for this enzyme in energy homeostasis. The human FAS gene (FAS) maps to chromosome 17q25, a region previously shown to have suggestive linkage to adiposity in a genome-wide linkage scan for genetic determinants of obesity in Pima Indians. To investigate the potential role of FAS in the pathophysiology of human obesity, the FAS gene was sequenced and 13 single nucleotide polymorphisms (SNPs) were identified. Five representative SNPs were genotyped in 216 full-blooded, nondiabetic Pima Indians for association analyses. A Val1483Ile polymorphism (GTC to ATC; allele frequency of A = 0.10) was associated with percentage of body fat and 24-h substrate oxidation rates measured in a respiratory chamber. Compared with homozygotes for the Val variant, subjects with Ile/x had a lower mean percentage of body fat (30 +/- 1 vs. 33 +/- 1%, P = 0.002; adjusted for age, sex, and family membership) and a lower mean carbohydrate oxidation rate (983 +/- 41 vs. 1,094 +/- 19 kcal/day, P = 0.03), which resulted in a lower mean 24-h respiratory quotient (0.845 +/- 0.01 vs. 0.850 +/- 0.01 kcal/day, P = 0.04; both adjusted for age, sex, family membership, percentage of body fat, and energy balance). Our findings indicate that the Val1483Ile substitution in FAS is protective against obesity in Pima Indians, an effect possibly explained by the role of this gene in the regulation of substrate oxidation.

  5. Severe dystrophy in DiGeorge syndrome

    PubMed Central

    Rózsai, Barnabás; Kiss, Ákos; Csábi, Györgyi; Czakó, Márta; Decsi, Tamás

    2009-01-01

    We present the case history of a 3-year-old girl who was examined because of severe dystrophy. In the background, cow’s milk allergy was found, but her body weight was unchanged after eliminating milk from her diet. Other types of malabsorption were excluded. Based on nasal regurgitation and facial dysmorphisms, the possibility of DiGeorge syndrome was suspected and was confirmed by fluorescence in situ hybridization. The authors suggest a new feature associated with DiGeorge syndrome. PMID:19294771

  6. Allosteric activation of exopolysaccharide synthesis through cyclic di-GMP-stimulated protein–protein interaction

    PubMed Central

    Steiner, Samuel; Lori, Christian; Boehm, Alex; Jenal, Urs

    2013-01-01

    In many bacterial pathogens, the second messenger c-di-GMP stimulates the production of an exopolysaccharide (EPS) matrix to shield bacteria from assaults of the immune system. How c-di-GMP induces EPS biogenesis is largely unknown. Here, we show that c-di-GMP allosterically activates the synthesis of poly-β-1,6-N-acetylglucosamine (poly-GlcNAc), a major extracellular matrix component of Escherichia coli biofilms. C-di-GMP binds directly to both PgaC and PgaD, the two inner membrane components of the poly-GlcNAc synthesis machinery to stimulate their glycosyltransferase activity. We demonstrate that the PgaCD machinery is a novel type c-di-GMP receptor, where ligand binding to two proteins stabilizes their interaction and promotes enzyme activity. This is the first example of a c-di-GMP-mediated process that relies on protein–protein interaction. At low c-di-GMP concentrations, PgaD fails to interact with PgaC and is rapidly degraded. Thus, when cells experience a c-di-GMP trough, PgaD turnover facilitates the irreversible inactivation of the Pga machinery, thereby temporarily uncoupling it from c-di-GMP signalling. These data uncover a mechanism of c-di-GMP-mediated EPS control and provide a frame for c-di-GMP signalling specificity in pathogenic bacteria. PMID:23202856

  7. Glutathione S-Transferase Pi-Ile 105 Val Polymorphism and Susceptibility to T2DM in Population from Turabah Region of Saudi Arabia.

    PubMed

    Mergani, Adil; Mansour, Ahmed Abdelkhalik; Askar, Tamer; Zahran, Rasha Nabeel; Mustafa, Adil Musa; Mohammed, Mukhtar Ahmed; Saleh, Osama Mosailhy

    2016-08-01

    Type 2 diabetes mellitus is characterized by chronic hyperglycemia and associated with oxidative stress resulting from accumulation of free radicals in body's tissues, which especially affects beta cells in pancreas and is an important factor in the development of diabetes and its complications. Glutathione S-transferases (GSTs) are a family of antioxidant enzymes that play important roles in decreasing ROS species and act as a kind of antioxidant defense. In a case-control study, we investigated the role of GSTP1 Ile105Val polymorphism in predisposition to T2DM in patients from Tarabah province, Saudi Arabia. The polymorphism was screened by PCR-RFLP in 90 T2DM patients and 87 healthy controls. The genotypes and alleles frequencies in cases and controls were assessed using Cochran-Armitage trend test and odds ratios (ORs), and 95 % confidence intervals (CIs) in different genetic models of inheritance were calculated. Our data indicate that G allele (Val) is associated with an increased risk for T2DM in this population in any combination (OR 4.101, 95 % CI 1.986-8.469, P = 0.00008). This indicates that individuals who are carriers for the mutant allele, either in homozygous (GG) or heterozygous (AG) state, are at fourfold higher risk for development of T2DM than other subjects in this population.

  8. Formation and growth rates of atmospheric nanoparticles: four years of observations at two West Siberian stations

    NASA Astrophysics Data System (ADS)

    Arshinov, Mikhail Yu.; Belan, Boris D.; Davydov, Denis K.; Kozlov, Artem V.; Arshinova, Victoria

    2015-04-01

    In spite of fact that the first report on the new particle formation (NPF) itself was done by John Aitken more than one century ago (Aitken, 1898), a phenomenon of NPF bursts taken place in the atmosphere was discovered not very long ago. Nevertheless, to date it is known that they may occur quite often in a variety of environments (Kulmala et al., 2004; Hirsikko et al., 2011). Siberia occupies a vast area covered by forests, but the comprehensive data on burst frequency, as well as on formation and growth rates of freshly nucleated particles in this key region are still lacking. Continuous measurements of aerosol size distribution carried out in recent years at two West Siberian stations (TOR-station - 56o28'41"N, 85o03'15"E; Fonovaya Observatory - 56o25'07"N, 84o04'27"E) allowed this gap in data to be filled up. Analysis of the size spectra classified in accordance with criteria proposed by Dal Maso et al. (2005) and Hammed et al. (2007) enabled a conclusion to be drawn that NPF events in Wets Siberia are more often observed during spring (from March to May) and early autumn (secondary frequency peak in September). On average, particle formation bursts took place on 23-28 % of all days. Such a seasonal pattern of the NPF occurrence is very similar to one observed at SMEAR II Station (Hyytiälä, Finland; Dal Maso et al. 2005, 2007). Formation rates (FR) of particles with diameters below 25 nm varied in a wide range from 0.1 to 10 cm-3 s-1. Mean values of FR for the entire period of observations were 1.7 cm-3s-1 (median = 1.13 cm-3 s-1) at TOR-station and 0.88 cm-3 s-1 (median = 0.69 cm-3 s-1) at Fonovaya Observatory. Enhanced values of FR are usually observed from spring to autumn. Mean growth rates of observed at TOR-station and Fonovaya Observatory were 6.5 nm h-1 (median = 5.0 nm h-1) and 8.3 nm h-1 (median = 6.4 nm h-1), respectively. This work was supported by the Branch of Geology, Geophysics and Mining Sciences of RAS (Program No. 5); State contracts of

  9. The Val{sup 192}Leu mutation in the {alpha}-subunit of {beta}-hexosaminidase A is not associated with the B1-variant form of Tay-Sachs disease

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Hou, Y.; Vavougios, G.; Hinek, A.

    1996-07-01

    Substitution mutations adversely affecting the {alpha}-subunit of {beta}-hexosaminidase A ({alpha}{beta}) (EC 3.2.1.52) result in Tay-Sachs disease. The majority affect the initial folding of the pro-{alpha} chain in the endoplasmic reticulum, resulting in its retention and degradation. A much less common occurrence is a mutation that specifically affects an {open_quotes}active-site{close_quotes} residue necessary for substrate binding and/or catalysis. In this case, hexosaminidase A is present in the lysosome, but it lacks all {alpha}-specific activity. This biochemical phenotype is referred to as the {open_quotes}B1-variant form{close_quotes} of Tay-Sachs disease. Kinetic analysis of suspected B1-variant mutations is complex because hexosaminidase A is heterodimeric and bothmore » subunits possess similar active sites. In this report, we examine a previously identified B1-variant mutation, {alpha}-Val{sup 192}Leu. Chinese hamster ovary cells were permanently cotransfected with an {alpha}-cDNA-construct encoding the substitution and a mutant {beta}-cDNA ({beta}-Arg{sup 211}Lys), encoding a {beta}-subunit that is inactive but normal in all other respects. We were surprised to find that the Val{sup 192}Leu substitution produced a pro-{alpha} chain that did not form {alpha}-{beta} dimers and was not transported to the lysosome. Finally, we reexamined the hexosaminidase activity and protein levels in the fibroblasts from the original patient. These data were also not consistent with the biochemical phenotype of the B1 variant of Tay-Sachs disease previously reported to be present. Thus, we conclude that the Val{sup 192}Leu substitution does not specifically affect the {alpha}-active site. 23 refs., 4 figs., 2 tabs.« less

  10. The oxidation of 2,6-di-tert-butyl-4-methylphenol

    USGS Publications Warehouse

    Yohe, G.R.; Dunbar, J.E.; Pedrotti, R.L.; Scheidt, F.M.; Lee, F.G.H.; Smith, E.C.

    1956-01-01

    The products formed in the oxidation of 2,6-di-tert-butyl-4-methylphenol with oxygen and sodium hydroxide at about 100?? are 3,5-di-tert-butyl-4-hydroxybenzaldehyde, trimethylacetic acid, an acidic compound C14H22O3, and probably 2,6-di-tert-butylbenzoquinone (which was actually isolated in the similar oxidation of the above-named benzaldehyde), in addition to compounds previously reported. Some of the properties of C14H22O3 are given, and the oxidation of it to 2,3-di-tert-butylsuccinic anhydride is described, but assignment of structure is reserved pending the completion of more experimental work.

  11. Limb anomalies in DiGeorge and CHARGE syndromes

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Prasad, C.; Quackenbush, E.J.; Whiteman, D.

    1997-01-20

    Limb anomalies are not common in the DiGeorge or CHARGE syndromes. We describe limb anomalies in two children, one with DiGeorge and the other with CHARGE syndrome. Our first patient had a bifid left thumb, Tetralogy of Fallot, absent thymus, right facial palsy, and a reduced number of T-cells. A deletion of 22q11 was detected by fluorescence in situ hybridization (FISH). The second patient, with CHARGE syndrome, had asymmetric findings that included right fifth finger clinodactyly, camptodactyly, tibial hemimelia and dimpling, and severe club-foot. The expanded spectrum of the DiGeorge and CHARGE syndromes includes limb anomalies. 14 refs., 4 figs.

  12. Di-n-butyl Phthalate (DNBP) and Diisobutyl Phthalate (DiBP) Metabolism in a Human Volunteer after Single Oral Doses [Journal Article

    EPA Science Inventory

    An individual (male, 36 years, 87 kg) ingested two separate doses of di-n-butyl phthalate (DnBP) and diisobutyl phthalate (DiBP) at a rate of ~60 µg/kg. Key monoester and oxidized metabolites were identified and quantified in urine continuously collected until 48 hours post dos...

  13. Val-->Ala mutations selectively alter helix-helix packing in the transmembrane segment of phage M13 coat protein.

    PubMed Central

    Deber, C M; Khan, A R; Li, Z; Joensson, C; Glibowicka, M; Wang, J

    1993-01-01

    Val-->Ala mutations within the effective transmembrane segment of a model single-spanning membrane protein, the 50-residue major coat (gene VIII) protein of bacteriophage M13, are shown to have sequence-dependent impacts on stabilization of membrane-embedded helical dimeric structures. Randomized mutagenesis performed on the coat protein hydrophobic segment 21-39 (YIGYAWAMV-VVIVGATIGI) produced a library of viable mutants which included those in which each of the four valine residues was replaced by an alanine residue. Significant variations found among these Val-->Ala mutants in the relative populations and thermal stabilities of monomeric and dimeric helical species observed on SDS/PAGE, and in the range of their alpha-helix-->beta-sheet transition temperatures confirmed that intramembranous valine residues are not simply universal contributors to membrane anchoring. Additional analyses of (i) nonmutatable sites in the mutant protein library, (ii) the properties of the double mutant V29A-V31A obtained by recycling mutant V31A DNA through mutagenesis procedures, and (iii) energy-minimized helical dimer structures of wild-type and mutant V31A transmembrane regions indicated that the transmembrane hydrophobic core helix of the M13 coat protein can be partitioned into alternating pairs of potential protein-interactive residues (V30, V31; G34, A35; G38, I39) and membrane-interactive residues (M28, V29; I32, V33; T36, I37). The overall results consitute an experimental approach to categorizing the distinctive contributions to structure of the residues comprising a protein-protein packing interface vs. those facing lipid and confirm the sequence-dependent capacity of specific residues within the transmembrane domain to modulate protein-protein interactions which underlie regulatory events in membrane proteins. Images Fig. 2 Fig. 4 PMID:8265602

  14. Val-->Ala mutations selectively alter helix-helix packing in the transmembrane segment of phage M13 coat protein.

    PubMed

    Deber, C M; Khan, A R; Li, Z; Joensson, C; Glibowicka, M; Wang, J

    1993-12-15

    Val-->Ala mutations within the effective transmembrane segment of a model single-spanning membrane protein, the 50-residue major coat (gene VIII) protein of bacteriophage M13, are shown to have sequence-dependent impacts on stabilization of membrane-embedded helical dimeric structures. Randomized mutagenesis performed on the coat protein hydrophobic segment 21-39 (YIGYAWAMV-VVIVGATIGI) produced a library of viable mutants which included those in which each of the four valine residues was replaced by an alanine residue. Significant variations found among these Val-->Ala mutants in the relative populations and thermal stabilities of monomeric and dimeric helical species observed on SDS/PAGE, and in the range of their alpha-helix-->beta-sheet transition temperatures confirmed that intramembranous valine residues are not simply universal contributors to membrane anchoring. Additional analyses of (i) nonmutatable sites in the mutant protein library, (ii) the properties of the double mutant V29A-V31A obtained by recycling mutant V31A DNA through mutagenesis procedures, and (iii) energy-minimized helical dimer structures of wild-type and mutant V31A transmembrane regions indicated that the transmembrane hydrophobic core helix of the M13 coat protein can be partitioned into alternating pairs of potential protein-interactive residues (V30, V31; G34, A35; G38, I39) and membrane-interactive residues (M28, V29; I32, V33; T36, I37). The overall results consitute an experimental approach to categorizing the distinctive contributions to structure of the residues comprising a protein-protein packing interface vs. those facing lipid and confirm the sequence-dependent capacity of specific residues within the transmembrane domain to modulate protein-protein interactions which underlie regulatory events in membrane proteins.

  15. Non-Double-Couple Component Analysis of Induced Microearthquakes in the Val D'Agri Basin (Italy)

    NASA Astrophysics Data System (ADS)

    Roselli, P.; Improta, L.; Saccorotti, G.

    2017-12-01

    In recent years it has become accepted that earthquake source can attain significant Non-Double-Couple (NDC) components. Among the driving factors of deviation from normal double-couple (DC) mechanisms there is the opening/closing of fracture networks and the activation of pre-existing faults by pore fluid pressure perturbations. This observation makes the thorough analysis of source mechanism of key importance for the understanding of withdrawal/injection induced seismicity from geothermal and hydrocarbon reservoirs, as well as of water reservoir induced seismicity. In addition to the DC component, seismic moment tensor can be decomposed into isotropic (ISO) and compensated linear vector dipole (CLVD) components. In this study we performed a careful analysis of the seismic moment tensor of induced microseismicity recorded in the Val d'Agri (Southern Apennines, Italy) focusing our attention on the NDC component. The Val d'Agri is a Quaternary extensional basin that hosts the largest onshore European oil field and a water reservoir (Pertusillo Lake impoundment) characterized by severe seasonal level oscillations. Our input data-set includes swarm-type induced micro-seismicity recorded between 2005-2006 by a high-performance network and accurately localized by a reservoir-scale local earthquake tomography. We analyze two different seismicity clusters: (i) a swarm of 69 earthquakes with 0.3 ≤ ML ≤ 1.8 induced by a wastewater disposal well of the oilfield during the initial daily injection tests (10 days); (ii) 526 earthquakes with -0.2 ≤ ML ≤ 2.7 induced by seasonal volume changes of the artificial lake. We perform the seismic moment tensor inversion by using HybridMT code. After a very accurate signal-to-noise selection and hand-made picking of P-pulses, we obtain %DC, %ISO, %CLVD for each event. DC and NDC components are analyzed and compared with the spatio-temporal distribution of seismicity, the local stress field, the injection parameters and the water

  16. 40 CFR 721.2094 - N,N′-di(alkyl heteromonocycle)amino chlorotriazine.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 31 2011-07-01 2011-07-01 false N,Nâ²-di(alkyl heteromonocycle)amino... Specific Chemical Substances § 721.2094 N,N′-di(alkyl heteromonocycle)amino chlorotriazine. (a) Chemical... as N,N′-di(alkyl heteromonocycle)amino chlorotriazine (PMN P-93-1369) is subject to reporting under...

  17. 40 CFR 721.2094 - N,N′-di(alkyl heteromonocycle)amino chlorotriazine.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false N,Nâ²-di(alkyl heteromonocycle)amino... Specific Chemical Substances § 721.2094 N,N′-di(alkyl heteromonocycle)amino chlorotriazine. (a) Chemical... as N,N′-di(alkyl heteromonocycle)amino chlorotriazine (PMN P-93-1369) is subject to reporting under...

  18. The NASA Soil Moisture Active Passive (SMAP) Mission - Algorithm and Cal/Val Activities and Synergies with SMOS and Other L-Band Missions

    NASA Technical Reports Server (NTRS)

    Njoku, Eni; Entekhabi, Dara; O'Neill, Peggy; Jackson, Tom; Kellogg, Kent; Entin, Jared

    2011-01-01

    applicable to soil moisture measurement, such as Aquarius, SAO COM, and ALOS-2. The algorithms and data products for SMAP are being developed in the SMAP Science Data System (SDS) Testbed. The algorithms are developed and evaluated in the SDS Testbed using simulated SMAP observations as well as observational data from current airborne and spaceborne L-band sensors including SMOS. The SMAP project is developing a Calibration and Validation (Cal/Val) Plan that is designed to support algorithm development (pre-launch) and data product validation (post-launch). A key component of the Cal/Val Plan is the identification, characterization, and instrumentation of sites that can be used to calibrate and validate the sensor data (Level I) and derived geophysical products (Level 2 and higher). In this presentation we report on the development status of the SMAP data product algorithms, and the planning and implementation of the SMAP Cal/Val program. Several components of the SMAP algorithm development and Cal/Val plans have commonality with those of SMOS, and for this reason there are shared activities and resources that can be utilized between the missions, including in situ networks, ancillary data sets, and long-term monitoring sites.

  19. Fish based preimplantation genetic diagnosis to prevent DiGeorge syndrome.

    PubMed

    Shefi, Shai; Raviv, Gil; Rienstein, Shlomit; Barkai, Gad; Aviram-Goldring, Ayala; Levron, Jacob

    2009-07-01

    To report the performance of fluorescence in-situ hybridization in the setting of preimplantation genetic diagnosis in order to diagnose embryos affected by DiGeorge syndrome. Case report. Academic referral center. A 32 year-old female affected by DiGeorge syndrome. History and physical examination, karyotyping, amniocentesis, preimplantation genetic diagnosis, fluorescence in-situ hybridization. Avoidance of pregnancy with embryo affected by DiGeorge syndrome. Termination of pregnancy with an affected embryo followed by fluorescence in-situ hybridization based preimplantation genetic diagnosis and delivery of healthy offspring. The combination of preimplantation genetic diagnosis with fluorescence in-situ hybridization is recommended to prevent pregnancies with DiGeorge syndrome affected embryos in properly selected patients.

  20. Occurrence of Cyclic di-GMP-Modulating Output Domains in Cyanobacteria: an Illuminating Perspective

    PubMed Central

    Agostoni, Marco; Koestler, Benjamin J.; Waters, Christopher M.; Williams, Barry L.; Montgomery, Beronda L.

    2013-01-01

    ABSTRACT Microorganisms use a variety of metabolites to respond to external stimuli, including second messengers that amplify primary signals and elicit biochemical changes in a cell. Levels of the second messenger cyclic dimeric GMP (c-di-GMP) are regulated by a variety of environmental stimuli and play a critical role in regulating cellular processes such as biofilm formation and cellular motility. Cyclic di-GMP signaling systems have been largely characterized in pathogenic bacteria; however, proteins that can impact the synthesis or degradation of c-di-GMP are prominent in cyanobacterial species and yet remain largely underexplored. In cyanobacteria, many putative c-di-GMP synthesis or degradation domains are found in genes that also harbor light-responsive signal input domains, suggesting that light is an important signal for altering c-di-GMP homeostasis. Indeed, c-di-GMP-associated domains are often the second most common output domain in photoreceptors—outnumbered only by a histidine kinase output domain. Cyanobacteria differ from other bacteria regarding the number and types of photoreceptor domains associated with c-di-GMP domains. Due to the widespread distribution of c-di-GMP domains in cyanobacteria, we investigated the evolutionary origin of a subset of genes. Phylogenetic analyses showed that c-di-GMP signaling systems were present early in cyanobacteria and c-di-GMP genes were both vertically and horizontally inherited during their evolution. Finally, we compared intracellular levels of c-di-GMP in two cyanobacterial species under different light qualities, confirming that light is an important factor for regulating this second messenger in vivo. PMID:23943760

  1. Sentinel-2: presentation of the CAL/VAL commissioning phase

    NASA Astrophysics Data System (ADS)

    Trémas, Thierry L.; Déchoz, Cécile; Lacherade, Sophie; Nosavan, Julien; Petrucci, Beatrice

    2015-10-01

    In partnership with the European Commission and in the frame of the Copernicus program, the European Space Agency (ESA) has developed the Sentinel-2 optical imaging mission devoted to the operational monitoring of land and coastal areas. The Sentinel-2 mission is based on a satellites constellation deployed in polar sun-synchronous orbits. Sentinel-2 will offer a unique combination of global coverage with a wide field of view (290km), a high revisit (5 days with two satellites), a high resolution (10m, 20m and 60m) and multi-spectral imagery (13 spectral bands in visible and shortwave infra-red domains). The first sentinel 2A has been launched on June 22nd, 2015, from Kourou, French Guyana. In this context, the Centre National d'Etudes Spatiales (CNES) supports ESA to insure the cal/val commissioning phase, for Image Quality aspects. This paper provides first, an overview of the Sentinel-2 system after the launch. Then the articles focuses on the means implemented and activated in CNES to perform the In Orbit Commissioning, the availability and performances of the different devices involved in the ground segment : the GPP in charge of producing the level 1 files, the "radiometric unit" that processes sensitivity parameters, the "geometric unit" in charge of fitting the images on a reference map, MACCS that will produce Level 2A files (computing reflectances at the Bottom of Atmosphere) and the TEC-S2 that will coordinate all the previous software and drive a database in which will be gather the incoming Level 0 files and the processed Level 1 files.

  2. Interdisciplinary investigations in support of project DI-MOD

    NASA Technical Reports Server (NTRS)

    Starks, Scott A.

    1991-01-01

    Interdisciplinary investigations in support of project DI-MOD are discussed. The following subject areas were covered: (1) potential extensions of Project DI-MOD to additional sites in Central America; (2) human migration patterns and their impact on malaria transmission; and (3) an investigation into possible computer-based approaches to the analysis of remotely sensed multispectral data.

  3. The Brain-Derived Neurotrophic Factor Val66Met Polymorphism, Delivery Method, Birth Weight, and Night Sleep Duration as Determinants of Obesity in Vietnamese Children of Primary School Age.

    PubMed

    Tuyet, Le Thi; Nhung, Bui Thi; Dao, Duong Thi Anh; Hanh, Nguyen Thi Hong; Tuyen, Le Danh; Binh, Tran Quang; Thuc, Vu Thi Minh

    2017-10-01

    Obesity is a complex disease that involves both environmental and genetic factors in its pathogenesis. Several studies have identified multiple obesity-associated loci in many populations. However, their contribution to obesity in the Vietnamese population is not fully described, especially in children. The study aimed to investigate the association of obesity with Val66Met polymorphism in brain-derived neurotrophic factor (BDNF) gene, delivery method, birth weight, and lifestyle factors in Vietnamese primary school children. A case-control study was conducted on 559 children aged 6-11 years (278 obese cases and 281 normal controls). The obesity of the children was classified using both criteria of International Obesity Task Force (IOTF, 2000) and World Health Organization (WHO, 2007). Lifestyle factors, birth delivery, and birth weight of the children were self-reported by parents. The BDNF genotype was analyzed using the polymerase chain reaction-restriction fragment length polymorphism method. Association was evaluated by multivariate logistic regression and cross-validated by the Bayesian model averaging method. The most significantly independent factors for obesity were delivery method (cesarean section vs. vaginal delivery, β = 0.56, p = 0.007), birth weight (>3500 to <4000 g vs. 2500-3500 g, β = 0.52, p = 0.035; ≥4000 g vs. 2500-3500 g, β = 1.06, p = 0.015), night sleep duration (<8 h/day vs. ≥8 h/day, β = 0.99, p < 0.0001), and BDNF Val66Met polymorphism (AA and GG vs. AG, β = 0.38, p = 0.039). The study suggested the significant association of delivery method, birth weight, night sleep duration, and BDNF Val66Met polymorphism, with obesity in Vietnamese primary school children.

  4. Di-hadron production at Jefferson Laboratory

    NASA Astrophysics Data System (ADS)

    Anefalos Pereira, Sergio; CLAS Collaboration

    2015-04-01

    Semi-inclusive deep inelastic scattering (SIDIS) has been used extensively in recent years as an important testing ground for QCD. Studies so far have concentrated on better determination of parton distribution functions, distinguishing between the quark and antiquark contributions, and understanding the fragmentation of quarks into hadrons. Pair of hadrons (di-hadron) SIDIS provides information on the nucleon structure and hadronization dynamics that complements single-hadron SIDIS. The study of di-hadrons allow us to study higher twist distribution functions and Dihadron Fragmentation Functions (DiFF). Together with the twist-2 PDFs (f 1, g 1, h 1), the Higher Twist (HT) e and hL functions are very interesting because they offer insights into the physics of the largely unexplored quark-gluon correlations which provide direct and unique insights into the dynamics inside hadrons. The CLAS spectrometer, installed in Hall-B at Jefferson Lab, has collected data using the CEBAF 6 GeV longitudinally polarized electron beam on longitudinally polarized solid NH3 targets. Preliminary results on beam-, target- and double-spin asymmetries will be presented.

  5. Upper limb malformations in DiGeorge syndrome

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Cormier-Daire, V.; Iserin, L.; Sidi, D.

    1995-03-13

    We report on upper limb anomalies in two children with a complete DiGeorge sequence: conotruncal defects, hypocalcemia, thymic aplasia, and facial anomalies. One child had preaxial polydactyly, and the other had club hands with hypoplastic first metacarpal. In both patients, molecular analysis documented a 22q11 deletion. To our knowledge, limb anomalies have rarely been reported in DiGeorge syndrome, and they illustrate the variable clinical expression of chromosome 22q11 deletions. 13 refs., 2 figs.

  6. Effects of nutrient profiling and price changes based on NuVal® scores on food purchasing in an online experimental supermarket.

    PubMed

    Epstein, Leonard H; Finkelstein, Eric A; Katz, David L; Jankowiak, Noelle; Pudlewski, Corrin; Paluch, Rocco A

    2016-08-01

    The goal of the present study was to apply experimental economic methods in an online supermarket to examine the effects of nutrient profiling, and differential pricing based on the nutrient profile, on the overall diet quality, energy and macronutrients of the foods purchased, and diet cost. Participants were provided nutrient profiling scores or price adjustments based on nutrient profile scores while completing a hypothetical grocery shopping task. Prices of foods in the top 20 % of nutrient profiling scores were reduced (subsidized) by 25 % while those in the bottom 20 % of scores were increased (taxed) by 25 %. We evaluated the independent and interactive effects of nutrient profiling or price adjustments on overall diet quality of foods purchased as assessed by the NuVal® score, energy and macronutrients purchased and diet cost in a 2×2 factorial design. A large (>10 000 food items) online experimental supermarket in the USA. Seven hundred and eighty-one women. Providing nutrient profiling scores improved overall diet quality of foods purchased. Price changes were associated with an increase in protein purchased, an increase in energy cost, and reduced carbohydrate and protein costs. Price changes and nutrient profiling combined were associated with no unique benefits beyond price changes or nutrient profiling alone. Providing nutrient profile score increased overall NuVal® score without a reduction in energy purchased. Combining nutrient profiling and price changes did not show an overall benefit to diet quality and may be less useful than nutrient profiling alone to consumers who want to increase overall diet quality of foods purchased.

  7. Di(2-ethylhexyl)adipate

    Integrated Risk Information System (IRIS)

    Di ( 2 - ethylhexyl ) adipate ; CASRN 103 - 23 - 1 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health Hazard Assessments for Non

  8. The Role of Catechol-O-Methyl Transferase Val(108/158)Met Polymorphism (rs4680) in the Effect of Green Tea on Resting Energy Expenditure and Fat Oxidation: A Pilot Study

    PubMed Central

    Hursel, Rick; Janssens, Pilou L. H. R.; Bouwman, Freek G.; Mariman, Edwin C.; Westerterp-Plantenga, Margriet S.

    2014-01-01

    Introduction Green tea(GT) is able to increase energy expenditure(EE) and fat oxidation(FATox) via inhibition of catechol-O-methyl transferase(COMT) by catechins. However, this does not always appear unanimously because of large inter-individual variability. This may be explained by different alleles of the functional COMT Val108/158Met polymorphism that are associated with COMT enzyme activity; high-activity enzyme, COMTH(Val/Val genotype), and low-activity COMTL(Met/Met genotype). Methods Fourteen Caucasian subjects (BMI: 22.2±2.3 kg/m2, age: 21.4±2.2 years) of whom 7 with the COMTH-genotype and 7 with the COMTL-genotype were included in a randomized, cross-over study in which EE and substrate oxidation were measured with a ventilated-hood system after decaffeinated GT and placebo(PL) consumption. Results At baseline, EE, RQ, FATox and carbohydrate oxidation(CHOox) did not differ between groups. Significant interactions were observed between COMT genotypes and treatment for RQ, FATox and CHOox (p<0.05). After GT vs. PL, EE(GT: 62.2 vs. PL: 35.4 kJ.3.5 hrs; p<0.01), RQ(GT: 0.80 vs. PL: 0.83; p<0.01), FATox(GT: 18.3 vs. PL: 15.3 g/d; p<0.001) and CHOox(GT: 18.5 vs. PL: 24.3 g/d; p<0.001) were significantly different for subjects carrying the COMTH genotype, but not for subjects carrying the COMTL genotype (EE, GT: 60.3 vs. PL: 51.7 kJ.3.5 hrs; NS), (RQ, GT: 0.81 vs. PL: 0.81; NS), (FATox, GT: 17.3 vs. PL: 17.0 g/d; NS), (CHOox, GT: 22.1 vs. PL: 21.4 g/d; NS). Conclusion Subjects carrying the COMTH genotype increased energy expenditure and fat-oxidation upon ingestion of green tea catechins vs, placebo, whereas COMTL genotype carriers reacted similarly to GT and PL ingestion. The differences in responses were due to the different responses on PL ingestion, but similar responses to GT ingestion, pointing to different mechanisms. The different alleles of the functional COMT Val108/158Met polymorphism appear to play a role in the inter-individual variability for EE

  9. Molecular studies on di-sodium tartrate molecule

    NASA Astrophysics Data System (ADS)

    Divya, P.; Jayakumar, S.; George, Preethamary; Shubashree, N. S.; Ahmed. M, Anees

    2015-06-01

    Structural characterization is important for the development of new material. The acoustical parameters such as Free Length, Internal Pressure have been measured from ultrasonic velocity, density for di sodium tartrate an optically active molecule at different temperatures using ultrasonic interferometer of frequency (2MHZ). The ultrasonic velocity increases with increase in concentration there is an increase in solute-solvent interaction. The stability constant had been calculated. SEM with EDAX studies has been done for Di-sodium tartrate an optically active molecule.

  10. Backbone and stereospecific (13)C methyl Ile (δ1), Leu and Val side-chain chemical shift assignments of Crc.

    PubMed

    Sharma, Rakhi; Sahu, Bhubanananda; Ray, Malay K; Deshmukh, Mandar V

    2015-04-01

    Carbon catabolite repression (CCR) allows bacteria to selectively assimilate a preferred compound among a mixture of several potential carbon sources, thus boosting growth and economizing the cost of adaptability to variable nutrients in the environment. The RNA-binding catabolite repression control (Crc) protein acts as a global post-transcriptional regulator of CCR in Pseudomonas species. Crc triggers repression by inhibiting the expression of genes involved in transport and catabolism of non-preferred substrates, thus indirectly favoring assimilation of preferred one. We report here a nearly complete backbone and stereospecific (13)C methyl side-chain chemical shift assignments of Ile (δ1), Leu and Val of Crc (~ 31 kDa) from Pseudomonas syringae Lz4W.

  11. Hb S [β6(A3)Glu→Val, GAG>GTG] and β-globin gene cluster haplotype distribution in Mauritania.

    PubMed

    Veten, Fatimetou M; Abdelhamid, Isselmou O; Meiloud, Ghlana M; Ghaber, Sidi M; Salem, Mohamed L; Abbes, Salem; Houmeida, Ahmed O

    2012-01-01

    Of 1050 Mauritanian blood donors screened from the two main racial groups, i.e., the Moors and Black Africans, 60 were found to carry Hb S [β6(A3)Glu→Val, GAG>GTG], giving a global frequency of 5.71%. The prevalence observed in the Black African Mauritanians (10.69%) is almost five times that found in the Moor group (2.25%). Four of the five main β(S) haplotypes were detected in this study: Senegal (77.8%), Benin (8.8%), Arab-Indian (5.5%) and Bantu (4.4%). These data showed that Hb S is a serious public health problem in Mauritania. They also confirm the ethnic heterogeneity of the Mauritanian population.

  12. Di(hydroxyphenyl)- 1,2,4-triazole monomers

    NASA Technical Reports Server (NTRS)

    Connell, John W. (Inventor); Hergenrother, Paul M. (Inventor); Wolf, Peter (Inventor)

    1993-01-01

    The di(hydroxyphenyl)- 1,2,4-triazole monomers were first synthesized by reacting bis (4-hydroxyphenyl) hydrazide with aniline hydrochloride at 250 C in the melt and also by reacting 1,3 or 1,4-bis- (4-hydroxyphenyl)- phenylene- dihydrazide with 2 moles of aniline hydrochloride in the melt. Purification of the di(hydroxyphenyl)- 1,2,4-triazole monomers was accomplished by recrystallization. Poly (1,2,4-triazoles) (PT) were prepared by the aromatic nucleophilic displacement reaction of di(hydroxyphenyl)- 1,2,4-triazole monomers with activated aromatic dihalides or activated aromatic dinitro compounds. The reactions were carried out in polar aprotic solvents such as sulfolane or diphenylsulfone using alkali metal bases such as potassium carbonate at elevated temperatures under nitrogen. This synthetic route has provided high molecular weight PT of new chemical structure, is economically and synthetically more favorable than other routes, and allows for facile chemical structure variation due to the availability of a large variety of activated aromatic dihalides.

  13. DiOlistic Labeling of Neurons in Tissue Slices: A Qualitative and Quantitative Analysis of Methodological Variations.

    PubMed

    Staffend, Nancy A; Meisel, Robert L

    2011-01-01

    Fine neuronal morphology, such as dendritic spines, classically has been studied using the Golgi technique; however, Golgi staining is difficult to combine with other histological techniques. With the increasing popularity of fluorescent imaging, a number of fluorescent dyes have been developed that enable the coupling of multiple fluorescent labels in a single preparation. These fluorescent dyes include the lipophilic dialkylcarbocyanine, DiI; traditionally used for anterograde and retrograde neuronal tracing. More recently, DiI labeling has been used in combination with the Gene Gun for "DiOlistic" labeling of neurons in slice preparations. DiI sequesters itself within and diffuses laterally along the neuronal membrane, however once the cell is permeabilized, the DiI begins to leak from the cell membrane. A DiI derivative, Cell Tracker™ CM-DiI, increases dye stability and labeling half-life in permeabilized tissue, however at much greater expense. Here, the DiI and CM-DiI DiOlistic labeling techniques were tested in side-by-side experiments evaluating dye stability within dendritic architecture in medium spiny neurons of the dorsal stratum in both non-permeabilized and permeabilized tissue sections. In tissue sections that were not permeabilized, spine density in DiI labeled sections was higher than in CM-DiI labeling. In contrast, tissue sections that were permeabilized had higher spine densities in CM-DiI labeled neurons. These results suggest that for experiments involving non-permeabilized tissue, traditional DiI will suffice, however for experiments involving permeabilized tissue CM-DiI provides more consistent data. These experiments provide the first quantitative analyses of the impact of methodological permutations on neuronal labeling with DiI.

  14. URINARY AND AMNIOTIC FLUID LEVELS OF PHTHALATE MONOESTERS IN RATS AFTER THE ORAL ADMINISTRATION OF DI(2-ETHYLHEXYL) PHTHALATE AND DI-N-BUTYL PHTHALATE

    EPA Science Inventory

    Two studies were designed to examine amniotic fluid and maternal urine concentrations of the di(2-ethylhexyl) phthalate (DEHP) metabolite mono(2-ethylhexyl) phthalate (MEHP) and the di-n-butyl phthalate (DBP) metabolite monobutyl phthalate (MBP) after administration of DEHP and D...

  15. c-di-GMP is an Effective Immunomodulator and Vaccine Adjuvant Against Pneumococcal Infection

    PubMed Central

    Ogunniyi, Abiodun D.; Paton, James C.; Kirby, Alun C.; McCullers, Jonathan A.; Cook, Jan; Hyodo, Mamoru; Hayakawa, Yoshihiro; Karaolis, David K. R.

    2009-01-01

    Cyclic diguanylate (c-di-GMP) is a unique bacterial intracellular signaling molecule capable of stimulating enhanced protective innate immunity against various bacterial infections. The effects of intranasal pretreatment with c-di-GMP, or intraperitoneal coadministration of c-di-GMP with the pneumolysin toxoid (PdB) or PspA before pneumococcal challenge, was investigated in mice. We found that c-di-GMP had no significant direct short-term effect on the growth rate of S. pneumoniae either in vitro or in vivo. However, intranasal pretreatment of mice with c-di-GMP resulted in significant decrease in bacterial load in lungs and blood after serotypes 2 and 3 challenge, and significant decrease in lung titers after serotype 4 challenge. Potential cellular mediators of these enhanced protective responses were identified in lungs and draining lymph nodes. Intraperitoneal coadministration of c-di-GMP with PdB or PspA before challenge resulted in significantly higher antigen-specific antibody titers and increased survival of mice, compared to that obtained with alum adjuvant. These findings demonstrate that local or systemic c-di-GMP administration stimulates innate and adaptive immunity against invasive pneumococcal disease. We propose that c-di-GMP can be used as an effective broad spectrum immunomodulator and vaccine adjuvant to prevent infectious diseases. PMID:18640167

  16. Nucleotide, c-di-GMP, c-di-AMP, cGMP, cAMP, (p)ppGpp signaling in bacteria and implications in pathogenesis.

    PubMed

    Kalia, Dimpy; Merey, Gökçe; Nakayama, Shizuka; Zheng, Yue; Zhou, Jie; Luo, Yiling; Guo, Min; Roembke, Benjamin T; Sintim, Herman O

    2013-01-07

    For an organism to survive, it must be able to sense its environment and regulate physiological processes accordingly. Understanding how bacteria integrate signals from various environmental factors and quorum sensing autoinducers to regulate the metabolism of various nucleotide second messengers c-di-GMP, c-di-AMP, cGMP, cAMP and ppGpp, which control several key processes required for adaptation is key for efforts to develop agents to curb bacterial infections. In this review, we provide an update of nucleotide signaling in bacteria and show how these signals intersect or integrate to regulate the bacterial phenotype. The intracellular concentrations of nucleotide second messengers in bacteria are regulated by synthases and phosphodiesterases and a significant number of these metabolism enzymes had been biochemically characterized but it is only in the last few years that the effector proteins and RNA riboswitches, which regulate bacterial physiology upon binding to nucleotides, have been identified and characterized by biochemical and structural methods. C-di-GMP, in particular, has attracted immense interest because it is found in many bacteria and regulate both biofilm formation and virulence factors production. In this review, we discuss how the activities of various c-di-GMP effector proteins and riboswitches are modulated upon c-di-GMP binding. Using V. cholerae, E. coli and B. subtilis as models, we discuss how both environmental factors and quorum sensing autoinducers regulate the metabolism and/or processing of nucleotide second messengers. The chemical syntheses of the various nucleotide second messengers and the use of analogs thereof as antibiofilm or immune modulators are also discussed.

  17. Dietary carotenoid-rich oil supplementation improves exercise-induced anisocytosis in runners: influences of haptoglobin, MnSOD (Val9Ala), CAT (21A/T) and GPX1 (Pro198Leu) gene polymorphisms in dilutional pseudoanemia (sports anemia).

    PubMed

    Miranda-Vilela, Ana L; Akimoto, Arthur K; Alves, Penha C Z; Pereira, Luiz C S; Klautau-Guimarães, Maria N; Grisolia, Cesar K

    2010-04-01

    Physical training induces beneficial adaptation, whereas exhaustive exercises increase reactive oxygen-species generation, thereby causing oxidative damage in plasma and erythrocytes, fractions susceptible to lipid peroxidation. Pequi (Caryocar brasiliense Camb.) is a Brazilian Cerrado fruit containing a carotenoid-rich oil. The aim was to investigate the effects of pequi-oil on exercise-induced oxidative damage in plasma and erythrocytes, after running in the same environment and undergoing weekly training under the same conditions as to type, intensity and length. Evaluations were accomplished after outdoor running on flat land before and after ingestion of 400 mg pequi-oil capsules for 14 days. Blood samples were taken after running and submitted to TBARS assay and erythrogram analysis. Haptoglobin, MnSOD (Val9Ala), CAT (21A/T) and GPX1 (Pro198Leu) gene polymorphisms were priorly investigated, so as to estimate genetic influence The reduction in erythrocytes, hemoglobin and hematocrit after pequi-oil treatment was notably associated with higher plasma expansion. Except for MCHC (mean corpuscular hemoglobin concentration) and RDW (red cell distribution width), the results were influenced by the polymorphisms studied. The best response to pequi-oil was presented by MnSOD Val/Val, CAT AA or AT genotypes and the GPX1 Pro allele. The significantly lower RDW and higher MHCH values were related to pequi-oil protective effects. Pequi oil, besides possessing other nutritional properties, showed protective blood effects.

  18. Cyclic di-GMP-dependent Signaling Pathways in the Pathogenic Firmicute Listeria monocytogenes

    PubMed Central

    Chen, Li-Hong; Köseoğlu, Volkan K.; Güvener, Zehra T.; Myers-Morales, Tanya; Reed, Joseph M.; D'Orazio, Sarah E. F.; Miller, Kurt W.; Gomelsky, Mark

    2014-01-01

    We characterized key components and major targets of the c-di-GMP signaling pathways in the foodborne pathogen Listeria monocytogenes, identified a new c-di-GMP-inducible exopolysaccharide responsible for motility inhibition, cell aggregation, and enhanced tolerance to disinfectants and desiccation, and provided first insights into the role of c-di-GMP signaling in listerial virulence. Genome-wide genetic and biochemical analyses of c-di-GMP signaling pathways revealed that L. monocytogenes has three GGDEF domain proteins, DgcA (Lmo1911), DgcB (Lmo1912) and DgcC (Lmo2174), that possess diguanylate cyclase activity, and three EAL domain proteins, PdeB (Lmo0131), PdeC (Lmo1914) and PdeD (Lmo0111), that possess c-di-GMP phosphodiesterase activity. Deletion of all phosphodiesterase genes (ΔpdeB/C/D) or expression of a heterologous diguanylate cyclase stimulated production of a previously unknown exopolysaccharide. The synthesis of this exopolysaccharide was attributed to the pssA-E (lmo0527-0531) gene cluster. The last gene of the cluster encodes the fourth listerial GGDEF domain protein, PssE, that functions as an I-site c-di-GMP receptor essential for exopolysaccharide synthesis. The c-di-GMP-inducible exopolysaccharide causes cell aggregation in minimal medium and impairs bacterial migration in semi-solid agar, however, it does not promote biofilm formation on abiotic surfaces. The exopolysaccharide also greatly enhances bacterial tolerance to commonly used disinfectants as well as desiccation, which may contribute to survival of L. monocytogenes on contaminated food products and in food-processing facilities. The exopolysaccharide and another, as yet unknown c-di-GMP-dependent target, drastically decrease listerial invasiveness in enterocytes in vitro, and lower pathogen load in the liver and gallbladder of mice infected via an oral route, which suggests that elevated c-di-GMP levels play an overall negative role in listerial virulence. PMID:25101646

  19. Coordinated Cyclic-Di-GMP Repression of Salmonella Motility through YcgR and Cellulose

    PubMed Central

    Zorraquino, Violeta; García, Begoña; Latasa, Cristina; Echeverz, Maite; Toledo-Arana, Alejandro; Valle, Jaione

    2013-01-01

    Cyclic di-GMP (c-di-GMP) is a secondary messenger that controls a variety of cellular processes, including the switch between a biofilm and a planktonic bacterial lifestyle. This nucleotide binds to cellular effectors in order to exert its regulatory functions. In Salmonella, two proteins, BcsA and YcgR, both of them containing a c-di-GMP binding PilZ domain, are the only known c-di-GMP receptors. BcsA, upon c-di-GMP binding, synthesizes cellulose, the main exopolysaccharide of the biofilm matrix. YcgR is dedicated to c-di-GMP-dependent inhibition of motility through its interaction with flagellar motor proteins. However, previous evidences indicate that in the absence of YcgR, there is still an additional element that mediates motility impairment under high c-di-GMP levels. Here we have uncovered that cellulose per se is the factor that further promotes inhibition of bacterial motility once high c-di-GMP contents drive the activation of a sessile lifestyle. Inactivation of different genes of the bcsABZC operon, mutation of the conserved residues in the RxxxR motif of the BcsA PilZ domain, or degradation of the cellulose produced by BcsA rescued the motility defect of ΔycgR strains in which high c-di-GMP levels were reached through the overexpression of diguanylate cyclases. High c-di-GMP levels provoked cellulose accumulation around cells that impeded flagellar rotation, probably by means of steric hindrance, without affecting flagellum gene expression, exportation, or assembly. Our results highlight the relevance of cellulose in Salmonella lifestyle switching as an architectural element that is both essential for biofilm development and required, in collaboration with YcgR, for complete motility inhibition. PMID:23161026

  20. Remote Sensing Global Surface Air Pressure Using Differential Absorption BArometric Radar (DiBAR)

    NASA Technical Reports Server (NTRS)

    Lin, Bing; Harrah, Steven; Lawrence, Wes; Hu, Yongxiang; Min, Qilong

    2016-01-01

    Tropical storms and severe weathers are listed as one of core events that need improved observations and predictions in World Meteorological Organization and NASA Decadal Survey (DS) documents and have major impacts on public safety and national security. This effort tries to observe surface air pressure, especially over open seas, from space using a Differential-absorption BArometric Radar (DiBAR) operating at the 50-55 gigahertz O2 absorption band. Air pressure is among the most important variables that affect atmospheric dynamics, and currently can only be measured by limited in-situ observations over oceans. Analyses show that with the proposed space radar the errors in instantaneous (averaged) pressure estimates can be as low as approximately 4 millibars (approximately 1 millibar under all weather conditions). With these sea level pressure measurements, the forecasts of severe weathers such as hurricanes will be significantly improved. Since the development of the DiBAR concept about a decade ago, NASA Langley DiBAR research team has made substantial progress in advancing the concept. The feasibility assessment clearly shows the potential of sea surface barometry using existing radar technologies. The team has developed a DiBAR system design, fabricated a Prototype-DiBAR (P-DiBAR) for proof-of-concept, conducted lab, ground and airborne P-DiBAR tests. The flight test results are consistent with the instrumentation goals. Observational system simulation experiments for space DiBAR performance based on the existing DiBAR technology and capability show substantial improvements in tropical storm predictions, not only for the hurricane track and position but also for the hurricane intensity. DiBAR measurements will lead us to an unprecedented level of the prediction and knowledge on global extreme weather and climate conditions.

  1. Cyclic di-GMP: the First 25 Years of a Universal Bacterial Second Messenger

    PubMed Central

    Galperin, Michael Y.; Gomelsky, Mark

    2013-01-01

    SUMMARY Twenty-five years have passed since the discovery of cyclic dimeric (3′→5′) GMP (cyclic di-GMP or c-di-GMP). From the relative obscurity of an allosteric activator of a bacterial cellulose synthase, c-di-GMP has emerged as one of the most common and important bacterial second messengers. Cyclic di-GMP has been shown to regulate biofilm formation, motility, virulence, the cell cycle, differentiation, and other processes. Most c-di-GMP-dependent signaling pathways control the ability of bacteria to interact with abiotic surfaces or with other bacterial and eukaryotic cells. Cyclic di-GMP plays key roles in lifestyle changes of many bacteria, including transition from the motile to the sessile state, which aids in the establishment of multicellular biofilm communities, and from the virulent state in acute infections to the less virulent but more resilient state characteristic of chronic infectious diseases. From a practical standpoint, modulating c-di-GMP signaling pathways in bacteria could represent a new way of controlling formation and dispersal of biofilms in medical and industrial settings. Cyclic di-GMP participates in interkingdom signaling. It is recognized by mammalian immune systems as a uniquely bacterial molecule and therefore is considered a promising vaccine adjuvant. The purpose of this review is not to overview the whole body of data in the burgeoning field of c-di-GMP-dependent signaling. Instead, we provide a historic perspective on the development of the field, emphasize common trends, and illustrate them with the best available examples. We also identify unresolved questions and highlight new directions in c-di-GMP research that will give us a deeper understanding of this truly universal bacterial second messenger. PMID:23471616

  2. Integration of the Second Messenger c-di-GMP into the Chemotactic Signaling Pathway

    PubMed Central

    Russell, Matthew H.; Bible, Amber N.; Fang, Xin; Gooding, Jessica R.; Campagna, Shawn R.; Gomelsky, Mark; Alexandre, Gladys

    2013-01-01

    ABSTRACT Elevated intracellular levels of the bacterial second messenger c-di-GMP are known to suppress motility and promote sessility. Bacterial chemotaxis guides motile cells in gradients of attractants and repellents over broad concentration ranges, thus allowing bacteria to quickly adapt to changes in their surroundings. Here, we describe a chemotaxis receptor that enhances, as opposed to suppresses, motility in response to temporary increases in intracellular c-di-GMP. Azospirillum brasilense’s preferred metabolism is adapted to microaerophily, and these motile cells quickly navigate to zones of low oxygen concentration by aerotaxis. We observed that changes in oxygen concentration result in rapid changes in intracellular c-di-GMP levels. The aerotaxis and chemotaxis receptor, Tlp1, binds c-di-GMP via its C-terminal PilZ domain and promotes persistent motility by increasing swimming velocity and decreasing swimming reversal frequency, which helps A. brasilense reach low-oxygen zones. If c-di-GMP levels remain high for extended periods, A. brasilense forms nonmotile clumps or biofilms on abiotic surfaces. These results suggest that association of increased c-di-GMP levels with sessility is correct on a long-term scale, while in the short-term c-di-GMP may actually promote, as opposed to suppress, motility. Our data suggest that sensing c-di-GMP by Tlp1 functions similar to methylation-based adaptation. Numerous chemotaxis receptors contain C-terminal PilZ domains or other sensory domains, suggesting that intracellular c-di-GMP as well as additional stimuli can be used to modulate adaptation of bacterial chemotaxis receptors. PMID:23512960

  3. QM/MM structural and spectroscopic analysis of the di-iron(II) and di-iron(III) ferroxidase site in M ferritin.

    PubMed

    Harris, Travis V; Morokuma, Keiji

    2013-08-05

    Ferritins are cage-like proteins composed of 24 subunits that take up iron(II) and store it as an iron(III) oxide mineral core. A critical step is the ferroxidase reaction, in which oxygen reacts with a di-iron(II) site, proceeding through a peroxo intermediate, to form μ-oxo/hydroxo-bridged di-iron(III) products. The recent crystal structures of copper(II)- and iron(III)-bound frog M ferritin at 2.8 Å resolution [Bertini; et al. J. Am. Chem. Soc. 2012, 134, 6169-6176] provided an opportunity to theoretically investigate the detailed structures of the reactant state and products. In this study, the quantum mechanical/molecular mechanical ONIOM method is used to structurally optimize a series of single-subunit models with various hydration, protonation, and coordination states of the ferroxidase site. Calculated exchange coupling constants (J), Mössbauer parameters, and time-dependent density functional theoretical (TD-DFT) circular dichroism spectra with electronic embedding are compared with the available experimental data. The di-iron(II) model with the most experimentally consistent structural and spectroscopic parameters has 5-coordinate iron centers with Glu23, Glu58, His61, and two waters completing one coordination sphere, and His54, Glu58, Glu103, and Asp140 completing the other. In contrast to a previously proposed structure, Gln137 is not directly coordinated, but it is involved in hydrogen bonding with several iron ligands. For the di-iron(III) products, we find that a μ-oxo-bridged and two doubly bridged (μ-hydroxo and μ-oxo/hydroxo) species are likely coproduced. Although four quadrupole doublets were observed experimentally, we find that two doublets may arise from a single asymmetrically coordinated ferroxidase site. These proposed key structures will help to explore the pathway connecting the di-Fe(II) state to the peroxo intermediate and the branching mechanisms leading to the multiple products.

  4. The influence of high intensity exercise and the Val66Met polymorphism on circulating BDNF and locomotor learning.

    PubMed

    Helm, Erin E; Matt, Kathleen S; Kirschner, Kenneth F; Pohlig, Ryan T; Kohl, Dave; Reisman, Darcy S

    2017-10-01

    Brain-derived neurotrophic factor (BDNF) has been directly related to exercise-enhanced motor performance in the neurologically injured animal model; however literature concerning the role of BDNF in the enhancement of motor learning in the human population is limited. Previous studies in healthy subjects have examined the relationship between intensity of an acute bout of exercise, increases in peripheral BDNF and motor learning of a simple isometric upper extremity task. The current study examined the role of high intensity exercise on upregulation of peripheral BDNF levels as well as the role of high intensity exercise in mediation of motor learning and retention of a novel locomotor task in neurologically intact adults. In addition, the impact of a single nucleotide polymorphism in the BDNF gene (Val66Met) in moderating the relationship between exercise and motor learning was explored. It was hypothesized that participation in high intensity exercise prior to practicing a novel walking task (split-belt treadmill walking) would elicit increases in peripheral BDNF as well as promote an increased rate and magnitude of within session learning and retention on a second day of exposure to the walking task. Within session learning and retention would be moderated by the presence or absence of Val66Met polymorphism. Fifty-four neurologically intact participants participated in two sessions of split-belt treadmill walking. Step length and limb phase were measured to assess learning of spatial and temporal parameters of walking. Serum BDNF was collected prior to and immediately following either high intensity exercise or 5min of quiet rest. The results demonstrated that high intensity exercise provides limited additional benefit to learning of a novel locomotor pattern in neurologically intact adults, despite increases in circulating BDNF. In addition, presence of a single nucleotide polymorphism on the BDNF gene did not moderate the magnitude of serum BDNF increases

  5. Di-Adenosine Tetraphosphate (Ap4A) Metabolism Impacts Biofilm Formation by Pseudomonas fluorescens via Modulation of c-di-GMP-Dependent Pathways▿

    PubMed Central

    Monds, Russell D.; Newell, Peter D.; Wagner, Jeffrey C.; Schwartzman, Julia A.; Lu, Wenyun; Rabinowitz, Joshua D.; O'Toole, George A.

    2010-01-01

    Dinucleoside tetraphosphates are common constituents of the cell and are thought to play diverse biological roles in organisms ranging from bacteria to humans. In this study we characterized two independent mechanisms by which di-adenosine tetraphosphate (Ap4A) metabolism impacts biofilm formation by Pseudomonas fluorescens. Null mutations in apaH, the gene encoding nucleoside tetraphosphate hydrolase, resulted in a marked increase in the cellular level of Ap4A. Concomitant with this increase, Pho regulon activation in low-inorganic-phosphate (Pi) conditions was severely compromised. As a consequence, an apaH mutant was not sensitive to Pho regulon-dependent inhibition of biofilm formation. In addition, we characterized a Pho-independent role for Ap4A metabolism in regulation of biofilm formation. In Pi-replete conditions Ap4A metabolism was found to impact expression and localization of LapA, the major adhesin regulating surface commitment by P. fluorescens. Increases in the level of c-di-GMP in the apaH mutant provided a likely explanation for increased localization of LapA to the outer membrane in response to elevated Ap4A concentrations. Increased levels of c-di-GMP in the apaH mutant were associated with increases in the level of GTP, suggesting that elevated levels of Ap4A may promote de novo purine biosynthesis. In support of this suggestion, supplementation with adenine could partially suppress the biofilm and c-di-GMP phenotypes of the apaH mutant. We hypothesize that changes in the substrate (GTP) concentration mediated by altered flux through nucleotide biosynthetic pathways may be a significant point of regulation for c-di-GMP biosynthesis and regulation of biofilm formation. PMID:20154123

  6. Di-adenosine tetraphosphate (Ap4A) metabolism impacts biofilm formation by Pseudomonas fluorescens via modulation of c-di-GMP-dependent pathways.

    PubMed

    Monds, Russell D; Newell, Peter D; Wagner, Jeffrey C; Schwartzman, Julia A; Lu, Wenyun; Rabinowitz, Joshua D; O'Toole, George A

    2010-06-01

    Dinucleoside tetraphosphates are common constituents of the cell and are thought to play diverse biological roles in organisms ranging from bacteria to humans. In this study we characterized two independent mechanisms by which di-adenosine tetraphosphate (Ap4A) metabolism impacts biofilm formation by Pseudomonas fluorescens. Null mutations in apaH, the gene encoding nucleoside tetraphosphate hydrolase, resulted in a marked increase in the cellular level of Ap4A. Concomitant with this increase, Pho regulon activation in low-inorganic-phosphate (P(i)) conditions was severely compromised. As a consequence, an apaH mutant was not sensitive to Pho regulon-dependent inhibition of biofilm formation. In addition, we characterized a Pho-independent role for Ap4A metabolism in regulation of biofilm formation. In P(i)-replete conditions Ap4A metabolism was found to impact expression and localization of LapA, the major adhesin regulating surface commitment by P. fluorescens. Increases in the level of c-di-GMP in the apaH mutant provided a likely explanation for increased localization of LapA to the outer membrane in response to elevated Ap4A concentrations. Increased levels of c-di-GMP in the apaH mutant were associated with increases in the level of GTP, suggesting that elevated levels of Ap4A may promote de novo purine biosynthesis. In support of this suggestion, supplementation with adenine could partially suppress the biofilm and c-di-GMP phenotypes of the apaH mutant. We hypothesize that changes in the substrate (GTP) concentration mediated by altered flux through nucleotide biosynthetic pathways may be a significant point of regulation for c-di-GMP biosynthesis and regulation of biofilm formation.

  7. A new adjuvant delivery system 'cyclic di-GMP/YSK05 liposome' for cancer immunotherapy.

    PubMed

    Miyabe, Hiroko; Hyodo, Mamoru; Nakamura, Takashi; Sato, Yusuke; Hayakawa, Yoshihiro; Harashima, Hideyoshi

    2014-06-28

    Cyclic dinucleotides are of importance in the field of microbiology and immunology. They function as second messengers and are thought to participate in the signal transduction of cytosolic DNA immune responses. One such dinucleotide, cyclic di-GMP (c-di-GMP), stimulates the immune system. It is thought that c-di-GMP is recognized by ATP dependent RNA helicase (DDX41) in the cytosol, forms a complex with the Stimulator of interferon genes protein (STING), triggers a signal via the tank binding kinase 1-interferon regulatory factor 3 (TBK1-IRF3) pathway and induces the production of type I interferons. Therefore c-di-GMP can be thought of as a new class of adjuvant. However, because c-di-GMP contains two phosphate groups, this prevents its use as an adjuvant because it cannot pass through the cell membrane, even though the target molecule of c-di-GMP is located in the cytoplasm. Our group has been developing a series of liposomal drug delivery systems and recently investigated YSK05 which is a synthetic, pH sensitive lipid that has a high fusogenicity. We utilized this lipid as a carrier to transport c-di-GMP into the cytosol to then use c-di-GMP as an adjuvant. Based on screening experiments, YSK05/POPE/cholesterol=40/25/35 was found to induce IFN-β in Raw264.7 cells. The induction of IFN-β from c-di-GMP liposomes was inhibited by adding BX795, a TBK1 inhibitor, indicating that the production of IFN-β caused the activation of the STING-TBK1 pathway. C-di-GMP liposomes also showed significantly higher levels of expression of CD80, CD86 and MHC class I. The c-di-GMP/YSK05 liposome facilitated antigen specific cytotoxic T cell activity and the inhibition of tumor growth in a mouse model. These findings indicate that c-di-GMP/YSK05 liposomes could be used, not only to transfer c-di-GMP to the cytosol and induce an innate immune system but also as a platform for investigating the mechanism of immune sensing with cyclic dinucleotides in vitro and in vivo. Copyright

  8. High-Performance Liquid Chromatography (HPLC)-Based Detection and Quantitation of Cellular c-di-GMP.

    PubMed

    Petrova, Olga E; Sauer, Karin

    2017-01-01

    The modulation of c-di-GMP levels plays a vital role in the regulation of various processes in a wide array of bacterial species. Thus, investigation of c-di-GMP regulation requires reliable methods for the assessment of c-di-GMP levels and turnover. Reversed-phase high-performance liquid chromatography (RP-HPLC) analysis has become a commonly used approach to accomplish these goals. The following describes the extraction and HPLC-based detection and quantification of c-di-GMP from Pseudomonas aeruginosa samples, a procedure that is amenable to modifications for the analysis of c-di-GMP in other bacterial species.

  9. COMT Val158Met polymorphism is associated with post-traumatic stress disorder and functional outcome following mild traumatic brain injury

    PubMed Central

    Winkler, Ethan A.; Yue, John K.; Ferguson, Adam R.; Temkin, Nancy R.; Stein, Murray B.; Barber, Jason; Yuh, Esther L.; Sharma, Sourabh; Satris, Gabriela G.; McAllister, Thomas W.; Rosand, Jonathan; Sorani, Marco D.; Lingsma, Hester F.; Tarapore, Phiroz E.; Burchard, Esteban G.; Hu, Donglei; Eng, Celeste; Wang, Kevin K.W.; Mukherjee, Pratik; Okonkwo, David O.; Diaz-Arrastia, Ramon; Manley, Geoffrey T.

    2017-01-01

    Mild traumatic brain injury (mTBI) results in variable clinical trajectories and outcomes. The source of variability remains unclear, but may involve genetic variations, such as single nucleotide polymorphisms (SNPs). A SNP in catechol-o-methyltransferase (COMT) is suggested to influence development of post-traumatic stress disorder (PTSD), but its role in TBI remains unclear. Here, we utilize the Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot (TRACK-TBI Pilot) study to investigate whether the COMT Val158Met polymorphism is associated with PTSD and global functional outcome as measured by the PTSD Checklist – Civilian Version and Glasgow Outcome Scale Extended (GOSE), respectively. Results in 93 predominately Caucasian subjects with mTBI show that the COMT Met158 allele is associated with lower incidence of PTSD (univariate odds ratio (OR) of 0.25, 95% CI [0.09–0.69]) and higher GOSE scores (univariate OR 2.87, 95% CI [1.20–6.86]) 6-months following injury. The COMT Val158Met genotype and PTSD association persists after controlling for race (multivariable OR of 0.29, 95% CI [0.10–0.83]) and pre-existing psychiatric disorders/substance abuse (multivariable OR of 0.32, 95% CI [0.11–0.97]). PTSD emerged as a strong predictor of poorer outcome on GOSE (multivariable OR 0.09, 95% CI [0.03–0.26]), which persists after controlling for age, GCS, and race. When accounting for PTSD in multivariable analysis, the association of COMT genotype and GOSE did not remain significant (multivariable OR 1.73, 95% CI [0.69–4.35]). Whether COMT genotype indirectly influences global functional outcome through PTSD remains to be determined and larger studies in more diverse populations are needed to confirm these findings. PMID:27769642

  10. COMT Val158Met polymorphism is associated with post-traumatic stress disorder and functional outcome following mild traumatic brain injury.

    PubMed

    Winkler, Ethan A; Yue, John K; Ferguson, Adam R; Temkin, Nancy R; Stein, Murray B; Barber, Jason; Yuh, Esther L; Sharma, Sourabh; Satris, Gabriela G; McAllister, Thomas W; Rosand, Jonathan; Sorani, Marco D; Lingsma, Hester F; Tarapore, Phiroz E; Burchard, Esteban G; Hu, Donglei; Eng, Celeste; Wang, Kevin K W; Mukherjee, Pratik; Okonkwo, David O; Diaz-Arrastia, Ramon; Manley, Geoffrey T

    2017-01-01

    Mild traumatic brain injury (mTBI) results in variable clinical trajectories and outcomes. The source of variability remains unclear, but may involve genetic variations, such as single nucleotide polymorphisms (SNPs). A SNP in catechol-o-methyltransferase (COMT) is suggested to influence development of post-traumatic stress disorder (PTSD), but its role in TBI remains unclear. Here, we utilize the Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot (TRACK-TBI Pilot) study to investigate whether the COMT Val 158 Met polymorphism is associated with PTSD and global functional outcome as measured by the PTSD Checklist - Civilian Version and Glasgow Outcome Scale Extended (GOSE), respectively. Results in 93 predominately Caucasian subjects with mTBI show that the COMT Met 158 allele is associated with lower incidence of PTSD (univariate odds ratio (OR) of 0.25, 95% CI [0.09-0.69]) and higher GOSE scores (univariate OR 2.87, 95% CI [1.20-6.86]) 6-months following injury. The COMT Val 158 Met genotype and PTSD association persists after controlling for race (multivariable OR of 0.29, 95% CI [0.10-0.83]) and pre-existing psychiatric disorders/substance abuse (multivariable OR of 0.32, 95% CI [0.11-0.97]). PTSD emerged as a strong predictor of poorer outcome on GOSE (multivariable OR 0.09, 95% CI [0.03-0.26]), which persists after controlling for age, GCS, and race. When accounting for PTSD in multivariable analysis, the association of COMT genotype and GOSE did not remain significant (multivariable OR 1.73, 95% CI [0.69-4.35]). Whether COMT genotype indirectly influences global functional outcome through PTSD remains to be determined and larger studies in more diverse populations are needed to confirm these findings. Copyright © 2016 Elsevier Ltd. All rights reserved.

  11. DiI Perfusion as a Method for Vascular Visualization in Ambystoma mexicanum.

    PubMed

    Saltman, Anna J; Barakat, May; Bryant, Donald M; Brodovskaya, Anastasia; Whited, Jessica L

    2017-06-16

    Perfusion techniques have been used for centuries to visualize the circulation of tissues. Axolotl (Ambystoma mexicanum) is a species of salamander that has emerged as an essential model for regeneration studies. Little is known about how revascularization occurs in the context of regeneration in these animals. Here we report a simple method for visualization of the vasculature in axolotl via perfusion of 1,1'-Dioctadecy-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI). DiI is a lipophilic carbocyanine dye that inserts into the plasma membrane of endothelial cells instantaneously. Perfusion is done using a peristaltic pump such that DiI enters the circulation through the aorta. During perfusion, dye flows through the axolotl's blood vessels and incorporates into the lipid bilayer of vascular endothelial cells upon contact. The perfusion procedure takes approximately one hour for an eight-inch axolotl. Immediately after perfusion with DiI, the axolotl can be visualized with a confocal fluorescent microscope. The DiI emits light in the red-orange range when excited with a green fluorescent filter. This DiI perfusion procedure can be used to visualize the vascular structure of axolotls or to demonstrate patterns of revascularization in regenerating tissues.

  12. The "Bestie di Satana" murders.

    PubMed

    Birkhoff, Jutta; Candelli, Chiara; Zeroli, Stefania; La Tegola, Donatella; Carabellese, Felice

    2013-11-01

    In recent years, satanic groups have been responsible for various types and degrees of crimes. We report the case of a number of murders committed in Italy by a group of young people calling themselves the "Bestie di Satana". Forensic psychiatric assessment of the members of a satanic sect charged with the crime revealed that all the young people had a fragile, immature personality, a very low level of education and were socially disadvantaged. The trial of the members of the "Bestie di Satana" sect was concluded with the verdict of deliberate murder, and all the members were given long jail sentences. This report should lead us to explore social and cultural responses to juvenile satanism, statistically shown to be a relatively rare phenomenon but with a high criminal potential. © 2013 American Academy of Forensic Sciences.

  13. The Interacting Effect of the BDNF Val66Met Polymorphism and Stressful Life Events on Adolescent Depression Is Not an Artifact of Gene-Environment Correlation: Evidence from a Longitudinal Twin Study

    ERIC Educational Resources Information Center

    Chen, Jie; Li, Xinying; McGue, Matt

    2013-01-01

    Background: Confounding introduced by gene-environment correlation (rGE) may prevent one from observing a true gene-environment interaction (G × E) effect on psychopathology. The present study investigated the interacting effect of the BDNF Val66Met polymorphism and stressful life events (SLEs) on adolescent depression while controlling for the…

  14. Electronic structure and magnetic properties of the half-metallic ferrimagnet Mn2VAl probed by soft x-ray spectroscopies

    NASA Astrophysics Data System (ADS)

    Nagai, K.; Fujiwara, H.; Aratani, H.; Fujioka, S.; Yomosa, H.; Nakatani, Y.; Kiss, T.; Sekiyama, A.; Kuroda, F.; Fujii, H.; Oguchi, T.; Tanaka, A.; Miyawaki, J.; Harada, Y.; Takeda, Y.; Saitoh, Y.; Suga, S.; Umetsu, R. Y.

    2018-01-01

    We have studied the electronic structure of ferrimagnetic Mn2VAl single crystals by means of soft x-ray absorption spectroscopy (XAS), x-ray absorption magnetic circular dichroism (XMCD), and resonant soft x-ray inelastic scattering (RIXS). We have successfully observed the XMCD signals for all the constituent elements. The Mn L2 ,3 XAS and XMCD spectra are reproduced by spectral simulations based on density-functional theory, indicating the itinerant character of the Mn 3 d states. On the other hand, the V 3 d electrons are rather localized since the ionic model can qualitatively explain the V L2 ,3 XAS and XMCD spectra. This picture is consistent with local d d excitations revealed by the V L3 RIXS.

  15. The cyclic-di-GMP signaling pathway in the Lyme disease spirochete, Borrelia burgdorferi

    PubMed Central

    Novak, Elizabeth A.; Sultan, Syed Z.; Motaleb, Md. A.

    2014-01-01

    In nature, the Lyme disease spirochete Borrelia burgdorferi cycles between the unrelated environments of the Ixodes tick vector and mammalian host. In order to survive transmission between hosts, B. burgdorferi must be able to not only detect changes in its environment, but also rapidly and appropriately respond to these changes. One manner in which this obligate parasite regulates and adapts to its changing environment is through cyclic-di-GMP (c-di-GMP) signaling. c-di-GMP has been shown to be instrumental in orchestrating the adaptation of B. burgdorferi to the tick environment. B. burgdorferi possesses only one set of c-di-GMP-metabolizing genes (one diguanylate cyclase and two distinct phosphodiesterases) and one c-di-GMP-binding PilZ-domain protein designated as PlzA. While studies in the realm of c-di-GMP signaling in B. burgdorferi have exploded in the last few years, there are still many more questions than answers. Elucidation of the importance of c-di-GMP signaling to B. burgdorferi may lead to the identification of mechanisms that are critical for the survival of B. burgdorferi in the tick phase of the enzootic cycle as well as potentially delineate a role (if any) c-di-GMP may play in the transmission and virulence of B. burgdorferi during the enzootic cycle, thereby enabling the development of effective drugs for the prevention and/or treatment of Lyme disease. PMID:24822172

  16. The Role of the Catechol-o-methyltransferase (COMT) Gene Val158Met in Aggressive Behavior, A Review of Genetic Studies

    PubMed Central

    Qayyum, Arqam; Zai, Clement C.; Hirata, Yuko; Tiwari, Arun K.; Cheema, Sheraz; Nowrouzi, Behdin; Beitchman, Joseph H.; Kennedy, James L.

    2015-01-01

    Aggressive behaviors have become a major public health problem, and early-onset aggression can lead to outcomes such as substance abuse, antisocial personality disorder among other issues. In recent years, there has been an increase in research in the molecular and genetic underpinnings of aggressive behavior, and one of the candidate genes codes for the catechol-O-methyltransferase (COMT). COMT is involved in catabolizing catecholamines such as dopamine. These neurotransmitters appear to be involved in regulating mood which can contribute to aggression. The most common gene variant studied in the COMT gene is the Valine (Val) to Methionine (Met) substitution at codon 158. We will be reviewing the current literature on this gene variant in aggressive behavior. PMID:26630958

  17. Structural Analysis of the GGDEF-EAL Domain-Containing c-di-GMP Receptor FimX

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Navarro, M.; De, N; Bae, N

    2009-01-01

    Bacterial pathogenesis involves social behavior including biofilm formation and swarming, processes that are regulated by the bacterially unique second messenger cyclic di-GMP (c-di-GMP). Diguanylate cyclases containing GGDEF and phosphodiesterases containing EAL domains have been identified as the enzymes controlling cellular c-di-GMP levels, yet less is known regarding signal transmission and the targets of c-di-GMP. FimX, a protein from Pseudomonas aeruginosa that governs twitching motility, belongs to a large subfamily containing both GGDEF and EAL domains. Biochemical and structural analyses reveals its function as a high-affinity receptor for c-di-GMP. A model for full-length FimX was generated combining solution scattering data andmore » crystal structures of the degenerate GGDEF and EAL domains. Although FimX forms a dimer in solution via the N-terminal domains, a crystallographic EAL domain dimer suggests modes for the regulation of FimX by c-di-GMP binding. The results provide the structural basis for c-di-GMP sensing via degenerate phosphodiesterases.« less

  18. Telemedicine in Primary Care for Patients With Chronic Conditions: The ValCrònic Quasi-Experimental Study

    PubMed Central

    2017-01-01

    Background The increase of chronic diseases prevalence has created the need to adapt care models and to provide greater home supervision. Objective The objective of our study was to evaluate the impact of telemonitoring on patients with long-term conditions at high risk for rehospitalization or an emergency department visit, in terms of target disease control (diabetes, hypertension, heart failure, and chronic obstructive pulmonary disease). Methods We conducted a quasi-experimental study with a before-and-after analysis to assess the effectiveness of the ValCrònic program after 1 year of primary care monitoring. The study included high-risk patients with 1 or more of the following conditions: diabetes, high blood pressure, heart failure, and chronic obstructive pulmonary disease. We assessed risk according to the Community Assessment Risk Screen. Participants used an electronic device (tablet) to self-report relevant health information, which was then automatically entered into their eHealth record for consultation. Results The total sample size was 521 patients. Compared with the preintervention year, there were significant reductions in weight (82.3 kg before vs 80.1 kg after; P=.001) and in the proportion of people with high systolic (≥140 mmHg; 190, 36.5% vs 170, 32.6%; P=.001) and diastolic (≥90 mmHg; 72, 13.8% vs 40, 7.7%; P=.01) blood pressures, and hemoglobin A1c ≥8% (186, 35.7% vs 104, 20.0%; P=.001). There was also a decrease in the proportion of participants who used emergency services in primary care (68, 13.1% vs 33, 6.3%; P<.001) and in hospital (98, 18.8% vs 67, 12.8%; P<.001). Likewise, fewer participants required hospital admission due to an emergency (105, 20.2% vs 71, 13.6%; P<.001) or disease exacerbation (55, 10.5% vs 42, 8.1%; P<.001). Conclusions The ValCrònic telemonitoring program in patients at high risk for rehospitalization or an emergency department visit appears to be useful to improve target disease control and to reduce the

  19. Fetal alpha 5-reductase Val89Leu mutation is associated with late miscarriage.

    PubMed

    Pérez-Nevot, Beatriz; Royo, Jose-Luis; Cortés, Miriam; Lendínez, Ana M; Reyes-Palomares, Arturo; Jiménez, Ana-José; Ruiz-Galdón, Maximiliano; Reyes-Engel, Armando

    2017-06-01

    The present study was undertaken to determine the role of different polymorphisms affecting the testosterone/oestrogen pathway in miscarriage. Alpha 5-reductase (SRD5A2) rs523349 and rs9282858, cytochrome P450 aromatase (CYP19A1) rs4646, rs10046 and rs2236722 and oestrogen receptor (ESR1) rs9340799, rs2234693 and rs6932902 polymorphisms were selected. The case group consisted of 94 samples of formalin-fixed and paraffin-embedded fetal tissue from a miscarriage at ≤24 weeks. The control group comprised a population of 331 young healthy subjects. Only those single nucleotide polymorphisms (SNPs) fitting the Hardy-Weinberg equilibrium (n = 4) and euploid miscarriage samples (n = 67) were included for downstream analysis. Interestingly, SRD5A2 rs523349 (Val89Leu) was significantly associated with the risk of undergoing miscarriage after Bonferroni correction (odds ratio = 11.245, P < 2.2 × 10 -9 ). Moreover, when Mantel-Cox regression analysis was performed, we observed that the effect was significantly constrained to the second trimester (P = 0.024, log rank). These results are compatible with an imbalance of testosterone/dihydrotestosterone, associated with a higher risk of miscarriage, especially in late pregnancy. Copyright © 2017 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

  20. Backbone and sidechain methyl Ile (δ1), Leu and Val chemical shift assignments of RDE-4 (1-243), an RNA interference initiation protein in C. elegans.

    PubMed

    Chiliveri, Sai Chaitanya; Kumar, Sonu; Marelli, Udaya Kiran; Deshmukh, Mandar V

    2012-10-01

    The RNAi pathway of several organisms requires presence of double stranded RNA binding proteins for functioning of Dicer in gene regulation. In C. elegans, a double stranded RNA binding protein, RDE-4 (385 aa, 44 kDa) recognizes long exogenous dsRNA and initiates the RNAi pathway. We have achieved complete backbone and stereospecific methyl sidechain Ile (δ1), Leu and Val chemical shifts of first 243 amino acids of RDE-4, namely RDE-4ΔC.

  1. Combination of diOlistic labeling with retrograde tract tracing and immunohistochemistry.

    PubMed

    Neely, M Diana; Stanwood, Gregg D; Deutch, Ariel Y

    2009-11-15

    Neuronal staining techniques have played a crucial role in the analysis of neuronal function. Several different staining techniques have been developed to allow morphological analyses of neurons. DiOlistic labeling, in which beads are coated with a lipophilic dye and then ballistically ejected onto brain tissue, has recently been introduced as a useful and simple means to label neurons and glia in their entirety. Although diOlistic labeling provides detailed information on the morphology of neurons, combining this approach with other staining methods is a significant advance. We have developed protocols that result in high quality diOlistically- and retrogradely-labeled or diOlistically-immunohistochemically labeled neurons. These dual-label methods require modification of fixation parameters and the restricted use of detergents for tissue permeabilization, and are readily applicable to a wide range of tracers and antibodies.

  2. Combination of DiOlistic Labeling with Retrograde Tract Tracing and Immunohistochemistry

    PubMed Central

    Diana Neely, M.; Stanwood, Gregg D; Deutch, Ariel Y.

    2009-01-01

    Neuronal staining techniques have played a crucial role in the analysis of neuronal function. Several different staining techniques have been developed to allow morphological analyses of neurons. Recently diOlistic labeling, in which beads are coated with a lipophilic dye and then ballistically ejected onto brain tissue, has been developed as a useful and simple means to label neurons and glia in their entirety. Although diOlistic labeling provides detailed information on the morphology of neurons, combining this approach with other staining methods is a significant advance. We have developed protocols that result in high quality diOlistically- and retrogradely-labeled or diOlistically-immunohistochemically labeled neurons. These dual-label methods require modification of fixation parameters and the use of detergents for tissue permeabilization, and are readily applicable to a wide range of tracers and antibodies. PMID:19712695

  3. Di (2-ethylhexyl)phthalate (DEHP)

    Integrated Risk Information System (IRIS)

    Di ( 2 - ethylhexyl ) phthalate ( DEHP ) ; CASRN 117 - 81 - 7 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health Hazard Assessme

  4. N-Nitroso-di-n-butylamine

    Integrated Risk Information System (IRIS)

    N - Nitroso - di - n - butylamine ; CASRN 924 - 16 - 3 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health Hazard Assessments for

  5. Di-epoxides of the three isomeric dicyclopenta-fused pyrenes: ultimate mutagenic active agents.

    PubMed

    Otero-Lobato, María José; Kaats-Richters, Veronica E M; Havenith, Remco W A; Jenneskens, Leonardus W; Seinen, Willem

    2004-11-14

    To rationalize the high bacterial mutagenic response recently found for the (di-) cyclopenta-fused pyrene congeners, viz. cyclopenta[cd]-(1), dicyclopenta[cd,mn]-(2), dicyclopenta[cd,fg]-(3) and dicyclopenta[cd,jk]pyrene (4), in the presence of a metabolic activation mixture (S9-mix), their (di-)epoxides at the externally fused unsaturated five-membered rings were previously proposed as the ultimate mutagenic active forms. In this study, cyclopenta[cd]pyrene-3,4-epoxide (5) and the novel dicyclopenta[cd,mn]pyrene-1,2,4,5-di-epoxide (6), dicyclopenta[cd,fg]pyrene-5,6,7,8-di-epoxide (7) and dicyclopenta[cd,jk]pyrene-1,2,6,7-di-epoxide (8) were synthesised from 1 to 4, respectively, and subsequently assayed for bacterial mutagenicity in the standard microsomal/histidine reverse mutation assay (Ames-assay with Salmonella typhimurium strain TA98). The di-epoxides 6-8 are present as a mixture of their cis- and trans-stereo-isomers in a close to 1:1 ratio ((1)H NMR spectroscopy and ab initio IGLO/III//RHF/6-31G** calculations). The direct-acting mutagenic activity and the strong cytotoxicity exerted by 5-8 both in the absence or presence of an exogenous metabolic activation system (+/-S9-mix) demonstrate that the ultimate mutagenic active forms are the proposed (di-)epoxides of 1-4.

  6. DR2DI: a powerful computational tool for predicting novel drug-disease associations

    NASA Astrophysics Data System (ADS)

    Lu, Lu; Yu, Hua

    2018-05-01

    Finding the new related candidate diseases for known drugs provides an effective method for fast-speed and low-risk drug development. However, experimental identification of drug-disease associations is expensive and time-consuming. This motivates the need for developing in silico computational methods that can infer true drug-disease pairs with high confidence. In this study, we presented a novel and powerful computational tool, DR2DI, for accurately uncovering the potential associations between drugs and diseases using high-dimensional and heterogeneous omics data as information sources. Based on a unified and extended similarity kernel framework, DR2DI inferred the unknown relationships between drugs and diseases using Regularized Kernel Classifier. Importantly, DR2DI employed a semi-supervised and global learning algorithm which can be applied to uncover the diseases (drugs) associated with known and novel drugs (diseases). In silico global validation experiments showed that DR2DI significantly outperforms recent two approaches for predicting drug-disease associations. Detailed case studies further demonstrated that the therapeutic indications and side effects of drugs predicted by DR2DI could be validated by existing database records and literature, suggesting that DR2DI can be served as a useful bioinformatic tool for identifying the potential drug-disease associations and guiding drug repositioning. Our software and comparison codes are freely available at https://github.com/huayu1111/DR2DI.

  7. DR2DI: a powerful computational tool for predicting novel drug-disease associations

    NASA Astrophysics Data System (ADS)

    Lu, Lu; Yu, Hua

    2018-04-01

    Finding the new related candidate diseases for known drugs provides an effective method for fast-speed and low-risk drug development. However, experimental identification of drug-disease associations is expensive and time-consuming. This motivates the need for developing in silico computational methods that can infer true drug-disease pairs with high confidence. In this study, we presented a novel and powerful computational tool, DR2DI, for accurately uncovering the potential associations between drugs and diseases using high-dimensional and heterogeneous omics data as information sources. Based on a unified and extended similarity kernel framework, DR2DI inferred the unknown relationships between drugs and diseases using Regularized Kernel Classifier. Importantly, DR2DI employed a semi-supervised and global learning algorithm which can be applied to uncover the diseases (drugs) associated with known and novel drugs (diseases). In silico global validation experiments showed that DR2DI significantly outperforms recent two approaches for predicting drug-disease associations. Detailed case studies further demonstrated that the therapeutic indications and side effects of drugs predicted by DR2DI could be validated by existing database records and literature, suggesting that DR2DI can be served as a useful bioinformatic tool for identifying the potential drug-disease associations and guiding drug repositioning. Our software and comparison codes are freely available at https://github.com/huayu1111/DR2DI.

  8. Quantum many-body intermetallics: Phase stability of Fe3Al and small-gap formation in Fe2VAl

    NASA Astrophysics Data System (ADS)

    Kristanovski, Oleg; Richter, Raphael; Krivenko, Igor; Lichtenstein, Alexander I.; Lechermann, Frank

    2017-01-01

    Various intermetallic compounds harbor subtle electronic correlation effects. To elucidate this fact for the Fe-Al system, we perform a realistic many-body investigation based on a combination of density functional theory with dynamical mean-field theory in a charge self-consistent manner. A better characterization and understanding of the phase stability of bcc-based D 03-Fe3Al through an improved description of the correlated charge density and the magnetic energy is achieved. Upon replacement of one Fe sublattice with V, the Heusler compound Fe2VAl is realized, known to display bad-metal behavior and increased specific heat. Here we document a charge-gap opening at low temperatures in line with previous experimental work. The gap structure does not match conventional band theory and is reminiscent of (pseudo)gap characteristics in correlated oxides.

  9. [Construction of thr461 --> Asn461 and Ile462 --> Val462 mutation vector of P4501A1 gene].

    PubMed

    Wei, Qing; Liu, Yi-Min; Wang, Hui; Zhao, Xiao-Lin; Ren, Tie-ling; Xiao, Yong-mei

    2006-09-01

    To construct Thr461 --> Asn461 and Ile462 --> Val462 mutation vector of P4501A1 gene and to provide scientific base for deeply researching on the function of cytochrome 1A1 gene (CYP1A1) and the mechanism of carcinogenesis. According to cDNA sequence of human CYP1A1 gene, universal primers (Pm3/Pm4) and mutant primers (Pt15/Pt16 and Pt17/Pt18) containing restriction enzyme site and mutation site were designed. The first set of primers involving Pm3/Pt16 and Pm3/Pt18 amplified a forward 1.5kb fragment from pGEM-T-CYP1A1 plasmid. The second set of primers involving Pt15/Pm4 and Pt17/Pm4 amplified a reverse 177-bp fragment from 10ng pGEM-T-CYP1A1 plasmid. The third set of primers involving Pm3/Pm4 amplified a 1.5kb fragment from the fomer PCR amplifications. The third PCR products were separated, purified and recovered from 1% agarose gel, then inserted into pMD-T vector. Subsequently the conjunct products were transformed into E. coil strain DH-5alpha., then the single clone was screened out and plasmids were extracted from such clone finally verified by restriction endonuclease analysis and sequencing. A 1.5kb fragment of tricycle PCR amplifications were digested by restriction endonucleases (BamHI and SailI) and sequenced bidirectionally by universal primers(T7p and SP6). The results verified that the cloned fragment including Asn461 and Val462 mutant site had 99.9% homology with the human cDNA of CYP1A1 gene in Genebank. The objective fragment containing Asn461 and Va462 mutant site with cDNA of the CYP1A1 gene has been successfully constructed in this experiment.

  10. Propulsion Diagnostic Method Evaluation Strategy (ProDiMES) User's Guide

    NASA Technical Reports Server (NTRS)

    Simon, Donald L.

    2010-01-01

    This report is a User's Guide for the Propulsion Diagnostic Method Evaluation Strategy (ProDiMES). ProDiMES is a standard benchmarking problem and a set of evaluation metrics to enable the comparison of candidate aircraft engine gas path diagnostic methods. This Matlab (The Mathworks, Inc.) based software tool enables users to independently develop and evaluate diagnostic methods. Additionally, a set of blind test case data is also distributed as part of the software. This will enable the side-by-side comparison of diagnostic approaches developed by multiple users. The Users Guide describes the various components of ProDiMES, and provides instructions for the installation and operation of the tool.

  11. Bacterial Signal Transduction by Cyclic Di-GMP and Other Nucleotide Second Messengers

    PubMed Central

    Gründling, Angelika; Jenal, Urs; Ryan, Robert; Yildiz, Fitnat

    2015-01-01

    The first International Symposium on c-Di-GMP Signaling in Bacteria (22 to 25 March 2015, Harnack-Haus, Berlin, Germany) brought together 131 molecular microbiologists from 17 countries to discuss recent progress in our knowledge of bacterial nucleotide second messenger signaling. While the focus was on signal input, synthesis, degradation, and the striking diversity of the modes of action of the current second messenger paradigm, i.e., cyclic di-GMP (c-di-GMP), “classics” like cAMP and (p)ppGpp were also presented, in novel facets, and more recent “newcomers,” such as c-di-AMP and c-AMP-GMP, made an impressive appearance. A number of clear trends emerged during the 30 talks, on the 71 posters, and in the lively discussions, including (i) c-di-GMP control of the activities of various ATPases and phosphorylation cascades, (ii) extensive cross talk between c-di-GMP and other nucleotide second messenger signaling pathways, and (iii) a stunning number of novel effectors for nucleotide second messengers that surprisingly include some long-known master regulators of developmental pathways. Overall, the conference made it amply clear that second messenger signaling is currently one of the most dynamic fields within molecular microbiology, with major impacts in research fields ranging from human health to microbial ecology. PMID:26055111

  12. [Trattamento della dipendenza da alcol. Alcol e persone senza fissa dimora: punto di vista sociale].

    PubMed

    Alessandrini, Giovanni; Ciccarelli, Rosaria; Battagliese, Gemma; Cereatti, Federica; Gencarelli, Simona; Messina, Marisa Patrizia; Vitali, Mario; De Rosa, Francesca; Ledda, Roberta; Mancini, Serena; Attilia, Maria Luisa

    2018-01-01

    RIASSUNTO. Il fenomeno delle persone senza fissa dimora sta assumendo in questi anni una rilevanza sociale devastante, con una prevalenza stimata in USA e in Europa compresa tra il 5,6% e il 13,9%. Queste persone hanno una scarsa qualità di vita, una limitata o assente vita sociale, sono spesso disoccupate o lavorano solo saltuariamente. Sono a rischio di problemi con la legge, sono spesso affette da dipendenza da droghe, da patologie psichiatriche e internistiche. L'alcol spesso non rappresenta la causa della loro condizione sociale, ma solo la conseguenza, contribuendo in questo modo al loro degrado bio-psico-sociale. Nel 2009 lo US Department of Housing and Urban Development's Homelessness Assistance Programs e nel 2010 la European Consensus Conference on Homelessness hanno segnato un grande passo avanti nella riabilitazione sociale di queste persone, utilizzando il concetto del "case management". In particolare lo Standard Case Management si è dimostrato in grado di migliorare la stabilità abitativa, di ridurre l'uso di droghe e di rimuovere le barriere lavorative. L'Assertive Community Treatment si è dimostrato, invece, in grado di migliorare la stabilità abitativa e ha un rapporto costo/beneficio migliore per i pazienti affetti da doppia diagnosi.

  13. [Donatori di Musica: when oncology meets music].

    PubMed

    Graiff, Claudio

    2014-10-01

    Donatori di Musica is a network of musicians - both physicians and volunteers - that was initially founded in 2009 with the aim to set up and coordinate classical music concerts in hospitals. This activity was initially started and led by the Oncology Departments at Carrara and Bolzano Hospitals, where high profile professional musicians make themselves available for concerts in support of Oncological in/out-patients of that specific Hospital. A live classical music performance is a deeply touching experience - particularly for those who live a critical condition like cancer. Main characteristics of Donatori di Musica concerts are: continuity (concerts are part of a regular and non-stopping music season); quality (concerts are held by well-established professional musicians); philanthropic attitude (musicians do not wear a suit and usually chat with patients; they also select an easy-to-listen program; a convivial event is usually organized after the performance with the aim of overcoming distinctions and barriers between physician and patient); no profit: musicians perform for free - travel expenses and/or overnight staying only can be claimed; concerts have free access for patients, their families and hospital staff.Patients and musicians therefore do get in close contact and music is able to merge each other experiences - with patients being treated by the beauty of music and musicians being treated theirselves by patients daily-life feedback. The Donatori di Musica experience is therefore able to help Medicine to retrieve its very first significance - the medical act regain that human and cultural dimension that seems to be abandoned in the last decades in favour of a mere technicism. This is the spirit and the deep significance of Donatori di Musica - «[…] the hope that Music can become a key support to medical treatments in every Oncology department» (by Gian Andrea Lodovici).

  14. VS2DI: Model use, calibration, and validation

    USGS Publications Warehouse

    Healy, Richard W.; Essaid, Hedeff I.

    2012-01-01

    VS2DI is a software package for simulating water, solute, and heat transport through soils or other porous media under conditions of variable saturation. The package contains a graphical preprocessor for constructing simulations, a postprocessor for displaying simulation results, and numerical models that solve for flow and solute transport (VS2DT) and flow and heat transport (VS2DH). Flow is described by the Richards equation, and solute and heat transport are described by advection-dispersion equations; the finite-difference method is used to solve these equations. Problems can be simulated in one, two, or three (assuming radial symmetry) dimensions. This article provides an overview of calibration techniques that have been used with VS2DI; included is a detailed description of calibration procedures used in simulating the interaction between groundwater and a stream fed by drainage from agricultural fields in central Indiana. Brief descriptions of VS2DI and the various types of problems that have been addressed with the software package are also presented.

  15. New Insights into the Cyclic Di-adenosine Monophosphate (c-di-AMP) Degradation Pathway and the Requirement of the Cyclic Dinucleotide for Acid Stress Resistance in Staphylococcus aureus.

    PubMed

    Bowman, Lisa; Zeden, Merve S; Schuster, Christopher F; Kaever, Volkhard; Gründling, Angelika

    2016-12-30

    Nucleotide signaling networks are key to facilitate alterations in gene expression, protein function, and enzyme activity in response to diverse stimuli. Cyclic di-adenosine monophosphate (c-di-AMP) is an important secondary messenger molecule produced by the human pathogen Staphylococcus aureus and is involved in regulating a number of physiological processes including potassium transport. S. aureus must ensure tight control over its cellular levels as both high levels of the dinucleotide and its absence result in a number of detrimental phenotypes. Here we show that in addition to the membrane-bound Asp-His-His and Asp-His-His-associated (DHH/DHHA1) domain-containing phosphodiesterase (PDE) GdpP, S. aureus produces a second cytoplasmic DHH/DHHA1 PDE Pde2. Although capable of hydrolyzing c-di-AMP, Pde2 preferentially converts linear 5'-phosphadenylyl-adenosine (pApA) to AMP. Using a pde2 mutant strain, pApA was detected for the first time in S. aureus, leading us to speculate that this dinucleotide may have a regulatory role under certain conditions. Moreover, pApA is involved in a feedback inhibition loop that limits GdpP-dependent c-di-AMP hydrolysis. Another protein linked to the regulation of c-di-AMP levels in bacteria is the predicted regulator protein YbbR. Here, it is shown that a ybbR mutant S. aureus strain has increased acid sensitivity that can be bypassed by the acquisition of mutations in a number of genes, including the gene coding for the diadenylate cyclase DacA. We further show that c-di-AMP levels are slightly elevated in the ybbR suppressor strains tested as compared with the wild-type strain. With this, we not only identified a new role for YbbR in acid stress resistance in S. aureus but also provide further insight into how c-di-AMP levels impact acid tolerance in this organism. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  16. New Insights into the Cyclic Di-adenosine Monophosphate (c-di-AMP) Degradation Pathway and the Requirement of the Cyclic Dinucleotide for Acid Stress Resistance in Staphylococcus aureus*

    PubMed Central

    Bowman, Lisa; Zeden, Merve S.; Kaever, Volkhard

    2016-01-01

    Nucleotide signaling networks are key to facilitate alterations in gene expression, protein function, and enzyme activity in response to diverse stimuli. Cyclic di-adenosine monophosphate (c-di-AMP) is an important secondary messenger molecule produced by the human pathogen Staphylococcus aureus and is involved in regulating a number of physiological processes including potassium transport. S. aureus must ensure tight control over its cellular levels as both high levels of the dinucleotide and its absence result in a number of detrimental phenotypes. Here we show that in addition to the membrane-bound Asp-His-His and Asp-His-His-associated (DHH/DHHA1) domain-containing phosphodiesterase (PDE) GdpP, S. aureus produces a second cytoplasmic DHH/DHHA1 PDE Pde2. Although capable of hydrolyzing c-di-AMP, Pde2 preferentially converts linear 5′-phosphadenylyl-adenosine (pApA) to AMP. Using a pde2 mutant strain, pApA was detected for the first time in S. aureus, leading us to speculate that this dinucleotide may have a regulatory role under certain conditions. Moreover, pApA is involved in a feedback inhibition loop that limits GdpP-dependent c-di-AMP hydrolysis. Another protein linked to the regulation of c-di-AMP levels in bacteria is the predicted regulator protein YbbR. Here, it is shown that a ybbR mutant S. aureus strain has increased acid sensitivity that can be bypassed by the acquisition of mutations in a number of genes, including the gene coding for the diadenylate cyclase DacA. We further show that c-di-AMP levels are slightly elevated in the ybbR suppressor strains tested as compared with the wild-type strain. With this, we not only identified a new role for YbbR in acid stress resistance in S. aureus but also provide further insight into how c-di-AMP levels impact acid tolerance in this organism. PMID:27834680

  17. The Val66Met brain-derived neurotrophic factor gene variant interacts with early pain exposure to predict cortisol dysregulation in 7-year-old children born very preterm: Implications for cognition.

    PubMed

    Chau, C M Y; Cepeda, I L; Devlin, A M; Weinberg, J; Grunau, R E

    2017-02-07

    Early stress in the form of repetitive neonatal pain, in infants born very preterm, is associated with long-term dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and with poorer cognitive performance. Brain-derived neurotrophic factor (BDNF) which is important in synaptic plasticity and cognitive functions is reduced by stress. Therefore the BDNF Val66Met variant, which affects secretion of BDNF, may interact with early exposure to pain-related stress in children born very preterm, to differentially affect HPA regulation that in turn may be associated with altered cognitive performance. The aims of this study were to investigate whether in children born very preterm, the BDNF Val66Met variant modulates the association between neonatal pain-related stress and cortisol levels at age 7years, and if cortisol levels were related to cognitive function. Furthermore, we examined whether these relationships were sex-specific. Using a longitudinal cohort design, N=90 children born very preterm (24-32weeks gestation) were followed from birth to age 7years. Cortisol was assayed from hair as an index of cumulative stress and from saliva to measure reactivity to a cognitive challenge. BDNF Val66Met variant was genotyped at 7years using real-time polymerase chain reaction (PCR). Using generalized linear modeling, in boys with the Met allele, greater neonatal pain-related stress (adjusted for clinical risk factors) predicted lower hair cortisol (p=0.006) and higher reactivity salivary cortisol (p=0.002). In both boys and girls with the Met allele, higher salivary cortisol reactivity was correlated with lower IQ (r=-0.60; p=0.001) and poorer visual-motor integration (r=-0.48; p=0.008). Our findings show associations between lower BDNF availability (presence of the Met allele) and vulnerability to neonatal pain/stress in boys, but not girls. This exploratory study suggests new directions for research into possible mechanisms underlying how neonatal pain/stress is

  18. The Val66Met Brain-Derived Neurotrophic Factor Gene Variant Interacts with Early Pain Exposure to Predict Cortisol Dysregulation in 7-year-old Children Born Very Preterm: Implications for Cognition

    PubMed Central

    Chau, Cecil MY; Cepeda, Ivan L; Devlin, Angela M.; Weinberg, Joanne; Grunau, Ruth E

    2015-01-01

    Early stress in the form of repetitive neonatal pain, in infants born very preterm, is associated with long-term dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and with poorer cognitive performance. Brain-derived neurotrophic factor (BDNF) which is important in synaptic plasticity and cognitive functions is reduced by stress. Therefore the BDNF Val66Met variant, which affects secretion of BDNF, may interact with early exposure to pain-related stress in children born very preterm, to differentially affect HPA regulation that in turn may be associated with altered cognitive performance. The aims of this study were to investigate whether in children born very preterm, the BDNF val66met variant modulates the association between neonatal pain-related stress and cortisol levels at age 7 years, and if cortisol levels were related to cognitive function. Furthermore, we examined whether these relationships were sex-specific. Using a longitudinal cohort design, N=90 children born very preterm (24–32 weeks gestation) were followed from birth to age 7 years. Cortisol was assayed from hair as an index of cumulative stress and from saliva to measure reactivity to a cognitive challenge. BDNF Val66Met variant was genotyped at 7 years using real time PCR. Using generalized linear modeling, in boys with the Met allele, greater neonatal pain-related stress (adjusted for clinical risk factors) predicted lower hair cortisol (p=0·006) and higher reactivity salivary cortisol (p=0.002). In both boys and girls with the Met allele, higher salivary cortisol reactivity was correlated with lower IQ (r= −0.60; p=0.001) and poorer visual-motor integration (r= −0.48; p=0.008). Our findings show associations between lower BDNF availability (presence of the Met allele) and vulnerability to neonatal pain/stress in boys, but not girls. This exploratory study suggests new directions for research into possible mechanisms underlying how neonatal pain/stress is related to cognitive

  19. Biomaterial based sulphur di oxide gas sensor

    NASA Astrophysics Data System (ADS)

    Ghosh, P. K.; Sarkar, A.

    2013-06-01

    Biomaterials are getting importance in the present research field of sensors. In this present paper performance of biomaterial based gas sensor made of gum Arabica and garlic extract had been studied. Extract of garlic clove with multiple medicinal and chemical utility can be proved to be useful in sensing Sulphur di Oxide gas. On exposure to Sulphur di Oxide gas the material under observation suffers some temporary structural change, which can be observed in form of amplified potentiometric change through simple electronic circuitry. Exploiting this very property a potentiometric gas sensor of faster response and recovery time can be designed. In this work sensing property of the said material has been studied through DC conductance, FTIR spectrum etc.

  20. Enhanced di-Higgs boson production in the complex Higgs singlet model

    DOE PAGES

    Dawson, S.; Sullivan, M.

    2018-01-31

    Here, we consider the standard model (SM) extended by the addition of a complex scalar singlet, with no assumptions about additional symmetries of the potential. This model provides for resonant di-Higgs production of Higgs particles with different masses. We demonstrate that regions of parameter space allowed by precision electroweak measurements, experimental limits on single Higgs production, and perturbative unitarity allow for large di-Higgs production rates relative to the SM rates. In this scenario, the dominant production mechanism of the new scalar states is di-Higgs production. Results are presented formore » $$\\sqrt{s}$$ = 13, 27 and 100 TeV.« less

  1. Enhanced di-Higgs boson production in the complex Higgs singlet model

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Dawson, S.; Sullivan, M.

    Here, we consider the standard model (SM) extended by the addition of a complex scalar singlet, with no assumptions about additional symmetries of the potential. This model provides for resonant di-Higgs production of Higgs particles with different masses. We demonstrate that regions of parameter space allowed by precision electroweak measurements, experimental limits on single Higgs production, and perturbative unitarity allow for large di-Higgs production rates relative to the SM rates. In this scenario, the dominant production mechanism of the new scalar states is di-Higgs production. Results are presented formore » $$\\sqrt{s}$$ = 13, 27 and 100 TeV.« less

  2. Structural and Biochemical Determinants of Ligand Binding by the c-di-GMP Riboswitch

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Smith, K.; Lipchock, S; Livingston,

    2010-01-01

    The bacterial second messenger c-di-GMP is used in many species to control essential processes that allow the organism to adapt to its environment. The c-di-GMP riboswitch (GEMM) is an important downstream target in this signaling pathway and alters gene expression in response to changing concentrations of c-di-GMP. The riboswitch selectively recognizes its second messenger ligand primarily through contacts with two critical nucleotides. However, these two nucleotides are not the most highly conserved residues within the riboswitch sequence. Instead, nucleotides that stack with c-di-GMP and that form tertiary RNA contacts are the most invariant. Biochemical and structural evidence reveals that themore » most common natural variants are able to make alternative pairing interactions with both guanine bases of the ligand. Additionally, a high-resolution (2.3 {angstrom}) crystal structure of the native complex reveals that a single metal coordinates the c-di-GMP backbone. Evidence is also provided that after transcription of the first nucleotide on the 3{prime}-side of the P1 helix, which is predicted to be the molecular switch, the aptamer is functional for ligand binding. Although large energetic effects occur when several residues in the RNA are altered, mutations at the most conserved positions, rather than at positions that base pair with c-di-GMP, have the most detrimental effects on binding. Many mutants retain sufficient c-di-GMP affinity for the RNA to remain biologically relevant, which suggests that this motif is quite resilient to mutation.« less

  3. A novel tank for DI water reduction in MEMS manufacturing

    NASA Astrophysics Data System (ADS)

    Raccurt, O.; Tardif, F.; Kerber, L.; Lardin, T.; Vareine, T.

    2003-05-01

    A new rinsing process is proposed based on the conclusions obtained by simulations. It consists of a combination of piston flows and internal top-to-bottom recycling steps, which decreases the DI water consumption (and associated cost) for the same rinsing efficiency. This novel concept re-using the DI water in situ in the rinsing tank is demonstrated using an industrial bath recently proposed on the market.

  4. Target Search & Selection for the DI/EPOXI Spacecraft

    NASA Technical Reports Server (NTRS)

    Grebow, Daniel J.; Bhaskaran, Shyam; Chesley, Steven R.

    2012-01-01

    Upon completion of the Hartley 2 flyby in November 2010, the Deep Impact (DI) spacecraft resided in a solar orbit without possibility for gravity assist with any large body. Conservative estimates of remaining fuel were enough to provide only an 18 m/s impulse on the spacecraft. We present our method and results of our systematic scan of potential small body encounters for DI, and our criteria to narrow the selection to the asteroid 2002 GT as the target flyby body. The mission profile has two deterministic maneuvers to achieve the encounter, the first of which executed on November 25, 2011.

  5. Occupational value and relationships to meaning and health: elaborations of the ValMO-model.

    PubMed

    Erlandsson, Lena-Karin; Eklund, Mona; Persson, Dennis

    2011-03-01

    This study investigates the theoretical assumption of the Value and Meaning in Occupations model. The aim was to explore the relationship between occupational value, perceived meaning, and subjective health in a sample of individuals of working age, 50 men and 250 women. Frequency of experienced values in occupations was assessed through the Occupational Value instrument with pre-defined items. Perceived meaning was operationalized and assessed by the Sense of Coherence measure. Subjective health was estimated by two questions from the SF-36 questionnaire. The analyses implied descriptive analyses, correlations, and logistic regression analyses in which sociodemographic variables were included. The findings showed highly significant relationships between occupational value and perceived meaning and when belonging to the high group of occupational value the likelihood was tripled of belonging to the high group of perceived meaning. When married or cohabitating there was double the likelihood of belonging to the high group of perceived meaning. Although perceived meaning was found to be positively associated with subjective health, working full time was the most important factor in explaining subjective health, compared with working less than full time. The results confirm assumptions in the ValMO-model, and the importance of focusing on occupational value in clinical practice is highlighted.

  6. Gender effects of the COMT Val 158 Met genotype on verbal fluency in healthy adults.

    PubMed

    Soeiro-De-Souza, Marcio Gerhardt; Bio, Danielle Soares; David, Denise Petresco; Missio, Giovani; Lima, Bruno; Fernandes, Fernando; Machado-Vieira, Rodrigo; Moreno, Ricardo Alberto

    2013-09-01

    Cognitive performance in healthy individuals is associated with gender differences in specific tests; a female advantage has been demonstrated in language tests, whereas a male advantage has been demonstrated in spatial relation examinations. The prefrontal cortex (PFC) mediates important cognitive domains and is influenced by dopamine (DA) activity. The single nucleotide polymorphism (SNP) rs4680 in the catechol‑O‑methyltransferase (COMT) gene results in an amino acid substitution from valine (Val) to methionine (Met). The Met allele has been demonstrated to decrease COMT enzyme activity and improve PFC cognitive function. COMT regulates DA activity in the PFC and exhibits gender effects. The aim of the present study was to investigate the gender‑specific effects of the COMT genotype on cognition in healthy young adults. Seventy‑six healthy subjects were genotyped for COMT rs4680 and submitted to an extensive range of neuropsychological tests assessing aspects of PFC function. The COMT Met allele influenced the performance of executive function. The results revealed gender effects of the COMT rs4680 Met allele on verbal fluency, with positive effects in males and negative effects in females. This suggested that DA activity affects cognitive function in different ways, according to gender.

  7. Active Site Metal Occupancy and Cyclic Di-GMP Phosphodiesterase Activity of Thermotoga maritima HD-GYP.

    PubMed

    Miner, Kyle D; Kurtz, Donald M

    2016-02-16

    HD-GYPs make up a subclass of the metal-dependent HD phosphohydrolase superfamily and catalyze conversion of cyclic di(3',5')-guanosine monophosphate (c-di-GMP) to 5'-phosphoguanylyl-(3'→5')-guanosine (pGpG) and GMP. Until now, the only reported crystal structure of an HD-GYP that also exhibits c-di-GMP phosphodiesterase activity contains a His/carboxylate ligated triiron active site. However, other structural and phylogenetic correlations indicate that some HD-GYPs contain dimetal active sites. Here we provide evidence that an HD-GYP c-di-GMP phosphodiesterase, TM0186, from Thermotoga maritima can accommodate both di- and trimetal active sites. We show that an as-isolated iron-containing TM0186 has an oxo/carboxylato-bridged diferric site, and that the reduced (diferrous) form is necessary and sufficient to catalyze conversion of c-di-GMP to pGpG, but that conversion of pGpG to GMP requires more than two metals per active site. Similar c-di-GMP phosphodiesterase activities were obtained with divalent iron or manganese. On the basis of activity correlations with several putative metal ligand residue variants and molecular dynamics simulations, we propose that TM0186 can accommodate both di- and trimetal active sites. Our results also suggest that a Glu residue conserved in a subset of HD-GYPs is required for formation of the trimetal site and can also serve as a labile ligand to the dimetal site. Given the anaerobic growth requirement of T. maritima, we suggest that this HD-GYP can function in vivo with either divalent iron or manganese occupying di- and trimetal sites.

  8. Constant DI pacing suppresses cardiac alternans formation in numerical cable models

    NASA Astrophysics Data System (ADS)

    Zlochiver, S.; Johnson, C.; Tolkacheva, E. G.

    2017-09-01

    Cardiac repolarization alternans describe the sequential alternation of the action potential duration (APD) and can develop during rapid pacing. In the ventricles, such alternans may rapidly turn into life risking arrhythmias under conditions of spatial heterogeneity. Thus, suppression of alternans by artificial pacing protocols, or alternans control, has been the subject of numerous theoretical, numerical, and experimental studies. Yet, previous attempts that were inspired by chaos control theories were successful only for a short spatial extent (<2 cm) from the pacing electrode. Previously, we demonstrated in a single cell model that pacing with a constant diastolic interval (DI) can suppress the formation of alternans at high rates of activation. We attributed this effect to the elimination of feedback between the pacing cycle length and the last APD, effectively preventing restitution-dependent alternans from developing. Here, we extend this idea into cable models to study the extent by which constant DI pacing can control alternans during wave propagation conditions. Constant DI pacing was applied to ventricular cable models of up to 5 cm, using human kinetics. Our results show that constant DI pacing significantly shifts the onset of both cardiac alternans and conduction blocks to higher pacing rates in comparison to pacing with constant cycle length. We also demonstrate that constant DI pacing reduces the propensity of spatially discordant alternans, a precursor of wavebreaks. We finally found that the protective effect of constant DI pacing is stronger for increased electrotonic coupling along the fiber in the sense that the onset of alternans is further shifted to higher activation rates. Overall, these results support the potential clinical applicability of such type of pacing in improving protocols of implanted pacemakers, in order to reduce the risk of life-threatening arrhythmias. Future research should be conducted in order to experimentally validate

  9. Liposomes loaded with a STING pathway ligand, cyclic di-GMP, enhance cancer immunotherapy against metastatic melanoma.

    PubMed

    Nakamura, Takashi; Miyabe, Hiroko; Hyodo, Mamoru; Sato, Yusuke; Hayakawa, Yoshihiro; Harashima, Hideyoshi

    2015-10-28

    Malignant melanomas escape immunosurveillance via the loss/down-regulation of MHC-I expression. Natural killer (NK) cells have the potential to function as essential effector cells for eliminating melanomas. Cyclic di-GMP (c-di-GMP), a ligand of the stimulator of interferon genes (STING) signal pathway, can be thought of as a new class of adjuvant against cancer. However, it is yet to be tested, because technologies for delivering c-di-GMP to the cytosol are required. Herein, we report that c-di-GMP efficiently activates NK cells and induces antitumor effects against malignant melanomas when loaded in YSK05 lipid containing liposomes, by assisting in the efficient delivery of c-di-GMP to the cytosol. The intravenous administration of c-di-GMP encapsulated within YSK05-liposomes (c-di-GMP/YSK05-Lip) into mice efficiently induced the production of type I interferon (IFN) as well as the activation of NK cells, resulting in a significant antitumor effect in a lung metastasis mouse model using B16-F10. This antitumor effect was dominated by NK cells. The infiltration of NK cells was observed in the lungs with B16-F10 melanomas. These findings indicate that the c-di-GMP/YSK05-Lip induces MHC-I non-restricted antitumor immunity mediated by NK cells. Consequently, c-di-GMP/YSK05-Lip represents a potentially new adjuvant system for use in immunotherapy against malignant melanomas. Copyright © 2015 Elsevier B.V. All rights reserved.

  10. Repression of mesodermal fate by foxa, a key endoderm regulator of the sea urchin embryo.

    PubMed

    Oliveri, Paola; Walton, Katherine D; Davidson, Eric H; McClay, David R

    2006-11-01

    The foxa gene is an integral component of the endoderm specification subcircuit of the endomesoderm gene regulatory network in the Strongylocentrotus purpuratus embryo. Its transcripts become confined to veg2, then veg1 endodermal territories, and, following gastrulation, throughout the gut. It is also expressed in the stomodeal ectoderm. gatae and otx genes provide input into the pregastrular regulatory system of foxa, and Foxa represses its own transcription, resulting in an oscillatory temporal expression profile. Here, we report three separate essential functions of the foxa gene: it represses mesodermal fate in the veg2 endomesoderm; it is required in postgastrular development for the expression of gut-specific genes; and it is necessary for stomodaeum formation. If its expression is reduced by a morpholino, more endomesoderm cells become pigment and other mesenchymal cell types, less gut is specified, and the larva has no mouth. Experiments in which blastomere transplantation is combined with foxa MASO treatment demonstrate that, in the normal endoderm, a crucial role of Foxa is to repress gcm expression in response to a Notch signal, and hence to repress mesodermal fate. Chimeric recombination experiments in which veg2, veg1 or ectoderm cells contained foxa MASO show which region of foxa expression controls each of the three functions. These experiments show that the foxa gene is a component of three distinct embryonic gene regulatory networks.

  11. Hadfield holds bubble detectors for the RaDI-N Experiment in the Columbus Module

    NASA Image and Video Library

    2013-01-25

    ISS034-E-034506 (25 Jan. 2013) --- Canadian Space Agency astronaut Chris Hadfield, Expedition 34 flight engineer, holds bubble detectors for the RaDI-N experiment in the International Space Station?s Kibo laboratory. RaDI-N measures neutron radiation levels onboard the space station. RaDI-N uses bubble detectors as neutron monitors which have been designed to only detect neutrons and ignore all other radiation.

  12. Dose-Specific Effects of Di-Isononyl Phthalate on the Endocannabinoid System and on Liver of Female Zebrafish.

    PubMed

    Forner-Piquer, Isabel; Maradonna, Francesca; Gioacchini, Giorgia; Santangeli, Stefania; Allarà, Marco; Piscitelli, Fabiana; Habibi, Hamid R; Di Marzo, Vincenzo; Carnevali, Oliana

    2017-10-01

    Phthalates, used as plasticizers, have become a ubiquitous contaminant and have been reported for their potential to induce toxicity in living organisms. Among them, di-isononyl phthalate (DiNP) has been recently used to replace di(2-ethylhexyl) phthalate (DEHP). Nowadays, there is evidence that DiNP is an endocrine-disrupting chemical; however, little is known about its effects on the endocannabinoid system (ECS) and lipid metabolism. Hence, the aim of our study was to investigate the effects of DiNP on the ECS in zebrafish liver and brain and on hepatic lipid storage. To do so, adult female zebrafish were exposed to three concentrations (0.42 µg/L, 4.2 µg/L, and 42 µg/L) of DiNP via water for 3 weeks. Afterwards, we investigated transcript levels for genes involved in the ECS of the brain and liver as well as liver histology and image analysis, Fourier-transform infrared spectroscopy imaging, and measurement of endocannabinoid levels. Our results demonstrate that DiNP upregulates orexigenic signals and causes hepatosteatosis together with deregulation of the peripheral ECS and lipid metabolism. A decrease in the levels of ECS components at the central level was observed after exposure to the highest DiNP concentration tested. These findings suggest that replacement of DEHP with DiNP should be considered with caution because of observed adverse DiNP effects on aquatic organisms. Copyright © 2017 Endocrine Society.

  13. Design type air engine Di Pietro

    NASA Astrophysics Data System (ADS)

    Zwierzchowski, Jaroslaw

    The article presents a pneumatic engine constructed by Angelo Di Pietro. 3D solid models of pneumatic engine components were presented therein. A directional valve is a key element of the control system. The valve functions as a camshaft distributing air to particular engine chambers. The construction designed by Angelo Di Pietro is modern and innovative. A pneumatic engine requires low pressure to start rotary movement. With the use of CFD software, the fields of velocity vectors' distribution were determined. Moreover, the author determined the distribution of pressure values in engine inlet and outlet channels. CFD model studies on engine operation were conducted for chosen stages of operating cycles. On the basis of simulation tests that were conducted, the values of flow rates for the engine were determined. The distribution of pressure values made it possible to evaluate the torque value on the rotating shaft.

  14. TU-FG-209-08: Distribution of the Deviation Index (DI) in Digital Radiography Practices Across the United States

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Jones, A; Shepard, S; Dave, J

    Purpose: To characterize the distribution of the deviation index (DI) in digital radiography practices across the United States. Methods: DI data was obtained from 10 collaborating institutions in the United States between 2012 and 2015. Each institution complied with the requirements of the Institutional Review Board at their site. DI data from radiographs of the body parts chest, abdomen, pelvis and extremity were analyzed for anteroposterior, posteroanterior, lateral, and decubitus views. The DI data was analyzed both in aggregate and stratified by exposure control method, image receptor technology, patient age, and participating site for each body part and view. Themore » number of exposures with DI falling within previously published control limits for DI and descriptive statistics were calculated. Results: DI data from 505,930 radiographic exposures was analyzed. The number of exposures with DI falling within published control limits for DI varied from 10 to 20% for adult patients and 10 to 23% for pediatric patients for different body parts and views. Mean DI values averaged over other parameters for radiographs of the abdomen, chest, pelvis, and extremities ranged from 0.3 to 1.0, −0.6 to 0.5, 0.8, and −0.9 to 0.5 for the different adult views and ranged from −1.6 to −0.1, −0.3 to 0.5, −0.1, −0.2 to 1.4 for the different pediatric views, respectively (DI data was solicited only for anteroposterior view of pelvis). Standard deviation values of DI from individual sites ranged from 1.3 to 3.6 and 1.3 to 3.0 for the different adult and pediatric views, respectively. Also of interest was that target exposure indicators varied by up to a factor of 6 between sites for certain body parts and views. Conclusion: Previously published DI control limits do not reflect the state of clinical practice in digital radiography. Mean DI and target exposure indicators are targets for quality improvement efforts in radiography.« less

  15. Monitoring Changes of Tropical Extreme Rainfall Events Using Differential Absorption Barometric Radar (DiBAR)

    NASA Technical Reports Server (NTRS)

    Lin, Bing; Harrah, Steven; Lawrence, R. Wes; Hu, Yongxiang; Min, Qilong

    2015-01-01

    This work studies the potential of monitoring changes in tropical extreme rainfall events such as tropical storms from space using a Differential-absorption BArometric Radar (DiBAR) operating at 50-55 gigahertz O2 absorption band to remotely measure sea surface air pressure. Air pressure is among the most important variables that affect atmospheric dynamics, and currently can only be measured by limited in-situ observations over oceans. Analyses show that with the proposed radar the errors in instantaneous (averaged) pressure estimates can be as low as approximately 5 millibars (approximately 1 millibar) under all weather conditions. With these sea level pressure measurements, the forecasts, analyses and understanding of these extreme events in both short and long time scales can be improved. Severe weathers, especially hurricanes, are listed as one of core areas that need improved observations and predictions in WCRP (World Climate Research Program) and NASA Decadal Survey (DS) and have major impacts on public safety and national security through disaster mitigation. Since the development of the DiBAR concept about a decade ago, our team has made substantial progress in advancing the concept. Our feasibility assessment clearly shows the potential of sea surface barometry using existing radar technologies. We have developed a DiBAR system design, fabricated a Prototype-DiBAR (P-DiBAR) for proof-of-concept, conducted lab, ground and airborne P-DiBAR tests. The flight test results are consistent with our instrumentation goals. Observational system simulation experiments for space DiBAR performance show substantial improvements in tropical storm predictions, not only for the hurricane track and position but also for the hurricane intensity. DiBAR measurements will lead us to an unprecedented level of the prediction and knowledge on tropical extreme rainfall weather and climate conditions.

  16. 4-(Di­methyl­amino)­pyridinium trichlorido[4-(di­methyl­amino)­pyridine-κN]cobaltate(II)

    PubMed Central

    Guenifa, Fatiha; Hadjadj, Nasreddine; Zeghouan, Ouahida; Bendjeddou, Lamia; Merazig, Hocine

    2013-01-01

    In the anion of the title compound, (C7H11N2)[CoCl3(C7H10N2)], the CoII ion is coordinated by one N atom from a 4-(di­methyl­amino)­pyridine (DMAP) ligand and three Cl atoms, forming a CoNCl3 polyhedron with a distorted tetra­hedral geometry. In the crystal, cations and anions are linked via weak N—H⋯Cl and C—H⋯Cl hydrogen bonds. Double layers of complex anions stack along the b- axis direction, which alternate with double layers of 4-(di­methyl­amino)-pyridinium cations. PMID:24046560

  17. Nuclease-resistant c-di-AMP derivatives that differentially recognize RNA and protein receptors

    PubMed Central

    Meehan, Robert E.; Torgerson, Chad D.; Gaffney, Barbara L.; Jones, Roger A.; Strobel, Scott A.

    2016-01-01

    The ability of bacteria to sense environmental cues and adapt is essential for their survival. The use of second-messenger signaling molecules to translate these cues into a physiological response is a common mechanism employed by bacteria. The second messenger 3’-5’-cyclic diadenosine monophosphate (c-di-AMP) has been linked to a diverse set of biological processes involved in maintaining cell viability and homeostasis, as well as pathogenicity. A complex network of both protein and RNA receptors inside the cell activate specific pathways and mediate phenotypic outputs in response to c-di-AMP. Structural analysis of these RNA and protein receptors has revealed the different recognition elements employed by these effectors to bind the same small molecule. Herein, using a series of c-di-AMP analogs, we probed the interactions made with a riboswitch and a phosphodiesterase protein to identify the features important for c-di-AMP binding and recognition. We found that the ydaO riboswitch binds c-di-AMP in two discrete sites with near identical affinity and a Hill coefficient of 1.6. The ydaO riboswitch distinguishes between c-di-AMP and structurally related second messengers by discriminating against an amine at the C2 position, more than a carbonyl at the C6 position. We also identified phosphate-modified analogs that bind both the ydaO RNA and GdpP protein with high affinity, while symmetrically-modified ribose analogs exhibited a substantial decrease in ydaO affinity, but retained high affinity for GdpP. These ligand modifications resulted in increased resistance to enzyme-catalyzed hydrolysis by the GdpP enzyme. Together, these data suggest that these c-di-AMP analogs could be useful as chemical tools to specifically target subsections of the second-messenger signaling pathways. PMID:26789423

  18. 40 CFR 721.10483 - Siloxanes and Silicones, di-Me, Me vinyl, hydroxy-terminated, reaction products with...

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Siloxanes and Silicones, di-Me, Me... Substances § 721.10483 Siloxanes and Silicones, di-Me, Me vinyl, hydroxy-terminated, reaction products with...) The chemical substance identified as Siloxanes and Silicones, di-Me, Me vinyl, hydroxy-terminated...

  19. 40 CFR 721.10483 - Siloxanes and Silicones, di-Me, Me vinyl, hydroxy-terminated, reaction products with...

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Siloxanes and Silicones, di-Me, Me... Substances § 721.10483 Siloxanes and Silicones, di-Me, Me vinyl, hydroxy-terminated, reaction products with...) The chemical substance identified as Siloxanes and Silicones, di-Me, Me vinyl, hydroxy-terminated...

  20. Studying distributed cognition of simulation-based team training with DiCoT.

    PubMed

    Rybing, Jonas; Nilsson, Heléne; Jonson, Carl-Oscar; Bang, Magnus

    2016-03-01

    Health care organizations employ simulation-based team training (SBTT) to improve skill, communication and coordination in a broad range of critical care contexts. Quantitative approaches, such as team performance measurements, are predominantly used to measure SBTTs effectiveness. However, a practical evaluation method that examines how this approach supports cognition and teamwork is missing. We have applied Distributed Cognition for Teamwork (DiCoT), a method for analysing cognition and collaboration aspects of work settings, with the purpose of assessing the methodology's usefulness for evaluating SBTTs. In a case study, we observed and analysed four Emergo Train System® simulation exercises where medical professionals trained emergency response routines. The study suggests that DiCoT is an applicable and learnable tool for determining key distributed cognition attributes of SBTTs that are of importance for the simulation validity of training environments. Moreover, we discuss and exemplify how DiCoT supports design of SBTTs with a focus on transfer and validity characteristics. Practitioner Summary: In this study, we have evaluated a method to assess simulation-based team training environments from a cognitive ergonomics perspective. Using a case study, we analysed Distributed Cognition for Teamwork (DiCoT) by applying it to the Emergo Train System®. We conclude that DiCoT is useful for SBTT evaluation and simulator (re)design.

  1. Enhancement of the thermostability of Hydrogenobacter thermophilus cytochrome c(552) through introduction of an extra methylene group into its hydrophobic protein interior.

    PubMed

    Tai, Hulin; Irie, Kiyofumi; Mikami, Shin-ichi; Yamamoto, Yasuhiko

    2011-04-19

    Careful scrutiny of the protein interior of Hydrogenobacter thermophilus cytochrome c(552) (HT) on the basis of its X-ray structure [Travaglini-Allocatelli, C., Gianni, S., Dubey, V. K., Borgia, A., Di Matteo, A., Bonivento, D., Cutruzzola, F., Bren, K. L., and Brunori, M. (2005) J. Biol. Chem. 280, 25729-25734] indicated that a void space, which is large enough to accommodate a methyl group, exists in the hydrophobic protein interior near the heme. We tried to reduce the void space through the replacement of a Val by Ile or Leu (Val/Ile or Val/Leu mutation), and then the structural and functional consequences of these two mutations were characterized in order to elucidate the relationship between the nature of the packing of hydrophobic residues and the functional properties of the protein. The study demonstrated striking differences in the structural and functional consequences between the two mutations. The Val/Ile mutation was found to cause further enhancement of the thermostability of the oxidized HT, as reflected in the increase of the denaturation temperature (T(m)) value by ∼ 3 deg, whereas the thermostability of the reduced form was essentially unaffected. As a result, the redox potential (E(m)) of the Val/Ile mutant exhibited a negative shift of ∼ 50 mV relative to that of the wild-type protein in an enthalpic manner, this being consistent with our previous finding that a protein with higher stability in its oxidized form exhibits a lower E(m) value [Terui, N., Tachiiri, N., Matsuo, H., Hasegawa, J., Uchiyama, S., Kobayashi, Y., Igarashi, Y., Sambongi, Y., and Yamamoto, Y. (2003) J. Am. Chem. Soc. 125, 13650-13651]. In contrast, the Val/Leu mutation led to a decrease in thermostability of both the redox forms of the protein, as reflected in the decreases of the T(m) values of the oxidized and reduced proteins by ∼ 3 and ∼ 5 deg, respectively, and the E(m) value of the Val/Leu mutant happened to be similar to that of the Val/Ile one. The E

  2. The Bacterial Second Messenger Cyclic di-GMP Regulates Brucella Pathogenesis and Leads to Altered Host Immune Response.

    PubMed

    Khan, Mike; Harms, Jerome S; Marim, Fernanda M; Armon, Leah; Hall, Cherisse L; Liu, Yi-Ping; Banai, Menachem; Oliveira, Sergio C; Splitter, Gary A; Smith, Judith A

    2016-12-01

    Brucella species are facultative intracellular bacteria that cause brucellosis, a chronic debilitating disease significantly impacting global health and prosperity. Much remains to be learned about how Brucella spp. succeed in sabotaging immune host cells and how Brucella spp. respond to environmental challenges. Multiple types of bacteria employ the prokaryotic second messenger cyclic di-GMP (c-di-GMP) to coordinate responses to shifting environments. To determine the role of c-di-GMP in Brucella physiology and in shaping host-Brucella interactions, we utilized c-di-GMP regulatory enzyme deletion mutants. Our results show that a ΔbpdA phosphodiesterase mutant producing excess c-di-GMP displays marked attenuation in vitro and in vivo during later infections. Although c-di-GMP is known to stimulate the innate sensor STING, surprisingly, the ΔbpdA mutant induced a weaker host immune response than did wild-type Brucella or the low-c-di-GMP guanylate cyclase ΔcgsB mutant. Proteomics analysis revealed that c-di-GMP regulates several processes critical for virulence, including cell wall and biofilm formation, nutrient acquisition, and the type IV secretion system. Finally, ΔbpdA mutants exhibited altered morphology and were hypersensitive to nutrient-limiting conditions. In summary, our results indicate a vital role for c-di-GMP in allowing Brucella to successfully navigate stressful and shifting environments to establish intracellular infection. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  3. Molecular basis for the recognition of cyclic-di-AMP by PstA, a PII-like signal transduction protein.

    PubMed

    Choi, Philip H; Sureka, Kamakshi; Woodward, Joshua J; Tong, Liang

    2015-06-01

    Cyclic-di-AMP (c-di-AMP) is a broadly conserved bacterial second messenger that is of importance in bacterial physiology. The molecular receptors mediating the cellular responses to the c-di-AMP signal are just beginning to be discovered. PstA is a previously uncharacterized PII -like protein which has been identified as a c-di-AMP receptor. PstA is widely distributed and conserved among Gram-positive bacteria in the phylum Firmicutes. Here, we report the biochemical, structural, and functional characterization of PstA from Listeria monocytogenes. We have determined the crystal structures of PstA in the c-di-AMP-bound and apo forms at 1.6 and 2.9 Å resolution, respectively, which provide the molecular basis for its specific recognition of c-di-AMP. PstA forms a homotrimer structure that has overall similarity to the PII protein family which binds ATP. However, PstA is markedly different from PII proteins in the loop regions, and these structural differences mediate the specific recognition of their respective nucleotide ligand. The residues composing the c-di-AMP binding pocket are conserved, suggesting that c-di-AMP recognition by PstA is of functional importance. Disruption of pstA in L. monocytogenes affected c-di-AMP-mediated alterations in bacterial growth and lysis. Overall, we have defined the PstA family as a conserved and specific c-di-AMP receptor in bacteria. © 2015 The Authors. MicrobiologyOpen published by John Wiley & Sons Ltd.

  4. DiRE: identifying distant regulatory elements of co-expressed genes

    PubMed Central

    Gotea, Valer; Ovcharenko, Ivan

    2008-01-01

    Regulation of gene expression in eukaryotic genomes is established through a complex cooperative activity of proximal promoters and distant regulatory elements (REs) such as enhancers, repressors and silencers. We have developed a web server named DiRE, based on the Enhancer Identification (EI) method, for predicting distant regulatory elements in higher eukaryotic genomes, namely for determining their chromosomal location and functional characteristics. The server uses gene co-expression data, comparative genomics and profiles of transcription factor binding sites (TFBSs) to determine TFBS-association signatures that can be used for discriminating specific regulatory functions. DiRE's unique feature is its ability to detect REs outside of proximal promoter regions, as it takes advantage of the full gene locus to conduct the search. DiRE can predict common REs for any set of input genes for which the user has prior knowledge of co-expression, co-function or other biologically meaningful grouping. The server predicts function-specific REs consisting of clusters of specifically-associated TFBSs and it also scores the association of individual transcription factors (TFs) with the biological function shared by the group of input genes. Its integration with the Array2BIO server allows users to start their analysis with raw microarray expression data. The DiRE web server is freely available at http://dire.dcode.org. PMID:18487623

  5. c-di-AMP: An Essential Molecule in the Signaling Pathways that Regulate the Viability and Virulence of Gram-Positive Bacteria

    PubMed Central

    Fahmi, Tazin; Port, Gary C.

    2017-01-01

    Signal transduction pathways enable organisms to monitor their external environment and adjust gene regulation to appropriately modify their cellular processes. Second messenger nucleotides including cyclic adenosine monophosphate (c-AMP), cyclic guanosine monophosphate (c-GMP), cyclic di-guanosine monophosphate (c-di-GMP), and cyclic di-adenosine monophosphate (c-di-AMP) play key roles in many signal transduction pathways used by prokaryotes and/or eukaryotes. Among the various second messenger nucleotides molecules, c-di-AMP was discovered recently and has since been shown to be involved in cell growth, survival, and regulation of virulence, primarily within Gram-positive bacteria. The cellular level of c-di-AMP is maintained by a family of c-di-AMP synthesizing enzymes, diadenylate cyclases (DACs), and degradation enzymes, phosphodiesterases (PDEs). Genetic manipulation of DACs and PDEs have demonstrated that alteration of c-di-AMP levels impacts both growth and virulence of microorganisms. Unlike other second messenger molecules, c-di-AMP is essential for growth in several bacterial species as many basic cellular functions are regulated by c-di-AMP including cell wall maintenance, potassium ion homeostasis, DNA damage repair, etc. c-di-AMP follows a typical second messenger signaling pathway, beginning with binding to receptor molecules to subsequent regulation of downstream cellular processes. While c-di-AMP binds to specific proteins that regulate pathways in bacterial cells, c-di-AMP also binds to regulatory RNA molecules that control potassium ion channel expression in Bacillus subtilis. c-di-AMP signaling also occurs in eukaryotes, as bacterially produced c-di-AMP stimulates host immune responses during infection through binding of innate immune surveillance proteins. Due to its existence in diverse microorganisms, its involvement in crucial cellular activities, and its stimulating activity in host immune responses, c-di-AMP signaling pathway has become an

  6. The environmental balance of the Alta Val d'Agri: a contribution to the evaluation of the industrial risk and strategic sustainable development

    NASA Astrophysics Data System (ADS)

    Loperte, S.; Cosmi, C.

    2015-09-01

    This study presents the preliminary environmental balance of the Alta Val d'Agri (Basilicata Region, Southern Italy), an area of great naturalistic interest characterized by the presence of huge oil and gas fields. The Driving Forces-Pressure-State-Impact-Responses (DPSIR) methodology was used to outline the background in terms of environmental impacts mainly caused by oil extraction activities, as well as potential existing responses. The study aims at providing stakeholders with an exhaustive framework to identify the existing data, the main sources of pollution, their potential impacts, the associated industrial risks and the existing policy strategies. Moreover, the DPSIR approach allows the identification of the vulnerable areas and the definition of targeted actions for a sustainable development of the area.

  7. Structural Insight into the Mechanism of c-di-GMP hydrolysis by EAL domain phosphodiesterases.

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Tchigvintsev, A.; Xu, X.; Singer, A.

    2010-08-01

    Cyclic diguanylate (or bis-(3'-5') cyclic dimeric guanosine monophosphate; c-di-GMP) is a ubiquitous second messenger that regulates diverse cellular functions, including motility, biofilm formation, cell cycle progression, and virulence in bacteria. In the cell, degradation of c-di-GMP is catalyzed by highly specific EAL domain phosphodiesterases whose catalytic mechanism is still unclear. Here, we purified 13 EAL domain proteins from various organisms and demonstrated that their catalytic activity is associated with the presence of 10 conserved EAL domain residues. The crystal structure of the TBD1265 EAL domain was determined in free state (1.8 {angstrom}) and in complex with c-di-GMP (2.35 {angstrom}), andmore » unveiled the role of conserved residues in substrate binding and catalysis. The structure revealed the presence of two metal ions directly coordinated by six conserved residues, two oxygens of c-di-GMP phosphate, and potential catalytic water molecule. Our results support a two-metal-ion catalytic mechanism of c-di-GMP hydrolysis by EAL domain phosphodiesterases.« less

  8. A minimalist biosensor: Quantitation of cyclic di-GMP using the conformational change of a riboswitch aptamer.

    PubMed

    Kellenberger, Colleen A; Sales-Lee, Jade; Pan, Yuchen; Gassaway, Madalee M; Herr, Amy E; Hammond, Ming C

    2015-01-01

    Cyclic di-GMP (c-di-GMP) is a second messenger that is important in regulating bacterial physiology and behavior, including motility and virulence. Many questions remain about the role and regulation of this signaling molecule, but current methods of detection are limited by either modest sensitivity or requirements for extensive sample purification. We have taken advantage of a natural, high affinity receptor of c-di-GMP, the Vc2 riboswitch aptamer, to develop a sensitive and rapid electrophoretic mobility shift assay (EMSA) for c-di-GMP quantitation that required minimal engineering of the RNA.

  9. Ancient DNA reveals genetic connections between early Di-Qiang and Han Chinese.

    PubMed

    Li, Jiawei; Zeng, Wen; Zhang, Ye; Ko, Albert Min-Shan; Li, Chunxiang; Zhu, Hong; Fu, Qiaomei; Zhou, Hui

    2017-12-04

    Ancient Di-Qiang people once resided in the Ganqing region of China, adjacent to the Central Plain area from where Han Chinese originated. While gene flow between the Di-Qiang and Han Chinese has been proposed, there is no evidence to support this view. Here we analyzed the human remains from an early Di-Qiang site (Mogou site dated ~4000 years old) and compared them to other ancient DNA across China, including an early Han-related site (Hengbei site dated ~3000 years old) to establish the underlying genetic relationship between the Di-Qiang and ancestors of Han Chinese. We found Mogou mtDNA haplogroups were highly diverse, comprising 14 haplogroups: A, B, C, D (D*, D4, D5), F, G, M7, M8, M10, M13, M25, N*, N9a, and Z. In contrast, Mogou males were all Y-DNA haplogroup O3a2/P201; specifically one male was further assigned to O3a2c1a/M117 using targeted unique regions on the non-recombining region of the Y-chromosome. We compared Mogou to 7 other ancient and 38 modern Chinese groups, in a total of 1793 individuals, and found that Mogou shared close genetic distances with Taojiazhai (a more recent Di-Qiang population), Hengbei, and Northern Han. We modeled their interactions using Approximate Bayesian Computation, and support was given to a potential admixture of ~13-18% between the Mogou and Northern Han around 3300-3800 years ago. Mogou harbors the earliest genetically identifiable Di-Qiang, ancestral to the Taojiazhai, and up to ~33% paternal and ~70% of its maternal haplogroups could be found in present-day Northern Han Chinese.

  10. Di- and tripeptide transport in vertebrates: the contribution of teleost fish models.

    PubMed

    Verri, Tiziano; Barca, Amilcare; Pisani, Paola; Piccinni, Barbara; Storelli, Carlo; Romano, Alessandro

    2017-04-01

    Solute Carrier 15 (SLC15) family, alias H + -coupled oligopeptide cotransporter family, is a group of membrane transporters known for their role in the cellular uptake of di- and tripeptides (di/tripeptides) and peptide-like molecules. Of its members, SLC15A1 (PEPT1) chiefly mediates intestinal absorption of luminal di/tripeptides from dietary protein digestion, while SLC15A2 (PEPT2) mainly allows renal tubular reabsorption of di/tripeptides from ultrafiltration, SLC15A3 (PHT2) and SLC15A4 (PHT1) possibly interact with di/tripeptides and histidine in certain immune cells, and SLC15A5 has unknown function. Our understanding of this family in vertebrates has steadily increased, also due to the surge of genomic-to-functional information from 'non-conventional' animal models, livestock, poultry, and aquaculture fish species. Here, we review the literature on the SLC15 transporters in teleost fish with emphasis on SLC15A1 (PEPT1), one of the solute carriers better studied amongst teleost fish because of its relevance in animal nutrition. We report on the operativity of the transporter, the molecular diversity, and multiplicity of structural-functional solutions of the teleost fish orthologs with respect to higher vertebrates, its relevance at the intersection of the alimentary and osmoregulative functions of the gut, its response under various physiological states and dietary solicitations, and its possible involvement in examples of total body plasticity, such as growth and compensatory growth. By a comparative approach, we also review the few studies in teleost fish on SLC15A2 (PEPT2), SLC15A4 (PHT1), and SLC15A3 (PHT2). By representing the contribution of teleost fish to the knowledge of the physiology of di/tripeptide transport and transporters, we aim to fill the gap between higher and lower vertebrates.

  11. Target Search and Selection for the DI/EPOXI Spacecraft

    NASA Technical Reports Server (NTRS)

    Grebow, Daniel J.; Bhaskaran, Shyam; Chesley, Steven R.

    2012-01-01

    Upon completion of the Hartley 2 flyby in November 2010, the Deep Impact (DI) spacecraft resided in a solar orbit without possibility for gravity assist with any large body. Conservative estimates of remaining fuel were enough to provide only an 18 m/s impulse on the spacecraft. We present our method and results of our systematic scan of potential small body encounters for DI, and our criteria to narrow the selection to the asteroid 2002 GT as the target flyby body. The mission profile has two deterministic maneuvers to achieve the encounter, the first of which executed on November 25, 2011.

  12. Compound heterozygosity for Hb S [beta6(A3)GluVal, GAG-->GTG] and a new thalassemic mutation [beta132(H10)Lys-->term, AAA-->TAA] detected in a family from West Africa.

    PubMed

    Frischknecht, Hannes; Troxler, Heinz; Greiner, Jeanette; Hengartner, Heinz; Dutly, Fabrizio

    2008-01-01

    We describe a Hb S/beta-thalassemia (beta-thal) mutation involving an AT transition at codon 132 of the beta-globin gene. The mutation, in the heterozygous state, unlike several other mutations in exon 3, shows no signs of dominant thalassemia but those of a typical beta(0) carrier. Compound heterozygosity with Hb S [beta6(A3)GluVal, GAGGTG] showed a severe clinical picture.

  13. Transition metal complexes of 2-amino-3,5-dihalopyridines: Syntheses, structures and magnetic properties of (3,5-diCAPH)2CuX4 and (3,5-diBAPH)2CuX4.

    PubMed

    Tremelling, Grant W; Foxman, Bruce M; Landee, Christopher P; Turnbull, Mark M; Willett, Roger D

    2009-12-21

    A family of bis(2-amino-3,5-dihalopyridinium)tetrahalocuprate(II) compounds has been synthesized, including (3,5-diCAPH)2CuCl4 (1), (3,5-diCAPH)2CuBr4 (2), (3,5-diBAPH)2CuCl4 (3), and (3,5-diBAPH)2CuBr4 (4) [3,5-diCAPH = 2-amino-3,5-dichloropyridinium; 3,5-diBAPH = 2-amino-3,5-dibromopyridinium]. These complexes have been analyzed through single crystal X-ray diffraction and temperature dependent magnetic susceptibility. Compound 1 crystallizes in the P-1 space group and the tetrachlorocuprate ion is best described as possessing a distorted square planar geometry. Compounds 2-4 are structurally similar and crystallized in the P2(1)/n, P2(1)/c, and P2(1)/n space groups respectively. The tetrahalocuprate ions are best described as distorted tetrahedra. All four compounds show antiferromagnetic interactions and were fit to the uniform chain Heisenberg model with resulting 2J/kB values of -11.71(2) K, -2.21(1) K, -12.43 (2) K, and -1.36(1) K, respectively. The exchange values correlate well with the two-halide exchange pathway parameters. The unusual observation that the chloride complexes show stronger magnetic exchange than the bromide complexes provides strong support that the exchange can be strongly dependent upon the Cu-X...X angles and Cu-X...X-Cu torsion angles.

  14. Three novel variants (p.Glu178Lys, p.Val245Met, p.Ser250Phe) of the phenylalanine hydroxylase (PAH) gene impair protein expression and function in vitro.

    PubMed

    Zong, Yanan; Liu, Ning; Ma, Shanshan; Bai, Ying; Guan, Fangxia; Kong, Xiangdong

    2018-08-20

    Phenylketonuria (PKU) is the most common inherited metabolic disease, an autosomal recessive disorder affecting >10,000 newborns each year globally. It can be caused by over 1000 different naturally occurring mutations in the phenylalanine hydroxylase (PAH) gene. We analyzed three novel naturally occurring PAH gene variants: p.Glu178Lys (c.532G>A), p.Val245Met (c.733G>A) and p.Ser250Phe (c.749C>T). The mutant effect on the PAH enzyme structure and function was predicted by bioinformatics software. Vectors expressing the corresponding PAH variants were generated for expression in E. coli and in HEK293T cells. The RNA expression of the three PAH variants was measured by quantitative reverse transcription polymerase chain reaction (RT-qPCR). The mutant PAH protein levels were determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), western blot and enzyme-linked immunosorbent assay (ELISA). All three variants were predicted to be pathogenic by bioinformatics analysis. The transcription of the three PAH variants was similar to the wild type PAH gene in HEK293T cells. In contrast, the levels of mutant PAH proteins decreased significantly compared to the wild type control, in both E. coli and HEK293T cells. Our results indicate that the three novel PAH gene variants (p.Glu178Lys, p.Val245Met, p.Ser250Phe) impair PAH protein expression and function in prokaryotic and eukaryotic cells. Copyright © 2018. Published by Elsevier B.V.

  15. TOXICOLOGY OF MONO- AND DI-ALKYLTIN CHLORIDES

    EPA Science Inventory

    Mono- and di-alkyltin chlorides are reactive compounds used in the production of stabilizers for polyvinyl chloride (PVC) plastics, primarily used for water distribution pipes. Health effects data were compiled or developed by the manufacturers for the EPA's HPV Challenge progra...

  16. TOXICOLOGY OF MONO- AND DI-ALKYLTIN CHLORIDES.

    EPA Science Inventory

    Mono- and di-alkyltin chlorides are reactive compounds used in the production of stabilizers for polyvinyl chloride (PVC) plastics, primarily used for water distribution pipes. Health effects data were compiled or developed by the manufacturers for the EPA's HPV Challenge progra...

  17. The Brain-Derived Neurotrophic Factor Val66Met Polymorphism Moderates an Effect of Physical Activity on Working Memory Performance

    PubMed Central

    Erickson, Kirk I.; Banducci, Sarah E.; Weinstein, Andrea M.; MacDonald, Angus W.; Ferrell, Robert E.; Halder, Indrani; Flory, Janine D.; Manuck, Stephen B.

    2014-01-01

    Physical activity enhances cognitive performance, yet individual variability in its effectiveness limits its widespread therapeutic application. Genetic differences might be one source of this variation. For example, carriers of the methionine-specifying (Met) allele of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism have reduced secretion of BDNF and poorer memory, yet physical activity increases BDNF levels. To determine whether the BDNF polymorphism moderated an association of physical activity with cognitive functioning among 1,032 midlife volunteers (mean age = 44.59 years), we evaluated participants’ performance on a battery of tests assessing memory, learning, and executive processes, and evaluated their physical activity with the Paffenbarger Physical Activity Questionnaire. BDNF genotype interacted robustly with physical activity to affect working memory, but not other areas of cognitive functioning. In particular, greater levels of physical activity offset a deleterious effect of the Met allele on working memory performance. These findings suggest that physical activity can modulate domain-specific genetic (BDNF) effects on cognition. PMID:23907543

  18. Biofilm Formation by the Acidophile Bacterium Acidithiobacillus thiooxidans Involves c-di-GMP Pathway and Pel exopolysaccharide.

    PubMed

    Díaz, Mauricio; Castro, Matias; Copaja, Sylvia; Guiliani, Nicolas

    2018-02-21

    Acidophile bacteria belonging to the Acidithiobacillus genus are pivotal players for the bioleaching of metallic values such as copper. Cell adherence to ores and biofilm formation, mediated by the production of extracellular polymeric substances, strongly favors bioleaching activity. In recent years, the second messenger cyclic diguanylate (c-di-GMP) has emerged as a central regulator for biofilm formation in bacteria. C-di-GMP pathways have been reported in different Acidithiobacillus species; however, c-di-GMP effectors and signal transduction networks are still largely uncharacterized in these extremophile species. Here we investigated Pel exopolysaccharide and its role in biofilm formation by sulfur-oxidizing species Acidithiobacillus thiooxidans . We identified 39 open reading frames (ORFs) encoding proteins involved in c-di-GMP metabolism and signal transduction, including the c-di-GMP effector protein PelD, a structural component of the biosynthesis apparatus for Pel exopolysaccharide production. We found that intracellular c-di-GMP concentrations and transcription levels of pel genes were higher in At . thiooxidans biofilm cells compared to planktonic ones. By developing an At . thiooxidans Δ pelD null-mutant strain we revealed that Pel exopolysaccharide is involved in biofilm structure and development. Further studies are still necessary to understand how Pel biosynthesis is regulated in Acidithiobacillus species, nevertheless these results represent the first characterization of a c-di-GMP effector protein involved in biofilm formation by acidophile species.

  19. Genetic sensitivity to the caregiving context: The influence of 5httlpr and BDNF val66met on indiscriminate social behavior

    PubMed Central

    Drury, Stacy S; Gleason, Mary Margaret; Theall, Katherine; Smyke, Anna T; Nelson, Charles A; Fox, Nathan A; Zeanah, Charles H

    2014-01-01

    Evidence that gene x environment interactions can reflect differential sensitivity to the environmental context, rather than risk or resilience, is increasing. To test this model, we examined the genetic contribution to indiscriminate social behavior, in the setting of a randomized controlled trial of foster care compared to institutional rearing. Children enrolled in the Bucharest Early Intervention Project (BEIP) were assessed comprehensively before the age of 30 months and subsequently randomized to either care as usual (CAUG) or high quality foster care (FCG). Indiscriminate social behavior was assessed at four time points, baseline, 30 months, 42 months and 54 months of age, using caregiver report with the Disturbances of Attachment Interview (DAI). General linear mixed-effects models were used to examine the effect of the interaction between group status and functional polymorphisms in Brain Derived Neurotrophic Factor (BDNF) and the Serotonin Transporter (5htt) on levels of indiscriminate behavior over time. Differential susceptibility, relative to levels of indiscriminate behavior, was demonstrated in children with either the s/s 5httlpr genotype or met 66 BDNF allele carriers. Specifically children with either the s/s 5httlpr genotype or met66 carriers in BDNF demonstrated the lowest levels of indiscriminate behavior in the FCG and the highest levels in the CAUG. Children with either the long allele of the 5httlpr or val/val genotype of BDNF demonstrated little difference in levels of indiscriminate behaviors over time and no group x genotype interaction. Children with both plasticity genotypes had the most signs of indiscriminate behavior at 54 months if they were randomized to the CAUG in the institution, while those with both plasticity genotypes randomized to the FCG intervention had the fewest signs at 54 months. Strikingly children with no plasticity alleles demonstrated no intervention effect on levels of indiscriminate behavior at 54 months. These

  20. C-Glycosyltransferases catalyzing the formation of di-C-glucosyl flavonoids in citrus plants.

    PubMed

    Ito, Takamitsu; Fujimoto, Shunsuke; Suito, Fumiaki; Shimosaka, Makoto; Taguchi, Goro

    2017-07-01

    Citrus plants accumulate many kinds of flavonoids, including di-C-glucosyl flavonoids, which have attracted considerable attention due to their health benefits. However, the biosynthesis of di-C-glucosyl flavonoids has not been elucidated at the molecular level. Here, we identified the C-glycosyltransferases (CGTs) FcCGT (UGT708G1) and CuCGT (UGT708G2) as the primary enzymes involved in the biosynthesis of di-C-glucosyl flavonoids in the citrus plants kumquat (Fortunella crassifolia) and satsuma mandarin (Citrus unshiu), respectively. The amino acid sequences of these CGTs were 98% identical, indicating that CGT genes are highly conserved in the citrus family. The recombinant enzymes FcCGT and CuCGT utilized 2-hydroxyflavanones, dihydrochalcone, and their mono-C-glucosides as sugar acceptors and produced corresponding di-C-glucosides. The K m and k cat values of FcCGT toward phloretin were <0.5 μm and 12.0 sec -1 , and those toward nothofagin (3'-C-glucosylphloretin) were 14.4 μm and 5.3 sec -1 , respectively; these values are comparable with those of other glycosyltransferases reported to date. Transcripts of both CGT genes were found to concentrate in various plant organs, and particularly in leaves. Our results suggest that di-C-glucosyl flavonoid biosynthesis proceeds via a single enzyme using either 2-hydroxyflavanones or phloretin as a substrate in citrus plants. In addition, Escherichia coli cells expressing CGT genes were found to be capable of producing di-C-glucosyl flavonoids, which is promising for commercial production of these valuable compounds. © 2017 The Authors The Plant Journal © 2017 John Wiley & Sons Ltd.

  1. Proton electron nuclear double resonance from nitrosyl horse heart myoglobin: the role of His-E7 and Val-E11.

    PubMed Central

    Flores, M; Wajnberg, E; Bemski, G

    2000-01-01

    Electron nuclear double resonance (ENDOR) spectroscopy has been used to study protons in nitrosyl horse heart myoglobin (MbNO). (1)H ENDOR spectra were recorded for different settings of the magnetic field. Detailed analysis of the ENDOR powder spectra, using computer simulation, based on the "orientation-selection" principle, leads to the identification of the available protons in the heme pocket. We observe hyperfine interactions of the N(HisF8)-Fe(2+)-N(NO) complex with five protons in axial and with eight protons in the rhombic symmetry along different orientations, including those of the principal axes of the g-tensor. Protons from His-E7 and Val-E11 residues are identified in the two symmetries, rhombic and axial, exhibited by MbNO. Our results indicate that both residues are present inside the heme pocket and help to stabilize one particular conformation. PMID:10733988

  2. Evaluation of unique identifiers used as keys to match identical publications in Pure and SciVal - a case study from health science.

    PubMed

    Madsen, Heidi Holst; Madsen, Dicte; Gauffriau, Marianne

    2016-01-01

    Unique identifiers (UID) are seen as an effective key to match identical publications across databases or identify duplicates in a database. The objective of the present study is to investigate how well UIDs work as match keys in the integration between Pure and SciVal, based on a case with publications from the health sciences. We evaluate the matching process based on information about coverage, precision, and characteristics of publications matched versus not matched with UIDs as the match keys. We analyze this information to detect errors, if any, in the matching process. As an example we also briefly discuss how publication sets formed by using UIDs as the match keys may affect the bibliometric indicators number of publications, number of citations, and the average number of citations per publication.  The objective is addressed in a literature review and a case study. The literature review shows that only a few studies evaluate how well UIDs work as a match key. From the literature we identify four error types: Duplicate digital object identifiers (DOI), incorrect DOIs in reference lists and databases, DOIs not registered by the database where a bibliometric analysis is performed, and erroneous optical or special character recognition. The case study explores the use of UIDs in the integration between the databases Pure and SciVal. Specifically journal publications in English are matched between the two databases. We find all error types except erroneous optical or special character recognition in our publication sets. In particular the duplicate DOIs constitute a problem for the calculation of bibliometric indicators as both keeping the duplicates to improve the reliability of citation counts and deleting them to improve the reliability of publication counts will distort the calculation of average number of citations per publication. The use of UIDs as a match key in citation linking is implemented in many settings, and the availability of UIDs may become

  3. [Molecular docking of chlorogenic acid, 3,4-di-O-caffeoylquinic acid and 3,5-di-O-caffeoylquinic acid with human serum albumin].

    PubMed

    Zhou, Jing; Ma, Hong-yue; Fan, Xin-sheng; Xiao, Wei; Wang, Tuan-jie

    2012-10-01

    To investigate the mechanism of binding of human serum albumin (HSA) with potential sensitinogen, including chlorogenic acid and two isochlorogenic acids (3,4-di-O-caffeoylquinic acid and 3,5-di-O-caffeoylquinic acid). By using the docking algorithm of computer-aided molecular design and the Molegro Virtual Docker, the crystal structures of HSA with warfarin and diazepam (Protein Data Bank ID: 2BXD and 2BXF) were selected as molecular docking receptors of HSA sites I and II. According to docking scores, key residues and H-bond, the molecular docking mode was selected and confirmed. The molecular docking of chlorogenic acid and two isochlorogenic acids on sites I and II was compared based on the above design. The results from molecular docking indicated that chlorogenic acid, 3,4-di-O-caffeoylquinic acid and 3,5-di-O-caffeoylquinic acid could bind to HSA site I by high affinity scores of -112.3, -155.3 and -153.1, respectively. They could bind to site II on HSA by high affinity scores of -101.7, -138.5 and -133.4, respectively. In site I, two isochlorogenic acids interacted with the key apolar side-chains of Leu238 and Ala291 by higher affinity scores than chlorogenic acid. Furthermore, the H-bonds of isochlorogenic acids with polar residues inside the pocket and at the entrance of the pocket were different from chlorogenic acid. Moreover, the second coffee acyl of isochlorogenic acid occupied the right-hand apolar compartment in the pocket of HSA site I. In site I, the second coffee acyl of isochlorogenic acid formed the H-bonds with polar side-chains, which contributed isochlorogenic acid to binding with site II of HSA. The isochlorogenic acids with two coffee acyls have higher binding abilities with HSA than chlorogenic acid with one coffee acyl, suggesting that isochlorogenic acids binding with HSA may be sensitinogen.

  4. Measurement of q ˆ in Relativistic Heavy Ion Collisions using di-hadron correlations

    DOE PAGES

    Tannenbaum, M. J.

    2017-06-06

    The propagation of partons from hard scattering through the Quark Gluon Plasma produced in A+A collisions at RHIC and the LHC is represented in theoretical analyses by the transport coefficientmore » $$\\hat{q}$$ and predicted to cause both energy loss of the outgoing partons, observed as suppression of particles or jets with large transverse momentum p T, and broadening of the azimuthal correlations of the outgoing di-jets or di-hadrons from the outgoing parton-pair, which has not been observed. The widths of azimuthal correlations of di-hadrons with the same trigger particle p Tt and associated p Ta transverse momenta in p+p and Au+Au are so-far statistically indistinguishable as shown in recent as well as older di-hadron measurements and also with jet-hadron and hadron-jet measurements. The azimuthal width of the di-hadron correlations in p+p collisions, beyond the fragmentation transverse momentum, j T, is dominated by k T, the so-called intrinsic transverse momentum of a parton in a nucleon, which can be measured. The broadening should produce a larger k T in A+A than in p+p collisions. The present work introduces the observation that the k T measured in p+p collisions for di-hadrons with p Tt and p Ta must be reduced to compensate for the energy loss of both the trigger and away parent partons when comparing to the k T measured with the same di-hadron p Tt and p Ta in Au+Au collisions. This idea is applied to a recent STAR di-hadron measurement, with result <$$\\hat{q}$$L>=2.1±0.6 GeV 2. This is more precise but in agreement with a theoretical calculation of <$$\\hat{q}$$L>=14$$+42\\atop{-14}$$ GeV 2 using the same data. Assuming a length ≈7 fm for central Au+Au collisions the present result gives $$\\hat{q}$$≈0.30±0.09 GeV 2/fm, in fair agreement with the JET collaboration result from single hadron suppression of $$\\hat{q}$$≈1.2±0.3 GeV 2/fm at an initial time τ 0=0.6 fm/c in Au+Au collisions at √sNN=200 GeV.« less

  5. Measurement of q ˆ in Relativistic Heavy Ion Collisions using di-hadron correlations

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Tannenbaum, M. J.

    The propagation of partons from hard scattering through the Quark Gluon Plasma produced in A+A collisions at RHIC and the LHC is represented in theoretical analyses by the transport coefficientmore » $$\\hat{q}$$ and predicted to cause both energy loss of the outgoing partons, observed as suppression of particles or jets with large transverse momentum p T, and broadening of the azimuthal correlations of the outgoing di-jets or di-hadrons from the outgoing parton-pair, which has not been observed. The widths of azimuthal correlations of di-hadrons with the same trigger particle p Tt and associated p Ta transverse momenta in p+p and Au+Au are so-far statistically indistinguishable as shown in recent as well as older di-hadron measurements and also with jet-hadron and hadron-jet measurements. The azimuthal width of the di-hadron correlations in p+p collisions, beyond the fragmentation transverse momentum, j T, is dominated by k T, the so-called intrinsic transverse momentum of a parton in a nucleon, which can be measured. The broadening should produce a larger k T in A+A than in p+p collisions. The present work introduces the observation that the k T measured in p+p collisions for di-hadrons with p Tt and p Ta must be reduced to compensate for the energy loss of both the trigger and away parent partons when comparing to the k T measured with the same di-hadron p Tt and p Ta in Au+Au collisions. This idea is applied to a recent STAR di-hadron measurement, with result <$$\\hat{q}$$L>=2.1±0.6 GeV 2. This is more precise but in agreement with a theoretical calculation of <$$\\hat{q}$$L>=14$$+42\\atop{-14}$$ GeV 2 using the same data. Assuming a length ≈7 fm for central Au+Au collisions the present result gives $$\\hat{q}$$≈0.30±0.09 GeV 2/fm, in fair agreement with the JET collaboration result from single hadron suppression of $$\\hat{q}$$≈1.2±0.3 GeV 2/fm at an initial time τ 0=0.6 fm/c in Au+Au collisions at √sNN=200 GeV.« less

  6. Vibrio cholerae VpsT Regulates Matrix Production and Motility by Directly Sensing Cyclic di-GMP

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Krasteva, P.; Fong, J; Shikuma, N

    2010-01-01

    Microorganisms can switch from a planktonic, free-swimming life-style to a sessile, colonial state, called a biofilm, which confers resistance to environmental stress. Conversion between the motile and biofilm life-styles has been attributed to increased levels of the prokaryotic second messenger cyclic di-guanosine monophosphate (c-di-GMP), yet the signaling mechanisms mediating such a global switch are poorly understood. Here we show that the transcriptional regulator VpsT from Vibrio cholerae directly senses c-di-GMP to inversely control extracellular matrix production and motility, which identifies VpsT as a master regulator for biofilm formation. Rather than being regulated by phosphorylation, VpsT undergoes a change in oligomerizationmore » on c-di-GMP binding.« less

  7. 4-Bromo-N-(di-n-propyl-carbamothioyl)-benzamide.

    PubMed

    Binzet, Gün; Flörke, Ulrich; Külcü, Nevzat; Arslan, Hakan

    2009-02-04

    The synthesis of the title compound, C(14)H(19)BrN(2)OS, involves the reaction of 4-bromo-benzoyl chloride with potassium thio-cyanate in acetone followed by condensation of the resulting 4-bromo-benzoyl isothio-cyanate with di-n-propyl-amine. Typical thio-urea carbonyl and thio-carbonyl double bonds, as well as shortened C-N bonds, are observed in the title compound. The short C-N bond lengths in the centre of the mol-ecule reveal the effects of resonance in this part of the mol-ecule. The asymmetric unit of the title compound contains two crystallographically independent mol-ecules, A and B. There is very little difference between the bond lengths and angles of these mol-ecules. In mol-ecule B, one di-n-propyl group is twisted in a -anti-periplanar conformation with C-C-C-H = -179.1 (3)° and the other adopts a -synclinal conformation with C-C-C-H = -56.7 (4)°; in mol-ecule A the two di-n-propyl groups are twisted in + and -anti-periplanar conformations, with C-C-C-H = -179.9 (3) and 178.2 (3)°, respectively. In the crystal, the mol-ecules are linked into dimeric pairs via pairs of N-H⋯S hydrogen bonds.

  8. 12,13-diHOME: An Exercise-Induced Lipokine that Increases Skeletal Muscle Fatty Acid Uptake.

    PubMed

    Stanford, Kristin I; Lynes, Matthew D; Takahashi, Hirokazu; Baer, Lisa A; Arts, Peter J; May, Francis J; Lehnig, Adam C; Middelbeek, Roeland J W; Richard, Jeffrey J; So, Kawai; Chen, Emily Y; Gao, Fei; Narain, Niven R; Distefano, Giovanna; Shettigar, Vikram K; Hirshman, Michael F; Ziolo, Mark T; Kiebish, Michael A; Tseng, Yu-Hua; Coen, Paul M; Goodyear, Laurie J

    2018-05-01

    Circulating factors released from tissues during exercise have been hypothesized to mediate some of the health benefits of regular physical activity. Lipokines are circulating lipid species that have recently been reported to affect metabolism in response to cold. Here, lipidomics analysis revealed that a bout of moderate-intensity exercise causes a pronounced increase in the circulating lipid 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) in male, female, young, old, sedentary, and active human subjects. In mice, both a single bout of exercise and exercise training increased circulating 12,13-diHOME and surgical removal of brown adipose tissue (BAT) negated the increase in 12,13-diHOME, suggesting that BAT is the tissue source for exercise-stimulated 12,13-diHOME. Acute 12,13-diHOME treatment of mice in vivo increased skeletal muscle fatty acid uptake and oxidation, but not glucose uptake. These data reveal that lipokines are novel exercise-stimulated circulating factors that may contribute to the metabolic changes that occur with physical exercise. Copyright © 2018 Elsevier Inc. All rights reserved.

  9. Hooked on the nicotine addiction thesis: a response to DiFranza.

    PubMed

    Dar, Reuven; Frenk, Hanan

    2013-11-18

    DiFranza's rebuttal to our critique of the "Hooked on Nicotine" research program misconstrues our arguments beyond recognition. The grossest misrepresentation of our critique by DiFranza is that we devise (by thwarting science) to rescue "the conventional wisdom" of the "threshold model of nicotine addiction." In fact, the difference between our positions lies elsewhere: We believe that nicotine is not an addictive drug and that its contribution to the smoking habit is secondary; DiFranza believes that nicotine is so powerfully addictive that novice smokers can lose autonomy over their smoking behavior after one cigarette or even following a single puff. Our review aimed to critically examine the empirical basis of this extreme version of the nicotine "addiction" model. In this brief commentary we illustrate how the commitment to the nicotine "addiction" theory has biased the methodology and the interpretation of the data in "Hooked on Nicotine" research program.

  10. DiMeX: A Text Mining System for Mutation-Disease Association Extraction

    PubMed Central

    Mahmood, A. S. M. Ashique; Wu, Tsung-Jung; Mazumder, Raja; Vijay-Shanker, K.

    2016-01-01

    The number of published articles describing associations between mutations and diseases is increasing at a fast pace. There is a pressing need to gather such mutation-disease associations into public knowledge bases, but manual curation slows down the growth of such databases. We have addressed this problem by developing a text-mining system (DiMeX) to extract mutation to disease associations from publication abstracts. DiMeX consists of a series of natural language processing modules that preprocess input text and apply syntactic and semantic patterns to extract mutation-disease associations. DiMeX achieves high precision and recall with F-scores of 0.88, 0.91 and 0.89 when evaluated on three different datasets for mutation-disease associations. DiMeX includes a separate component that extracts mutation mentions in text and associates them with genes. This component has been also evaluated on different datasets and shown to achieve state-of-the-art performance. The results indicate that our system outperforms the existing mutation-disease association tools, addressing the low precision problems suffered by most approaches. DiMeX was applied on a large set of abstracts from Medline to extract mutation-disease associations, as well as other relevant information including patient/cohort size and population data. The results are stored in a database that can be queried and downloaded at http://biotm.cis.udel.edu/dimex/. We conclude that this high-throughput text-mining approach has the potential to significantly assist researchers and curators to enrich mutation databases. PMID:27073839

  11. DiMeX: A Text Mining System for Mutation-Disease Association Extraction.

    PubMed

    Mahmood, A S M Ashique; Wu, Tsung-Jung; Mazumder, Raja; Vijay-Shanker, K

    2016-01-01

    The number of published articles describing associations between mutations and diseases is increasing at a fast pace. There is a pressing need to gather such mutation-disease associations into public knowledge bases, but manual curation slows down the growth of such databases. We have addressed this problem by developing a text-mining system (DiMeX) to extract mutation to disease associations from publication abstracts. DiMeX consists of a series of natural language processing modules that preprocess input text and apply syntactic and semantic patterns to extract mutation-disease associations. DiMeX achieves high precision and recall with F-scores of 0.88, 0.91 and 0.89 when evaluated on three different datasets for mutation-disease associations. DiMeX includes a separate component that extracts mutation mentions in text and associates them with genes. This component has been also evaluated on different datasets and shown to achieve state-of-the-art performance. The results indicate that our system outperforms the existing mutation-disease association tools, addressing the low precision problems suffered by most approaches. DiMeX was applied on a large set of abstracts from Medline to extract mutation-disease associations, as well as other relevant information including patient/cohort size and population data. The results are stored in a database that can be queried and downloaded at http://biotm.cis.udel.edu/dimex/. We conclude that this high-throughput text-mining approach has the potential to significantly assist researchers and curators to enrich mutation databases.

  12. Dimeric c-di-GMP is required for post-translational regulation of alginate production in Pseudomonas aeruginosa

    DOE PAGES

    Whitney, John C.; Robinson, Howard; Whitfield, Gregory B.; ...

    2015-05-15

    Pseudomonas aeruginosa is an opportunistic human pathogen that secretes the exopolysaccharide alginate during infection of the respiratory tract of individuals afflicted with cystic fibrosis and chronic obstructive pulmonary disease. Among the proteins required for alginate production, Alg44 has been identified as an inner membrane protein whose bis-(3',5')-cyclic dimeric guanosine monophosphate (c-di-GMP) binding activity post-translationally regulates alginate secretion. In this study, we report the 1.8 Å crystal structure of the cytoplasmic region of Alg44 in complex with dimeric self-intercalated c-di-GMP and characterize its dinucleotide-binding site using mutational analysis. The structure shows that the c-di-GMP binding region of Alg44 adopts a PilZmore » domain fold with a dimerization mode not previously observed for this family of proteins. Moreover, calorimetric binding analysis of residues in the c-di-GMP binding site demonstrate that mutation of Arg-17 and Arg-95 alters the binding stoichiometry between c-di-GMP and Alg44 from 2:1 to 1:1. Introduction of these mutant alleles on the P. aeruginosa chromosome show that the residues required for binding of dimeric c-di-GMP in vitro are also required for efficient alginate production in vivo. Our results suggest that the dimeric form of c-di-GMP represents the biologically active signaling molecule needed for the secretion of an important virulence factor produced by P. aeruginosa.« less

  13. Dimeric c-di-GMP is required for post-translational regulation of alginate production in Pseudomonas aeruginosa

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Whitney, John C.; Robinson, Howard; Whitfield, Gregory B.

    Pseudomonas aeruginosa is an opportunistic human pathogen that secretes the exopolysaccharide alginate during infection of the respiratory tract of individuals afflicted with cystic fibrosis and chronic obstructive pulmonary disease. Among the proteins required for alginate production, Alg44 has been identified as an inner membrane protein whose bis-(3',5')-cyclic dimeric guanosine monophosphate (c-di-GMP) binding activity post-translationally regulates alginate secretion. In this study, we report the 1.8 Å crystal structure of the cytoplasmic region of Alg44 in complex with dimeric self-intercalated c-di-GMP and characterize its dinucleotide-binding site using mutational analysis. The structure shows that the c-di-GMP binding region of Alg44 adopts a PilZmore » domain fold with a dimerization mode not previously observed for this family of proteins. Moreover, calorimetric binding analysis of residues in the c-di-GMP binding site demonstrate that mutation of Arg-17 and Arg-95 alters the binding stoichiometry between c-di-GMP and Alg44 from 2:1 to 1:1. Introduction of these mutant alleles on the P. aeruginosa chromosome show that the residues required for binding of dimeric c-di-GMP in vitro are also required for efficient alginate production in vivo. Our results suggest that the dimeric form of c-di-GMP represents the biologically active signaling molecule needed for the secretion of an important virulence factor produced by P. aeruginosa.« less

  14. Dimeric c-di-GMP Is Required for Post-translational Regulation of Alginate Production in Pseudomonas aeruginosa*

    PubMed Central

    Whitney, John C.; Whitfield, Gregory B.; Marmont, Lindsey S.; Yip, Patrick; Neculai, A. Mirela; Lobsanov, Yuri D.; Robinson, Howard; Ohman, Dennis E.; Howell, P. Lynne

    2015-01-01

    Pseudomonas aeruginosa is an opportunistic human pathogen that secretes the exopolysaccharide alginate during infection of the respiratory tract of individuals afflicted with cystic fibrosis and chronic obstructive pulmonary disease. Among the proteins required for alginate production, Alg44 has been identified as an inner membrane protein whose bis-(3′,5′)-cyclic dimeric guanosine monophosphate (c-di-GMP) binding activity post-translationally regulates alginate secretion. In this study, we report the 1.8 Å crystal structure of the cytoplasmic region of Alg44 in complex with dimeric self-intercalated c-di-GMP and characterize its dinucleotide-binding site using mutational analysis. The structure shows that the c-di-GMP binding region of Alg44 adopts a PilZ domain fold with a dimerization mode not previously observed for this family of proteins. Calorimetric binding analysis of residues in the c-di-GMP binding site demonstrate that mutation of Arg-17 and Arg-95 alters the binding stoichiometry between c-di-GMP and Alg44 from 2:1 to 1:1. Introduction of these mutant alleles on the P. aeruginosa chromosome show that the residues required for binding of dimeric c-di-GMP in vitro are also required for efficient alginate production in vivo. These results suggest that the dimeric form of c-di-GMP represents the biologically active signaling molecule needed for the secretion of an important virulence factor produced by P. aeruginosa. PMID:25817996

  15. Targeted killing of myofibroblasts by biosurfactant di-rhamnolipid suggests a therapy against scar formation

    PubMed Central

    Shen, Chong; Jiang, Lifang; Shao, Huawei; You, Chuangang; Zhang, Guoliang; Ding, Sitong; Bian, Tingwei; Han, Chunmao; Meng, Qin

    2016-01-01

    Pathological myofibroblasts are often involved in skin scarring via generating contractile force and over-expressing collagen fibers, but no compound has been found to inhibit the myofibroblasts without showing severe toxicity to surrounding physiological cells. Here we report that di-rhamnolipid, a biosurfactant secreted by Pseudomonas aeruginosa, showed potent effects on scar therapy via a unique mechanism of targeted killing the myofibroblasts. In cell culture, the fibroblasts-derived myofibroblasts were more sensitive to di-rhamnolipid toxicity than fibroblasts at a concentration-dependent manner, and could be completely inhibited of their specific functions including α-SMA expression and collagen secretion/contraction. The anti-fibrotic function of di-rhamnolipid was further verified in rabbit ear hypertrophic scar models by presenting the significant reduction of scar elevation index, type I collagen fibers and α-SMA expression. In this regard, di-rhamnolipid treatment could be suggested as a therapy against skin scarring. PMID:27901027

  16. Di-22:6-bis(monoacylglycerol)phosphate: A clinical biomarker of drug-induced phospholipidosis for drug development and safety assessment

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Liu, Nanjun; Tengstrand, Elizabeth A.; Chourb, Lisa

    The inability to routinely monitor drug-induced phospholipidosis (DIPL) presents a challenge in pharmaceutical drug development and in the clinic. Several nonclinical studies have shown di-docosahexaenoyl (22:6) bis(monoacylglycerol) phosphate (di-22:6-BMP) to be a reliable biomarker of tissue DIPL that can be monitored in the plasma/serum and urine. The aim of this study was to show the relevance of di-22:6-BMP as a DIPL biomarker for drug development and safety assessment in humans. DIPL shares many similarities with the inherited lysosomal storage disorder Niemann–Pick type C (NPC) disease. DIPL and NPC result in similar changes in lysosomal function and cholesterol status that leadmore » to the accumulation of multi-lamellar bodies (myeloid bodies) in cells and tissues. To validate di-22:6-BMP as a biomarker of DIPL for clinical studies, NPC patients and healthy donors were classified by receiver operator curve analysis based on urinary di-22:6-BMP concentrations. By showing 96.7-specificity and 100-sensitivity to identify NPC disease, di-22:6-BMP can be used to assess DIPL in human studies. The mean concentration of di-22:6-BMP in the urine of NPC patients was 51.4-fold (p ≤ 0.05) above the healthy baseline range. Additionally, baseline levels of di-22:6-BMP were assessed in healthy non-medicated laboratory animals (rats, mice, dogs, and monkeys) and human subjects to define normal reference ranges for nonclinical/clinical studies. The baseline ranges of di-22:6-BMP in the plasma, serum, and urine of humans and laboratory animals were species dependent. The results of this study support the role of di-22:6-BMP as a biomarker of DIPL for pharmaceutical drug development and health care settings. - Highlights: • A reliable biomarker of drug-induced phospholipidosis (DIPL) is needed for humans. • Di-22:6-BMP is specific/sensitive for DIPL in animals as published in literatures. • The di-22:6-BMP biomarker can be validated for humans via NPC patients.

  17. Stressful life events, perceived stress, and 12-month course of geriatric depression: direct effects and moderation by the 5-HTTLPR and COMT Val158Met polymorphisms.

    PubMed

    Zannas, Anthony S; McQuoid, Douglas R; Steffens, David C; Chrousos, George P; Taylor, Warren D

    2012-07-01

    Although the relation between stressful life events (SLEs) and risk of major depressive disorder is well established, important questions remain about the effects of stress on the course of geriatric depression. Our objectives were (1) to examine how baseline stress and change in stress is associated with course of geriatric depression and (2) to test whether polymorphisms of serotonin transporter (5-HTTLPR) and catechol-O-methyltransferase (COMT Val158Met) genes moderate this relation. Two-hundred and sixteen depressed subjects aged 60 years or older were categorized by remission status (Montgomery-Asberg depression rating scale≤6) at 6 and 12 months. At 6 months, greater baseline numbers of self-reported negative and total SLEs and greater baseline perceived stress severity were associated with lower odds of remission. At 12 months, only baseline perceived stress predicted remission. When we examined change in stress, 12-month decrease in negative SLEs and level of perceived stress were associated with improved odds of 12-month remission. When genotype data were included, COMT Val158Met genotype did not influence these relations. However, when compared with 5-HTTLPR L/L homozygotes, S allele carriers with greater baseline numbers of negative SLEs and with greater decrease in negative SLEs were more likely to remit at 12 months. This study demonstrates that baseline SLEs and perceived stress severity may influence the 12-month course of geriatric depression. Moreover, changes in these stress measures over time correlate with depression outcomes. 5-HTTLPR S carriers appear to be more susceptible to both the effects of enduring stress and the benefit of interval stress reduction.

  18. COMT Val(108/158)Met polymorphism effects on emotional brain function and negativity bias.

    PubMed

    Williams, Leanne M; Gatt, Justine M; Grieve, Stuart M; Dobson-Stone, Carol; Paul, Robert H; Gordon, Evian; Schofield, Peter R

    2010-11-15

    Biases toward processing negative versus positive information vary as a function of level of awareness, and are modulated by monoamines. Excessive biases are associated with individual differences in mood and emotional stability, and emotional disorder. Here, we examined the impact of the catechol-O-methyltransferase (COMT) Val(108/158)Met polymorphism, involved in dopamine and norepinephrine catabolism, on both emotional brain function and self-reported negativity bias. COMT genotyping and self-reported level of negativity bias were completed for 46 healthy participants taking part in the Brain Resource International Database. Functional MRI was undertaken during perception of facial expressions of fear and happiness presented under unmasked (consciously identified) and masked (to prevent conscious detection) conditions. Structural MR images were also acquired. A greater number of COMT Met alleles predicted increased activation in brainstem, amygdala, basal ganglia and medial prefrontal regions for conscious fear, but decreased activation for conscious happiness. This pattern was also apparent for brainstem activation for the masked condition. Effects were most apparent for females. These differences could not be explained by gray matter variations. The Met-related profile of activation, particularly prefrontally, predicted greater negativity bias associated with risk for emotional disorder. The findings suggest that the COMT Met allele modulates neural substrates of negative versus positive emotion processing. This effect may contribute to negativity biases, which confer susceptibility for emotional disorders. Copyright 2010 Elsevier Inc. All rights reserved.

  19. c-di-GMP enhances protective innate immunity in a murine model of pertussis.

    PubMed

    Elahi, Shokrollah; Van Kessel, Jill; Kiros, Tedele G; Strom, Stacy; Hayakawa, Yoshihiro; Hyodo, Mamoru; Babiuk, Lorne A; Gerdts, Volker

    2014-01-01

    Innate immunity represents the first line of defense against invading pathogens in the respiratory tract. Innate immune cells such as monocytes, macrophages, dendritic cells, NK cells, and granulocytes contain specific pathogen-recognition molecules which induce the production of cytokines and subsequently activate the adaptive immune response. c-di-GMP is a ubiquitous second messenger that stimulates innate immunity and regulates biofilm formation, motility and virulence in a diverse range of bacterial species with potent immunomodulatory properties. In the present study, c-di-GMP was used to enhance the innate immune response against pertussis, a respiratory infection mainly caused by Bordetella pertussis. Intranasal treatment with c-di-GMP resulted in the induction of robust innate immune responses to infection with B. pertussis characterized by enhanced recruitment of neutrophils, macrophages, natural killer cells and dendritic cells. The immune responses were associated with an earlier and more vigorous expression of Th1-type cytokines, as well as an increase in the induction of nitric oxide in the lungs of treated animals, resulting in significant reduction of bacterial numbers in the lungs of infected mice. These results demonstrate that c-di-GMP is a potent innate immune stimulatory molecule that can be used to enhance protection against bacterial respiratory infections. In addition, our data suggest that priming of the innate immune system by c-di-GMP could further skew the immune response towards a Th1 type phenotype during subsequent infection. Thus, our data suggest that c-di-GMP might be useful as an adjuvant for the next generation of acellular pertussis vaccine to mount a more protective Th1 phenotype immune response, and also in other systems where a Th1 type immune response is required.

  20. c-di-GMP Enhances Protective Innate Immunity in a Murine Model of Pertussis

    PubMed Central

    Elahi, Shokrollah; Van Kessel, Jill; Kiros, Tedele G.; Strom, Stacy; Hayakawa, Yoshihiro; Hyodo, Mamoru; Babiuk, Lorne A.; Gerdts, Volker

    2014-01-01

    Innate immunity represents the first line of defense against invading pathogens in the respiratory tract. Innate immune cells such as monocytes, macrophages, dendritic cells, NK cells, and granulocytes contain specific pathogen-recognition molecules which induce the production of cytokines and subsequently activate the adaptive immune response. c-di-GMP is a ubiquitous second messenger that stimulates innate immunity and regulates biofilm formation, motility and virulence in a diverse range of bacterial species with potent immunomodulatory properties. In the present study, c-di-GMP was used to enhance the innate immune response against pertussis, a respiratory infection mainly caused by Bordetella pertussis. Intranasal treatment with c-di-GMP resulted in the induction of robust innate immune responses to infection with B. pertussis characterized by enhanced recruitment of neutrophils, macrophages, natural killer cells and dendritic cells. The immune responses were associated with an earlier and more vigorous expression of Th1-type cytokines, as well as an increase in the induction of nitric oxide in the lungs of treated animals, resulting in significant reduction of bacterial numbers in the lungs of infected mice. These results demonstrate that c-di-GMP is a potent innate immune stimulatory molecule that can be used to enhance protection against bacterial respiratory infections. In addition, our data suggest that priming of the innate immune system by c-di-GMP could further skew the immune response towards a Th1 type phenotype during subsequent infection. Thus, our data suggest that c-di-GMP might be useful as an adjuvant for the next generation of acellular pertussis vaccine to mount a more protective Th1 phenotype immune response, and also in other systems where a Th1 type immune response is required. PMID:25333720