ADHD and Disruptive behavior scores – associations with MAO-A and 5-HTT genes and with platelet MAO-B activity in adolescents

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Larsson Jan-Olov

2008-04-01

Full Text Available Abstract Background Pharmacological and genetic studies suggest the importance of the dopaminergic, serotonergic, and noradrenergic systems in the pathogenesis of Attention Deficit Hyperactivity Disorder (ADHD and Disruptive Behavior Disorder (DBD. We have, in a population-based sample, studied associations between dimensions of the ADHD/DBD phenotype and Monoamine Oxidase B (MAO-B activity in platelets and polymorphisms in two serotonergic genes: the Monoamine Oxidase A Variable Number of Tandem Repeats (MAO-A VNTR and the 5-Hydroxytryptamine Transporter gene-Linked Polymorphic Region (5-HTT LPR. Methods A population-based sample of twins, with an average age of 16 years, was assessed for ADHD/DBD with a clinical interview; Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL. Blood was drawn from 247 subjects and analyzed for platelet MAO-B activity and polymorphisms in the MAO-A and 5-HTT genes. Results We found an association in girls between low platelet MAO-B activity and symptoms of Oppositional Defiant Disorder (ODD. In girls, there was also an association between the heterozygote long/short 5-HTT LPR genotype and symptoms of conduct disorder. Furthermore the heterozygote 5-HTT LPR genotype in boys was found to be associated with symptoms of Conduct Disorder (CD. In boys, hemizygosity for the short MAO-A VNTR allele was associated with disruptive behavior. Conclusion Our study suggests that the serotonin system, in addition to the dopamine system, should be further investigated when studying genetic influences on the development of Disruptive Behavior Disorders.

Pre-clinical evaluation of AAV5-miHTT gene therapy of Huntington´s disease

Czech Academy of Sciences Publication Activity Database

Konstantinová, P.; Miniarikova, J.; Blits, B.; Zimmer, V.; Spoerl, A.; Southwell, A.; Hayden, M.; van Deventer, S.; Deglon, N.; Motlík, Jan; Juhás, Štefan; Juhásová, Jana; Richard, Ch.; Petry, H.

2015-01-01

Roč. 78, Supl 2 (2015), s. 8-8 ISSN 1210-7859. [Conference on Animal Models for neurodegenerative Diseases /3./. 08.11.2015-10.11.2015, Liblice] R&D Projects: GA MŠk ED2.1.00/03.0124 Institutional support: RVO:67985904 Keywords : Huntington ´s disease * gene therapy * AAV5-miHTT Subject RIV: EB - Genetics ; Molecular Biology

Hydrothermal Treatment (HTT) of Microalgae: Evaluation of the Process As Conversion Method in an Algae Biorefinery Concept

NARCIS (Netherlands)

Garcia Alba, Laura; Torri, C.; Samori, C.; van der Spek, J.J.; Fabbri, D.; Kersten, Sascha R.A.; Brilman, Derk Willem Frederik

2012-01-01

The hydrothermal treatment (HTT) technology is evaluated for its potential as a process to convert algae and algal debris into a liquid fuel, within a sustainable algae biorefinery concept in which, next to fuels (gaseous and liquid), high value products are coproduced, nutrients and water are

A SNP in the HTT promoter alters NF-κB binding and is a bidirectional genetic modifier of Huntington disease

DEFF Research Database (Denmark)

Bečanović, Kristina; Nørremølle, Anne; Neal, Scott J

2015-01-01

Cis-regulatory variants that alter gene expression can modify disease expressivity, but none have previously been identified in Huntington disease (HD). Here we provide in vivo evidence in HD patients that cis-regulatory variants in the HTT promoter are bidirectional modifiers of HD age of onset....

Negative social acts and pain: evidence of a workplace bullying and 5-HTT genotype interaction.

Science.gov (United States)

Jacobsen, Daniel Pitz; Nielsen, Morten Birkeland; Einarsen, Ståle; Gjerstad, Johannes

2018-05-01

Objectives Long-term exposure to systematic negative acts at work, usually labeled workplace bullying, is a prevalent problem at many workplaces. The adverse effects of such exposure may range from psychological symptoms, such as depression and anxiety to somatic ailments like cardiovascular disease and musculoskeletal complaints. In this study, we examined the relationships among exposure to negative acts, genetic variability in the 5-HTT gene SLC6A4 and pain. Methods The study was based on a nationally representative survey of 987 Norwegian employees drawn from the Norwegian Central Employee Register by Statistics Norway. Exposure to bullying in the workplace was measured with the 9-item version of the Negative Acts Questionnaire - Revised (NAQ-R) inventory. Pain was rated using an 11-point (0-10) numeric rating scale (NRS). Genotyping with regard to SLC6A4 was carried out using a combination of gel-electrophoresis and TaqMan assay. Results The data revealed a significant interaction between exposure to negative acts and the SLC6A4 genotype with regard to pain (linear regression with 5000 resamples; age, sex, tobacco use and education were included as covariates). The relationship between negative acts and pain intensity was significantly stronger for subjects with the LALA genotype than for subjects with the SLA/LALG/SLG genotype. No significant difference between subjects with the LALA genotype and SS genotype was observed. Conclusions Our data demonstrated that the relationship between bullying and pain was modified by the 5-HTT genotype, ie, genetic variation in SLC6A4. The association between negative acts and health among vulnerable individuals appeared more potent than previously reported.

Generation of KCL028 research grade human embryonic stem cell line carrying a mutation in the HTT gene

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Laureen Jacquet

2016-03-01

Full Text Available The KCL028 human embryonic stem cell line was derived from an embryo donated for research that carried an autosomal dominant mutation affecting one allele of the HTT gene encoding huntingtin (43 trinucleotide repeats; 21 for the normal allele. The ICM was isolated using laser microsurgery and plated on γ-irradiated human foreskin fibroblasts. Both the derivation and cell line propagation were performed in an animal product-free environment. Pluripotent state and differentiation potential were confirmed by in vitro and in vivo assays.

Serotonin Transporter (5-HTT) and gamma-Aminobutyric Acid Receptor Subunit beta3 (GABRB3) Gene Polymorphisms are not Associated with Autism in the IMGSA Families

DEFF Research Database (Denmark)

Maestrini, E.; Lai, C.; Marlow, A.

1999-01-01

Previous studies have suggested that the serotonin transporter (5-HTT) gene and the gamma-aminobutyric acid receptor subunit beta3 (GABRB3) gene, or other genes in the 15q11-q13 region, are possibly involved in susceptibility to autism. To test this hypothesis we performed an association study on...

Impact of Institutional Care on Attachment Disorganization and Insecurity of Ukrainian Preschoolers: Protective Effect of the Long Variant of the Serotonin Transporter Gene (5HTT)

Science.gov (United States)

Bakermans-Kranenburg, Marian J.; Dobrova-Krol, Natasha; van IJzendoorn, Marinus

2012-01-01

Institutional care has been shown to lead to insecure and disorganized attachments and indiscriminate friendliness. Some children, however, are surprisingly resilient to the adverse environment. Here the protective role of the long variant of the serotonin receptor gene (5HTT) is explored in a small hypothesis-generating study of 37 Ukrainian…

Kõlar Hi-Waf / Ell-Maaja Randküla

Index Scriptorium Estoniae

Randküla, Ell-Maaja, 1939-2016

2005-01-01

Disain: Galina Burnakova. Tootja: AS Sarkop. Kõlar Hi-Waf tehti Brüsselis galeriis Creneau International toimuvale näitusele viimiseks. Galina Burnakovast, tema erialasest tegevusest. Ill.: kõlari vaade, foto sisearhtektist

Life satisfaction in the new country: a multilevel longitudinal analysis of effects of culture and 5-HTT allele frequency distribution in country of origin.

Science.gov (United States)

Kashima, Emiko S; Kent, Stephen; Kashima, Yoshihisa

2015-01-01

Life satisfaction of migrants to Australia from 17 countries, assessed at 4-5 months, 16-17 months and 3½ years after arrival, was analyzed with a longitudinal, multilevel analysis. The results indicated that migrants were more satisfied, if the national average life satisfaction was higher in their country of origin, after adjustment for individual-level income, age, and sex and a linear temporal trend. Simultaneously, the migrants were also happier if people in their country of origin had a higher frequency of 5-HTT long allele, a genotype known to be associated with resilience under life stresses. These two relationships were independent, suggesting that both culture and gene matter in international transitions. © The Author (2014). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

Influence of 5-HTT variation, childhood trauma and self-efficacy on anxiety traits: a gene-environment-coping interaction study.

Science.gov (United States)

Schiele, Miriam A; Ziegler, Christiane; Holitschke, Karoline; Schartner, Christoph; Schmidt, Brigitte; Weber, Heike; Reif, Andreas; Romanos, Marcel; Pauli, Paul; Zwanzger, Peter; Deckert, Jürgen; Domschke, Katharina

2016-08-01

Environmental vulnerability factors such as adverse childhood experiences in interaction with genetic risk variants, e.g., the serotonin transporter gene linked polymorphic region (5-HTTLPR), are assumed to play a role in the development of anxiety and affective disorders. However, positive influences such as general self-efficacy (GSE) may exert a compensatory effect on genetic disposition, environmental adversity, and anxiety traits. We, thus, assessed childhood trauma (Childhood Trauma Questionnaire, CTQ) and GSE in 678 adults genotyped for 5-HTTLPR/rs25531 and their interaction on agoraphobic cognitions (Agoraphobic Cognitions Questionnaire, ACQ), social anxiety (Liebowitz Social Anxiety Scale, LSAS), and trait anxiety (State-Trait Anxiety Inventory, STAI-T). The relationship between anxiety traits and childhood trauma was moderated by self-efficacy in 5-HTTLPR/rs25531 LALA genotype carriers: LALA probands maltreated as children showed high anxiety scores when self-efficacy was low, but low anxiety scores in the presence of high self-efficacy despite childhood maltreatment. Our results extend previous findings regarding anxiety-related traits showing an interactive relationship between 5-HTT genotype and adverse childhood experiences by suggesting coping-related measures to function as an additional dimension buffering the effects of a gene-environment risk constellation. Given that anxiety disorders manifest already early in childhood, this insight could contribute to the improvement of psychotherapeutic interventions by including measures strengthening self-efficacy and inform early targeted preventive interventions in at-risk populations, particularly within the crucial time window of childhood and adolescence.

Huntingtin Protein is Essential for Mitochondrial Metabolism, Bioenergetics and Structure in Murine Embryonic Stem Cells

Science.gov (United States)

Ismailoglu, Ismail; Chen, Qiuying; Popowski, Melissa; Yang, Lili; Gross, Steven S.; Brivanlou, Ali H.

2014-01-01

Mutations in the Huntington locus (htt) have devastating consequences. Gain-of-poly-Q repeats in Htt protein causes Huntington's disease (HD), while htt-/- mutants display early embryonic lethality. Despite its importance, the function of Htt remains elusive. To address this, we compared more than 3,700 compounds in three syngeneic mouse embryonic stem cell (mESC) lines: htt-/-, extended poly-Q (Htt-Q140/7), and wildtype mESCs (Htt-Q7/7) using untargeted metabolite profiling. While Htt-Q140/7 cells, did not show major differences in cellular bioenergetics, we find extensive metabolic aberrations in htt-/- mESCs, including: (i) complete failure of ATP production despite preservation of the mitochondrial membrane potential; (ii) near-maximal glycolysis, with little or no glycolytic reserve; (iii) marked ketogenesis; (iv) depletion of intracellular NTPs; (v) accelerated purine biosynthesis and salvage; and (vi) loss of mitochondrial structural integrity. Together, our findings reveal that Htt is necessary for mitochondrial structure and function from the earliest stages of embryogenesis, providing a molecular explanation for htt-/- early embryonic lethality. PMID:24780625

Preventing mutant huntingtin proteolysis and intermittent fasting promote autophagy in models of Huntington disease.

Science.gov (United States)

Ehrnhoefer, Dagmar E; Martin, Dale D O; Schmidt, Mandi E; Qiu, Xiaofan; Ladha, Safia; Caron, Nicholas S; Skotte, Niels H; Nguyen, Yen T N; Vaid, Kuljeet; Southwell, Amber L; Engemann, Sabine; Franciosi, Sonia; Hayden, Michael R

2018-03-06

Huntington disease (HD) is caused by the expression of mutant huntingtin (mHTT) bearing a polyglutamine expansion. In HD, mHTT accumulation is accompanied by a dysfunction in basal autophagy, which manifests as specific defects in cargo loading during selective autophagy. Here we show that the expression of mHTT resistant to proteolysis at the caspase cleavage site D586 (C6R mHTT) increases autophagy, which may be due to its increased binding to the autophagy adapter p62. This is accompanied by faster degradation of C6R mHTT in vitro and a lack of mHTT accumulation the C6R mouse model with age. These findings may explain the previously observed neuroprotective properties of C6R mHTT. As the C6R mutation cannot be easily translated into a therapeutic approach, we show that a scheduled feeding paradigm is sufficient to lower mHTT levels in YAC128 mice expressing cleavable mHTT. This is consistent with a previous model, where the presence of cleavable mHTT impairs basal autophagy, while fasting-induced autophagy remains functional. In HD, mHTT clearance and autophagy may become increasingly impaired as a function of age and disease stage, because of gradually increased activity of mHTT-processing enzymes. Our findings imply that mHTT clearance could be enhanced by a regulated dietary schedule that promotes autophagy.

Full-length huntingtin levels modulate body weight by influencing insulin-like growth factor 1 expression

DEFF Research Database (Denmark)

Pouladi, Mahmoud A; Xie, Yuanyun; Skotte, Niels Henning

2010-01-01

of the IGF-1 pathway in mediating the effect of htt on body weight. IGF-1 expression was examined in transgenic mouse lines expressing different levels of FL wild-type (WT) htt (YAC18 mice), FL mutant htt (YAC128 and BACHD mice) and truncated mutant htt (shortstop mice). We demonstrate that htt influences...... body weight by modulating the IGF-1 pathway. Plasma IGF-1 levels correlate with body weight and htt levels in the transgenic YAC mice expressing human htt. The effect of htt on IGF-1 expression is independent of CAG size. No effect on body weight is observed in transgenic YAC mice expressing...... and decreases the body weight of YAC128 animals to WT levels. Furthermore, given the ubiquitous expression of IGF-1 within the central nervous system, we also examined the impact of FL htt levels on IGF-1 expression in different regions of the brain, including the striatum, cerebellum of YAC18, YAC128...

Hyalinizing trabecular tumor of the thyroid: Diagnosed of a rare tumor using ultrasonography, cytology, and intraoperative frozen sections

Energy Technology Data Exchange (ETDEWEB)

Jang, Hyun Sik; Kim, Eun Kyung; Kwak, Jin Young; Moon, Hee Jung; Yoon, Jung Hyun [Dept. of Radiology, Severance Hospital, Research Institute of Radiological Science, Yonsei University, College of Medicine, Seoul (Korea, Republic of); Park, Cheol Keun; Son, Eun Ju [Gangnam Severance Hospital, Yonsei University, College of Medicine, Seoul (Korea, Republic of)

2016-03-15

The goal of this study was to evaluate the clinicopathological and imaging features of thyroid nodules surgically diagnosed as hyaline trabecular tumor (HTT), and to assess the role of cytology and frozen sections (FS) in the diagnosis of HTT. This study included 21 thyroid nodules in 21 patients treated from August 2005 to March 2015 (mean age, 53.3 years) who were either diagnosed as HTT or had HTT suggested as a possible diagnosis based on cytology, FS, or the final pathology report. Patients' medical records were retrospectively reviewed for cytopathologic results and outcomes during the course of follow-up. Sonograms were reviewed and categorized. Twelve nodules from 12 patients were surgically confirmed as HTT. Ultrasonography (US)-guided fine needle aspiration (FNA) was performed on 11 nodules, of which six (54.5%) were papillary thyroid carcinoma (PTC) or suspicious for PTC and three (27.3%) were HTT or suspicious for HTT. Intraoperative FS suggested the possibility of HTT in seven nodules, of which four (57.1%) were confirmed as HTT. US-FNA suggested the diagnosis of HTT in 10 nodules, of which three (30.0%) were confirmed as HTT. Common US features of the 12 pathologically confirmed cases of HTT were hypoechogenicity or marked hypoechogenicity (83.4%), absence of calcifications (91.7%), parallel shape (100.0%), presence of vascularity (75.0%), and probable benignity (58.3%). HTT should be included in the differential diagnosis of solid tumors with hypoechogenicity or marked hypoechogenicity and otherwise benign US features that have been diagnosed as PTC through cytology.

Hyalinizing trabecular tumor of the thyroid: Diagnosed of a rare tumor using ultrasonography, cytology, and intraoperative frozen sections

International Nuclear Information System (INIS)

Jang, Hyun Sik; Kim, Eun Kyung; Kwak, Jin Young; Moon, Hee Jung; Yoon, Jung Hyun; Park, Cheol Keun; Son, Eun Ju

2016-01-01

The goal of this study was to evaluate the clinicopathological and imaging features of thyroid nodules surgically diagnosed as hyaline trabecular tumor (HTT), and to assess the role of cytology and frozen sections (FS) in the diagnosis of HTT. This study included 21 thyroid nodules in 21 patients treated from August 2005 to March 2015 (mean age, 53.3 years) who were either diagnosed as HTT or had HTT suggested as a possible diagnosis based on cytology, FS, or the final pathology report. Patients' medical records were retrospectively reviewed for cytopathologic results and outcomes during the course of follow-up. Sonograms were reviewed and categorized. Twelve nodules from 12 patients were surgically confirmed as HTT. Ultrasonography (US)-guided fine needle aspiration (FNA) was performed on 11 nodules, of which six (54.5%) were papillary thyroid carcinoma (PTC) or suspicious for PTC and three (27.3%) were HTT or suspicious for HTT. Intraoperative FS suggested the possibility of HTT in seven nodules, of which four (57.1%) were confirmed as HTT. US-FNA suggested the diagnosis of HTT in 10 nodules, of which three (30.0%) were confirmed as HTT. Common US features of the 12 pathologically confirmed cases of HTT were hypoechogenicity or marked hypoechogenicity (83.4%), absence of calcifications (91.7%), parallel shape (100.0%), presence of vascularity (75.0%), and probable benignity (58.3%). HTT should be included in the differential diagnosis of solid tumors with hypoechogenicity or marked hypoechogenicity and otherwise benign US features that have been diagnosed as PTC through cytology

A series of N-terminal epitope tagged Hdh knock-in alleles expressing normal and mutant huntingtin: their application to understanding the effect of increasing the length of normal huntingtin’s polyglutamine stretch on CAG140 mouse model pathogenesis

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Zheng Shuqiu

2012-08-01

Full Text Available Abstract Background Huntington’s disease (HD is an autosomal dominant neurodegenerative disease that is caused by the expansion of a polyglutamine (polyQ stretch within Huntingtin (htt, the protein product of the HD gene. Although studies in vitro have suggested that the mutant htt can act in a potentially dominant negative fashion by sequestering wild-type htt into insoluble protein aggregates, the role of the length of the normal htt polyQ stretch, and the adjacent proline-rich region (PRR in modulating HD mouse model pathogenesis is currently unknown. Results We describe the generation and characterization of a series of knock-in HD mouse models that express versions of the mouse HD gene (Hdh encoding N-terminal hemaglutinin (HA or 3xFlag epitope tagged full-length htt with different polyQ lengths (HA7Q-, 3xFlag7Q-, 3xFlag20Q-, and 3xFlag140Q-htt and substitution of the adjacent mouse PRR with the human PRR (3xFlag20Q- and 3xFlag140Q-htt. Using co-immunoprecipitation and immunohistochemistry analyses, we detect no significant interaction between soluble full-length normal 7Q- htt and mutant (140Q htt, but we do observe N-terminal fragments of epitope-tagged normal htt in mutant htt aggregates. When the sequences encoding normal mouse htt’s polyQ stretch and PRR are replaced with non-pathogenic human sequence in mice also expressing 140Q-htt, aggregation foci within the striatum, and the mean size of htt inclusions are increased, along with an increase in striatal lipofuscin and gliosis. Conclusion In mice, soluble full-length normal and mutant htt are predominantly monomeric. In heterozygous knock-in HD mouse models, substituting the normal mouse polyQ and PRR with normal human sequence can exacerbate some neuropathological phenotypes.

Huntingtin coordinates the dynein-mediated dynamic positioning of endosomes and lysosomes

Science.gov (United States)

Caviston, Juliane P.; Zajac, Allison L.; Tokito, Mariko; Holzbaur, Erika L.F.

2011-01-01

Huntingtin (Htt) is a membrane-associated scaffolding protein that interacts with microtubule motors as well as actin-associated adaptor molecules. We examined a role for Htt in the dynein-mediated intracellular trafficking of endosomes and lysosomes. In HeLa cells depleted of either Htt or dynein, early, recycling, and late endosomes (LE)/lysosomes all become dispersed. Despite altered organelle localization, kinetic assays indicate only minor defects in intracellular trafficking. Expression of full-length Htt is required to restore organelle localization in Htt-depleted cells, supporting a role for Htt as a scaffold that promotes functional interactions along its length. In dynein-depleted cells, LE/lysosomes accumulate in tight patches near the cortex, apparently enmeshed by cortactin-positive actin filaments; Latrunculin B-treatment disperses these patches. Peripheral LE/lysosomes in dynein-depleted cells no longer colocalize with microtubules. Htt may be required for this off-loading, as the loss of microtubule association is not seen in Htt-depleted cells or in cells depleted of both dynein and Htt. Inhibition of kinesin-1 relocalizes peripheral LE/lysosomes induced by Htt depletion but not by dynein depletion, consistent with their detachment from microtubules upon dynein knockdown. Together, these data support a model of Htt as a facilitator of dynein-mediated trafficking that may regulate the cytoskeletal association of dynamic organelles. PMID:21169558

Når der bliver sat pris på teatret

DEFF Research Database (Denmark)

Kuhlmann, Annelis

2006-01-01

Galina Polischujs forestilling Put, bejini! (Blow, wind!), der vandt flere priser ved Spelmanu Nakts i november 2005. Forestillingen anmeldes og perspektiveres til diskussioner om historieskrivning og national kanon. Udgivelsesdato: marts...

The cryo-electron microscopy structure of huntingtin

Science.gov (United States)

Guo, Qiang; Bin Huang; Cheng, Jingdong; Seefelder, Manuel; Engler, Tatjana; Pfeifer, Günter; Oeckl, Patrick; Otto, Markus; Moser, Franziska; Maurer, Melanie; Pautsch, Alexander; Baumeister, Wolfgang; Fernández-Busnadiego, Rubén; Kochanek, Stefan

2018-03-01

Huntingtin (HTT) is a large (348 kDa) protein that is essential for embryonic development and is involved in diverse cellular activities such as vesicular transport, endocytosis, autophagy and the regulation of transcription. Although an integrative understanding of the biological functions of HTT is lacking, the large number of identified HTT interactors suggests that it serves as a protein-protein interaction hub. Furthermore, Huntington’s disease is caused by a mutation in the HTT gene, resulting in a pathogenic expansion of a polyglutamine repeat at the amino terminus of HTT. However, only limited structural information regarding HTT is currently available. Here we use cryo-electron microscopy to determine the structure of full-length human HTT in a complex with HTT-associated protein 40 (HAP40; encoded by three F8A genes in humans) to an overall resolution of 4 Å. HTT is largely α-helical and consists of three major domains. The amino- and carboxy-terminal domains contain multiple HEAT (huntingtin, elongation factor 3, protein phosphatase 2A and lipid kinase TOR) repeats arranged in a solenoid fashion. These domains are connected by a smaller bridge domain containing different types of tandem repeats. HAP40 is also largely α-helical and has a tetratricopeptide repeat-like organization. HAP40 binds in a cleft and contacts the three HTT domains by hydrophobic and electrostatic interactions, thereby stabilizing the conformation of HTT. These data rationalize previous biochemical results and pave the way for improved understanding of the diverse cellular functions of HTT.

Scalable production in human cells and biochemical characterization of full-length normal and mutant huntingtin.

Directory of Open Access Journals (Sweden)

Bin Huang

Full Text Available Huntingtin (Htt is a 350 kD intracellular protein, ubiquitously expressed and mainly localized in the cytoplasm. Huntington's disease (HD is caused by a CAG triplet amplification in exon 1 of the corresponding gene resulting in a polyglutamine (polyQ expansion at the N-terminus of Htt. Production of full-length Htt has been difficult in the past and so far a scalable system or process has not been established for recombinant production of Htt in human cells. The ability to produce Htt in milligram quantities would be a prerequisite for many biochemical and biophysical studies aiming in a better understanding of Htt function under physiological conditions and in case of mutation and disease. For scalable production of full-length normal (17Q and mutant (46Q and 128Q Htt we have established two different systems, the first based on doxycycline-inducible Htt expression in stable cell lines, the second on "gutless" adenovirus mediated gene transfer. Purified material has then been used for biochemical characterization of full-length Htt. Posttranslational modifications (PTMs were determined and several new phosphorylation sites were identified. Nearly all PTMs in full-length Htt localized to areas outside of predicted alpha-solenoid protein regions. In all detected N-terminal peptides methionine as the first amino acid was missing and the second, alanine, was found to be acetylated. Differences in secondary structure between normal and mutant Htt, a helix-rich protein, were not observed in our study. Purified Htt tends to form dimers and higher order oligomers, thus resembling the situation observed with N-terminal fragments, although the mechanism of oligomer formation may be different.

Bagatellid / Mirjam Tally

Index Scriptorium Estoniae

Tally, Mirjam, 1976-

2007-01-01

Galina Rostropovitš-Višnevskaja kunstikollektsioon ja Ambrose Gauntletti autogrammikogu oksionidel. Hiroshima aatiomipommirünnakus kahjustada saanud klaver taastatud. Bayreuthi ooperifestival otsib uut juhti Richard Wagneri sugulaste hulgas. Parim poogen valmib pernambuco'st

Podarok fotografov k 8 Marta / A. Shurina

Index Scriptorium Estoniae

Shurina, A.

1999-01-01

Naistepäevaeelsest fotonäitusest 'Objektiiv kui elu peegel' Narva kindluses. Enamik autoreid ja fotografeerituid on naised. Osalevad Tatjana Novikova, Irina Ivanen, Irina Kivimäe, Galina Bannikova, Sergei Andrejev, Valeri Boltushin jt.

Reduced availability of serotonin transporters in obsessive-compulsive disorder correlates with symptom severity - a [11C]DASB PET study

International Nuclear Information System (INIS)

Reimold, M.; Smolka, M.N.; Zimmer, A.

2007-01-01

Reduced availability of brainstem serotonin transporters (5-HTT) has been observed in vivo in obsessive-compulsive disorder (OCD). However, results vary and may be influenced by competition with endogenous serotonin. Using positron emission tomography (PET) and [ 11 C]DASB, a specific 5-HTT ligand that showed no competition with serotonin for 5-HTT binding in vitro, we tested the hypothesis that 5-HTT availability is reduced in OCD patients and correlated with OCD severity. 5-HTT availability in the thalamus and the midbrain was measured in nine drug-free OCD patients and compared with 19 healthy controls, matched for the individual combination of 5-HTT genotype, gender and smoking status. OCD severity was assessed with the Yale-Brown obsessive compulsive scale (Y-BOCS). 5-HTT availability was significantly reduced in the thalamus and midbrain of OCD patients. Age and 5-HTT in the thalamus explained 83 % of OCD severity in patients that were drug-free for at least 1 year. This PET study confirms a central role of the serotonergic system, particularly the thalamus in the pathogenesis of obsessive compulsive disorder. (author)

Heinekeni baar = Heineken bar

Index Scriptorium Estoniae

2012-01-01

Heinekeni baari (Tallinn, Harju 6) sisekujundusest, mis on inspireeritud õlletootja reklaamist, kus tegevus toimub walk-in-külmkapi ümber. Autorid: sisearhitekt Galina Burnakova, arhitekt Gert Sarv (November AB), loetletud nende tehtud töid

Abielupaar süüdistas Maximat depressiooni ja peavalu tekitamises / Kristina Traks

Index Scriptorium Estoniae

Traks, Kristina, 1976-

2008-01-01

Viktor ja Galina Petkevitsh vaidlesid Maxima Eestiga kuni riigikohtuni välja, süüdistades kauplust oma akende all kolistamises ning inimväärse elu rikkumises. Riigikohus poelt kahjutasu välja ei nõudnud

Клетка для зверя

Index Scriptorium Estoniae

2009-01-01

Emil Lotjanu filmi "Mu hell ja õrn metsloom" saamislugu (1978). Film põhineb Anton Tšehhovi jutustusel "Draama jahil". Peaosatäitja Galina Beljajeva meenutab. Ka filmi helilooja Jevgeni Doga oma kuulsaks saanud valsi sünniloost

Maintenance of Chronic Fatigue Syndrome (CFS in Young CFS Patients Is Associated with the 5-HTTLPR and SNP rs25531 A > G Genotype.

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Benedicte Meyer

Full Text Available Earlier studies have shown that genetic variability in the SLC6A4 gene encoding the serotonin transporter (5-HTT may be important for the re-uptake of serotonin (5-HT in the central nervous system. In the present study we investigated how the 5-HTT genotype i.e. the short (S versus long (L 5-HTTLPR allele and the SNP rs25531 A > G affect the physical and psychosocial functioning in patients with chronic fatigue syndrome (CFS. All 120 patients were recruited from The Department of Paediatrics at Oslo University Hospital, Norway, a national referral center for young CFS patients (12-18 years. Main outcomes were number of steps per day obtained by an accelerometer and disability scored by the Functional Disability Inventory (FDI. Patients with the 5-HTT SS or SLG genotype had a significantly lower number of steps per day than patients with the 5-HTT LALG, SLA or LALA genotype. Patients with the 5-HTT SS or SLG genotype also had a significantly higher FDI score than patients with the 5-HTT LALG, SLA or LALA genotype. Thus, CFS patients with the 5-HTT SS or SLG genotype had worse 30 weeks outcome than CFS patients with the 5-HTT LALG, SLA or LALA genotype. The present study suggests that the 5-HTT genotype may be a factor that contributes to maintenance of CFS.

From social cognition to social epistemology (in memory of G.M. Andreeva

Directory of Open Access Journals (Sweden)

Dmitry A. Khoroshilov

2016-09-01

Full Text Available This paper is dedicated to scientific and literary heritage of Galina M. Andreeva. The methodology of social cognition, for more than half a century developed by Galina M. Andreeva as a tool of social analysis, is discussed. The problem of social cognition, first indicated by V. Turner, Z. Bauman and M. Mamardashvili, is analysed in terms of mentalization, interpersonal interaction and mass consciousness. Based on G. Andreeva’s theoretical research, the correlation between micro-processes of individual cognition construction and macro-processes of society in communication, dialogue and discourse is proved. The issue of finding the correct definition of a group, mass or public consciousness epistemological status is taken as a result of an old trend toward anthropomorphizing the collective cognition subject. This impedes the correlation between personality and society in psychology, meaning “agency” and “structure” in sociology. G.Andreeva discusses the last one, connecting cognitive psychology, social constructionism and activity theory. Theoretical assumptions of social cognition as the process of world image construction are formulated as follows: 1 presumption of general knowledge; 2 active constructive nature; 3 categorization and classification as the basic process; 4 the relationship between discourse and cognition; 5 emotionality; 6 critical orientation; 7 prospective for the clinical analysis of sociocultural realities. With respect to the abovementioned facts, it can be said that the ideas of scientific school founded by Galina М. Andreeva allow to innovatively define social psychology as a modern social and cultural epistemology.

Russian officials attempt to smash "myths" about the Mari / Ksenia Repson

Index Scriptorium Estoniae

Repson, Ksenia

2005-01-01

7. juulil kohtusid Vene Riigiduuma saadik Valeri Komissarov ja Marimaa regiooni aseminister Galina Shirjajeva Tallinnas Vene suursaadikuga Eestis Konstantin Provaloviga ja regionaalministri nõuniku Aarne Veedlaga, et lükata ümber kuulujutud maride inimõiguste rikkumisest Venemaal

Calcium Handling by Endoplasmic Reticulum and Mitochondria in a Cell Model of Huntington’s Disease

Science.gov (United States)

De Mario, Agnese; Scarlatti, Chiara; Costiniti, Veronica; Primerano, Simona; Lopreiato, Raffaele; Calì, Tito; Brini, Marisa; Giacomello, Marta; Carafoli, Ernesto

2016-01-01

Huntington disease (HD) is caused by the CAG (Q) expansion in exon 1 of the IT15 gene encoding a polyglutamine (poly-Q) stretch of the Huntingtin protein (Htt). In the wild type protein, the repeats specify a stretch of up 34 Q in the N-terminal portion of Htt. In the pathological protein (mHtt) the poly-Q tract is longer. Proteolytic cleavage of the protein liberates an N-terminal fragment containing the expanded poly-Q tract becomes harmful to cells, in particular to striatal neurons. The fragments cause the transcriptional dysfunction of genes that are essential for neuronal survival. Htt, however, could also have non-transcriptional effects, e.g. it could directly alter Ca2+ homeostasis and/or mitochondrial morphology and function. Ca2+ dyshomeostasis and mitochondrial dysfunction are considered important in the molecular aetiology of the disease. Here we have analyzed the effect of the overexpression of Htt fragments (18Q, wild type form, wtHtt and 150Q mutated form, mHtt) on Ca2+ homeostasis in striatal neuronal precursor cells (Q7/7). We have found that the transient overexpression of the Htt fragments increases Ca2+ transients in the mitochondria of cells stimulated with Ca2+-mobilizing agonists. The bulk Ca2+ transients in the cytosol were unaffected, but the Ca2+ content of the endoplasmic reticulum was significantly decreased in the case of mHtt expression. To rule out possible transcriptional effects due to the presence of mHtt, we have measured the mRNA level of a subunit of the respiratory chain complex II, whose expression is commonly altered in many HD models. No effects on the mRNA level was found suggesting that, in our experimental condition, transcriptional action of Htt is not occurring and that the effects on Ca2+ homeostasis were dependent to non-transcriptional mechanisms. PMID:26819834

Calcium Handling by Endoplasmic Reticulum and Mitochondria in a Cell Model of Huntington's Disease.

Science.gov (United States)

De Mario, Agnese; Scarlatti, Chiara; Costiniti, Veronica; Primerano, Simona; Lopreiato, Raffaele; Calì, Tito; Brini, Marisa; Giacomello, Marta; Carafoli, Ernesto

2016-01-06

Huntington disease (HD) is caused by the CAG (Q) expansion in exon 1 of the IT15 gene encoding a polyglutamine (poly-Q) stretch of the Huntingtin protein (Htt). In the wild type protein, the repeats specify a stretch of up 34 Q in the N-terminal portion of Htt. In the pathological protein (mHtt) the poly-Q tract is longer. Proteolytic cleavage of the protein liberates an N-terminal fragment containing the expanded poly-Q tract becomes harmful to cells, in particular to striatal neurons. The fragments cause the transcriptional dysfunction of genes that are essential for neuronal survival. Htt, however, could also have non-transcriptional effects, e.g. it could directly alter Ca2+ homeostasis and/or mitochondrial morphology and function. Ca2+ dyshomeostasis and mitochondrial dysfunction are considered important in the molecular aetiology of the disease. Here we have analyzed the effect of the overexpression of Htt fragments (18Q, wild type form, wtHtt and 150Q mutated form, mHtt) on Ca2+ homeostasis in striatal neuronal precursor cells (Q7/7). We have found that the transient overexpression of the Htt fragments increases Ca2+ transients in the mitochondria of cells stimulated with Ca2+-mobilizing agonists. The bulk Ca2+ transients in the cytosol were unaffected, but the Ca2+ content of the endoplasmic reticulum was significantly decreased in the case of mHtt expression. To rule out possible transcriptional effects due to the presence of mHtt, we have measured the mRNA level of a subunit of the respiratory chain complex II, whose expression is commonly altered in many HD models. No effects on the mRNA level was found suggesting that, in our experimental condition, transcriptional action of Htt is not occurring and that the effects on Ca2+ homeostasis were dependent to non-transcriptional mechanisms.

A new model for separation between brain dopamine and serotonin transporters in {sup 123}I-{beta}-CIT SPECT measurements: normal values and sex and age dependence

Energy Technology Data Exchange (ETDEWEB)

Ryding, Erik; Rosen, Ingmar [Department of Clinical Neurophysiology, University Hospital, Lund (Sweden); Lindstroem, Mats; Bosson, Peter; Traeskman-Bendz, Lil [Department of Psychiatry, University Hospital, Lund (Sweden); Braadvik, Bjoern; Grabowski, Martin [Department of Neurology, University Hospital, Lund (Sweden)

2004-08-01

{sup 123}I-{beta}-CIT is a radioactive ligand for single-photon emission computed tomography (SPECT) imaging of the pre-synaptic (transporter) re-uptake sites for dopamine (DAT) and serotonin (5HTT), and it is widely used to visualize monoamine turnover. Since {sup 123}I-{beta}-CIT uptake occurs at 5HTT and DAT sites in conjunction with the presence of freely soluble {sup 123}I-{beta}-CIT in brain tissue, adequate separation of these three components is necessary. However, only partial separation is possible with current methods. Two main strategies have previously been used for {sup 123}I-{beta}-CIT component separation, based on the following considerations: (1) the faster uptake rate for 5HTT compared with DAT enables temporal separation by performing 5HTT imaging at 1-2 h and DAT imaging at 20-24 h; (2) blocking the 5HTT re-uptake with citalopram renders {sup 123}I-{beta}-CIT imaging DAT (non-5HTT) specific. In a new analytical model, we combined these two approaches with methods to isolate the passively dissolved {sup 123}I-{beta}-CIT in brain tissue from the monoamine transporter uptake, and to correct the 5HTT and DAT values for concomitant uptake. The new analytical model was used to study brain 5HTT and DAT in 23 normal subjects, with the aim of clarifying the effect of age and sex. A significant correlation between 5HTT and DAT values was found only in the thalamus, indicating successful component separation. Negative correlations between age and DAT were found for basal ganglia, thalami, brain stem and temporal lobes, but not for the frontal, parietal or occipital regions. No correlation with age was found for 5HTT. We found no sex difference for 5HTT or DAT. (orig.)

V Novõi god s novõmi võstavkami / Vitali Shkola

Index Scriptorium Estoniae

Shkola, Vitali

2008-01-01

Kunstinäitustest Sillamäe raamatukogus. Kuni 30. jaanuarini on raamatukogus avatud Galina Perova käsitööstuudio näitus "Tikkimiskunst - see on kaunis!" ja "Taru" kunstiklasside õpilaste tööd "Ida-Virumaa pildid"

Midbrain serotonin transporter binding potential measured with [11C]DASB is affected by serotonin transporter genotype

International Nuclear Information System (INIS)

Reimold, M.; Bares, R.; Reischl, G.; Solbach, C.; Machulla, H.-J.; Smolka, M.N.; Mann, K.; Schumann, G.; Zimmer, A.; Wrase, J.; Hu, X.-Z.; Goldman, D.; Heinz, A.

2007-01-01

Homozygote carriers of two long (L) alleles of the serotonin transporter (5-HTT) regulatory region displayed in vitro a twofold increase in 5-HTT expression compared with carriers of one or two short (S) alleles. However, in vivo imaging studies yielded contradictory results. Recently, an A > G exchange leading to differential transcriptional activation of 5-HTT mRNA in lymphobalstoid cell lines was discovered in the 5-HTT regulatory region. In vitro and in vivo evidence suggests that [ 11 C]DASB, a new 5-HTT ligand offers some advantages over the ligands used in previous studies in measuring 5-HTT density independent of synaptic levels of serotonin. We assessed 5-HTT binding potential (BP 2) in the midbrain of 19 healthy subjects with positron emission tomography and [ 11 C]DASB. Accounting for the hypothesized functional similarity of L G and S in driving 5-HTT transcription, we assessed whether L A L A homozygotes display increased midbrain BP 2 compared with carriers of at least one S allele. BP 2 in the midbrain was significantly increased in L A L A homozygotes compared with carriers of at least one S allele. Interestingly, the genotype effect on the midbrain was significantly different from that on the thalamus and the amygdala where no group differences were detected. This in vivo study provides further evidence that subjects homozygous for the L A allele display increased expression of 5-HTT in the midbrain, the origin of central serotonergic projections. (author)

SUMO-2 and PIAS1 Modulate Insoluble Mutant Huntingtin Protein Accumulation

Directory of Open Access Journals (Sweden)

Jacqueline Gire O’Rourke

2013-07-01

Full Text Available A key feature in Huntington disease (HD is the accumulation of mutant Huntingtin (HTT protein, which may be regulated by posttranslational modifications. Here, we define the primary sites of SUMO modification in the amino-terminal domain of HTT, show modification downstream of this domain, and demonstrate that HTT is modified by the stress-inducible SUMO-2. A systematic study of E3 SUMO ligases demonstrates that PIAS1 is an E3 SUMO ligase for both HTT SUMO-1 and SUMO-2 modification and that reduction of dPIAS in a mutant HTT Drosophila model is protective. SUMO-2 modification regulates accumulation of insoluble HTT in HeLa cells in a manner that mimics proteasome inhibition and can be modulated by overexpression and acute knockdown of PIAS1. Finally, the accumulation of SUMO-2-modified proteins in the insoluble fraction of HD postmortem striata implicates SUMO-2 modification in the age-related pathogenic accumulation of mutant HTT and other cellular proteins that occurs during HD progression.

Moskovski desant / Galina Balashova

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Balashova, Galina

2006-01-01

Tallinna Vene saatkonna galerii osalemisest Madridi ja Moskva kunstilaatadel. Moskva kunstiajakirjast "Iskusstvo" ja selle esitlusest peatoimetaja Leonid Lerneri poolt Tallinna Vene saatkonna galeriis. Samas toimuvast Vene kaasaegse kunsti näitusest "Moskva ja teised". Tööd on Moskva galerii Artgentum (direktor Leonid Lerner) kogust. Lähemalt Damir Muratovi, Ruslan Vashkevitshi ja Rinata Voligamsi loomingust

Sad naslazhdeni / Galina Balashova

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Balashova, Galina

2003-01-01

Eesti Metallikunstnike Liidu korraldatud ehtekunsti näitusest "Palve. Puudutus. Patt" Tallinna Kunstihoone galeriis. Taimi Soo kujundusest. Jaanika Pajuste, Julia Pihlaku, Urve Küttneri, Andrei Balashovi, Jaan Pärna, Lilian Linnaksi, Kärt Summataveti, Rein Metsa ja Harvi Varkki töödest näitusel

Golosa pamjati / Galina Balashova

Index Scriptorium Estoniae

Balashova, Galina

2005-01-01

Tallinna Vene saatkonna galeriis avatud sõjateemalist vene kaasaegse kunsti näitust tutvustab näituse kuraator Bogdan Mamonov. Peterburi uue põlvkonna kunstniku Vitali Pushnitski, Moskva fotograafi Vladimir Kuprijanovi ja Peterburi kunstniku Natalja Pershina-Jakimanskaja töödest näitusel

Iskusstvo objekta / Galina Balashova

Index Scriptorium Estoniae

Balashova, Galina

2006-01-01

Tallinna IV rakenduskunsti triennaalist "Kaks lähedast" Eesti Tarbekunsti- ja Disainimuuseumis. Triennaali erikülalise inglise ehtekunstniku Wendy Ramshaw ehtesarjast "Picasso's ladies". Maris Galise, Krista Leesi, Andrea Petrakovièi, Rozemarijn Van der Moleni, Kärt Summataveti, Hilde Foksi, Jurgita Erminaite, Piret Valgu, Jurate Petruskeviciene, Tine Deweerdt'i, Ave Maseri ja Kadri Pärnametsa töödest näitusel

Perspektiva sozvutshi / Galina Balashova

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Balashova, Galina

2004-01-01

Kultuurifestivalil Trialogos-2004 osaleb Ukraina kreeka-katoliku kiriku Tallinna koguduse vanempreester ja kunstnik Anatoli Ljutjuk. Tallinna Laboratooriumi tänaval asuvast kirikust kui kultuurikeskusest, mille keldrisaalis korraldatakse kunstinäitusi ja joonistatakse pühapäevakooli-lastega Looduse Punast Raamatut. Festivali raames avati seal Reti Saksa tööde näitus

Frequency of nuclear mutant huntingtin inclusion formation in neurons and glia is cell-type-specific

NARCIS (Netherlands)

Jansen, Anne H. P.; van Hal, Maurik; Op den Kelder, Ilse C.; Meier, Romy T.; de Ruiter, Anna-Aster; Schut, Menno H.; Smith, Donna L.; Grit, Corien; Brouwer, Nieske; Kamphuis, Willem; Boddeke, H. W. G. M.; den Dunnen, Wilfred F. A.; van Roon, Willeke M. C.; Bates, Gillian P.; Hol, Elly M.; Reits, Eric A.

2017-01-01

Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disorder that is caused by a CAG expansion in the Huntingtin (HTT) gene, leading to HTT inclusion formation in the brain. The mutant huntingtin protein (mHTT) is ubiquitously expressed and therefore nuclear inclusions

Frequency of Nuclear Mutant Huntingtin Inclusion Formation in Neurons and Glia is Cell-Type-Specific

NARCIS (Netherlands)

Jansen, Anne H P; van Hal, Maurik; op den Kelder, Ilse C.; Meier, Romy T.; de Ruiter, Anna-Aster; Schut, Menno H.; Smith, Donna L.; Grit, Corien; Brouwer, Nieske; Kamphuis, Willem; Boddeke, H. W. G. M.; den Dunnen, Wilfred F. A.; van Roon, Willeke M. C.; Bates, Gillian P.; Hol, Elly M.; Reits, Eric A.

Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disorder that is caused by a CAG expansion in the Huntingtin (HTT) gene, leading to HTT inclusion formation in the brain. The mutant huntingtin protein (mHTT) is ubiquitously expressed and therefore nuclear inclusions

Гости в нашем доме / Марианна Тарасенко

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Тарасенко, Марианна

2009-01-01

ETV2 ekraanil on alates sügisest kolm uut venekeelset saatesarja: 15-osaline "Lähme külla", 30-osaline "Eestimaa kuulsad inimesed", autor Galina Velman; 15-osaline "Ela sajani", autor-režissöör Aljona Suržikova

Ensiling and hydrothermal pretreatment of grass: Consequences for enzymatic biomass conversion and total monosaccharide yields

DEFF Research Database (Denmark)

Ambye-Jensen, Morten; Johansen, Katja Salomon; Didion, Thomas

2014-01-01

Ensiling may act as a pretreatment of fresh grass biomass and increase the enzymatic conversion of structural carbohydrates to fermentable sugars. However, ensiling does not provide sufficient severity to be a standalone pretreatment method. Here, ensiling of grass is combined with hydrothermal...... treatment (HTT) with the aim of improving the enzymatic biomass convertibility and decrease the required temperature of the HTT. Results: Grass silage (Festulolium Hykor) was hydrothermally treated at temperatures of 170, 180, and 190°C for 10 minutes. Relative to HTT treated dry grass, ensiling increased...... convertibility). The effect of ensiling of grass prior to HTT improved the enzymatic conversion of cellulose for HTT at 170 and 180°C, but the increased glucose release did not make up for the loss of water soluble carbohydrates (WSC) during ensiling. Overall, sugar yields (C6 + C5) were similar for HTT of grass...

2305-7432. htt

African Journals Online (AJOL)

Peter Berglez

film actor Hope Chisanu expressing the feeling commonly shared in the country about ... David Kerr's Dance, Media, Entertainment and Performance in south east Africa (Kerr, ... Africanus Aveh in the Rise of video film industry & its social .... commonly known as adventures of Sam Mperu (Magalasi, personal experience).

A novel humanized mouse model of Huntington disease for preclinical development of therapeutics targeting mutant huntingtin alleles

DEFF Research Database (Denmark)

Southwell, Amber L; Skotte, Niels H; Villanueva, Erika B

2017-01-01

transgenes in Hu128/21 mice match the human HTT exon 1 reference sequence. Conversely, the BACHD transgene carries a floxed, synthetic exon 1 sequence. Hu128/21 mice will be useful for investigations of human HTT that cannot be addressed in Hu97/18 mice, for developing therapies targeted to exon 1......Huntington disease (HD) is a neurodegenerative disease caused by a mutation in the huntingtin (HTT) gene. HTT is a large protein, interacts with many partners and is involved in many cellular pathways, which are perturbed in HD. Therapies targeting HTT directly are likely to provide the most global......-length, genomic human HTT transgenes heterozygous for the HD mutation and polymorphisms associated with HD in populations of East Asian descent and in a minority of patients from other ethnic groups. Hu128/21 mice display a wide variety of HD-like phenotypes that are similar to YAC128 mice. Additionally, both...

Expression analysis for inverted effects of serotonin transporter inactivation

International Nuclear Information System (INIS)

Ichikawa, Manabu; Okamura-Oho, Yuko; Shimokawa, Kazuro; Kondo, Shinji; Nakamura, Sakiko; Yokota, Hideo; Himeno, Ryutaro; Lesch, Klaus-Peter; Hayashizaki, Yoshihide

2008-01-01

Inactivation of serotonin transporter (HTT) by pharmacologically in the neonate or genetically increases risk for depression in adulthood, whereas pharmacological inhibition of HTT ameliorates symptoms in depressed patients. The differing role of HTT function during early development and in adult brain plasticity in causing or reversing depression remains an unexplained paradox. To address this we profiled the gene expression of adult Htt knockout (Htt KO) mice and HTT inhibitor-treated mice. Inverted profile changes between the two experimental conditions were seen in 30 genes. Consistent results of the upstream regulatory element search and the co-localization search of these genes indicated that the regulation may be executed by Pax5, Pax7 and Gata3, known to be involved in the survival, proliferation, and migration of serotonergic neurons in the developing brain, and these factors are supposed to keep functioning to regulate downstream genes related to serotonin system in the adult brain

Muusiku maja Tallinnas / Tomomi Hayashi

Index Scriptorium Estoniae

Hayashi, Tomomi, 1971-

2011-01-01

Tallinna südalinna lähedal miljööväärtuslikus piirkonnas asuva 1950. aastate alguses ehitatud kivihoone (kunagi limonaaditehas) renoveerimine ja kohandamine koos juurdeehitusega elamuks. Arhitektid Tomomi Hayashi, Liis Voksepp (HG Arhitektuur), sisearhitekt Galina Burnakova. Projekt ja ehitus: 2005-2010

Kuressaare 2008. aasta parimad ehitised selgunud / kommenteerinud Hannes Koppel

Index Scriptorium Estoniae

2009-01-01

Parim terviklahendus golfiala (golfiväljaku projekteerija soome arhitekt Lassi Pekka Tilander, klubihoone projekteeris arhitektuuristuudio Siim & Kreis arhitekt Andres Siim). Parim uusehitis eramu Merikotka 45 (projekteerija Ösel Plan arhitekt Terje Truumaa) ja parim renoveeritud ehitis vana pritsumaja (Kuressaare Kommunaalprojekt projekteerija Galina Kanemägi)

Potent and selective antisense oligonucleotides targeting single-nucleotide polymorphisms in the Huntington disease gene / allele-specific silencing of mutant huntingtin

DEFF Research Database (Denmark)

Carroll, Jeffrey B; Warby, Simon C; Southwell, Amber L

2011-01-01

Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by CAG-expansion in the huntingtin gene (HTT) that results in a toxic gain of function in the mutant huntingtin protein (mHTT). Reducing the expression of mHTT is therefore an attractive therapy for HD. However, wild...

Discovery of novel isoforms of huntingtin reveals a new hominid-specific exon.

Directory of Open Access Journals (Sweden)

Albert Ruzo

Full Text Available Huntington's disease (HD is a devastating neurological disorder that is caused by an expansion of the poly-Q tract in exon 1 of the Huntingtin gene (HTT. HTT is an evolutionarily conserved and ubiquitously expressed protein that has been linked to a variety of functions including transcriptional regulation, mitochondrial function, and vesicle transport. This large protein has numerous caspase and calpain cleavage sites and can be decorated with several post-translational modifications such as phosphorylations, acetylations, sumoylations, and palmitoylations. However, the exact function of HTT and the role played by its modifications in the cell are still not well understood. Scrutiny of HTT function has been focused on a single, full length mRNA. In this study, we report the discovery of 5 novel HTT mRNA splice isoforms that are expressed in normal and HTT-expanded human embryonic stem cell (hESC lines as well as in cortical neurons differentiated from hESCs. Interestingly, none of the novel isoforms generates a truncated protein. Instead, 4 of the 5 new isoforms specifically eliminate domains and modifications to generate smaller HTT proteins. The fifth novel isoform incorporates a previously unreported additional exon, dubbed 41b, which is hominid-specific and introduces a potential phosphorylation site in the protein. The discovery of this hominid-specific isoform may shed light on human-specific pathogenic mechanisms of HTT, which could not be investigated with current mouse models of the disease.

Discovery of Novel Isoforms of Huntingtin Reveals a New Hominid-Specific Exon

Science.gov (United States)

Popowski, Melissa; Haremaki, Tomomi; Croft, Gist F.; Deglincerti, Alessia; Brivanlou, Ali H.

2015-01-01

Huntington’s disease (HD) is a devastating neurological disorder that is caused by an expansion of the poly-Q tract in exon 1 of the Huntingtin gene (HTT). HTT is an evolutionarily conserved and ubiquitously expressed protein that has been linked to a variety of functions including transcriptional regulation, mitochondrial function, and vesicle transport. This large protein has numerous caspase and calpain cleavage sites and can be decorated with several post-translational modifications such as phosphorylations, acetylations, sumoylations, and palmitoylations. However, the exact function of HTT and the role played by its modifications in the cell are still not well understood. Scrutiny of HTT function has been focused on a single, full length mRNA. In this study, we report the discovery of 5 novel HTT mRNA splice isoforms that are expressed in normal and HTT-expanded human embryonic stem cell (hESC) lines as well as in cortical neurons differentiated from hESCs. Interestingly, none of the novel isoforms generates a truncated protein. Instead, 4 of the 5 new isoforms specifically eliminate domains and modifications to generate smaller HTT proteins. The fifth novel isoform incorporates a previously unreported additional exon, dubbed 41b, which is hominid-specific and introduces a potential phosphorylation site in the protein. The discovery of this hominid-specific isoform may shed light on human-specific pathogenic mechanisms of HTT, which could not be investigated with current mouse models of the disease. PMID:26010866

Normal aging modulates the neurotoxicity of mutant huntingtin.

Directory of Open Access Journals (Sweden)

Elsa Diguet

Full Text Available Aging likely plays a role in neurodegenerative disorders. In Huntington's disease (HD, a disorder caused by an abnormal expansion of a polyglutamine tract in the protein huntingtin (Htt, the role of aging is unclear. For a given tract length, the probability of disease onset increases with age. There are mainly two hypotheses that could explain adult onset in HD: Either mutant Htt progressively produces cumulative defects over time or "normal" aging renders neurons more vulnerable to mutant Htt toxicity. In the present study, we directly explored whether aging affected the toxicity of mutant Htt in vivo. We studied the impact of aging on the effects produced by overexpression of an N-terminal fragment of mutant Htt, of wild-type Htt or of a beta-Galactosidase (beta-Gal reporter gene in the rat striatum. Stereotaxic injections of lentiviral vectors were performed simultaneously in young (3 week and old (15 month rats. Histological evaluation at different time points after infection demonstrated that the expression of mutant Htt led to pathological changes that were more severe in old rats, including an increase in the number of small Htt-containing aggregates in the neuropil, a greater loss of DARPP-32 immunoreactivity and striatal neurons as assessed by unbiased stereological counts.The present results support the hypothesis that "normal" aging is involved in HD pathogenesis, and suggest that age-related cellular defects might constitute potential therapeutic targets for HD.

Prior fear conditioning does not impede enhanced active avoidance in serotonin transporter knockout rats.

Science.gov (United States)

Schipper, Pieter; Henckens, Marloes J A G; Borghans, Bart; Hiemstra, Marlies; Kozicz, Tamas; Homberg, Judith R

2017-05-30

Stressors can be actively or passively coped with, and adequate adaption of the coping response to environmental conditions can reduce their potential deleterious effects. One major factor influencing stress coping behaviour is serotonin transporter (5-HTT) availability. Abolishment of 5-HTT is known to impair fear extinction but facilitates acquisition of signalled active avoidance (AA), a behavioural task in which an animal learns to avoid an aversive stimulus that is predicted by a cue. Flexibility in adapting coping behaviour to the nature of the stressor shapes resilience to stress-related disorders. Therefore, we investigated the relation between 5-HTT expression and ability to adapt a learned coping response to changing environmental conditions. To this end, we first established and consolidated a cue-conditioned passive fear response in 5-HTT -/- and wildtype rats. Next, we used the conditioned stimulus (CS) to signal oncoming shocks during signalled AA training in 5-HTT -/- and wildtype rats to study their capability to acquire an active coping response to the CS following fear conditioning. Finally, we investigated the behavioural response to the CS in a novel environment and measured freezing, exploration and self-grooming, behaviours reflective of stress coping strategy. We found that fear conditioned and sham conditioned 5-HTT -/- animals acquired the signalled AA response faster than wildtypes, while prior conditioning briefly delayed AA learning similarly in both genotypes. Subsequent exposure to the CS in the novel context reduced freezing and increased locomotion in 5-HTT -/- compared to wildtype rats. This indicates that improved AA performance in 5-HTT -/- rats resulted in a weaker residual passive fear response to the CS in a novel context. Fear conditioning prior to AA training did not affect freezing upon re-encountering the CS, although it did reduce locomotion in 5-HTT -/- rats. We conclude that independent of 5-HTT signalling, prior fear

Loss of Huntingtin stimulates capture of retrograde dense-core vesicles to increase synaptic neuropeptide stores.

Science.gov (United States)

Bulgari, Dinara; Deitcher, David L; Levitan, Edwin S

2017-08-01

The Huntington's disease protein Huntingtin (Htt) regulates axonal transport of dense-core vesicles (DCVs) containing neurotrophins and neuropeptides. DCVs travel down axons to reach nerve terminals where they are either captured in synaptic boutons to support later release or reverse direction to reenter the axon as part of vesicle circulation. Currently, the impact of Htt on DCV dynamics in the terminal is unknown. Here we report that knockout of Drosophila Htt selectively reduces retrograde DCV flux at proximal boutons of motoneuron terminals. However, initiation of retrograde transport at the most distal bouton and transport velocity are unaffected suggesting that synaptic capture rate of these retrograde DCVs could be altered. In fact, tracking DCVs shows that retrograde synaptic capture efficiency is significantly elevated by Htt knockout or knockdown. Furthermore, synaptic boutons contain more neuropeptide in Htt knockout larvae even though bouton size, single DCV fluorescence intensity, neuropeptide release in response to electrical stimulation and subsequent activity-dependent capture are unaffected. Thus, loss of Htt increases synaptic capture as DCVs travel by retrograde transport through boutons resulting in reduced transport toward the axon and increased neuropeptide in the terminal. These results therefore identify native Htt as a regulator of synaptic capture and neuropeptide storage. Copyright © 2017 Elsevier GmbH. All rights reserved.

Sequestration of Sup35 by aggregates of huntingtin fragments causes toxicity of [PSI+] yeast.

Science.gov (United States)

Zhao, Xiaohong; Park, Yang-Nim; Todor, Horia; Moomau, Christine; Masison, Daniel; Eisenberg, Evan; Greene, Lois E

2012-07-06

Expression of huntingtin fragments with 103 glutamines (HttQ103) is toxic in yeast containing either the [PIN(+)] prion, which is the amyloid form of Rnq1, or [PSI(+)] prion, which is the amyloid form of Sup35. We find that HttQP103, which has a polyproline region at the C-terminal end of the polyQ repeat region, is significantly more toxic in [PSI(+)] yeast than in [PIN(+)], even though HttQP103 formed multiple aggregates in both [PSI(+)] and [PIN(+)] yeast. This toxicity was only observed in the strong [PSI(+)] variant, not the weak [PSI(+)] variant, which has more soluble Sup35 present than the strong variant. Furthermore, expression of the MC domains of Sup35, which retains the C-terminal domain of Sup35, but lacks the N-terminal prion domain, almost completely rescued HttQP103 toxicity, but was less effective in rescuing HttQ103 toxicity. Therefore, the toxicity of HttQP103 in yeast containing the [PSI(+)] prion is primarily due to sequestration of the essential protein, Sup35.

Cardiac mTORC1 Dysregulation Impacts Stress Adaptation and Survival in Huntington’s Disease

Directory of Open Access Journals (Sweden)

Daniel D. Child

2018-04-01

Full Text Available Summary: Huntington’s disease (HD is a dominantly inherited neurological disorder caused by CAG-repeat expansion in exon 1 of Huntingtin (HTT. But in addition to the neurological disease, mutant HTT (mHTT, which is ubiquitously expressed, impairs other organ systems. Indeed, epidemiological and animal model studies suggest higher incidence of and mortality from heart disease in HD. Here, we show that the protein complex mTORC1 is dysregulated in two HD mouse models through a mechanism that requires intrinsic mHTT expression. Moreover, restoring cardiac mTORC1 activity with constitutively active Rheb prevents mortality and relieves the mHTT-induced block to hypertrophic adaptation to cardiac stress. Finally, we show that chronic mTORC1 dysregulation is due in part to mislocalization of endogenous Rheb. These data provide insight into the increased cardiac-related mortality of HD patients, with cardiac mHTT expression inhibiting mTORC1 activity, limiting heart growth, and decreasing the heart’s ability to compensate to chronic stress. : Child et al. demonstrate that mTORC1 dysregulation is a key molecular mechanism in the Huntington’s disease (HD heart phenotype. Impaired cardiac mTORC1 activity in HD mouse models requires intrinsic mHTT expression and explains the limited adaptation to cardiac stress. Keywords: Huntington’s disease, heart, mTOR, Rheb

Vene tüng / Arvo Pesti

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Pesti, Arvo, 1956-2010

2006-01-01

28. aprillist kuni 4. maini Tallinnas toimunud II Vene Kino festivalist Baltimaades. Lähemalt mõnest nähtud filmist : Aleksandr Atanesjani "Lurjused" ("Svolotshi"), Deniss Neimandi "Vanaraud" ("Zhest"), Nikolai Dostali "Maailmarändur Kolja" ("Kolja-perekati-polje"), Roman Hrushtshi "Vedamine" ("Fart"), Marina Migunova "Krahv Montenegro" ja Galina Jevtushenko "Pööningulugu"

Folding Landscape of Mutant Huntingtin Exon1: Diffusible Multimers, Oligomers and Fibrils, and No Detectable Monomer.

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Bankanidhi Sahoo

Full Text Available Expansion of the polyglutamine (polyQ track of the Huntingtin (HTT protein above 36 is associated with a sharply enhanced risk of Huntington's disease (HD. Although there is general agreement that HTT toxicity resides primarily in N-terminal fragments such as the HTT exon1 protein, there is no consensus on the nature of the physical states of HTT exon1 that are induced by polyQ expansion, nor on which of these states might be responsible for toxicity. One hypothesis is that polyQ expansion induces an alternative, toxic conformation in the HTT exon1 monomer. Alternative hypotheses posit that the toxic species is one of several possible aggregated states. Defining the nature of the toxic species is particularly challenging because of facile interconversion between physical states as well as challenges to identifying these states, especially in vivo. Here we describe the use of fluorescence correlation spectroscopy (FCS to characterize the detailed time and repeat length dependent self-association of HTT exon1-like fragments both with chemically synthesized peptides in vitro and with cell-produced proteins in extracts and in living cells. We find that, in vitro, mutant HTT exon1 peptides engage in polyQ repeat length dependent dimer and tetramer formation, followed by time dependent formation of diffusible spherical and fibrillar oligomers and finally by larger, sedimentable amyloid fibrils. For expanded polyQ HTT exon1 expressed in PC12 cells, monomers are absent, with tetramers being the smallest molecular form detected, followed in the incubation time course by small, diffusible aggregates at 6-9 hours and larger, sedimentable aggregates that begin to build up at 12 hrs. In these cell cultures, significant nuclear DNA damage appears by 6 hours, followed at later times by caspase 3 induction, mitochondrial dysfunction, and cell death. Our data thus defines limits on the sizes and concentrations of different physical states of HTT exon1 along the

Analysis of proteolytic processes and enzymatic activities in the generation of huntingtin n-terminal fragments in an HEK293 cell model.

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Andrew T N Tebbenkamp

Full Text Available N-terminal fragments of mutant huntingtin (htt that terminate between residues 90-115, termed cleavage product A or 1 (cp-A/1, form intracellular and intranuclear inclusion bodies in the brains of patients with Huntington's disease (HD. These fragments appear to be proteolytic products of the full-length protein. Here, we use an HEK293 cell culture model to investigate huntingtin proteolytic processing; previous studies of these cells have demonstrated cleavage of htt to cp-A/1 like htt fragments.Recombinant N-terminal htt fragments, terminating at residue 171 (also referred to as cp-B/2 like, were efficiently cleaved to produce cp-A/1 whereas fragments representing endogenous caspase, calpain, and metalloproteinase cleavage products, terminating between residues 400-600, were inefficiently cleaved. Using cysteine-labeling techniques and antibody binding mapping, we localized the C-terminus of the cp-A/1 fragments produced by HEK293 cells to sequences minimally limited by cysteine 105 and an antibody epitope composed of residues 115-124. A combination of genetic and pharmacologic approaches to inhibit potential proteases, including γ-secretase and calpain, proved ineffective in preventing production of cp-A/1.Our findings indicate that HEK293 cells express a protease that is capable of efficiently cleaving cp-B/2 like fragments of htt with normal or expanded glutamine repeats. For reasons that remain unclear, this protease cleaves longer htt fragments, with normal or expanded glutamine expansions, much less efficiently. The protease in HEK293 cells that is capable of generating a cp-A/1 like htt fragment may be a novel protease with a high preference for a cp-B/2-like htt fragment as substrate.

Cystathionine γ-lyase deficiency mediates neurodegeneration in Huntington’s disease

Science.gov (United States)

Paul, Bindu D.; Sbodio, Juan I.; Xu, Risheng; Vandiver, M. Scott; Cha, Jiyoung Y.; Snowman, Adele M.; Snyder, Solomon H.

2015-01-01

Huntington’s disease is an autosomal dominant disease associated with a mutation in the gene encoding huntingtin (Htt) leading to expanded polyglutamine repeats of mutant Htt (mHtt) that elicit oxidative stress, neurotoxicity, and motor and behavioural changes1. Huntington’s disease is characterized by highly selective and profound damage to the corpus striatum, which regulates motor function. Striatal selectivity of Huntington’s disease may reflect the striatally selective small G protein Rhes binding to mHtt and enhancing its neurotoxicity2. Specific molecular mechanisms by which mHtt elicits neurodegeneration have been hard to determine. Here we show a major depletion of cystathionine γ-lyase (CSE), the biosynthetic enzyme for cysteine, in Huntington’s disease tissues, which may mediate Huntington’s disease pathophysiology. The defect occurs at the transcriptional level and seems to reflect influences of mHtt on specificity protein 1, a transcriptional activator for CSE. Consistent with the notion of loss of CSE as a pathogenic mechanism, supplementation with cysteine reverses abnormalities in cultures of Huntington’s disease tissues and in intact mouse models of Huntington’s disease, suggesting therapeutic potential. PMID:24670645

Evidence for the Association of a Deleted Variant in the 5′-Flanking Region of the Chicken serotonin transporter (5-HTT Gene with a Temporary Increase in Feed Intake and Growth Rate

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Joergen B. Kjaer

2016-10-01

Full Text Available The serotonergic system has been shown to be implicated in the regulation of mood and feeding behavior. Previous studies have identified a polymorphism in the 5′-flanking region of the serotonin transporter ( 5 - HTT gene of Lohmann Brown (LB laying hens. The deleted variant D was found to be associated with increased body weight. The objective of this study was to address whether the increased body weight may be due to an increased feed intake. After hatching, hens were kept under ad libitum feeding conditions, and their body weight and feed intake were weekly determined. From 5 weeks of age, the body weight of hens with the D/D and W/D genotypes was significantly greater than that of W/W carrying hens. Interestingly, we found that the feed intake of D/D carrying hens, relative to body weight, was transiently increased only between 4 and 7 weeks of age ( p < 0.05, leading to a higher growth rate ( p < 0.05, compared with that of W/W carrying hens. These results suggest that the presence of variant D may be correlated with a transiently increased appetite of D/D carrying hens.

Anneli Remme soovitab : Kriguli ja Grigorjeva uued teosed / Anneli Remme

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Remme, Anneli, 1968-

2008-01-01

Ülo Kriguli "Preces ad lucem" ("Palve valguse poole") ja Galina Grigorjeva "Nature Morte" ettekandest Eesti Filharmoonia Kammerkoori (dirigent Daniel Reuss) esituses 23. okt. Tallinnas Niguliste kirikus ja 24. okt. Pärnu Eliisabeti kirikus. Tallinna kontserdil esitusel ka Sofia Gubaidulina "Nüüd aina lumi"ja Pärnu kontserdil Frank Martini "Missa"

Highly purified, multi-wall carbon nanotubes induce light-chain 3B expression in human lung cells

International Nuclear Information System (INIS)

Tsukahara, Tamotsu; Matsuda, Yoshikazu; Usui, Yuki; Haniu, Hisao

2013-01-01

Highlights: •HTT2800-treated BEAS-2B cells induced LC3B in a time-dependent manner. •HTT2800-treated BEAS-2B cells showed decreased cell proliferation that was both time- and dose-dependent. •Addition of 3-MA, LC3B-II protein and mRNA levels were significantly decreased. •3-MA and E64-d + pepstatin A, but not brefeldin A, provided protection against HTT2800-induced cell death. •These results suggest that HTT2800 predominantly causes autophagy rather than apoptotic cell death in BEAS-2B cells. -- Abstract: Bronchial epithelial cells are targets of inhalation and play a critical role in the maintenance of mucosal integrity as mechanical barriers against various particles. Our previous result suggest that vapor-grown carbon fiber, HTT2800, which is one of the most highly purified multi-wall carbon nanotubes (MWCNT) showed cellular uptake of the carbon nanotube, increased cell death, enhanced DNA damage, and induced cytokine release. Increasing evidence suggests that autophagy may critically influence vital cellular processes such as apoptosis, cell proliferation and inflammation and thereby may play a critical role in pulmonary diseases. Autophagy was recently recognized as a critical cell death pathway, and autophagosome accumulation has been found to be associated with the exposure of various nanoparticles. In this study, the authors focus on the autophagic responses of HTT2800 exposure. The HTT2800-exposed cells induced LC3B expression and induced cell growth inhibition

Highly purified, multi-wall carbon nanotubes induce light-chain 3B expression in human lung cells

Energy Technology Data Exchange (ETDEWEB)

Tsukahara, Tamotsu, E-mail: ttamotsu@kanazawa-med.ac.jp [Department of Hematology and Immunology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa 920-0293 (Japan); Matsuda, Yoshikazu [Clinical Pharmacology Educational Center, Nihon Pharmaceutical University, Ina-machi, Saitama 362-0806 (Japan); Usui, Yuki [Research Center for Exotic Nanocarbons, Shinshu University, 4-17-1 Wakasato, Nagano-shi, Nagano 380-8553 (Japan); Haniu, Hisao [Department of Orthopaedic Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621 (Japan)

2013-10-18

Highlights: •HTT2800-treated BEAS-2B cells induced LC3B in a time-dependent manner. •HTT2800-treated BEAS-2B cells showed decreased cell proliferation that was both time- and dose-dependent. •Addition of 3-MA, LC3B-II protein and mRNA levels were significantly decreased. •3-MA and E64-d + pepstatin A, but not brefeldin A, provided protection against HTT2800-induced cell death. •These results suggest that HTT2800 predominantly causes autophagy rather than apoptotic cell death in BEAS-2B cells. -- Abstract: Bronchial epithelial cells are targets of inhalation and play a critical role in the maintenance of mucosal integrity as mechanical barriers against various particles. Our previous result suggest that vapor-grown carbon fiber, HTT2800, which is one of the most highly purified multi-wall carbon nanotubes (MWCNT) showed cellular uptake of the carbon nanotube, increased cell death, enhanced DNA damage, and induced cytokine release. Increasing evidence suggests that autophagy may critically influence vital cellular processes such as apoptosis, cell proliferation and inflammation and thereby may play a critical role in pulmonary diseases. Autophagy was recently recognized as a critical cell death pathway, and autophagosome accumulation has been found to be associated with the exposure of various nanoparticles. In this study, the authors focus on the autophagic responses of HTT2800 exposure. The HTT2800-exposed cells induced LC3B expression and induced cell growth inhibition.

Fluorinated Nucleotide Modifications Modulate Allele Selectivity of SNP-Targeting Antisense Oligonucleotides

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Michael E. Østergaard

2017-06-01

Full Text Available Antisense oligonucleotides (ASOs have the potential to discriminate between subtle RNA mismatches such as SNPs. Certain mismatches, however, allow ASOs to bind at physiological conditions and result in RNA cleavage mediated by RNase H. We showed that replacing DNA nucleotides in the gap region of an ASO with other chemical modification can improve allele selectivity. Herein, we systematically substitute every position in the gap region of an ASO targeting huntingtin gene (HTT with fluorinated nucleotides. Potency is determined in cell culture against mutant HTT (mtHTT and wild-type HTT (wtHTT mRNA and RNase H cleavage intensities, and patterns are investigated. This study profiled five different fluorinated nucleotides and showed them to have predictable, site-specific effects on RNase H cleavage, and the cleavage patterns were rationalized from a published X-ray structure of human RNase H1. The results herein can be used as a guide for future projects where ASO discrimination of SNPs is important.

Central serotonin transporter availability in highly obese individuals compared with non-obese controls: A [11C] DASB positron emission tomography study

International Nuclear Information System (INIS)

Hesse, Swen; Sabri, Osama; Rullmann, Michael; Luthardt, Julia; Becker, Georg-Alexander; Bresch, Anke; Patt, Marianne; Meyer, Philipp M.; Winter, Karsten; Hankir, Mohammed K.; Zientek, Franziska; Reissig, Georg; Drabe, Mandy; Regenthal, Ralf; Schinke, Christian; Arelin, Katrin; Lobsien, Donald; Fasshauer, Mathias; Fenske, Wiebke K.; Stumvoll, Michael; Blueher, Matthias

2016-01-01

The role of the central serotonin (5-hydroxytryptamine, 5-HT) system in feeding has been extensively studied in animals with the 5-HT family of transporters (5-HTT) being identified as key molecules in the regulation of satiety and body weight. Aberrant 5-HT transmission has been implicated in the pathogenesis of human obesity by in vivo positron emission tomography (PET) and single-photon emission computed tomography (SPECT) imaging techniques. However, results obtained thus far from studies of central 5-HTT availability have been inconsistent, which is thought to be brought about mainly by the low number of individuals with a high body mass index (BMI) previously used. The aim of this study was therefore to assess 5-HTT availability in the brains of highly obese otherwise healthy individuals compared with non-obese healthy controls. We performed PET using the 5-HTT selective radiotracer [ 11 C] DASB on 30 highly obese (BMI range between 35 and 55 kg/m 2 ) and 15 age- and sex-matched non-obese volunteers (BMI range between 19 and 27 kg/m 2 ) in a cross-sectional study design. The 5-HTT binding potential (BP ND ) was used as the outcome parameter. On a group level, there was no significant difference in 5-HTT BP ND in various cortical and subcortical regions in individuals with the highest BMI compared with non-obese controls, while statistical models showed minor effects of age, sex, and the degree of depression on 5-HTT BP ND . The overall finding of a lack of significantly altered 5-HTT availability together with its high variance in obese individuals justifies the investigation of individual behavioral responses to external and internal cues which may further define distinct phenotypes and subgroups in human obesity. (orig.)

Central serotonin transporter availability in highly obese individuals compared with non-obese controls: A [{sup 11}C] DASB positron emission tomography study

Energy Technology Data Exchange (ETDEWEB)

Hesse, Swen; Sabri, Osama [University of Leipzig, Department of Nuclear Medicine, Leipzig (Germany); Integrated Research and Treatment Centre Adiposity Diseases Leipzig, Leipzig (Germany); Rullmann, Michael [University of Leipzig, Department of Nuclear Medicine, Leipzig (Germany); Integrated Research and Treatment Centre Adiposity Diseases Leipzig, Leipzig (Germany); Max Planck Institute for Human Cognitive and Brain Sciences Leipzig, Leipzig (Germany); Luthardt, Julia; Becker, Georg-Alexander; Bresch, Anke; Patt, Marianne; Meyer, Philipp M. [University of Leipzig, Department of Nuclear Medicine, Leipzig (Germany); Winter, Karsten [University of Leipzig, Centre for Translational Regenerative Medicine, Leipzig (Germany); University of Leipzig, Institute for Medical Informatics, Statistics, and Epidemiology, Leipzig (Germany); Hankir, Mohammed K.; Zientek, Franziska; Reissig, Georg; Drabe, Mandy [Integrated Research and Treatment Centre Adiposity Diseases Leipzig, Leipzig (Germany); Regenthal, Ralf [University of Leipzig, Division of Clinical Pharmacology, Rudolf Boehm Institute of Pharmacology and Toxicology, Leipzig (Germany); Schinke, Christian [University of Leipzig, Department of Neurology, Leipzig (Germany); Arelin, Katrin [Max Planck Institute for Human Cognitive and Brain Sciences Leipzig, Leipzig (Germany); University of Leipzig, Day Clinic for Cognitive Neurology, Leipzig (Germany); Lobsien, Donald [University of Leipzig, Department of Neuroradiology, Leipzig (Germany); Fasshauer, Mathias; Fenske, Wiebke K.; Stumvoll, Michael [Integrated Research and Treatment Centre Adiposity Diseases Leipzig, Leipzig (Germany); University of Leipzig, Medical Department III, Leipzig (Germany); Blueher, Matthias [University of Leipzig, Medical Department III, Leipzig (Germany); University of Leipzig, Collaborative Research Centre 1052 Obesity Mechanisms, Leipzig (Germany)

2016-06-15

The role of the central serotonin (5-hydroxytryptamine, 5-HT) system in feeding has been extensively studied in animals with the 5-HT family of transporters (5-HTT) being identified as key molecules in the regulation of satiety and body weight. Aberrant 5-HT transmission has been implicated in the pathogenesis of human obesity by in vivo positron emission tomography (PET) and single-photon emission computed tomography (SPECT) imaging techniques. However, results obtained thus far from studies of central 5-HTT availability have been inconsistent, which is thought to be brought about mainly by the low number of individuals with a high body mass index (BMI) previously used. The aim of this study was therefore to assess 5-HTT availability in the brains of highly obese otherwise healthy individuals compared with non-obese healthy controls. We performed PET using the 5-HTT selective radiotracer [{sup 11}C] DASB on 30 highly obese (BMI range between 35 and 55 kg/m{sup 2}) and 15 age- and sex-matched non-obese volunteers (BMI range between 19 and 27 kg/m{sup 2}) in a cross-sectional study design. The 5-HTT binding potential (BP{sub ND}) was used as the outcome parameter. On a group level, there was no significant difference in 5-HTT BP{sub ND} in various cortical and subcortical regions in individuals with the highest BMI compared with non-obese controls, while statistical models showed minor effects of age, sex, and the degree of depression on 5-HTT BP{sub ND}. The overall finding of a lack of significantly altered 5-HTT availability together with its high variance in obese individuals justifies the investigation of individual behavioral responses to external and internal cues which may further define distinct phenotypes and subgroups in human obesity. (orig.)

Vtoroje dõhanije / Galina Balashova

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Balashova, Galina

2001-01-01

Ehtekunstnik Jaan Pärna projektist Meistrite hoov. Dolomiidi kasutamist kunstis kajastavast näitusest "Pae aeg" Meistrite hoovi galeriis. Kujundas Urve Küttner. Jaan Pärna, Urve Küttneri, Andrei Balashovi ja Helmet Raja töödest näitusel

Golosa manezhnogo Peterburga / Galina Balashova

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Balashova, Galina

2004-01-01

Peterburi kaasaegsest kunstist seoses kunstiteadlase Larissa Skobkina kureeritud näitusega Tallinna Vene saatkonna galeriis. Tutvustatakse underground-kunstnikke Anatoli Basinit, Vjatsheslav Mihhailovit, Valeri Lukkat, Vladimir Vidermani, Gleb Bogomolovit, Gennadi Ustjugovit, Natalja Zhilinat, rühmitust Mitki ja selle liikmeid Vladimir Shinkarjovi, Aleksandr Florenskit, Olga Florenskajat ning Peterburi fotokoolkonda esindavat Andrei Tshezhinit

Dialog s Miro / Galina Balashova

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Balashova, Galina

1999-01-01

11 kuulsa kunstniku tööde müüginäitusest 'Mir̤ ja tema sõbrad' Tallinnas galeriis Vaal : eksponeeritud on J. Mir̤, P. Picasso, A. Derain, A. Tapies, V. Vasarely jt. Põhiliselt graafika jt. väikesed tööd.

Iskusstvo bumazhnogo lista / Galina Balashova

Index Scriptorium Estoniae

Balashova, Galina

2006-01-01

Tšehhi Vabariigi suursaatkonna vahendatud tšehhi graafika näitus "10 isiksust tšehhi graafikas" Eesti Rahvusraamatukogus. Tsehhi graafika ajaloost ja töödest näitusel. Esindatud on kunstnikud Eduard Ovèaèek, Kveta Pacovska, Alena Kuèerova, Mikolash Axman, Adolf Born, Ladislav €epelak, Jiri Shalamoun, Lubomir Paeibyl, Jaroslav Kralik ja Jiri Anderle

ARS - Helsinki - 2006 / Galina Balashova

Index Scriptorium Estoniae

Balashova, Galina

2006-01-01

Steven Holli projekteeritud Kiasma muuseumihoonest Helsingis. Kontseptuaalkunsti näitusest ARS 06 "Reaalsustunne" Kiasmas. Eestlastest esineb Mark Raidpere. Vene kunstnikegrupi AEC+F ja vene kunstnike Juri Vassiljevi ning Aleksandr Ponomarjovi töödest näitusel. Ka Gerda Steineri & Jörg Lenzlingeri (Šveits), Martin & Munoz'i (USA, Hispaania), arvutigraafik Charles Sandisoni (SB), videokunstnik Bill Viola (USA) jt. töödest

Birjuza iz Iznika / Galina Balashova

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Balashova, Galina

2006-01-01

Türgi keraamika ja ebru kunsti näitus Tallinna juveelikeskuses Bindes. Izniki ajaloolisest keraamikast ja iidse ebru kunsti ajaloost ning tehnikast. Näha on kaasaegsete türgi kunstnike keraamilisi pannoosid, ehteid, suveniire jm. Izniki galeriist "Anikya" ning kaasaegse türgi kunstniku Hikmet Barutcugili ebru kunst

Ser46 phosphorylation and prolyl-isomerase Pin1-mediated isomerization of p53 are key events in p53-dependent apoptosis induced by mutant huntingtin.

Science.gov (United States)

Grison, Alice; Mantovani, Fiamma; Comel, Anna; Agostoni, Elena; Gustincich, Stefano; Persichetti, Francesca; Del Sal, Giannino

2011-11-01

Huntington disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the gene coding for huntingtin protein. Several mechanisms have been proposed by which mutant huntingtin (mHtt) may trigger striatal neurodegeneration, including mitochondrial dysfunction, oxidative stress, and apoptosis. Furthermore, mHtt induces DNA damage and activates a stress response. In this context, p53 plays a crucial role in mediating mHtt toxic effects. Here we have dissected the pathway of p53 activation by mHtt in human neuronal cells and in HD mice, with the aim of highlighting critical nodes that may be pharmacologically manipulated for therapeutic intervention. We demonstrate that expression of mHtt causes increased phosphorylation of p53 on Ser46, leading to its interaction with phosphorylation-dependent prolyl isomerase Pin1 and consequent dissociation from the apoptosis inhibitor iASPP, thereby inducing the expression of apoptotic target genes. Inhibition of Ser46 phosphorylation by targeting homeodomain-interacting protein kinase 2 (HIPK2), PKCδ, or ataxia telangiectasia mutated kinase, as well as inhibition of the prolyl isomerase Pin1, prevents mHtt-dependent apoptosis of neuronal cells. These results provide a rationale for the use of small-molecule inhibitors of stress-responsive protein kinases and Pin1 as a potential therapeutic strategy for HD treatment.

Cystathionine γ-lyase deficiency mediates neurodegeneration in Huntington’s disease

OpenAIRE

Paul, Bindu D.; Sbodio, Juan I.; Xu, Risheng; Vandiver, M. Scott; Cha, Jiyoung Y.; Snowman, Adele M.; Snyder, Solomon H.

2014-01-01

Huntington’s disease is an autosomal dominant disease associated with a mutation in the gene encoding huntingtin (Htt) leading to expanded polyglutamine repeats of mutant Htt (mHtt) that elicit oxidative stress, neurotoxicity, and motor and behavioural changes1. Huntington’s disease is characterized by highly selective and profound damage to the corpus striatum, which regulates motor function. Striatal selectivity of Huntington’s disease may reflect the striatally selective small G protein Rh...

Round-table discussion at Tallinn City Council (March 8, 2010). Part one : The European Union strategy for the Baltic Sea Region - a challenge for cooperation on local and regional levels

Index Scriptorium Estoniae

2010-01-01

Konverentsi ümarlaual võtsid sõna Erik Terk, Toomas Vitsut, Thomas Johansson, Katrin Savomägi, Jasmin Etelämäki, Edvins Karnitis, Ulf Johansson, Per Gudmund Lindencrona, Mika Keränen, Uno Aldegren, Georg Sootla, Heikki Telakivi, Piret Hedin, Mart Repnau, Jüri Riives, Madis Kanarbik, Enn Saar, Tiiu Evert, Galina Gribanova, Keijo Sahrman, Linda Talve

Prevalence of Huntington's disease gene CAG trinucleotide repeat alleles in patients with bipolar disorder.

Science.gov (United States)

Ramos, Eliana Marisa; Gillis, Tammy; Mysore, Jayalakshmi S; Lee, Jong-Min; Alonso, Isabel; Gusella, James F; Smoller, Jordan W; Sklar, Pamela; MacDonald, Marcy E; Perlis, Roy H

2015-06-01

Huntington's disease is a neurodegenerative disorder characterized by motor, cognitive, and psychiatric symptoms that are caused by huntingtin gene (HTT) CAG trinucleotide repeat alleles of 36 or more units. A greater than expected prevalence of incompletely penetrant HTT CAG repeat alleles observed among individuals diagnosed with major depressive disorder raises the possibility that another mood disorder, bipolar disorder, could likewise be associated with Huntington's disease. We assessed the distribution of HTT CAG repeat alleles in a cohort of individuals with bipolar disorder. HTT CAG allele sizes from 2,229 Caucasian individuals diagnosed with DSM-IV bipolar disorder were compared to allele sizes in 1,828 control individuals from multiple cohorts. We found that HTT CAG repeat alleles > 35 units were observed in only one of 4,458 chromosomes from individuals with bipolar disorder, compared to three of 3,656 chromosomes from control subjects. These findings do not support an association between bipolar disorder and Huntington's disease. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Modulation of Human Serotonin Transporter Expression by 5-HTTLPR in Colon Cells

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Tewin Tencomnao

2011-10-01

Full Text Available Serotonin (5-HT is a monoamine neurotransmitter and plays important roles in several of the human body’s systems. Known as a primary target for psychoactive drug development, the 5-HT transporter (5-HTT, SERT plays a critical role in the regulation of serotonergic function by reuptaking 5-HT. The allelic variation of 5-HTT expression is caused by functional gene promoter polymorphism with two principal variant alleles, 5-HTT gene-linked polymorphic region (5-HTTLPR. It has been demonstrated that 5-HTTLPR is associated with numerous neuropsychiatric disorders. The functional roles of 5-HTTLPR have been reported in human choriocarcinoma (JAR, lymphoblast and raphe cells. To date, the significance of 5-HTTLPR in gastrointestinal tract-derived cells has never been elucidated. Thus, the impact of 5-HTTLPR on 5-HTT transcription was studied in SW480 human colon carcinoma cells, which were shown to express 5-HTT. We found 42-bp fragment in long (L allele as compared to short (S allele, and this allelic difference resulted in 2-fold higher transcriptional efficiency of L allele (P < 0.05 as demonstrated using a functional reporter gene assay. Nevertheless, the transcriptional effect of estrogen and glucocorticoid on 5-HTT expression via 5-HTTLPR was not found in this cell line. Our study was the first to demonstrate the molecular role of this allelic variation in gastrointestinal tract cells.

The role of polyglutamine expansion and protein context in disease-related huntingtin/lipid interactions

Science.gov (United States)

Burke, Kathleen Anne

Huntington's Disease (HD) is a neurodegenerative disorder that is defined by the accumulation of nanoscale aggregates comprised of the huntingtin (htt) protein. Aggregation is directly caused by an expanded polyglutamine (polyQ) domain in htt, leading to a diverse population of aggregate species, such as oligomers, fibrils, and annular aggregates. Furthermore, the length of this polyQ domain is directly related to onset and severity of disease. The first 17 amino acids on the N-terminus (N17) and the polyproline domain on the C-terminal side of the polyQ domain have been shown to further modulate the aggregation process. Additionally, N17 appears to have lipid binding properties as htt interacts with a variety of membrane-containing structures present in cells, such as organelles, and interactions with these membrane surfaces may further modulate htt aggregation. To investigate the interaction between htt exon1 and lipid bilayers, in situ atomic force microscopy (AFM) was used to directly monitor the aggregation of htt exon1 constructs with varying Q-length (35Q, 46Q, 51Q, and myc- 53Q) or synthetic peptides with different polyQ domain flanking sequences (KK-Q35-KK, KK-Q 35-P10-KK, N17-Q35-KK, and N 17-Q35-P10-KK) on supported lipid membranes comprised of total brain lipid extract. The exon1 fragments accumulated on the lipid membranes, causing disruption of the membrane, in a polyQ dependent manner. By adding N-terminal tags to the htt exon1 fragments, the interaction with the lipid bilayer was impeded. The KK-Q35-KK and KK-Q 35-P10-KK peptides had no appreciable interaction with lipid bilayers. Interestingly, polyQ peptides with the N17 flanking sequence interacted with the bilayer. N17-Q35-KK formed discrete aggregates on the bilayer, but there was minimal membrane disruption. The N17-Q35-P10-KK peptide interacted more aggressively with the lipid bilayer in a manner reminiscent of the htt exon1 proteins.

Acute inescapable stress alleviates fear extinction recall deficits caused by serotonin transporter abolishment.

Science.gov (United States)

Schipper, Pieter; Henckens, Marloes J A G; Lopresto, Dora; Kozicz, Tamas; Homberg, Judith R

2018-07-02

Life stress increases risk for developing post-traumatic stress disorder (PTSD), and more prominently so in short-allele carriers of the serotonin transporter linked polymorphic region (5-HTTLPR). Serotonin transporter knockout (5-HTT -/- ) rats show compromised extinction (recall) of conditioned fear, which might mediate the increased risk for PTSD and reduce the therapeutic efficacy of exposure therapy. Here, we assessed whether acute inescapable stress (IS) differentially affects fear extinction and extinction recall in 5-HTT -/- rats and wildtype controls. Surprisingly, IS experience improved fear extinction recall in 5-HTT -/- rats to the level of wildtype animals, while wildtypes were unaffected by this IS. Thus, whereas 5-HTT -/- rats evidently were more responsive to the stressor, the behavioral consequences presented themselves as adaptive. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

ROCK and PRK-2 Mediate the Inhibitory Effect of Y-27632 on Polyglutamine Aggregation

Science.gov (United States)

Shao, Jieya; Welch, William J.; Diamond, Marc I.

2009-01-01

Polyglutamine expansion in huntingtin (Htt) and the androgen receptor (AR) causes untreatable neurodegenerative diseases. Y-27632, a therapeutic lead, reduces Htt and AR aggregation in cultured cells, and Htt-induced neurodegeneration in Drosophila. Y-27632 inhibits both Rho-associated kinases ROCK and PRK-2, making its precise intracellular target uncertain. Over-expression of either kinase increases Htt and AR aggregation. Three ROCK inhibitors (Y-27632, H-1077, HA-1152), and a specific ROCK inhibitory peptide reduce polyglutamine protein aggregation, as does knockdown of ROCK or PRK-2 by RNAi. RNAi also indicates that each kinase is required for the inhibitory effects of Y-27632 to manifest fully. These two actin regulatory kinases are thus involved in polyglutamine aggregation, and their simultaneous inhibition may be an important therapeutic goal. PMID:18423405

Anorexigen-induced pulmonary hypertension and the serotonin (5-HT hypothesis: lessons for the future in pathogenesis

Directory of Open Access Journals (Sweden)

Adnot Serge

2002-01-01

Full Text Available Abstract Epidemiological studies have established that fenfluramine, D-fenfluramine, and aminorex, but not other appetite suppressants, increase the risk of primary pulmonary hypertension (PH. One current hypothesis suggests that fenfluramine-like medications may act through interactions with the serotonin (5-hydroxytryptamine [5-HT] transporter (5-HTT located on pulmonary artery smooth muscle cells and responsible for the mitogenic action of 5-HT. Anorexigens may contribute to PH by boosting 5-HT levels in the bloodstream, directly stimulating smooth muscle cell growth, or altering 5-HTT expression. We suggest that individuals with a high basal level of 5-HTT expression related to the presence of the long 5-HTT gene promoter variant may be particularly susceptible to one or more of these potential mechanisms of appetite-suppressant-related PH.

Eliisabeti kirikus kõlavad kooriteosed

Index Scriptorium Estoniae

2008-01-01

Ülo Kriguli "Preces ad lucem" ("Palve valguse poole") ja Galina Grigorjeva "Nature morte" esiettekandest Eesti Filharmoonia Kammerkoori (dirigent Daniel Reuss) esituses 23. okt. Tallinnas Niguliste kirikus ja 24. okt. Pärnu Eliisabeti kirikus. Pärnu kontserdil kavas ka Cyrillus Kreegi "Taaveti" laulud ja Frank Martini "Missa". Pärnust sõidab koor Riiga professionaalsele kooride festivalile "Tenso päevad"

Uudiseid maailmast / Nele-Eva Steinfeld

Index Scriptorium Estoniae

Steinfeld, Nele-Eva

2013-01-01

Lühisõnumeid muusikamaailmast: Michel van der Aa pälvis Grawemeyeri muusikaauhinna. Norra rahvusooper tellis Jüri Reinverelt ooperi "Peer Gynt". Dirigent Santtu-Matias Rouvali tõus. New Yorgi Filharmoonikud teevad koostööd Hiinaga. Lahkus Galina Višnevskaja. Suri Charles Rosen. Daniel Barenboim rajab Berliini uue muusikaakadeemia. Viiulikaupmehele vanglakaristus. Toronto linnast valmib sümfoonia jt.

Lugusid möödunud aegadest / Andrus Kivirähk

Index Scriptorium Estoniae

Kivirähk, Andrus, 1970-

2007-01-01

Autor toob viimasel ajal loetud kirjandusteoste hulgast välja oma põnevaimad leiud: Mart Kivastik. Külmetava kunstniku portree ; Mart Kivastik. Põrgu wärk ; Mart Kivastik. Kits õnge ja viiuliga ; Galina Vishnevskaja. Aeg ja elu ; Maurice Druon. Neetud kuningad : raudne kuningas ; Maurice Druon. Neetud kuningad : kägistatud kuninganna ; Maurice Druon. Neetud kuningad : kuningavõimu mürgitajad

CTG repeat-targeting oligonucleotides for down-regulating Huntingtin expression

DEFF Research Database (Denmark)

Zaghloul, Eman M; Gissberg, Olof; Moreno, Pedro M D

2017-01-01

Huntington's disease (HD) is a fatal, neurodegenerative disorder in which patients suffer from mobility, psychological and cognitive impairments. Existing therapeutics are only symptomatic and do not significantly alter the disease progression or increase life expectancy. HD is caused by expansion....... Thus, reduction of both muHTT mRNA and protein levels would ideally be the most useful therapeutic option. We herein present a novel strategy for HD treatment using oligonucleotides (ONs) directly targeting the HTT trinucleotide repeat DNA. A partial, but significant and potentially long-term, HTT...

Environmental enrichment reduces innate anxiety with no effect on depression-like behaviour in mice lacking the serotonin transporter.

Science.gov (United States)

Rogers, Jake; Li, Shanshan; Lanfumey, Laurence; Hannan, Anthony J; Renoir, Thibault

2017-08-14

Along with being the main target of many antidepressant medications, the serotonin transporter (5-HTT) is known to be involved in the pathophysiology of depression and anxiety disorders. In line with this, mice with varying 5-HTT genotypes are invaluable tools to study depression- and anxiety-like behaviours as well as the mechanisms mediating potential therapeutics. There is clear evidence that both genetic and environmental factors play a role in the aetiology of psychiatric disorders. In that regard, housing paradigms which seek to enhance cognitive stimulation and physical activity have been shown to exert beneficial effects in animal models of neuropsychiatric disorders. In the present study, we examined the effects of environmental enrichment on affective-like behaviours and sensorimotor gating function of 5-HTT knock-out (KO) mice. Using the elevated-plus maze and the light-dark box, we found that environmental enrichment ameliorated the abnormal innate anxiety of 5-HTT KO mice on both tests. In contrast, environmental enrichment did not rescue the depression-like behaviour displayed by 5-HTT KO mice in the forced-swim test. Finally, measuring pre-pulse inhibition, we found no effect of genotype or treatment on sensorimotor gating. In conclusion, our data suggest that environmental enrichment specifically reduces innate anxiety of 5-HTT KO mice with no amelioration of the depression-like behaviour. This has implications for the current use of clinical interventions for patients with symptoms of both anxiety and depression. Copyright © 2017 Elsevier B.V. All rights reserved.

A new Caenorhabditis elegans model of human huntingtin 513 aggregation and toxicity in body wall muscles.

Directory of Open Access Journals (Sweden)

Amy L Lee

Full Text Available Expanded polyglutamine repeats in different proteins are the known determinants of at least nine progressive neurodegenerative disorders whose symptoms include cognitive and motor impairment that worsen as patients age. One such disorder is Huntington's Disease (HD that is caused by a polyglutamine expansion in the human huntingtin protein (htt. The polyglutamine expansion destabilizes htt leading to protein misfolding, which in turn triggers neurodegeneration and the disruption of energy metabolism in muscle cells. However, the molecular mechanisms that underlie htt proteotoxicity have been somewhat elusive, and the muscle phenotypes have not been well studied. To generate tools to elucidate the basis for muscle dysfunction, we engineered Caenorhabditis elegans to express a disease-associated 513 amino acid fragment of human htt in body wall muscle cells. We show that this htt fragment aggregates in C. elegans in a polyglutamine length-dependent manner and is toxic. Toxicity manifests as motor impairment and a shortened lifespan. Compared to previous models, the data suggest that the protein context in which a polyglutamine tract is embedded alters aggregation propensity and toxicity, likely by affecting interactions with the muscle cell environment.

BDNF val66met association with serotonin transporter binding in healthy humans

DEFF Research Database (Denmark)

Fisher, P. M.; Ozenne, B.; Svarer, C.

2017-01-01

The serotonin transporter (5-HTT) is a key feature of the serotonin system, which is involved in behavior, cognition and personality and implicated in neuropsychiatric illnesses including depression. The brain-derived neurotrophic factor (BDNF) val66met and 5-HTTLPR polymorphisms have predicted......-carriers have increased subcortical 5-HTT binding. The small difference suggests limited statistical power may explain previously reported null effects. Our finding adds to emerging evidence that BDNF val66met contributes to differences in the human brain serotonin system, informing how variability in the 5-HTT...

Helmet Sensor - Transfer Function and Model Development

Science.gov (United States)

2010-09-01

that helmets be examined forensically when estimating the impact direction and location and the electronic HMSS data not be used in that determination... forensic analysis of the helmet itself is therefore recommended to determine the direction and severity of the ballistic impact 5. The helmet shell does...ot83 HTI l ot 8J HT1 lot S ,HTt IOt S , HTI l otiH HTt lotSS HTt l vt85 HTI l o)t 85 HT1 Front Level Acceleration ~~,--~----~--,30’p~g

The Role of Heat Tolerance Testing in Recovery and Return to Duty

Science.gov (United States)

2008-10-01

CV diseases Hyperthyroidism Pheochromocytoma Infectious diseases Diabetes mellitus Psychiatric illness Parkinsonism Congenital abnormalities: CF...environments. To assess the heat tolerance status of prior heat stroke patient. Heat tolerance test (HTT) “HTT was effective in evaluating the heat tolerance

Brain Networks Implicated in Seasonal Affective Disorder

DEFF Research Database (Denmark)

Nørgaard, Martin; Ganz, Melanie; Svarer, Claus

2017-01-01

, patients with SAD fail to globally downregulate their cerebral serotonin transporter (5-HTT) in winter, and that this effect seemed to be particularly pronounced in female S-carriers of the 5-HTTLPR genotype. The purpose of this study was to identify a 5-HTT brain network that accounts for the adaption...... without SAD; it included the right superior frontal gyrus, brainstem, globus pallidus (bilaterally) and the left hippocampus. Across seasons, female S' carriers without SAD showed nominally higher 5-HTT levels in these regions compared to female S' carriers with SAD, but the group difference was only...... winter compared to female S' carriers without SAD. Limitations: The study is preliminary and limited by small sample size in the SAD group (N = 6). Conclusions: These findings provide novel exploratory evidence for a wintertime state-dependent difference in 5-HTT levels that may leave SAD females...

Quantum Metaphotonics

Science.gov (United States)

2016-03-24

National Laboratories), Ricky Gibson, Sander Zandbergen, Jasmine Sears , and Patrick Keiffer. Professor: Galina Khitrova References 1. M...Gehl, S. Zandbergen, R. Gibson, M. Béchu, N. Nader, J. Hendrickson, J. Sears , P. Keiffer, M. Wegener, and G. Khitrova, “Spectroscopic studies of...2012). 12. M. Gehl, R. Gibson, S. Zandbergen, P. Keiffer, J. Sears , and G. Khitrova, “Superconductivity in epitaxially grown self-assembled indium

Msh2 acts in medium-spiny striatal neurons as an enhancer of CAG instability and mutant huntingtin phenotypes in Huntington's disease knock-in mice.

Directory of Open Access Journals (Sweden)

Marina Kovalenko

Full Text Available The CAG trinucleotide repeat mutation in the Huntington's disease gene (HTT exhibits age-dependent tissue-specific expansion that correlates with disease onset in patients, implicating somatic expansion as a disease modifier and potential therapeutic target. Somatic HTT CAG expansion is critically dependent on proteins in the mismatch repair (MMR pathway. To gain further insight into mechanisms of somatic expansion and the relationship of somatic expansion to the disease process in selectively vulnerable MSNs we have crossed HTT CAG knock-in mice (HdhQ111 with mice carrying a conditional (floxed Msh2 allele and D9-Cre transgenic mice, in which Cre recombinase is expressed specifically in MSNs within the striatum. Deletion of Msh2 in MSNs eliminated Msh2 protein in those neurons. We demonstrate that MSN-specific deletion of Msh2 was sufficient to eliminate the vast majority of striatal HTT CAG expansions in HdhQ111 mice. Furthermore, MSN-specific deletion of Msh2 modified two mutant huntingtin phenotypes: the early nuclear localization of diffusely immunostaining mutant huntingtin was slowed; and the later development of intranuclear huntingtin inclusions was dramatically inhibited. Therefore, Msh2 acts within MSNs as a genetic enhancer both of somatic HTT CAG expansions and of HTT CAG-dependent phenotypes in mice. These data suggest that the selective vulnerability of MSNs may be at least in part contributed by the propensity for somatic expansion in these neurons, and imply that intervening in the expansion process is likely to have therapeutic benefit.

Huntingtin gene repeat size variations affect risk of lifetime depression.

Science.gov (United States)

Gardiner, Sarah L; van Belzen, Martine J; Boogaard, Merel W; van Roon-Mom, Willeke M C; Rozing, Maarten P; van Hemert, Albert M; Smit, Johannes H; Beekman, Aartjan T F; van Grootheest, Gerard; Schoevers, Robert A; Oude Voshaar, Richard C; Roos, Raymund A C; Comijs, Hannie C; Penninx, Brenda W J H; van der Mast, Roos C; Aziz, N Ahmad

2017-12-11

Huntington disease (HD) is a severe neuropsychiatric disorder caused by a cytosine-adenine-guanine (CAG) repeat expansion in the HTT gene. Although HD is frequently complicated by depression, it is still unknown to what extent common HTT CAG repeat size variations in the normal range could affect depression risk in the general population. Using binary logistic regression, we assessed the association between HTT CAG repeat size and depression risk in two well-characterized Dutch cohorts─the Netherlands Study of Depression and Anxiety and the Netherlands Study of Depression in Older Persons─including 2165 depressed and 1058 non-depressed persons. In both cohorts, separately as well as combined, there was a significant non-linear association between the risk of lifetime depression and HTT CAG repeat size in which both relatively short and relatively large alleles were associated with an increased risk of depression (β = -0.292 and β = 0.006 for the linear and the quadratic term, respectively; both P < 0.01 after adjustment for the effects of sex, age, and education level). The odds of lifetime depression were lowest in persons with a HTT CAG repeat size of 21 (odds ratio: 0.71, 95% confidence interval: 0.52 to 0.98) compared to the average odds in the total cohort. In conclusion, lifetime depression risk was higher with both relatively short and relatively large HTT CAG repeat sizes in the normal range. Our study provides important proof-of-principle that repeat polymorphisms can act as hitherto unappreciated but complex genetic modifiers of depression.

Synthesis, radiolabeling and baboon SPECT imaging of 2β-carbomethoxy-3β-(3'-[123I]iodophenyl)tropane ([123I]YP256) as a serotonin transporter radiotracer

International Nuclear Information System (INIS)

Bois, Frederic; Baldwin, Ronald M.; Amici, Louis; Al-Tikriti, Mohammed S.; Kula, Nora; Baldessarini, Ross; Innis, Robert B.; Staley, Julie K.; Tamagnan, Gilles D.

2008-01-01

To develop a potential SPECT probe to evaluate the integrity of the serotoninergic system (5-HTT) whose dysfunction is linked to several disease conditions such as Parkinson's disease, Alzheimer's disease and depression, we report the synthesis, radiolabeling and in vivo baboon imaging of 2β-carbomethoxy-3β-(3'-[ 123 I]iodophenyl) tropane (YP256, ). The radiolabeling was performed by iododestannylation using sodium [ 123 I]iodide and peracetic acid. Although the ligand displayed high selectivity for 5-HTT over dopamine transporter in vitro, SPECT imaging in baboons did not reveal selective 5-HTT accumulation in brain in vivo

Early life stress predicts negative urgency through brooding, depending on 5-HTTLPR genotype: A pilot study with 6-month follow-up examining suicide ideation.

Science.gov (United States)

Valderrama, Jorge; Miranda, Regina

2017-12-01

The present study examined the interaction between early life stress and 5-HTT genotypes in predicting two risk factors for suicidal behavior - the brooding subtype of rumination and impulsivity, in the form of negative urgency - over time. Furthermore, we examined early life stress, brooding, and impulsivity as predictors of suicidal ideation over time. Participants with and without a history of early life stress were genotyped for the 5-HTTLPR polymorphism and completed assessments assessing brooding and negative urgency at baseline and 6-month follow up. Early life emotional abuse was associated with negative urgency at follow-up. We found an indirect effect of early life emotional abuse on negative urgency through brooding among individuals with 5-HTT low expressing genotypes but not among individuals with 5-HTT high expressing genotypes. Further, a logistic regression analysis revealed that negative urgency was associated with higher odds (O.R. = 16.2) of reporting suicide ideation (versus no ideation) at follow-up. Our findings suggest that brooding and negative urgency may result from the interaction between early life emotional abuse and 5-HTT low expressing genotypes. Further research is necessary to understand how early life stress interacts with 5-HTT genotypes to confer risk for suicidal behavior through psychological mechanisms. Copyright © 2017 Elsevier B.V. All rights reserved.

Favoritõ imperatorskogo dvora / Galina Balashova

Index Scriptorium Estoniae

Balashova, Galina

2004-01-01

Eestiga seotud vene keiserliku fotograafi Carl Bulla ja vene keiserliku juveliiri Carl Faberge elust ja loomingust. Kirjeldatud on kuulsaid Faberge juveliir-mune. Carl Bulla elas Saaremaal 1916-1929, Carl Faberge isa Gustav oli pärit Pärnust

'Kazhdogo vletshjot jego strast' / Galina Balashova

Index Scriptorium Estoniae

Balashova, Galina

1999-01-01

Johannes Käbini kollektsiooni kuulunud taiestest (27 eesti kunstiklassikasse kuuluvat tööd Kölerilt, Reindorffilt, Mäelt, Vabbelt, Kitselt jt.), mida pakutakse müüa galerii RIOS korraldatud oksjonil.

Hydrothermal emergence model for ripgut brome (Bromus diandrus)

Science.gov (United States)

A model that describes the emergence of ripgut brome (Bromus diandrus) was developed using a two-season data set from a no-tilled field in northeastern Spain. The relationship between cumulative emergence and hydrothermal time (HTT) was described by a sigmoid growth function (Chapman equation). HTT ...

Assessment of motor function, sensory motor gating and recognition memory in a novel BACHD transgenic rat model for Huntington disease

NARCIS (Netherlands)

Abada, Yah-se K.; Nguyen, Huu Phuc; Schreiber, Rudy; Ellenbroek, Bart

2013-01-01

Rationale: Huntington disease (HD) is frequently first diagnosed by the appearance of motor symptoms; the diagnosis is subsequently confirmed by the presence of expanded CAG repeats (> 35) in the HUNTINGTIN (HTT) gene. A BACHD rat model for HD carrying the human full length mutated HTT with 97

Huntingtin gene repeat size variations affect risk of lifetime depression

DEFF Research Database (Denmark)

Gardiner, Sarah L.; van Belzen, Martine J.; Boogaard, Merel W.

2017-01-01

Huntington disease (HD) is a severe neuropsychiatric disorder caused by a cytosine-adenine-guanine (CAG) repeat expansion in the HTT gene. Although HD is frequently complicated by depression, it is still unknown to what extent common HTT CAG repeat size variations in the normal range could affect...

Cellular cytotoxic response induced by highly purified multi-wall carbon nanotube in human lung cells.

Science.gov (United States)

Tsukahara, Tamotsu; Haniu, Hisao

2011-06-01

Carbon nanotubes, a promising nanomaterial with unique characteristics, have applications in a variety of fields. The cytotoxic effects of carbon nanotubes are partially due to the induction of oxidative stress; however, the detailed mechanisms of nanotube cytotoxicity and their interaction with cells remain unclear. In this study, the authors focus on the acute toxicity of vapor-grown carbon fiber, HTT2800, which is one of the most highly purified multi-wall carbon nanotubes (MWCNT) by high-temperature thermal treatment. The authors exposed human bronchial epithelial cells (BEAS-2B) to HTT2800 and measured the cellular uptake, mitochondrial function, cellular LDH release, apoptotic signaling, reactive oxygen species (ROS) generation and pro-inflammatory cytokine release. The HTT2800-exposed cells showed cellular uptake of the carbon nanotube, increased cell death, enhanced DNA damage, and induced cytokine release. However, the exposed cells showed no obvious intracellular ROS generation. These cellular and molecular findings suggest that HTT2800 could cause a potentially adverse inflammatory response in BEAS-2B cells.

Electrochemical reversibility of reticulated vitreous carbon electrodes heat treated at different carbonization temperatures

Directory of Open Access Journals (Sweden)

Emerson Sarmento Gonçalves

2006-06-01

Full Text Available Electrochemical response of ferri/ferrocyanide redox couple is discussed for a system that uses reticulated vitreous carbon (RVC three dimensional electrodes prepared at five different Heat Treatment Temperatures (HTT in the range of 700 °C to 1100 °C. Electrical resistivity, scanning electron microscopy and X ray Diffraction analyses were performed for all prepared samples. It was observed that the HTT increasing promotes an electrical conductivity increasing while the Bragg distance d002 decreases. The correlation between reversibility behavior of ferri/ferrocyanide redox couple and both surface morphology and chemical properties of the RVC electrodes demonstrated a strong dependence on the HTT used to prepare the RVC.

Synthesis, radiolabeling and baboon SPECT imaging of 2{beta}-carbomethoxy-3{beta}-(3'-[{sup 123}I]iodophenyl)tropane ([{sup 123}I]YP256) as a serotonin transporter radiotracer

Energy Technology Data Exchange (ETDEWEB)

Bois, Frederic; Baldwin, Ronald M.; Amici, Louis; Al-Tikriti, Mohammed S. [Yale University, School of Medicine, VA Connecticut HCS (116A2), West Haven, CT 06516 (United States); Kula, Nora; Baldessarini, Ross [Department of Psychiatry and Neuroscience Program, Harvard Medical School, Mailman Research Center McLean Division of Massachusetts General Hospital, Belmont, MA 02478 (United States); Innis, Robert B.; Staley, Julie K. [Yale University, School of Medicine, VA Connecticut HCS (116A2), West Haven, CT 06516 (United States); Tamagnan, Gilles D. [Yale University, School of Medicine, VA Connecticut HCS (116A2), West Haven, CT 06516 (United States); Institute for Neurodegenerative Disorders, New Haven, CT 06510 (United States)], E-mail: gtamagnan@indd.org

2008-01-15

To develop a potential SPECT probe to evaluate the integrity of the serotoninergic system (5-HTT) whose dysfunction is linked to several disease conditions such as Parkinson's disease, Alzheimer's disease and depression, we report the synthesis, radiolabeling and in vivo baboon imaging of 2{beta}-carbomethoxy-3{beta}-(3'-[{sup 123}I]iodophenyl) tropane (YP256, ). The radiolabeling was performed by iododestannylation using sodium [{sup 123}I]iodide and peracetic acid. Although the ligand displayed high selectivity for 5-HTT over dopamine transporter in vitro, SPECT imaging in baboons did not reveal selective 5-HTT accumulation in brain in vivo.

(Online & Print): 2305-7432. htt

African Journals Online (AJOL)

Peter Berglez

could afford after working for a good five years in the public service as a teacher. ... image of the Life President, the Malawi Congress Party and the Ngwazi's diplomatic friends. Note that ... too close to be bribed and corrupted by that friendship.

Impaired heat shock response in cells expressing full-length polyglutamine-expanded huntingtin.

Directory of Open Access Journals (Sweden)

Sidhartha M Chafekar

Full Text Available The molecular mechanisms by which polyglutamine (polyQ-expanded huntingtin (Htt causes neurodegeneration in Huntington's disease (HD remain unclear. The malfunction of cellular proteostasis has been suggested as central in HD pathogenesis and also as a target of therapeutic interventions for the treatment of HD. We present results that offer a previously unexplored perspective regarding impaired proteostasis in HD. We find that, under non-stress conditions, the proteostatic capacity of cells expressing full length polyQ-expanded Htt is adequate. Yet, under stress conditions, the presence of polyQ-expanded Htt impairs the heat shock response, a key component of cellular proteostasis. This impaired heat shock response results in a reduced capacity to withstand the damage caused by cellular stress. We demonstrate that in cells expressing polyQ-expanded Htt the levels of heat shock transcription factor 1 (HSF1 are reduced, and, as a consequence, these cells have an impaired a heat shock response. Also, we found reduced HSF1 and HSP70 levels in the striata of HD knock-in mice when compared to wild-type mice. Our results suggests that full length, non-aggregated polyQ-expanded Htt blocks the effective induction of the heat shock response under stress conditions and may thus trigger the accumulation of cellular damage during the course of HD pathogenesis.

Genetic variation in 5-hydroxytryptamine transporter expression causes adaptive changes in 5-HT4 receptor levels

DEFF Research Database (Denmark)

Jennings, Katie Ann; Licht, Cecilie Löe; Bruce, Aynsley

2012-01-01

+/+ mice in all brain regions. Compared to wild-type (WT) littermate controls, 5-HTT OE mice had increased 5-HT4 binding density across all brain regions, except amygdala (118-164% of WT) and this difference between genotypes was reduced by the 5-HTT inhibitor, fluoxetine (20 mg/kg twice daily, 3 d...

AAV-mediated delivery of the transcription factor XBP1s into the striatum reduces mutant Huntingtin aggregation in a mouse model of Huntington’s disease

International Nuclear Information System (INIS)

Zuleta, Amparo; Vidal, Rene L.; Armentano, Donna; Parsons, Geoffrey; Hetz, Claudio

2012-01-01

Highlights: ► The contribution of ER stress to HD has not been directly addressed. ► Expression of XBP1s using AAVs decreases Huntingtin aggregation in vivo. ► We describe a new in vivo model of HD based on the expression of a large fragment of mHtt-RFP. -- Abstract: Huntington’s disease (HD) is caused by mutations that expand a polyglutamine region in the amino-terminal domain of Huntingtin (Htt), leading to the accumulation of intracellular inclusions and progressive neurodegeneration. Recent reports indicate the engagement of endoplasmic reticulum (ER) stress responses in human HD post mortem samples and animal models of the disease. Adaptation to ER stress is mediated by the activation of the unfolded protein response (UPR), an integrated signal transduction pathway that attenuates protein folding stress by controlling the expression of distinct transcription factors including X-Box binding protein 1 (XBP1). Here we targeted the expression of XBP1 on a novel viral-based model of HD. We delivered an active form of XBP1 locally into the striatum of adult mice using adeno-associated vectors (AAVs) and co-expressed this factor with a large fragment of mutant Htt as a fusion protein with RFP (Htt588 Q95 -mRFP) to directly visualize the accumulation of Htt inclusions in the brain. Using this approach, we observed a significant reduction in the accumulation of Htt588 Q95 -mRFP intracellular inclusion when XBP1 was co-expressed in the striatum. These results contrast with recent findings indicating a protective effect of XBP1 deficiency in neurodegeneration using knockout mice, and suggest a potential use of gene therapy strategies to manipulate the UPR in the context of HD.

Short G-rich oligonucleotides as a potential therapeutic for Huntington's Disease

Directory of Open Access Journals (Sweden)

Parekh-Olmedo Hetal

2006-10-01

Full Text Available Abstract Background Huntington's Disease (HD is an inherited autosomal dominant genetic disorder in which neuronal tissue degenerates. The pathogenesis of the disease appears to center on the development of protein aggregates that arise initially from the misfolding of the mutant HD protein. Mutant huntingtin (Htt is produced by HD genes that contain an increased number of glutamine codons within the first exon and this expansion leads to the production of a protein that misfolds. Recent studies suggest that mutant Htt can nucleate protein aggregation and interfere with a multitude of normal cellular functions. Results As such, efforts to find a therapy for HD have focused on agents that disrupt or block the mutant Htt aggregation pathway. Here, we report that short guanosine monotonic oligonucleotides capable of adopting a G-quartet structure, are effective inhibitors of aggregation. By utilizing a biochemical/immunoblotting assay as an initial screen, we identified a 20-mer, all G-oligonucleotide (HDG as an active molecule. Subsequent testing in a cell-based assay revealed that HDG was an effective inhibitor of aggregation of a fusion protein, comprised of a mutant Htt fragment and green fluorescent protein (eGFP. Taken together, our results suggest that a monotonic G-oligonucleotide, capable of adopting a G-quartet conformation is an effective inhibitor of aggregation. This oligonucleotide can also enable cell survival in PC12 cells overexpressing a mutant Htt fragment fusion gene. Conclusion Single-stranded DNA oligonucleotides capable of forming stable G-quartets can inhibit aggregation of the mutant Htt fragment protein. This activity maybe an important part of the pathogenecity of Huntington's Disease. Our results reveal a new class of agents that could be developed as a therapeutic approach for Huntington's Disease.

Hydrothermal time models for conidial germination and mycelial growth of the seed pathogen Pyrenophora semeniperda

Science.gov (United States)

Connor W. Barth; Susan E. Meyer; Julie Beckstead; Phil S. Allen

2015-01-01

Population-based threshold models using hydrothermal time (HTT) have been widely used to model seed germination. We used HTT to model conidial germination and mycelial growth for the seed pathogen Pyrenophora semeniperda in a novel approach to understanding its interactions with host seeds. Germination time courses and mycelial growth rates for P.semeniperda were...

Homsed disaini- ja furnituurilahendused

Index Scriptorium Estoniae

2007-01-01

Müügijuht Galina Sepp 2006. a. asutatud mööbliettevõttest AIS Furniture (Advanced Interior Solutions), mille tootmistsehh asub Harjumaal Loo alevikus, salong Tallinnas Pärnu mnt. 66. Toodetakse eritellimusel mööblit kööki, elu- ja vannituppa, garderoobi, büroosse ning abiruumidesse. AIS Furniture disaineritelt saab tellida kogu maja või korteri sisekujunduse koos mööbliga. Köökide tehnilised lahendused on pärit furnituuritootjatelt

CAG Expansions Are Genetically Stable and Form Nontoxic Aggregates in Cells Lacking Endogenous Polyglutamine Proteins

Directory of Open Access Journals (Sweden)

Ashley A. Zurawel

2016-09-01

Full Text Available Proteins containing polyglutamine (polyQ regions are found in almost all eukaryotes, albeit with various frequencies. In humans, proteins such as huntingtin (Htt with abnormally expanded polyQ regions cause neurodegenerative diseases such as Huntington’s disease (HD. To study how the presence of endogenous polyQ aggregation modulates polyQ aggregation and toxicity, we expressed polyQ expanded Htt fragments (polyQ Htt in Schizosaccharomyces pombe. In stark contrast to other unicellular fungi, such as Saccharomyces cerevisiae, S. pombe is uniquely devoid of proteins with more than 10 Q repeats. We found that polyQ Htt forms aggregates within S. pombe cells only with exceedingly long polyQ expansions. Surprisingly, despite the presence of polyQ Htt aggregates in both the cytoplasm and nucleus, no significant growth defect was observed in S. pombe cells. Further, PCR analysis showed that the repetitive polyQ-encoding DNA region remained constant following transformation and after multiple divisions in S. pombe, in contrast to the genetic instability of polyQ DNA sequences in other organisms. These results demonstrate that cells with a low content of polyQ or other aggregation-prone proteins can show a striking resilience with respect to polyQ toxicity and that genetic instability of repetitive DNA sequences may have played an important role in the evolutionary emergence and exclusion of polyQ expansion proteins in different organisms.

Intravitreal administration of HA-1077, a ROCK inhibitor, improves retinal function in a mouse model of huntington disease.

Directory of Open Access Journals (Sweden)

Mei Li

Full Text Available Huntington disease (HD is an inherited neurodegenerative disease that affects multiple brain regions. It is caused by an expanded polyglutamine tract in huntingtin (Htt. The development of therapies for HD and other neurodegenerative diseases has been hampered by multiple factors, including the lack of clear therapeutic targets, and the cost and complexity of testing lead compounds in vivo. The R6/2 HD mouse model is widely used for pre-clinical trials because of its progressive and robust neural dysfunction, which includes retinal degeneration. Profilin-1 is a Htt binding protein that inhibits Htt aggregation. Its binding to Htt is regulated by the rho-associated kinase (ROCK, which phosphorylates profilin at Ser-137. ROCK is thus a therapeutic target in HD. The ROCK inhibitor Y-27632 reduces Htt toxicity in fly and mouse models. Here we characterized the progressive retinopathy of R6/2 mice between 6-19 weeks of age to determine an optimal treatment window. We then tested a clinically approved ROCK inhibitor, HA-1077, administered intravitreally via liposome-mediated drug delivery. HA-1077 increased photopic and flicker ERG response amplitudes in R6/2 mice, but not in wild-type littermate controls. By targeting ROCK with a new inhibitor, and testing its effects in a novel in vivo model, these results validate the in vivo efficacy of a therapeutic candidate, and establish the feasibility of using the retina as a readout for CNS function in models of neurodegenerative disease.

Näiteid ja nimesid läti teatri seest / Rait Avestik

Index Scriptorium Estoniae

Avestik, Rait, 1974-

2008-01-01

Sügisel Riias toimunud teatrifestivalist "Spelmanu nakts", kus võis näha Läti teatri 2006/2007. aasta hooaja parimaid lavastusi. Pikemalt lavastustest: Alvis Hermanise "Vaikuse hääl", "Pikk elu" ja "Läti armastus" Riia Uues Teatris; Nabokovi "Lolita" Dzh. Dzh. Dzhilindzhersi tõlgenduses Daile teatris; Ostrovski näidendi "Äike" põhjal Galina Polishtshuki "Meie" Läti Rahvusteater koostöös Teatriobservatooriumiga; Rudolfs Baumanise "Surma varjus", lavastanud Martinsh Eihe Valmiera teatris

JPRS Report, Soviet Union, Political Affairs

Science.gov (United States)

1989-09-27

the popular "On-Duty Reporter" column , Yeliza- veta Bogoslovskaya, Sergey Chesnokov, and Galina Sapunova, literally have not gotten off the telephone...Affairs E . A. Didorenko. He has demonstrated the kind of admirable energy that he has failed to show in the fight against crime. Back on 23 February...Our editorial welcomed E . A. Didorenko’s and TASH- KENTSKAYA PRAVDA’s desire to shed light on many problems of interethnic relations and the

A dual-process account of auditory change detection.

Science.gov (United States)

McAnally, Ken I; Martin, Russell L; Eramudugolla, Ranmalee; Stuart, Geoffrey W; Irvine, Dexter R F; Mattingley, Jason B

2010-08-01

Listeners can be "deaf" to a substantial change in a scene comprising multiple auditory objects unless their attention has been directed to the changed object. It is unclear whether auditory change detection relies on identification of the objects in pre- and post-change scenes. We compared the rates at which listeners correctly identify changed objects with those predicted by change-detection models based on signal detection theory (SDT) and high-threshold theory (HTT). Detected changes were not identified as accurately as predicted by models based on either theory, suggesting that some changes are detected by a process that does not support change identification. Undetected changes were identified as accurately as predicted by the HTT model but much less accurately than predicted by the SDT models. The process underlying change detection was investigated further by determining receiver-operating characteristics (ROCs). ROCs did not conform to those predicted by either a SDT or a HTT model but were well modeled by a dual-process that incorporated HTT and SDT components. The dual-process model also accurately predicted the rates at which detected and undetected changes were correctly identified.

Application of hybrid organic/inorganic polymers as coatings on metallic substrates

Science.gov (United States)

Augustinho, T. R.; Motz, G.; Ihlow, S.; Machado, R. A. F.

2016-09-01

Acrylic polymers, particularly poly (methyl methacrylate) (PMMA), have certain specific properties, such as good film formation, transparency, and good mechanical properties, which have been widely used in paints, coatings and adhesives. However, the limited chemical and physical stability of these pure polymers limits their applications when exposed to hostile conditions, as in ship hulls, for example. A suitable way to enhance PMMA properties is the addition of silicon polymers with very good protective characteristics. In this study, a PMMA and HTT 1800 (commercial silazane) copolymer were applied on metallic substrate and compared to pure PMMA and HTT 1800. All the materials were applied as coatings. They were applied on stainless steel via dip-coating to investigate the coating properties. Thermal cycling was employed to analyze coating durability at high temperatures (50 °C to 600 °C). Optical microscopy (OM) and scanning electron microscopy (SEM) were used to characterize the coated surfaces, and the adhesion of pure PMMA, pure HTT 1800 and PMMA/HTT 1800 coatings on metallic substrate was investigated by Cross-Cut-Test (ASTM D 3359). The sessile drop method was used to determine the contact angle. PMMA coatings presented complete degradation from 250 °C, while hybrid coatings of PMMA and HTT 1800 have good protection until 400 °C. The adherence of the coating on metallic substrate showed improvement in all synthesized materials when compared to pure PMMA, obtaining the best adherence possible. The contact angle test showed that the hydrophobicity of the hybrid coatings is higher than that of the pure coatings.

Rossija molodaja / Ivan Glazunov ; interv. Galina Balashova

Index Scriptorium Estoniae

Glazunov, Ivan

2002-01-01

Vene saatkonna galeriis avatud vene noorte kunstnike rahvuslikke revolutsioonieelseid maalikunsti traditsioone järgivast näitusest: Vladimir Shteini portreed, Pavel Rõzhenko ajaloomaal, Stanislav Moskvitini ja Andrei Grigorjevi loodusmaal

Argentina - Estonija. Metshta i realnost / Galina Balashova

Index Scriptorium Estoniae

Balashova, Galina

2006-01-01

Argentiina fotograafi Marcos Lopez'i ja eesti fotograafi Peeter Lauritsa ühisnäitusest "Lopez & Laurits" Tallinna Kunstihoones. Kuraator Reet Varblane ja kujundaja Rosita Raud. Fotograafidest ja nende loomingust

Kak gotovjatsja art-delikatesõ / Galina Balashova

Index Scriptorium Estoniae

Balashova, Galina

2002-01-01

Uue galerii MAGNON avamisest Tallinnas Vene tänaval (galerist Tatjana Mangus) erootikateemalise näitusega "Art-delikatess". Vladimir Makarenko, Slava Semerikovi, Vladimir Baciu, Igor Balashovi, Anatoli Strahhovi, skulptorite Mihhail Duhhomjonoki, Simsoni Seakülast jt. töödest näitusel

The Human Terrain System: Achieving a Competitive Advantage Through Enhanced Population-Centric Knowledge Flows

Science.gov (United States)

2008-09-01

of behavior ( Fetterman , 1998, p. 35). Moreover, the goal of the participating observer is to internalize fundamental “beliefs, fears, hopes and...expectations of the people under study” ( Fetterman , 1998, p. 35). Additionally, HTT members frequently conduct informal interviews (open ended casual...techniques, and questionnaires ( Fetterman , 1998, p. 35). The third principle method HTT members use to learn the population is the semi- structured

Huntingtin interacting proteins are genetic modifiers of neurodegeneration.

Directory of Open Access Journals (Sweden)

Linda S Kaltenbach

2007-05-01

Full Text Available Huntington's disease (HD is a fatal neurodegenerative condition caused by expansion of the polyglutamine tract in the huntingtin (Htt protein. Neuronal toxicity in HD is thought to be, at least in part, a consequence of protein interactions involving mutant Htt. We therefore hypothesized that genetic modifiers of HD neurodegeneration should be enriched among Htt protein interactors. To test this idea, we identified a comprehensive set of Htt interactors using two complementary approaches: high-throughput yeast two-hybrid screening and affinity pull down followed by mass spectrometry. This effort led to the identification of 234 high-confidence Htt-associated proteins, 104 of which were found with the yeast method and 130 with the pull downs. We then tested an arbitrary set of 60 genes encoding interacting proteins for their ability to behave as genetic modifiers of neurodegeneration in a Drosophila model of HD. This high-content validation assay showed that 27 of 60 orthologs tested were high-confidence genetic modifiers, as modification was observed with more than one allele. The 45% hit rate for genetic modifiers seen among the interactors is an order of magnitude higher than the 1%-4% typically observed in unbiased genetic screens. Genetic modifiers were similarly represented among proteins discovered using yeast two-hybrid and pull-down/mass spectrometry methods, supporting the notion that these complementary technologies are equally useful in identifying biologically relevant proteins. Interacting proteins confirmed as modifiers of the neurodegeneration phenotype represent a diverse array of biological functions, including synaptic transmission, cytoskeletal organization, signal transduction, and transcription. Among the modifiers were 17 loss-of-function suppressors of neurodegeneration, which can be considered potential targets for therapeutic intervention. Finally, we show that seven interacting proteins from among 11 tested were able to

Changes of biomechanical properties of the shoulder bone of white rate on the background of the deffects of the greater bone and the possibility of their pharmacological correction

OpenAIRE

Lukyantseva, Galina

2017-01-01

Lukyantseva Galina. Changes of biomechanical properties of the shoulder bone of white rate on the background of the deffects of the greater bone and the possibility of their pharmacological correction. Journal of Education, Health and Sport. 2017;7(6):767-777. eISSN 2391-8306. DOI http://dx.doi.org/10.5281/zenodo.1000949 http://ojs.ukw.edu.pl/index.php/johs/article/view/4946 The journal has had 7 points in Ministry of Science and Higher Education parametric eva...

Functions of huntingtin in germ layer specification and organogenesis.

Directory of Open Access Journals (Sweden)

Giang D Nguyen

Full Text Available Huntington's disease (HD is a neurodegenerative disease caused by abnormal polyglutamine expansion in the huntingtin protein (Htt. Although both Htt and the HD pathogenic mutation (mHtt are implicated in early developmental events, their individual involvement has not been adequately explored. In order to better define the developmental functions and pathological consequences of the normal and mutant proteins, respectively, we employed embryonic stem cell (ESC expansion, differentiation and induction experiments using huntingtin knock-out (KO and mutant huntingtin knock-in (Q111 mouse ESC lines. In KO ESCs, we observed impairments in the spontaneous specification and survival of ectodermal and mesodermal lineages during embryoid body formation and under inductive conditions using retinoic acid and Wnt3A, respectively. Ablation of BAX improves cell survival, but failed to correct defects in germ layer specification. In addition, we observed ensuing impairments in the specification and maturation of neural, hepatic, pancreatic and cardiomyocyte lineages. These developmental deficits occurred in concert with alterations in Notch, Hes1 and STAT3 signaling pathways. Moreover, in Q111 ESCs, we observed differential developmental stage-specific alterations in lineage specification and maturation. We also observed changes in Notch/STAT3 expression and activation. Our observations underscore essential roles of Htt in the specification of ectoderm, endoderm and mesoderm, in the specification of neural and non-neural organ-specific lineages, as well as cell survival during early embryogenesis. Remarkably, these developmental events are differentially deregulated by mHtt, raising the possibility that HD-associated early developmental impairments may contribute not only to region-specific neurodegeneration, but also to non-neural co-morbidities.

OF MICE, RATS AND MEN: REVISITING THE QUINOLINIC ACID HYPOTHESIS OF HUNTINGTON’S DISEASE

Science.gov (United States)

Schwarcz, R.; Guidetti, P.; Sathyasaikumar, K. V.; Muchowski, P. J.

2009-01-01

The neurodegenerative disease Huntington’s Disease (HD) is caused by an expanded polyglutamine (polyQ) tract in the protein huntingtin (htt). Although the gene encoding htt was identified and cloned more than 15 years ago, and in spite of impressive efforts to unravel the mechanism(s) by which mutant htt induces nerve cell death, these studies have so far not led to a good understanding of pathophysiology or an effective therapy. Set against a historical background, we review data supporting the idea that metabolites of the kynurenine pathway (KP) of tryptophan degradation provide a critical link between mutant htt and the pathophysiology of HD. New studies in HD brain and genetic model organisms suggest that the disease may in fact be causally related to early abnormalities in KP metabolism, favoring the formation of two neurotoxic metabolites, 3-hydroxykynurenine and quinolinic acid, over the related neuroprotective agent kynurenic acid. These findings not only link the excitotoxic hypothesis of HD pathology to an impairment of the KP but also define new drug targets and therefore have direct therapeutic implications. Thus, pharmacological normalization of the imbalance in brain KP metabolism may provide clinical benefits, which could be especially effective in the early stages of the disease. PMID:19394403

How the cerebral serotonin homeostasis predicts environmental changes

DEFF Research Database (Denmark)

Kalbitzer, Jan; Kalbitzer, Urs; Knudsen, Gitte Moos

2013-01-01

Molecular imaging studies with positron emission tomography have revealed that the availability of serotonin transporter (5-HTT) in the human brain fluctuates over the course of the year. This effect is most pronounced in carriers of the short allele of the 5-HTT promoter region (5-HTTLPR), which...... has in several previous studies been linked to an increased risk to develop mood disorders. We argue that long-lasting fluctuations in the cerebral serotonin transmission, which is regulated via the 5-HTT, are responsible for mediating responses to environmental changes based on an assessment...... of cerebral serotonin transmission to seasonal and other forms of environmental change imparts greater behavioral flexibility, at the expense of increased vulnerability to stress. This model may explain the somewhat higher prevalence of the s-allele in some human populations dwelling at geographic latitudes...

ニヴフ語東サハリン方言の昔話テキスト ： チハロシュとウサギ

OpenAIRE

蔡, 熙鏡

2013-01-01

This folktale was told by Mrs. Valentina Nikolaevna Sachgun who was born in the village Ygbo (Nogliki District) in 1935. The folktale was recorded in February 27, 2011 during my fieldwork in the village of Nogliki. Then I transcribed the folktale with the help of Mrs. Galina Ivanova Paklina, another speaker of the East-Sakhalin Dialect of Nivkh, in September 14, 2012. Caror and Rabbit In the old days, People took some of rabbit skins and brought it with them when they go to Pot...

Genetic variation in the serotonin transporter gene (5-HTTLPR, rs25531) influences the analgesic response to the short acting opioid Remifentanil in humans

OpenAIRE

Schalling Martin; Lonsdorf Tina B; Jensen Karin B; Kosek Eva; Ingvar Martin

2009-01-01

Abstract Background There is evidence from animal studies that serotonin (5-HT) can influence the antinociceptive effects of opioids at the spinal cord level. Therefore, there could be an influence of genetic polymorphisms in the serotonin system on individual variability in response to opioid treatment of pain. The serotonin transporter (5-HTT) is a key regulator of serotonin metabolism and availability and its gene harbors several known polymorphisms that are known to affect 5-HTT expressio...

Dysregulation of gene expression in the striatum of BACHD rats expressing full-length mutant huntingtin and associated abnormalities on molecular and protein levels.

Science.gov (United States)

Yu-Taeger, Libo; Bonin, Michael; Stricker-Shaver, Janice; Riess, Olaf; Nguyen, Hoa Huu Phuc

2017-05-01

Huntington disease (HD) is an autosomal dominantly inherited neurodegenerative disorder caused by a CAG repeat expansion in the gene coding for the huntingtin protein (HTT). Mutant HTT (mHTT) has been proposed to cause neuronal dysfunction and neuronal loss through multiple mechanisms. Transcriptional changes may be a core pathogenic feature of HD. Utilizing the Affymetrix platform we performed a genome-wide RNA expression analysis in two BACHD transgenic rat lines (TG5 and TG9) at 12 months of age, both of which carry full-length human mHTT but with different expression levels. By defining the threshold of significance at p < 0.01, we found 1608 genes and 871 genes differentially expressed in both TG5 and TG9 rats when compared to the wild type littermates, respectively. We only chose the highly up-/down-regulated genes for further analysis by setting an additional threshold of 1.5 fold change. Comparing gene expression profiles of human HD brains and BACHD rats revealed a high concordance in both functional and IPA (Ingenuity Pathway Analysis) canonical pathways relevant to HD. In addition, we investigated the causes leading to gene expression changes at molecular and protein levels in BACHD rats including the involvement of polyQ-containing transcription factors TATA box-binding protein (TBP), Sp1 and CBP as well as the chromatin structure. We demonstrate that the BACHD rat model recapitulates the gene expression changes of the human disease supporting its role as a preclinical research animal model. We also show for the first time that TFIID complex formation is reduced, while soluble TBP is increased in an HD model. This finding suggests that mHTT is a competitor instead of a recruiter of polyQ-containing transcription factors in the transcription process in HD. Copyright © 2017 Elsevier Ltd. All rights reserved.

The effects of smoking and nicotine ingestion on exercise heat tolerance.

Science.gov (United States)

Druyan, Amit; Atias, Danit; Ketko, Itay; Cohen-Sivan, Yoav; Heled, Yuval

2017-03-01

Smoking has a thermogenic effect and is associated with low physical performance. Nevertheless, a direct, quantitative effect of acute smoking on exercise heat tolerance has not been reported. Sixteen healthy young male volunteers, eight cigarette smokers, and eight non-smokers participated in the study. All subjects performed a maximal oxygen consumption test (VO2max) and a standardized heat tolerance test (HTT) after at least 12 h without smoking under the following conditions: no nicotine exposure, 10 min after nicotine exposure (2 mg nicotine lozenge), and 10 min after smoking two cigarettes (0.8 mg nicotine in each cigarette, smokers only). There was no significant effect of nicotine exposure on physiological performance and heat tolerance in the non-smokers group. In the smokers group, cigarette smoking, but not nicotine ingestion, resulted with higher heart rate (by 9±9 bpm) at the end of the HTT (psmoking and nicotine ingestion increased smokers' rectal temperature at the end of the HTT (by 0.24±0.16°C and 0.21±0.26°C, respectively, psmoking in the smokers group compared with no exposure (2.13±2.57 and 2.48±2.76, respectively, psmoking and nicotine ingestion increase the physiological strain during a HTT in smokers. Acute smoking may, therefore, increase heat intolerance and the risk to heat injuries.

Mitochondrial fragmentation in neuronal degeneration: Toward an understanding of HD striatal susceptibility

International Nuclear Information System (INIS)

Cherubini, Marta; Ginés, Silvia

2017-01-01

Huntington's disease (HD) is an autosomal-dominant progressive neurodegenerative disorder that primarily affects medium spiny neurons within the striatum. HD is caused by inheritance of an expanded CAG repeat in the HTT gene, resulting in a mutant huntingtin (mHtt) protein containing extra glutamine residues. Despite the advances in understanding the molecular mechanisms involved in HD the preferential vulnerability of the striatum remains an intriguing question. This review discusses current knowledge that links altered mitochondrial dynamics with striatal susceptibility in HD. We also highlight how the modulation of mitochondrial function may constitute an attractive therapeutic approach to reduce mHtt-induced toxicity and therefore prevent the selective striatal neurodegeneration. - Highlights: • Mitochondrial dynamics is unbalanced towards fission in HD. • Excessive mitochondrial fragmentation plays a critical role in the selective vulnerability of the striatum in HD. • Therapeutic approaches aimed to inhibit mitochondrial fission could contribute to prevent striatal neurodegeneration in HD.

Hydrothermal treatment and enzymatic hydrolysis of Tamarix ramosissima: evaluation of the process as a conversion method in a biorefinery concept.

Science.gov (United States)

Xiao, Ling-Ping; Shi, Zheng-Jun; Xu, Feng; Sun, Run-Cang

2013-05-01

The present work investigated the effects of hydrothermal treatment (HTT) of Tamarix ramosissima by determination of sugar and inhibitor formation in the liquid fraction, and chemical and morphological changes of the pretreated solid material coupled with an evaluation of enzymatic hydrolysis. HTT was carried out in a batch reactor system at a maximal temperature (TMAX 180-240 °C) and evaluated for severities logRo ranging from 2.40 to 4.17. The liquid fractions were analyzed by HPLC, GPC, and GC-MS. The morphology and composition of the solid residues were characterized using an array of techniques, such as SEM, XRD, BET surface area, and CP/MAS (13)C NMR. Using a variety of tools, we have developed a better understanding of how HTT process affects biomass structure and cellulose properties that impact on its digestibility. These results provided new insights into the factors limiting enzymatic digestibility and mechanism of biomass deconstruction during hydrothermal process. Crown Copyright © 2012. Published by Elsevier Ltd. All rights reserved.

Coordination preference and magnetic properties of FeII assemblies with a bis-azole bearing 1,2,4-triazole and tetrazole

Science.gov (United States)

Naik, Anil D.; Railliet, Antoine P.; Dîrtu, Marinela M.; Garcia, Yann

2012-03-01

With a new bis-azole molecular fragment ( Htt) bearing 1,2,4-triazole and tetrazole, a mononuclear complex [Fe(tt)2(H2O)4]·2H2O ( 1), a trinuclear complex [Fe3(tt)6(H2O)6]·2H2O ( 2) and a 1D coordination polymer [Fe(tt)(Htt)2]BF4·2CH3OH ( 3) were obtained by varying reaction conditions. Htt acts either as an anionic or neutral ligand depending upon the reaction medium and pH. Thermal variation of spin states of 1- 3 were investigated in the range 77-300 K by 57Fe Mössbauer spectroscopy. 1 totally remains in high-spin state over the entire temperature range whereas no spin crossover was evidenced in 2. Nearly 1:1 high-spin and low-spin population ratio is found in 3, which remains constant over the entire temperature range investigated.

Romantitsheskaja utopia, ili Progulka s fotokameroi / Galina Balashova

Index Scriptorium Estoniae

Balashova, Galina

2007-01-01

Fotonäitus "The Belarusian Identity cArt" Tallinna Kunstihoone galeriis. Eksponeeritud on Artur Klinovi (Klinau) fotoseeria "Minsk - unenägude päikeselinn", Igor Savtshenko fotoseeria "Kommenteeritav maastik" ja Andrei Liankevitshi fotod

Educational changes in Latvia and Estonia / Galina Bondarenko

Index Scriptorium Estoniae

Bondarenko, Galina

2004-01-01

Eesti ja Läti venekeelsete koolide üleminekust riigikeelsele õppele. Autori hinnangul integreeruvad Eesti venelased ühiskonda kiiremini kui Läti vähemusrahvused. Lisatud kasutatud allikate internetiaadressid

Kak prodat "Babushku" / Maria Melnikova ; interv. Galina Balashova

Index Scriptorium Estoniae

Melnikova, Maria

2005-01-01

Eesti Vene saatkonna "Vene galerii" osalemisest Madridis kunstilaadal ARCO-2005. Galerii esitles Ene-Liis Semperi videofilmi "Nimetu" ja vene kunstnike Bogdan Mamonovi ning Anton Litvini töid. Semperi ja Mamonovi töödest

Kiasma - muzei s vidom na Laplandiju / Galina Balashova

Index Scriptorium Estoniae

Balashova, Galina

2006-01-01

Steven Holli projekteeritud Kiasma muuseumihoonest Helsingis. Kontseptuaalkunsti näitusest ARS 06 "Reaalsustunne" Kiasmas. Eestlastest esineb Mark Raidpere. Vene kunstnikegrupi AEC+F ja vene kunstnike Juri Vassiljevi ning Aleksandr Ponomarjovi töödest näitusel. Ka Gerda Steineri & Jörg Lenzlingeri (Šveits), Martin & Munoz'i (USA, Hispaania), videokunstnik Bill Viola (USA) töödest

Haplotype-based stratification of Huntington's disease.

Science.gov (United States)

Chao, Michael J; Gillis, Tammy; Atwal, Ranjit S; Mysore, Jayalakshmi Srinidhi; Arjomand, Jamshid; Harold, Denise; Holmans, Peter; Jones, Lesley; Orth, Michael; Myers, Richard H; Kwak, Seung; Wheeler, Vanessa C; MacDonald, Marcy E; Gusella, James F; Lee, Jong-Min

2017-11-01

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by expansion of a CAG trinucleotide repeat in HTT, resulting in an extended polyglutamine tract in huntingtin. We and others have previously determined that the HD-causing expansion occurs on multiple different haplotype backbones, reflecting more than one ancestral origin of the same type of mutation. In view of the therapeutic potential of mutant allele-specific gene silencing, we have compared and integrated two major systems of HTT haplotype definition, combining data from 74 sequence variants to identify the most frequent disease-associated and control chromosome backbones and revealing that there is potential for additional resolution of HD haplotypes. We have used the large collection of 4078 heterozygous HD subjects analyzed in our recent genome-wide association study of HD age at onset to estimate the frequency of these haplotypes in European subjects, finding that common genetic variation at HTT can distinguish the normal and CAG-expanded chromosomes for more than 95% of European HD individuals. As a resource for the HD research community, we have also determined the haplotypes present in a series of publicly available HD subject-derived fibroblasts, induced pluripotent cells, and embryonic stem cells in order to facilitate efforts to develop inclusive methods of allele-specific HTT silencing applicable to most HD patients. Our data providing genetic guidance for therapeutic gene-based targeting will significantly contribute to the developments of rational treatments and implementation of precision medicine in HD.

Waste-to-energy: Dehalogenation of plastic-containing wastes.

Science.gov (United States)

Shen, Yafei; Zhao, Rong; Wang, Junfeng; Chen, Xingming; Ge, Xinlei; Chen, Mindong

2016-03-01

The dehalogenation measurements could be carried out with the decomposition of plastic wastes simultaneously or successively. This paper reviewed the progresses in dehalogenation followed by thermochemical conversion of plastic-containing wastes for clean energy production. The pre-treatment method of MCT or HTT can eliminate the halogen in plastic wastes. The additives such as alkali-based metal oxides (e.g., CaO, NaOH), iron powders and minerals (e.g., quartz) can work as reaction mediums and accelerators with the objective of enhancing the mechanochemical reaction. The dehalogenation of waste plastics could be achieved by co-grinding with sustainable additives such as bio-wastes (e.g., rice husk), recyclable minerals (e.g., red mud) via MCT for solid fuels production. Interestingly, the solid fuel properties (e.g., particle size) could be significantly improved by HTT in addition with lignocellulosic biomass. Furthermore, the halogenated compounds in downstream thermal process could be eliminated by using catalysts and adsorbents. Most dehalogenation of plastic wastes primarily focuses on the transformation of organic halogen into inorganic halogen in terms of halogen hydrides or salts. The integrated process of MCT or HTT with the catalytic thermal decomposition is a promising way for clean energy production. The low-cost additives (e.g., red mud) used in the pre-treatment by MCT or HTT lead to a considerable synergistic effects including catalytic effect contributing to the follow-up thermal decomposition. Copyright © 2015 Elsevier Ltd. All rights reserved.

When cytokinin, a plant hormone, meets the adenosine A2A receptor: a novel neuroprotectant and lead for treating neurodegenerative disorders?

Directory of Open Access Journals (Sweden)

Yi-Chao Lee

Full Text Available It is well known that cytokinins are a class of phytohormones that promote cell division in plant roots and shoots. However, their targets, biological functions, and implications in mammalian systems have rarely been examined. In this study, we show that one cytokinin, zeatin riboside, can prevent pheochromocytoma (PC12 cells from serum deprivation-induced apoptosis by acting on the adenosine A(2A receptor (A(2A-R, which was blocked by an A(2A-R antagonist and a protein kinase A (PKA inhibitor, demonstrating the functional ability of zeatin riboside by mediating through A(2A-R signaling event. Since the A(2A-R was implicated as a therapeutic target in treating Huntington's disease (HD, a cellular model of HD was applied by transfecting mutant huntingtin in PC12 cells. By using filter retardation assay and confocal microscopy we found that zeatin riboside reversed mutant huntingtin (Htt-induced protein aggregations and proteasome deactivation through A(2A-R signaling. PKA inhibitor blocked zeatin riboside-induced suppression of mutant Htt aggregations. In addition, PKA activated proteasome activity and reduced mutant Htt protein aggregations. However, a proteasome inhibitor blocked both zeatin riboside-and PKA activator-mediated suppression of mutant Htt aggregations, confirming mediation of the A(2A-R/PKA/proteasome pathway. Taken together, zeatin riboside might have therapeutic potential as a novel neuroprotectant and a lead for treating neurodegenerative disorders.

5-HTTLPR modulates the recognition accuracy and exploration of emotional facial expressions

Directory of Open Access Journals (Sweden)

Sabrina eBoll

2014-07-01

Full Text Available Individual genetic differences in the serotonin transporter-linked polymorphic region (5-HTTLPR have been associated with variations in the sensitivity to social and emotional cues as well as altered amygdala reactivity to facial expressions of emotion. Amygdala activation has further been shown to trigger gaze changes towards diagnostically relevant facial features. The current study examined whether altered socio-emotional reactivity in variants of the 5-HTTLPR promoter polymorphism reflects individual differences in attending to diagnostic features of facial expressions. For this purpose, visual exploration of emotional facial expressions was compared between a low (n=39 and a high (n=40 5-HTT expressing group of healthy human volunteers in an eye tracking paradigm. Emotional faces were presented while manipulating the initial fixation such that saccadic changes towards the eyes and towards the mouth could be identified. We found that the low versus the high 5-HTT group demonstrated greater accuracy with regard to emotion classifications, particularly when faces were presented for a longer duration. No group differences in gaze orientation towards diagnostic facial features could be observed. However, participants in the low 5-HTT group exhibited more and faster fixation changes for certain emotions when faces were presented for a longer duration and overall face fixation times were reduced for this genotype group. These results suggest that the 5-HTT gene influences social perception by modulating the general vigilance to social cues rather than selectively affecting the pre-attentive detection of diagnostic facial features.

Desorption of cesium ions from vermiculite with sea water by hydrothermal process

International Nuclear Information System (INIS)

Yin, Xiangbiao; Takahashi, Hideharu; Inaba, Yusuke; Takeshita, Kenji

2016-01-01

Cesium ions (Cs + ) strongly intercalated in vermiculite clay (Verm) had been effectively removed using sea water for its free utility, totally environmental friendly feature, and within containing numerous salt by the hydrothermal treatment process (HTT), which can help significantly promote desorption by the cation-exchange mechanism in subcritical condition. >74-100% removal was achieved to the interacted Cs + for a loading capacity of 4.8-50 mg g −1 . XRD results indicated that cation exchange proceeded between the intercalated Cs + and various cations in sea water during HTT. (author)

Correlations of behavioral deficits with brain pathology assessed through longitudinal MRI and histopathology in the R6/1 mouse model of Huntington's disease.

Directory of Open Access Journals (Sweden)

Ivan Rattray

Full Text Available Huntington's disease (HD is caused by the expansion of a CAG repeat in the huntingtin (HTT gene. The R6 mouse models of HD express a mutant version of exon 1 HTT and typically develop motor and cognitive impairments, a widespread huntingtin (HTT aggregate pathology and brain atrophy. Unlike the more commonly used R6/2 mouse line, R6/1 mice have fewer CAG repeats and, subsequently, a less rapid pathological decline. Compared to the R6/2 line, fewer descriptions of the progressive pathologies exhibited by R6/1 mice exist. The association between the molecular and cellular neuropathology with brain atrophy, and with the development of behavioral phenotypes remains poorly understood in many models of HD. In attempt to link these factors in the R6/1 mouse line, we have performed detailed assessments of behavior and of regional brain abnormalities determined through longitudinal, in vivo magnetic resonance imaging (MRI, as well as an end-stage, ex vivo MRI study and histological assessment. We found progressive decline in both motor and non-motor related behavioral tasks in R6/1 mice, first evident at 11 weeks of age. Regional brain volumes were generally unaffected at 9 weeks, but by 17 weeks there was significant grey matter atrophy. This age-related brain volume loss was validated using a more precise, semi-automated Tensor Based morphometry assessment. As well as these clear progressive phenotypes, mutant HTT (mHTT protein, the hallmark of HD molecular pathology, was widely distributed throughout the R6/1 brain and was accompanied by neuronal loss. Despite these seemingly concomitant, robust pathological phenotypes, there appeared to be little correlation between the three main outcome measures: behavioral performance, MRI-detected brain atrophy and histopathology. In conclusion, R6/1 mice exhibit many features of HD, but the underlying mechanisms driving these clear behavioral disturbances and the brain volume loss, still remain unclear.

Serotonin Transporter Gene 5-HTTLPR Polymorphism as a Protective Factor Against the Progression of Post-Stroke Depression.

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Zhao, Qiang; Guo, Yi; Yang, Dong; Yang, Tiansong; Meng, Xianghui

2016-04-01

Polymorphisms in the 5-HTT and BDNF genes are shown to affect their function at the molecular and serum level. Prior work has tried to correlate the polymorphisms with post-stroke depression (PSD), the results nevertheless remain indefinitive. A plausible reason accounting for the uncertainty relates to the small sample of each published trial. In this study, we have performed a comprehensive meta-analysis in order to evaluate the effects of 5-HTT and BDNF polymorphisms (5-HTTLPR, STin2 VNTR, 5-HTR2a 102 T/C, Val66Met) on genetic risk of PSD. Human case-control trials were identified by computer-assisted and manual searches. The article search was performed until October 2014. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using the fixed effects meta-analysis to measure the effects 5-HTT and BDNF polymorphisms exerted on PSD. We also performed test of heterogeneity, test of publication bias, and sensitivity analysis to examine the reliability and stability of combined effects. 5-HTTLPR was clearly associated with genetic risk of PSD. The association seemed to be more pronounced in the homozygous model (OR = 0.34, 95% CI = 0.23-0.51, P(Q-test) = 0.63). Both the heterozygous model and the recessive model showed 50% decreased risk of PSD (OR = 0.50, 95% CI = 0.37-0.67, P(Q-test) = 0.91; OR = 0.50, 95% CI = 0.36-0.70, P(Q-test) = 0.43, respectively). Such significant association was also detected for Caucasian and Asian. These results were reliable and stable based on related analyses. Taken together, 5-HTTLPR polymorphism of the 5-HTT gene seems to protect against the occurrence of PSD. Small sample size for the polymorphisms within 5-HTT and BDNF genes may have caused underestimated associations, and a larger study is required to further assess the relations.

The Unexpected Effects of Beneficial and Adverse Social Experiences during Adolescence on Anxiety and Aggression and Their Modulation by Genotype

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Meyer, Neele; Richter, S. Helene; Schreiber, Rebecca S.; Kloke, Vanessa; Kaiser, Sylvia; Lesch, Klaus-Peter; Sachser, Norbert

2016-01-01

Anxiety and aggression are part of the behavioral repertoire of humans and animals. However, in their exaggerated form both can become maladaptive and result in psychiatric disorders. On the one hand, genetic predisposition has been shown to play a crucial modulatory role in anxiety and aggression. On the other hand, social experiences have been implicated in the modulation of these traits. However, so far, mainly experiences in early life phases have been considered crucial for shaping anxiety-like and aggressive behavior, while the phase of adolescence has largely been neglected. Therefore, the aim of the present study was to elucidate how levels of anxiety-like and aggressive behavior are shaped by social experiences during adolescence and serotonin transporter (5-HTT) genotype. For this purpose, male mice of a 5-HTT knockout mouse model including all three genotypes (wildtype, heterozygous and homozygous 5-HTT knockout mice) were either exposed to an adverse social situation or a beneficial social environment during adolescence. This was accomplished in a custom-made cage system where mice experiencing the adverse environment were repeatedly introduced to the territory of a dominant opponent but had the possibility to escape to a refuge cage. Mice encountering beneficial social conditions had free access to a female mating partner. Afterwards, anxiety-like and aggressive behavior was assessed in a battery of tests. Surprisingly, unfavorable conditions during adolescence led to a decrease in anxiety-like behavior and an increase in exploratory locomotion. Additionally, aggressive behavior was augmented in animals that experienced social adversity. Concerning genotype, homozygous 5-HTT knockout mice were more anxious and less aggressive than heterozygous 5-HTT knockout and wildtype mice. In summary, adolescence is clearly an important phase in which anxiety-like and aggressive behavior can be shaped. Furthermore, it seems that having to cope with challenge during

Size distribution of carbon layer planes in biochar from different plant type of feedstock with different heating temperatures.

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Lu, Guan-Yang; Ikeya, Kosuke; Watanabe, Akira

2016-11-01

Biochar application to soil is a strategy to decelerate the increase in the atmospheric carbon concentration. The composition of condensed aromatic clusters appears to be an important determinant of the degradation rate of char in soil. The objective of the present study was to determine the size distribution of carbon layer planes in biochars produced from different types of feedstock (a broadleaf and a coniferous tree and two herbs) using different heating treatment temperatures (HTT; 400 °C-800 °C) using X-ray diffraction 11 band profile analysis. (13)C nuclear magnetic resonance with the phase-adjusted spinning side bands of the chars indicated different spectral features depending on the HTT and similar carbon composition among the plant types at each HTT. Both the content and composition of carbon layer planes in biochar produced using the same HTT were also similar among the plant types. The carbon layer plane size in the 400 °C and 600 °C chars was distributed from 0.24 to 1.68 or 1.92 nm (corresponding to 37 or 52 rings) with the mean size of 0.79-0.92 and 0.80-1.14 nm, respectively. The carbon layer planes in the 800 °C chars ranged from 0.72-0.96 nm (7-14 rings) to 2.64-3.60 nm (91-169 rings) and the mean values were 1.47-1.89 nm. The relative carbon layer plane content in the 600 °C and 800 °C chars was typically 2 and 3 times that in the 400 °C chars. These results indicate the progression of the formation and/or the size development of graphite-like structures, suggesting that a char produced at a higher HTT would have better carbon sequestrating characteristics. Copyright © 2016 Elsevier Ltd. All rights reserved.

The unexpected effects of beneficial and adverse social experiences during adolescence on anxiety and aggression and their modulation by genotype.

Directory of Open Access Journals (Sweden)

Neele eMeyer

2016-05-01

Full Text Available Anxiety and aggression are part of the behavioral repertoire of humans and animals. However, in their exaggerated form both can become maladaptive and result in psychiatric disorders. On the one hand, genetic predisposition has been shown to play a crucial modulatory role in anxiety and aggression. On the other hand, social experiences have been implicated in the modulation of these traits. However, so far, mainly experiences in early life phases have been considered crucial for shaping anxiety-like and aggressive behavior while the phase of adolescence has mainly been neglected. Therefore, the aim of the present study was to elucidate how levels of anxiety-like and aggressive behavior are shaped by social experiences during adolescence and serotonin transporter (5-HTT genotype. For this purpose, male mice of a 5-HTT knockout mouse model including all three genotypes (wildtype, heterozygous and homozygous 5-HTT knockout mice were either exposed to an adverse social situation or a beneficial social environment during adolescence. This was accomplished in a custom-made cage system where mice experiencing the adverse environment were repeatedly introduced to the territory of a dominant opponent but had the possibility to escape to a refuge cage. Mice encountering beneficial social conditions had free access to a female mating partner. Afterwards, anxiety-like and aggressive behavior was assessed in a battery of tests. Surprisingly, unfavorable conditions during adolescence led to a decrease in anxiety-like behavior and an increase in exploratory locomotion. Additionally, aggressive behavior was augmented in animals that experienced social adversity. Concerning genotype, homozygous 5-HTT knockout mice were more anxious and less aggressive than heterozygous 5-HTT knockout and wildtype mice. In summary, adolescence is clearly an important phase in which anxiety-like and aggressive behavior can be shaped. Furthermore, it seems that having to cope with

Modulating Neurotrophin Receptor Signaling as a Therapeutic Strategy for Huntington’s Disease

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Simmons, Danielle A.

2017-01-01

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by CAG repeat expansions in the IT15 gene which encodes the huntingtin (HTT) protein. Currently, no treatments capable of preventing or slowing disease progression exist. Disease modifying therapeutics for HD would be expected to target a comprehensive set of degenerative processes given the diverse mechanisms contributing to HD pathogenesis including neuroinflammation, excitotoxicity, and transcription dysregulation. A major contributor to HD-related degeneration is mutant HTT-induced loss of neurotrophic support. Thus, neurotrophin (NT) receptors have emerged as therapeutic targets in HD. The considerable overlap between NT signaling networks and those dysregulated by mutant HTT provides strong theoretical support for this approach. This review will focus on the contributions of disrupted NT signaling in HD-related neurodegeneration and how targeting NT receptors to augment pro-survival signaling and/or to inhibit degenerative signaling may combat HD pathologies. Therapeutic strategies involving NT delivery, peptidomimetics, and the targeting of specific NT receptors (e.g., Trks or p75NTR), particularly with small molecule ligands, are discussed. PMID:29254102

Length and sequence dependence in the association of Huntingtin protein with lipid membranes

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Jawahery, Sudi; Nagarajan, Anu; Matysiak, Silvina

2013-03-01

There is a fundamental gap in our understanding of how aggregates of mutant Huntingtin protein (htt) with overextended polyglutamine (polyQ) sequences gain the toxic properties that cause Huntington's disease (HD). Experimental studies have shown that the most important step associated with toxicity is the binding of mutant htt aggregates to lipid membranes. Studies have also shown that flanking amino acid sequences around the polyQ sequence directly affect interactions with the lipid bilayer, and that polyQ sequences of greater than 35 glutamine repeats in htt are a characteristic of HD. The key steps that determine how flanking sequences and polyQ length affect the structure of lipid bilayers remain unknown. In this study, we use atomistic molecular dynamics simulations to study the interactions between lipid membranes of varying compositions and polyQ peptides of varying lengths and flanking sequences. We find that overextended polyQ interactions do cause deformation in model membranes, and that the flanking sequences do play a role in intensifying this deformation by altering the shape of the affected regions.

Possible association between serotonin transporter promoter region polymorphism and extremely violent crime in Chinese males.

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Liao, Ding-Lieh; Hong, Chen-Jee; Shih, Hao-Ling; Tsai, Shih-Jen

2004-01-01

The neurotransmitter, serotonin, has been implicated in aggressive behavior. The serotonin transporter (5-HTT), which reuptakes serotonin into the nerve terminal, plays a critical role in the regulation of serotonergic function. Previous western reports have demonstrated that the low-activity short (S) allele of the 5-HTT gene-linked polymorphic-region (5-HTTLPR) polymorphism is associated with aggressive behavior and associated personality traits. In the present study, we investigated this 5-HTTLPR genetic polymorphism in a group of Chinese males who had been convicted for extremely violent crime (n = 135) and a normal control group (n = 111). The proportion of S-allele carriers was significantly higher in the criminal group than in the controls (p = 0.006). A significant association was not demonstrated for the relationship between the 5-HTTLPR polymorphism and antisocial personality disorder, substance abuse or alcohol abuse in the criminal group. Our findings demonstrate that carriage of the low-activity S allele is associated with extremely violent criminal behavior in Chinese males, and suggests that the 5-HTT may be implicated in the mechanisms underlying violent behaviors.

Inhibition of PIP4Kγ ameliorates the pathological effects of mutant huntingtin protein.

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Al-Ramahi, Ismael; Panapakkam Giridharan, Sai Srinivas; Chen, Yu-Chi; Patnaik, Samarjit; Safren, Nathaniel; Hasegawa, Junya; de Haro, Maria; Wagner Gee, Amanda K; Titus, Steven A; Jeong, Hyunkyung; Clarke, Jonathan; Krainc, Dimitri; Zheng, Wei; Irvine, Robin F; Barmada, Sami; Ferrer, Marc; Southall, Noel; Weisman, Lois S; Botas, Juan; Marugan, Juan Jose

2017-12-26

The discovery of the causative gene for Huntington's disease (HD) has promoted numerous efforts to uncover cellular pathways that lower levels of mutant huntingtin protein (mHtt) and potentially forestall the appearance of HD-related neurological defects. Using a cell-based model of pathogenic huntingtin expression, we identified a class of compounds that protect cells through selective inhibition of a lipid kinase, PIP4Kγ. Pharmacological inhibition or knock-down of PIP4Kγ modulates the equilibrium between phosphatidylinositide (PI) species within the cell and increases basal autophagy, reducing the total amount of mHtt protein in human patient fibroblasts and aggregates in neurons. In two Drosophila models of Huntington's disease, genetic knockdown of PIP4K ameliorated neuronal dysfunction and degeneration as assessed using motor performance and retinal degeneration assays respectively. Together, these results suggest that PIP4Kγ is a druggable target whose inhibition enhances productive autophagy and mHtt proteolysis, revealing a useful pharmacological point of intervention for the treatment of Huntington's disease, and potentially for other neurodegenerative disorders.

Transcriptomic study to understand thermal adaptation in a high temperature-tolerant strain of Pyropia haitanensis.

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Wang, Wenlei; Teng, Fei; Lin, Yinghui; Ji, Dehua; Xu, Yan; Chen, Changsheng; Xie, Chaotian

2018-01-01

Pyropia haitanensis, a high-yield commercial seaweed in China, is currently undergoing increasing levels of high-temperature stress due to gradual global warming. The mechanisms of plant responses to high temperature stress vary with not only plant type but also the degree and duration of high temperature. To understand the mechanism underlying thermal tolerance in P. haitanensis, gene expression and regulation in response to short- and long-term temperature stresses (SHS and LHS) was investigated by performing genome-wide high-throughput transcriptomic sequencing for a high temperature tolerant strain (HTT). A total of 14,164 differential expression genes were identified to be high temperature-responsive in at least one time point by high-temperature treatment, representing 41.10% of the total number of unigenes. The present data indicated a decrease in the photosynthetic and energy metabolic rates in HTT to reduce unnecessary energy consumption, which in turn facilitated in the rapid establishment of acclimatory homeostasis in its transcriptome during SHS. On the other hand, an increase in energy consumption and antioxidant substance activity was observed with LHS, which apparently facilitates in the development of resistance against severe oxidative stress. Meanwhile, ubiquitin-mediated proteolysis, brassinosteroids, and heat shock proteins also play a vital role in HTT. The effects of SHS and LHS on the mechanism of HTT to resist heat stress were relatively different. The findings may facilitate further studies on gene discovery and the molecular mechanisms underlying high-temperature tolerance in P. haitanensis, as well as allow improvement of breeding schemes for high temperature-tolerant macroalgae that can resist global warming.

First molecular modeling report on novel arylpyrimidine kynurenine monooxygenase inhibitors through multi-QSAR analysis against Huntington's disease: A proposal to chemists!

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Amin, Sk Abdul; Adhikari, Nilanjan; Jha, Tarun; Gayen, Shovanlal

2016-12-01

Huntington's disease (HD) is caused by mutation of huntingtin protein (mHtt) leading to neuronal cell death. The mHtt induced toxicity can be rescued by inhibiting the kynurenine monooxygenase (KMO) enzyme. Therefore, KMO is a promising drug target to address the neurodegenerative disorders such as Huntington's diseases. Fiftysix arylpyrimidine KMO inhibitors are structurally explored through regression and classification based multi-QSAR modeling, pharmacophore mapping and molecular docking approaches. Moreover, ten new compounds are proposed and validated through the modeling that may be effective in accelerating Huntington's disease drug discovery efforts. Copyright © 2016 Elsevier Ltd. All rights reserved.

Mid-infrared spectrometry of milk for dairy metabolomics: a comparison of two sampling techniques and effect of homogenization.

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Aernouts, Ben; Polshin, Evgeny; Saeys, Wouter; Lammertyn, Jeroen

2011-10-31

Milk production is a dominant factor in the metabolism of dairy cows involving a very intensive interaction with the blood circulation. As a result, the extracted milk contains valuable information on the metabolic status of the cow. On-line measurement of milk components during milking two or more times a day would promote early detection of systemic and local alterations, thus providing a great input for strategic and management decisions. The objective of this study was to investigate the potential of mid-infrared (mid-IR) spectroscopy to measure the milk composition using two different measurement modes: micro attenuated total reflection (μATR) and high throughput transmission (HTT). Partial least squares (PLS) regression was used for prediction of fat, crude protein, lactose and urea after preprocessing IR data and selecting the most informative wavenumber variables. The prediction accuracies were determined separately for raw and homogenized copies of a wide range of milk samples in order to estimate the possibility for on-line analysis of the milk. In case of fat content both measurement modes resulted in an excellent prediction for homogenized samples (R(2)>0.92) but in poor results for raw samples (R(2)protein and lactose with both μATR and HTT, and urea with μATR spectroscopy. Excellent results were obtained for prediction of crude protein, lactose and urea content (R(2)>0.99, 0.98 and 0.86 respectively) in raw and homogenized milk using μATR IR spectroscopy. These results were significantly better than those obtained by HTT IR spectroscopy. However, the prediction performance of HTT was still good for crude protein and lactose content (R(2)>0.86 and 0.78 respectively) in raw and homogenized samples. However, the detection of urea in milk with HTT spectroscopy was significantly better (R(2)=0.69 versus 0.16) after homogenization of the milk samples. Based on these observations it can be concluded that μATR approach is most suitable for rapid at line

Inhibition of serotonin transporters disrupts the enhancement of fear memory extinction by 3,4-methylenedioxymethamphetamine (MDMA).

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Young, Matthew B; Norrholm, Seth D; Khoury, Lara M; Jovanovic, Tanja; Rauch, Sheila A M; Reiff, Collin M; Dunlop, Boadie W; Rothbaum, Barbara O; Howell, Leonard L

2017-10-01

3,4-Methylenedioxymethamphetamine (MDMA) persistently improves symptoms of post-traumatic stress disorder (PTSD) when combined with psychotherapy. Studies in rodents suggest that these effects can be attributed to enhancement of fear memory extinction. Therefore, MDMA may improve the effects of exposure-based therapy for PTSD, particularly in treatment-resistant patients. However, given MDMA's broad pharmacological profile, further investigation is warranted before moving to a complex clinical population. We aimed to inform clinical research by providing a translational model of MDMA's effect, and elucidating monoaminergic mechanisms through which MDMA enhances fear extinction. We explored the importance of monoamine transporters targeted by MDMA to fear memory extinction, as measured by reductions in conditioned freezing and fear-potentiated startle (FPS) in mice. Mice were treated with selective inhibitors of individual monoamine transporters prior to combined MDMA treatment and fear extinction training. MDMA enhanced the lasting extinction of FPS. Acute and chronic treatment with a 5-HT transporter (5-HTT) inhibitor blocked MDMA's effect on fear memory extinction. Acute inhibition of dopamine (DA) and norepinephrine (NE) transporters had no effect. 5-HT release alone did not enhance extinction. Blockade of MDMA's effect by 5-HTT inhibition also downregulated 5-HT 2A -mediated behavior, and 5-HT 2A antagonism disrupted MDMA's effect on extinction. We validate enhancement of fear memory extinction by MDMA in a translational behavioral model, and reveal the importance of 5-HTT and 5-HT 2A receptors to this effect. These observations support future clinical research of MDMA as an adjunct to exposure therapy, and provide important pharmacological considerations for clinical use in a population frequently treated with 5-HTT inhibitors.

Pathophysiology and molecular basis of selected metabolic abnormalities in Huntington’s disease

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Jolanta Krzysztoń-Russjan

2016-12-01

Full Text Available Huntington’s disease (HD is an incurable, devastating neurodegenerative disease with a known genetic background and autosomally dominant inheritance pattern. HTT gene mutation (mHTT is associated with polymorphic fragment elongation above 35 repeats of the CAG triplet. The mHTT product is an altered protein with a poly-Q elongated fragment, with the highest expression determined in the central nervous system (CNS and with differentiated expression outside the CNS. A drastic loss of striatal and deeper layers of the cerebral cortex neurons was determined in the CNS, but muscle and body weight mass loss with dysfunction of many organs was also observed. HD symptoms include neurological disturbances, such as choreal movements with dystonia, speech and swallowing impairments, and additionally a variety of psychiatric and behavioral symptoms with cognitive decline have been described.They are the result of disturbances of several cellular pathways related to signal transmission, mitochondrial dysfunction and energy metabolism impairment shown by gene and protein expression and alteration of their functions. Impairment of energy processes demonstrated by a decrease of ATP production and increase of oxidative stress markers was determined in- and outside of the CNS in glycolysis, the Krebs cycle and the electron transport chain. A correlation between the increase of energy metabolism impairment level and the increase in number of CAG repeats in HTT has often been described. The energy metabolism study is an initial stage of sensitive biomarkers and a new therapeutic investigative option for early application in order to inhibit pathological processes in HD.Identification of pathological changes outside the CNS requires a reevaluation of diagnostic and therapeutic rules in HD.

Pathophysiology and molecular basis of selected metabolic abnormalities in Huntington's disease.

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Krzysztoń-Russjan, Jolanta

2016-12-30

Huntington's disease (HD) is an incurable, devastating neurodegenerative disease with a known genetic background and autosomally dominant inheritance pattern. HTT gene mutation (mHTT) is associated with polymorphic fragment elongation above 35 repeats of the CAG triplet. The mHTT product is an altered protein with a poly-Q elongated fragment, with the highest expression determined in the central nervous system (CNS) and with differentiated expression outside the CNS. A drastic loss of striatal and deeper layers of the cerebral cortex neurons was determined in the CNS, but muscle and body weight mass loss with dysfunction of many organs was also observed. HD symptoms include neurological disturbances, such as choreal movements with dystonia, speech and swallowing impairments, and additionally a variety of psychiatric and behavioral symptoms with cognitive decline have been described. They are the result of disturbances of several cellular pathways related to signal transmission, mitochondrial dysfunction and energy metabolism impairment shown by gene and protein expression and alteration of their functions. Impairment of energy processes demonstrated by a decrease of ATP production and increase of oxidative stress markers was determined in- and outside of the CNS in glycolysis, the Krebs cycle and the electron transport chain. A correlation between the increase of energy metabolism impairment level and the increase in number of CAG repeats in HTT has often been described. The energy metabolism study is an initial stage of sensitive biomarkers and a new therapeutic investigative option for early application in order to inhibit pathological processes in HD. Identification of pathological changes outside the CNS requires a reevaluation of diagnostic and therapeutic rules in HD.

The study of genetic polymorphisms related to serotonin in Alzheimer's disease: a new perspective in a heterogenic disorder

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Oliveira J.R.M.

1999-01-01

Full Text Available Genetic and environmental factors have been implicated in the development of Alzheimer's disease (AD, the most common form of dementia in the elderly. Mutations in 3 genes mapped on chromosomes 21, 14 and 1 are related to the rare early onset forms of AD while the e4 allele of the apolipoprotein E (APOE gene (on chromosome 19 is the major susceptibility locus for the most common late onset AD (LOAD. Serotonin (5-hydroxytryptamine or 5-HT is a key neurotransmitter implicated in the control of mood, sleep, appetite and a variety of traits and behaviors. Recently, a polymorphism in the transcriptional control region upstream of the 5-HT transporter (5-HTT gene has been studied in several psychiatric diseases and personality traits. It has been demonstrated that the short variant(s of this 5-HTT gene-linked polymorphic region (5-HTTLPR is associated with a different transcriptional efficiency of the 5-HTT gene promoter resulting in decreased 5-HTT expression and 5-HT uptake in lymphocytes. An increased frequency of this 5-HTTLPR short variant polymorphism in LOAD was recently reported. In addition, another common polymorphic variation in the 5-HT2A and 5-HT2C serotonin receptor genes previously analyzed in schizophrenic patients was associated with auditory and visual hallucinations in AD. These observations suggest that the involvement of the serotonin pathway might provide an explanation for some aspects of the affective symptoms commonly observed in AD patients. In summary, research on genetic polymorphisms related to AD and involved in receptors, transporter proteins and the enzymatic machinery of serotonin might enhance our understanding of this devastating neurodegenerative disorder.

Establishing whether the structural feature controlling the mechanical properties of starch films is molecular or crystalline.

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Li, Ming; Xie, Fengwei; Hasjim, Jovin; Witt, Torsten; Halley, Peter J; Gilbert, Robert G

2015-03-06

The effects of molecular and crystalline structures on the tensile mechanical properties of thermoplastic starch (TPS) films from waxy, normal, and high-amylose maize were investigated. Starch structural variations were obtained through extrusion and hydrothermal treatment (HTT). The molecular and crystalline structures were characterized using size-exclusion chromatography and X-ray diffractometry, respectively. TPS from high-amylose maize showed higher elongation at break and tensile strength than those from normal maize and waxy maize starches when processed with 40% plasticizer. Within the same amylose content, the mechanical properties were not affected by amylopectin molecular size or the crystallinity of TPS prior to HTT. This lack of correlation between the molecular size, crystallinity and mechanical properties may be due to the dominant effect of the plasticizer on the mechanical properties. Further crystallization of normal maize TPS by HTT increased the tensile strength and Young's modulus, while decreasing the elongation at break. The results suggest that the crystallinity from the remaining ungelatinized starch granules has less significant effect on the mechanical properties than that resulting from starch recrystallization, possibly due to a stronger network from leached-out amylose surrounding the remaining starch granules. Copyright © 2014 Elsevier Ltd. All rights reserved.

Use of anti-depressants and the risk of fracture of the hip or femur.

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van den Brand, M W M; Pouwels, S; Samson, M M; van Staa, T P; Thio, B; Cooper, C; Leufkens, H G M; Egberts, A C G; Verhaar, H J J; de Vries, F

2009-10-01

Anti-depressants are used largely, but have serious side effects. We show that both selective serotonin re-uptake inhibitors (SSRIs) and tricyclic anti-depressants (TCAs) increase the risk of hip/femur fracture and that this risk is time related and depends on the degree of serotonin transporter inhibition. This should be considered when prescribing anti-depressants to patients. Anti-depressants are known to have serious side effects. We examined the association between the use of anti-depressants and the risk of hip/femur fractures with a special focus on the relation with the degree of 5-hydroxytryptamine transporter (5-HTT) inhibition and the duration of use. A case-control study was conducted within the Dutch PHARMO-RLS database. Cases (n = 6,763) were adult patients with a first hip/femur fracture during the study period. For each case, four controls (n = 26341) were matched by age, gender and geographic region. The risk of hip/femur fracture increased with current use of SSRIs (adjusted odds ratio (OR(adj)) 2.35 [95% confidence interval (CI) 1.94-2.84]) and TCAs (ORadj 1.76 [95% CI 1.45-2.15]). The risk of hip/femur fracture declined rapidly after discontinuation of use. The risk of hip/femur fracture increased as the degree of 5-HTT inhibition of all anti-depressants increased from OR(adj) 1.64 [95% CI 1.14-2.35] for drugs with low 5-HTT inhibition to OR(adj) 2.31 [95% CI 1.94-2.76] for those with high 5-HTT inhibiting properties. Current use of both SSRIs and TCAs increase hip/femur fracture risk. Further studies are needed to elucidate the mechanistic pathways and the relation with the underlying pathophysiology. Until then, the elevated fracture risk should be considered when prescribing anti-depressants.

Perturbation with intrabodies reveals that calpain cleavage is required for degradation of huntingtin exon 1.

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Amber L Southwell

2011-01-01

Full Text Available Proteolytic processing of mutant huntingtin (mHtt, the protein that causes Huntington's disease (HD, is critical for mHtt toxicity and disease progression. mHtt contains several caspase and calpain cleavage sites that generate N-terminal fragments that are more toxic than full-length mHtt. Further processing is then required for the degradation of these fragments, which in turn, reduces toxicity. This unknown, secondary degradative process represents a promising therapeutic target for HD.We have used intrabodies, intracellularly expressed antibody fragments, to gain insight into the mechanism of mutant huntingtin exon 1 (mHDx-1 clearance. Happ1, an intrabody recognizing the proline-rich region of mHDx-1, reduces the level of soluble mHDx-1 by increasing clearance. While proteasome and macroautophagy inhibitors reduce turnover of mHDx-1, Happ1 is still able to reduce mHDx-1 under these conditions, indicating Happ1-accelerated mHDx-1 clearance does not rely on these processes. In contrast, a calpain inhibitor or an inhibitor of lysosomal pH block Happ1-mediated acceleration of mHDx-1 clearance. These results suggest that mHDx-1 is cleaved by calpain, likely followed by lysosomal degradation and this process regulates the turnover rate of mHDx-1. Sequence analysis identifies amino acid (AA 15 as a potential calpain cleavage site. Calpain cleavage of recombinant mHDx-1 in vitro yields fragments of sizes corresponding to this prediction. Moreover, when the site is blocked by binding of another intrabody, V(L12.3, turnover of soluble mHDx-1 in living cells is blocked.These results indicate that calpain-mediated removal of the 15 N-terminal AAs is required for the degradation of mHDx-1, a finding that may have therapeutic implications.

Inhibition of serotonin but not norepinephrine transport during development produces delayed, persistent perturbations of emotional behaviors in mice.

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Ansorge, Mark S; Morelli, Emanuela; Gingrich, Jay A

2008-01-02

Serotonin (5-HT) acts as a neurotransmitter, but also modulates brain maturation during early development. The demonstrated influence of genetic variants on brain function, personality traits, and susceptibility to neuropsychiatric disorders suggests a critical importance of developmental mechanisms. However, little is known about how and when developmentally perturbed 5-HT signaling affects circuitry and resulting behavior. The 5-HT transporter (5-HTT) is a key regulator of extracellular 5-HT levels and we used pharmacologic strategies to manipulate 5-HTT function during development and determine behavioral consequences. Transient exposure to the 5-HTT inhibitors fluoxetine, clomipramine, and citalopram from postnatal day 4 (P4) to P21 produced abnormal emotional behaviors in adult mice. Similar treatment with the norepinephrine transporter (NET) inhibitor, desipramine, did not adversely affect adult behavior, suggesting that 5-HT and norepinephrine (NE) do not share the same effects on brain development. Shifting our period of treatment/testing to P90/P185 failed to mimic the effect of earlier exposure, demonstrating that 5-HT effects on adult behavior are developmentally specific. We have hypothesized that early-life perturbations of 5-HT signaling affect corticolimbic circuits that do not reach maturity until the peri-adolescent period. In support of this idea, we found that abnormal behaviors resulting from postnatal fluoxetine exposure have a post-pubescent onset and persist long after reaching adult age. A better understanding of the underlying 5-HT sensitive circuits and how they are perturbed should lead to new insights into how various genetic polymorphisms confer their risk to carriers. Furthermore, these studies should help determine whether in utero exposure to 5-HTT blocking drugs poses a risk for behavioral abnormalities in later life.

The association study between the interaction of serotonin and norepinephrine transporter gene polymorphisms and the effects of selective serotonin reuptake inhibitors%5-羟色胺和去甲肾上腺素转运体基因多态性的交互作用与重性抑郁障碍临床疗效的关联研究

Institute of Scientific and Technical Information of China (English)

孟亚琴; 孙宁; 王彦芳; 段慧君; 李素萍; 彭菊意; 杜巧荣; 张克让

2013-01-01

Objective To explore the relevance of the interaction of serotonin and norepinephrine transporter gene polymorphisms and the effects of selective serotonin reuptake inhibitors.Methods The subjects comprised 246 patients according to the diagnostic and statistical manual of mental disorders in the fourth edition (DSM-Ⅳ) criterion for major depressive disorder(MDD).The clinical efficacy were assessed by using 17 Hamilton depression quantity (HAMD) scale after selective serotonin reuptake inhibitors(SSRIs) citalopram (20 to 60 mg/d) or paroxetine (20 to 60 mg/d) were used randomly for 1,2,4,6 weeks.Polymerase chain reaction(PCR),sodium dodecyl sulfate polyacrylamide gel electrophoresis(SDS-PAGE)and DNA sequencing analysis were used to detect the genotype of 5-HTT gene single nucleotide polymorphisms (SNP) of VNTR and LPR and SNPs at rs2242446 and rs5569 of NET.SPSS13.0 software were used for statistical analysis.Results (1) An association between 5-HTT LPR and the efficacy of SSRIs was found after 6 weeks in these samples (P =0.023).The clinical efficiency of LL genotype was higher than SS + LS genotype(OR =2.225,OR 95％ CI=1.118,4.427).(2) The interaction of 5-HTT LPR and NET rs5569 and the SSRIs antidepressant effects was statistical significance (P =0.01).Conclusion Preliminary study found that the interaction of 5-HTT LPR and NET rs5569 may be related to SSRIs antidepressant effects in China' s patients with MDD.%目的 探讨5-羟色胺和去甲肾上腺素转运体基因多态性的交互作用与选择性5-羟色胺再摄取抑制剂临床疗效的关联研究.方法 收集符合美国精神障碍诊断与统计手册第四版(DSM-Ⅳ)重性抑郁障碍(MDD)诊断标准的患者246例,给予选择性5-羟色胺再摄取抑制剂(SSRIs)西酞普兰(20～ 60mg/d)或帕罗西汀(20 ～ 60 mg/d),在治疗后1,2,4,6周运用17�

Electron spin resonance and its application to heat treated carbonaceous materials

International Nuclear Information System (INIS)

Emmerich, Francisco Guilherme

1993-01-01

This work presents the basic characteristics of the electron spin resonance technique, also called paramagnetic resonance, being discussed its application to heat treated carbonaceous materials. In the low heat treatment temperature (HTT) range (below 700 deg C) the organic free radical are the predominant unpaired spin center, which play a key role in the process of carbonization and meso phase formation. At higher temperatures, it is possible to make correlations between the low H T T range and the high HTT range (above 130 deg C), where the predominant unpaired spin center are the free charge carriers (free electrons) of the graphite like crystallites of the material, which are formed by the carbonization process. (author)

Electron spin resonance and its application to heat treated carbonaceous materials; A ressonancia de spin eletronico e sua aplicacao aos materiais carbonosos tratados termicamente

Energy Technology Data Exchange (ETDEWEB)

Emmerich, Francisco Guilherme [Espirito Santo Univ., Vitoria, ES (Brazil). Laboratorio de Materiais Carbonosos e Plasma Termico

1994-12-31

This work presents the basic characteristics of the electron spin resonance technique, also called paramagnetic resonance, being discussed its application to heat treated carbonaceous materials. In the low heat treatment temperature (HTT) range (below 700 deg C) the organic free radical are the predominant unpaired spin center, which play a key role in the process of carbonization and meso phase formation. At higher temperatures, it is possible to make correlations between the low H T T range and the high HTT range (above 130 deg C), where the predominant unpaired spin center are the free charge carriers (free electrons) of the graphite like crystallites of the material, which are formed by the carbonization process. (author) 10 refs., 3 figs.

Assembly of Huntingtin headpiece into α-helical bundles.

Science.gov (United States)

Ozgur, Beytullah; Sayar, Mehmet

2017-05-24

Protein aggregation is a hallmark of neurodegenerative disorders. In this group of brain-related disorders, a disease-specific "host" protein or fragment misfolds and adopts a metastatic, aggregate-prone conformation. Often, this misfolded conformation is structurally and thermodynamically different from its native state. Intermolecular contacts, which arise in this non-native state, promote aggregation. In this regard, understanding the molecular principles and mechanisms that lead to the formation of such a non-native state and further promote the formation of the critical nucleus for fiber growth is essential. In this study, the authors analyze the aggregation propensity of Huntingtin headpiece (htt NT ), which is known to facilitate the polyQ aggregation, in relation to the helix mediated aggregation mechanism proposed by the Wetzel group. The authors demonstrate that even though htt NT displays a degenerate conformational spectrum on its own, interfaces of macroscopic or molecular origin can promote the α-helix conformation, eliminating all other alternatives in the conformational phase space. Our findings indicate that htt NT molecules do not have a strong orientational preference for parallel or antiparallel orientation of the helices within the aggregate. However, a parallel packed bundle of helices would support the idea of increased polyglutamine concentration, to pave the way for cross-β structures.

A broad phenotypic screen identifies novel phenotypes driven by a single mutant allele in Huntington's disease CAG knock-in mice.

Directory of Open Access Journals (Sweden)

Sabine M Hölter

Full Text Available Huntington's disease (HD is an autosomal dominant neurodegenerative disorder caused by the expansion of a CAG trinucleotide repeat in the HTT gene encoding huntingtin. The disease has an insidious course, typically progressing over 10-15 years until death. Currently there is no effective disease-modifying therapy. To better understand the HD pathogenic process we have developed genetic HTT CAG knock-in mouse models that accurately recapitulate the HD mutation in man. Here, we describe results of a broad, standardized phenotypic screen in 10-46 week old heterozygous HdhQ111 knock-in mice, probing a wide range of physiological systems. The results of this screen revealed a number of behavioral abnormalities in HdhQ111/+ mice that include hypoactivity, decreased anxiety, motor learning and coordination deficits, and impaired olfactory discrimination. The screen also provided evidence supporting subtle cardiovascular, lung, and plasma metabolite alterations. Importantly, our results reveal that a single mutant HTT allele in the mouse is sufficient to elicit multiple phenotypic abnormalities, consistent with a dominant disease process in patients. These data provide a starting point for further investigation of several organ systems in HD, for the dissection of underlying pathogenic mechanisms and for the identification of reliable phenotypic endpoints for therapeutic testing.

Genetic exchange in eukaryotes through horizontal transfer: connected by the mobilome.

Science.gov (United States)

Wallau, Gabriel Luz; Vieira, Cristina; Loreto, Élgion Lúcio Silva

2018-01-01

All living species contain genetic information that was once shared by their common ancestor. DNA is being inherited through generations by vertical transmission (VT) from parents to offspring and from ancestor to descendant species. This process was considered the sole pathway by which biological entities exchange inheritable information. However, Horizontal Transfer (HT), the exchange of genetic information by other means than parents to offspring, was discovered in prokaryotes along with strong evidence showing that it is a very important process by which prokaryotes acquire new genes. For some time now, it has been a scientific consensus that HT events were rare and non-relevant for evolution of eukaryotic species, but there is growing evidence supporting that HT is an important and frequent phenomenon in eukaryotes as well. Here, we will discuss the latest findings regarding HT among eukaryotes, mainly HT of transposons (HTT), establishing HTT once and for all as an important phenomenon that should be taken into consideration to fully understand eukaryotes genome evolution. In addition, we will discuss the latest development methods to detect such events in a broader scale and highlight the new approaches which should be pursued by researchers to fill the knowledge gaps regarding HTT among eukaryotes.

Skazka, zakutannaja v tsvetnoi tuman / Svetlana Aleksejeva ; interv. Galina Balashova

Index Scriptorium Estoniae

Aleksejeva, Svetlana

2002-01-01

Kunstnik Sveta Aleksejevaga raamatu "Cupido & Psyche" illustreerimisest, koostööst loo tõlkijaga, USA-s raamatudisaini õppiva Leelo Märjamaaga. Raamatuillustratsioonide näitus on Rahvusraamatukogus

Sensitivity and Specificity of Clinical and Laboratory Otolith Function Tests.

Science.gov (United States)

Kumar, Lokesh; Thakar, Alok; Thakur, Bhaskar; Sikka, Kapil

2017-10-01

To evaluate clinic based and laboratory tests of otolith function for their sensitivity and specificity in demarcating unilateral compensated complete vestibular deficit from normal. Prospective cross-sectional study. Tertiary care hospital vestibular physiology laboratory. Control group-30 healthy adults, 20-45 years age; Case group-15 subjects post vestibular shwannoma excision or post-labyrinthectomy with compensated unilateral complete audio-vestibular loss. Otolith function evaluation by precise clinical testing (head tilt test-HTT; subjective visual vertical-SVV) and laboratory testing (headroll-eye counterroll-HR-ECR; vesibular evoked myogenic potentials-cVEMP). Sensitivity and specificity of clinical and laboratory tests in differentiating case and control subjects. Measurable test results were universally obtained with clinical otolith tests (SVV; HTT) but not with laboratory tests. The HR-ECR test did not indicate any definitive wave forms in 10% controls and 26% cases. cVEMP responses were absent in 10% controls.HTT test with normative cutoff at 2 degrees deviations from vertical noted as 93.33% sensitive and 100% specific. SVV test with normative cutoff at 1.3 degrees noted as 100% sensitive and 100% specific. Laboratory tests demonstrated poorer specificities owing primarily to significant unresponsiveness in normal controls. Clinical otolith function tests, if conducted with precision, demonstrate greater ability than laboratory testing in discriminating normal controls from cases with unilateral complete compensated vestibular dysfunction.

Characterisation of the ruminal fermentation and microbiome in lambs supplemented with hydrolysable and condensed tannins.

Science.gov (United States)

Salami, Saheed A; Valenti, Bernardo; Bella, Marco; O'Grady, Michael N; Luciano, Giuseppe; Kerry, Joseph P; Jones, Eleanor; Priolo, Alessandro; Newbold, Charles J

2018-05-01

This study characterised the response of ruminal fermentation and the rumen microbiome in lambs fed commercial vegetal sources of hydrolysable tannins (HT) and condensed tannins (CT). Forty-four lambs (19.56 ± 2.06 kg) were randomly assigned to either a concentrate diet (CON, n = 8) or CON supplemented with 4% of two HT [chestnut (Castanea sativa, HT-c) and tara (Caesalpinia spinosa, HT-t)] and CT [mimosa (Acacia negra, CT-m) and gambier (Uncaria gambir, CT-g)] extracts (all, n = 9) for 75 days pre-slaughter. Tannin supplementation did not influence ruminal fermentation traits. Quantitative PCR demonstrated that tannins did not affect the absolute abundance of ruminal bacteria or fungi. However, CT-m (-12.8%) and CT-g (-11.5%) significantly reduced the abundance of methanogens, while HT-t (-20.7%) and CT-g (-20.8%) inhibited protozoal abundance. Ribosomal amplicon sequencing revealed that tannins caused changes in the phylogenetic structure of the bacterial and methanogen communities. Tannins inhibited the fibrolytic bacterium, Fibrobacter and tended to suppress the methanogen genus, Methanosphaera. Results demonstrated that both HT and CT sources could impact the ruminal microbiome when supplemented at 4% inclusion level. HT-t, CT-m and CT-g extracts displayed specific antimicrobial activity against methanogens and protozoa without compromising ruminal fermentation in a long-term feeding trial.

The Wnt receptor Ryk reduces neuronal and cell survival capacity by repressing FOXO activity during the early phases of mutant huntingtin pathogenicity.

Directory of Open Access Journals (Sweden)

Cendrine Tourette

2014-06-01

Full Text Available The Wnt receptor Ryk is an evolutionary-conserved protein important during neuronal differentiation through several mechanisms, including γ-secretase cleavage and nuclear translocation of its intracellular domain (Ryk-ICD. Although the Wnt pathway may be neuroprotective, the role of Ryk in neurodegenerative disease remains unknown. We found that Ryk is up-regulated in neurons expressing mutant huntingtin (HTT in several models of Huntington's disease (HD. Further investigation in Caenorhabditis elegans and mouse striatal cell models of HD provided a model in which the early-stage increase of Ryk promotes neuronal dysfunction by repressing the neuroprotective activity of the longevity-promoting factor FOXO through a noncanonical mechanism that implicates the Ryk-ICD fragment and its binding to the FOXO co-factor β-catenin. The Ryk-ICD fragment suppressed neuroprotection by lin-18/Ryk loss-of-function in expanded-polyQ nematodes, repressed FOXO transcriptional activity, and abolished β-catenin protection of mutant htt striatal cells against cell death vulnerability. Additionally, Ryk-ICD was increased in the nucleus of mutant htt cells, and reducing γ-secretase PS1 levels compensated for the cytotoxicity of full-length Ryk in these cells. These findings reveal that the Ryk-ICD pathway may impair FOXO protective activity in mutant polyglutamine neurons, suggesting that neurons are unable to efficiently maintain function and resist disease from the earliest phases of the pathogenic process in HD.

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Lifescience Database Archive (English)

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File list: Unc.Kid.20.AllAg.Nephrectomy_sample [Chip-atlas[Archive

Lifescience Database Archive (English)

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Interaction between genetic polymorphisms and stressful life events in first episode depression

DEFF Research Database (Denmark)

Bukh, Jens Drachmann; Bock, Camilla; Vinberg, Maj

2009-01-01

of depression among participants. METHOD: We applied a case-only design, including 290 ethnically homogeneous patients suffering exclusively from first episode depression. Psychiatric mo-morbidity, personality traits and disorders and stressful life events in a six months period preceding onset of depression......BACKGROUND: A polymorphism in the serotonin transporter (5-HTT) gene seems to moderate the influence of stressful life events on depression. However, the results from previous studies of gene-environment interactions in depression are inconsistent and might be confounded by the history......A, 2A, and 2C. RESULTS: The low activity variants of the 5-HTT-linked polymorphic region in the serotonin transporter gene and the Met-allele of a single nucleotide polymorphism (Val66Met) in the gene encoding brain derived neurotrophic factor were independently associated with the presence...

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Lifescience Database Archive (English)

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Lifescience Database Archive (English)

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Early-onset sleep defects in Drosophila models of Huntington's disease reflect alterations of PKA/CREB signaling

Science.gov (United States)

Gonzales, Erin D.; Tanenhaus, Anne K.; Zhang, Jiabin; Chaffee, Ryan P.; Yin, Jerry C.P.

2016-01-01

Huntington's disease (HD) is a progressive neurological disorder whose non-motor symptoms include sleep disturbances. Whether sleep and activity abnormalities are primary molecular disruptions of mutant Huntingtin (mutHtt) expression or result from neurodegeneration is unclear. Here, we report Drosophila models of HD exhibit sleep and activity disruptions very early in adulthood, as soon as sleep patterns have developed. Pan-neuronal expression of full-length or N-terminally truncated mutHtt recapitulates sleep phenotypes of HD patients: impaired sleep initiation, fragmented and diminished sleep, and nighttime hyperactivity. Sleep deprivation of HD model flies results in exacerbated sleep deficits, indicating that homeostatic regulation of sleep is impaired. Elevated PKA/CREB activity in healthy flies produces patterns of sleep and activity similar to those in our HD models. We were curious whether aberrations in PKA/CREB signaling were responsible for our early-onset sleep/activity phenotypes. Decreasing signaling through the cAMP/PKA pathway suppresses mutHtt-induced developmental lethality. Genetically reducing PKA abolishes sleep/activity deficits in HD model flies, restores the homeostatic response and extends median lifespan. In vivo reporters, however, show dCREB2 activity is unchanged, or decreased when sleep/activity patterns are abnormal, suggesting dissociation of PKA and dCREB2 occurs early in pathogenesis. Collectively, our data suggest that sleep defects may reflect a primary pathological process in HD, and that measurements of sleep and cAMP/PKA could be prodromal indicators of disease, and serve as therapeutic targets for intervention. PMID:26604145

Association of Anxiety-Related Polymorphisms with Sports Performance in Chilean Long Distance Triathletes: A Pilot Study

Science.gov (United States)

Sanhueza, Jorge A.; Zambrano, Tomás; Bahamondes-Avila, Carlos; Salazar, Luis A.

2016-01-01

Different factors affecting athletic performance are well established: intensity and type of training, anthropometric characteristics as well as an important psychological component. However, the contribution of the genetic background has been less investigated. The aim of the present study was to investigate the influence of polymorphisms within genes associated with stress and anxiety (5HTT, CRH2R, ACE, NK1R, 5HT1AR and CRF-BP) on the physical capability and sports performance in triathletes. One hundred and ninety two (192) unrelated Chilean triathletes who participated in the 2014 70.3 Pucón city triathlon were divided into opposite subgroups of sports performance according to their time results. We identified significant associations for five polymorphisms (5HTT 5-HTTLPR, ACE I/D, NK1R rs6715729, 5HT1AR -1019C>G and CRF-BP CRF-BPs11) with athletic performance. Our results indicate that these polymorphisms are associated with differential sports performance in Chilean triathletes, establishing an initial background for better understanding the relationship between physical performance, genetics and anxiety disorders. Key points Genetic factors influencing sports performance in the Chilean population are unknown. Differential outcomes from athletes who completed a triathlon competition were associated with five polymorphisms (5HTT 5-HTTLPR, ACE I/D, NK1R rs6715729, 5HT1AR -1019C>G and CRF-BP CRF-BPs11). We show that genetic variants within stress- and anxiety-related genes affect athletic performance. PMID:27928199

Horizontal transfer of transposons between and within crustaceans and insects.

Science.gov (United States)

Dupeyron, Mathilde; Leclercq, Sébastien; Cerveau, Nicolas; Bouchon, Didier; Gilbert, Clément

2014-01-29

Horizontal transfer of transposable elements (HTT) is increasingly appreciated as an important source of genome and species evolution in eukaryotes. However, our understanding of HTT dynamics is still poor in eukaryotes because the diversity of species for which whole genome sequences are available is biased and does not reflect the global eukaryote diversity. In this study we characterized two Mariner transposable elements (TEs) in the genome of several terrestrial crustacean isopods, a group of animals particularly underrepresented in genome databases. The two elements have a patchy distribution in the arthropod tree and they are highly similar (>93% over the entire length of the element) to insect TEs (Diptera and Hymenoptera), some of which were previously described in Ceratitis rosa (Crmar2) and Drosophila biarmipes (Mariner-5_Dbi). In addition, phylogenetic analyses and comparisons of TE versus orthologous gene distances at various phylogenetic levels revealed that the taxonomic distribution of the two elements is incompatible with vertical inheritance. We conclude that the two Mariner TEs each underwent at least three HTT events. Both elements were transferred once between isopod crustaceans and insects and at least once between isopod crustacean species. Crmar2 was also transferred between tephritid and drosophilid flies and Mariner-5 underwent HT between hymenopterans and dipterans. We demonstrate that these various HTTs took place recently (most likely within the last 3 million years), and propose iridoviruses and/or Wolbachia endosymbionts as potential vectors of these transfers.

Stemcell Information: SKIP000385 [SKIP Stemcell Database[Archive

Lifescience Database Archive (English)

Full Text Available Teratoma formation ... Yes ... Yes ... National Research Institute for Child Health and Development htt...p://www.ncbi.nlm.nih.gov/geo/ Akihiro Umezawa 梅澤　明弘 Available National Research Institute for Child Health a

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Lifescience Database Archive (English)

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Lifescience Database Archive (English)

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Lifescience Database Archive (English)

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File list: Pol.Adl.20.AllAg.Adult_male_fatbody [Chip-atlas[Archive

Lifescience Database Archive (English)

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A probabilistic approach to delineating functional brain regions

DEFF Research Database (Denmark)

Kalbitzer, Jan; Svarer, Claus; Frokjaer, Vibe G

2009-01-01

The purpose of this study was to develop a reliable observer-independent approach to delineating volumes of interest (VOIs) for functional brain regions that are not identifiable on structural MR images. The case is made for the raphe nuclei, a collection of nuclei situated in the brain stem known...... to be densely packed with serotonin transporters (5-hydroxytryptaminic [5-HTT] system). METHODS: A template set for the raphe nuclei, based on their high content of 5-HTT as visualized in parametric (11)C-labeled 3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile PET images, was created for 10...... healthy subjects. The templates were subsequently included in the region sets used in a previously published automatic MRI-based approach to create an observer- and activity-independent probabilistic VOI map. The probabilistic map approach was tested in a different group of 10 subjects and compared...

Simvastatin mitigates functional and structural impairment of lung and right ventricle in a rat model of cigarette smoke-induced COPD.

Science.gov (United States)

Wang, Yajie; Jiang, Xue; Zhang, Lihai; Wang, Lihong; Li, Zhu; Sun, Wuzhuang

2014-01-01

This study is conducted to investigate an effect of simvastatin on cigarette smoke-induced COPD. Rats were exposed to air (control) and cigarette smoke (smoking) in presence and absence of simvastatin. Heart and lung tissues were harvested for histopathologic and morphometric analysis. Body weight of rat, mean liner intercept (MLI), mean alveolar number (MAN), lung function test, mean pulmonary artery pressure (mPAP), right ventricular hypertrophy index (RVHI) and 5-HTT level in serum and BALF were examined in experimental rats, respectively. Application of simvastatin mitigated peribronchiolar inflammation and pulmonary bullae formed in the smoke-exposed lungs with weight gain as compared to the smoking rats (P reversal of lung function decline (all P reverses lung function decline and attenuates structural impairments of lung and right ventricle possibly through reducing 5-HTT content in the model of COPD.

File list: Oth.NoD.10.Epitope_tags.AllCell [Chip-atlas[Archive

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Experiment list: SRX122491 [Chip-atlas[Archive

Lifescience Database Archive (English)

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Experiment list: SRX122468 [Chip-atlas[Archive

Lifescience Database Archive (English)

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Experiment list: SRX122409 [Chip-atlas[Archive

Lifescience Database Archive (English)

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Experiment list: SRX122490 [Chip-atlas[Archive

Lifescience Database Archive (English)

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Experiment list: SRX122492 [Chip-atlas[Archive

Lifescience Database Archive (English)

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Tolerance for uncertainty in elderly people

Directory of Open Access Journals (Sweden)

KHRYSTYNA KACHMARYK

2014-09-01

Full Text Available The aim of the study. The aim of the paper is a comparison of tolerance to uncertainty in two groups of elderly: the students of the University of the Third Age (UTA and older people who are not enrolled but help to educate grandchildren. A relation to uncertainty was shown to influence on decision making strategy of elderly that indicates on importance of the researches. Methods. To obtain the objectives of the paper the following methods were used: 1 Personal change readiness survey (PCRS adapted by Nickolay Bazhanov and Galina Bardiyer; 2 Tolerance Ambiguity Scale (TAS adapted by Galina Soldatova; 3 Freiburg personality inventory (FPI and 4 The questionnaire of self-relation by Vladimir Stolin and Sergej Panteleev. 40 socially involved elderly people were investigated according the above methods, 20 from UTA and 20 who are not studied and served as control group. Results. It was shown that relations of tolerance to uncertainty in the study group of students of the University of the Third Age substantially differ from relations of tolerance to uncertainty in group of older people who do not learn. The majority of students of the University of the Third Age have an inherent low tolerance for uncertainty, which is associated with an increase in expression personality traits and characteristics in self-relation. The group of the elderly who are not enrolled increasingly shows tolerance of uncertainty, focusing on the social and trusting relationship to meet the needs of communication, and the ability to manage their own emotions and desires than a group of Third Age university students. Conclusions. The results of experimental research of the third age university student’s peculiarities of the tolerance to uncertainty were outlined. It was found that decision making in the ambiguity situations concerning social interaction is well developed in elderly who do not study. The students of the University of Third Age have greater needs in

Raginal rannavormi / kommenteerinud Reet Puks, Merily Lehis, Helle Nurmsalu, Galina Sepp

Index Scriptorium Estoniae

2010-01-01

Ilusalongides pakutavatest salendavatest kehahooldusprotseduuridest aparaatidega - LPG edermoloogiline massaaž, Universal Contour Wrap, ULTRATONE intensiivne tselluliidiravi ja mittekirurgiline facelift, Shockmaster AWT meetod (akustilise laine ravi)

Erotitsheski konspekt / Vladimir Makarenko, Mihhail Duhhomjonok, Ado Lill ; interv. Galina Balashova

Index Scriptorium Estoniae

Makarenko, Vladimir

2002-01-01

Näitusel "Art-delikatess" osalevate kunstnikega nende töödest erootikanäitusel galeriis Magnon Tallinnas. Vestlevad Vladimir Makarenko, Mihhail Duhhomjonok, Ado Lill, Valeri Vinogradov, Anatoli Strahhov, Slava Semerikov, Andrei Balashov

File list: InP.Oth.20.AllAg.Pancreas_and_brain [Chip-atlas[Archive

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Production of 2^nd generation Bioethanol from Lucerne - Optimization of Hydrothermal Pretreatment

DEFF Research Database (Denmark)

Thomsen, Sune Tjalfe; Jensen, Morten; Schmidt, Jens Ejbye

2012-01-01

Lucerne (Medicago sativa) has many qualities associated with sustainable agriculture such as nitrogen fixation and high biomass yield. Therefore, there is interest in whether lucerne is a suitable biomass substrate for bioethanol production, and if hydrothermal pretreatment (HTT) of lucerne impro...

Understanding the Biology and Technology of ToxCast and Tox21 Assays

Science.gov (United States)

The ToxCast high-throughput toxicity (HTT) testing methods have been developed to evaluate the hazard potential of diverse environmental, industrial and consumer product chemicals. The main goal is prioritizing the compounds of greatest concern for more detailed toxicological stu...

Perseverative instrumental and Pavlovian responding to conditioned stimuli in serotonin transporter knockout rats

NARCIS (Netherlands)

Nonkes, L.J.P.; Homberg, J.R.

2013-01-01

Environmental stimuli can influence behavior via the process of Pavlovian conditioning. Recent genetic research suggests that some individuals are more sensitive to environmental stimuli for behavioral guidance than others. One important mediator of this effect is serotonin transporter (5-HTT)

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20180416 - Understanding the Biology and Technology of ToxCast and Tox21 Assays (SETAC Durham NC)

Science.gov (United States)

The ToxCast high-throughput toxicity (HTT) testing methods have been developed to evaluate the hazard potential of diverse environmental, industrial and consumer product chemicals. The main goal is prioritizing the compounds of greatest concern for more detailed toxicological stu...

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Early life adversity and serotonin transporter gene variation interact to affect DNA methylation of the corticotropin-releasing factor gene promoter region in the adult rat brain

NARCIS (Netherlands)

Doelen, R.H.A. van der; Arnoldussen, I.A.C.; Ghareh, H.; Och, L. van; Homberg, J.R.; Kozicz, L.T.

2015-01-01

The interaction between childhood maltreatment and the serotonin transporter (5-HTT) gene linked polymorphic region has been associated with increased risk to develop major depression. This Gene x Environment interaction has furthermore been linked with increased levels of anxiety and glucocorticoid

Temperament, character and serotonin activity in the human brain

DEFF Research Database (Denmark)

Tuominen, L; Salo, J; Hirvonen, J

2013-01-01

The psychobiological model of personality by Cloninger and colleagues originally hypothesized that interindividual variability in the temperament dimension 'harm avoidance' (HA) is explained by differences in the activity of the brain serotonin system. We assessed brain serotonin transporter (5-HTT...

Experiment list: SRX122551 [Chip-atlas[Archive

Lifescience Database Archive (English)

Full Text Available antibody=Stat1 || treatment=LPS || time=0 min || chip antibody manufacturer 1=Santa Cruz || chip antibody ca...talog number 1=sc-346 || chip antibody manufacturer 2=Bethyl || chip antibody catalog number 2=A302-753A htt

An extension of hypotheses regarding rapid-acting, treatment-refractory, and conventional antidepressant activity of dextromethorphan and dextrorphan.

Science.gov (United States)

Lauterbach, Edward C

2012-06-01

It was previously hypothesized that dextromethorphan (DM) and dextrorphan (DX) may possess antidepressant properties, including rapid and conventional onsets of action and utility in treatment-refractory depression, based on pharmacodynamic similarities to ketamine. These similarities included sigma-1 (σ(1)) agonist and NMDA antagonist properties, calcium channel blockade, muscarinic binding, serotonin transporter (5HTT) inhibition, and μ receptor potentiation. Here, six specific hypotheses are developed in light of additional mechanisms and evidence. Comparable potencies to ketamine for DM and DX are detailed for σ(1) (DX>DM>ketamine), NMDA PCP site (DX>ketamine>DM), and muscarinic (DX>ketamine>DM) receptors, 5HTT (DM>DX≫ketamine), and NMDA antagonist potentiation of μ receptor stimulation (DM>ketamine). Rapid acting antidepressant properties of DM include NMDA high-affinity site, NMDR-2A, and functional NMDR-2B receptor antagonism, σ(1) stimulation, putative mTOR activation (by σ(1) stimulation, μ potentiation, and 5HTT inhibition), putative AMPA receptor trafficking (by mTOR activation, PCP antagonism, σ(1) stimulation, μ potentiation, and 5HTT inhibition), and dendritogenesis, spinogenesis, synaptogenesis, and neuronal survival by NMDA antagonism and σ(1) and mTOR signaling. Those for dextrorphan include NMDA high-affinity site and NMDR-2A antagonism, σ(1) stimulation, putative mTOR activation (by σ(1) stimulation and ß adrenoreceptor stimulation), putative AMPA receptor trafficking (by mTOR activation, PCP antagonism, σ(1) stimulation, ß stimulation, and μ antagonism), and dendritogenesis, spinogenesis, synaptogenesis, and neuronal survival by NMDA antagonism and σ(1) and mTOR signaling. Conventional antidepressant properties for dextromethorphan and dextrorphan include 5HTT and norepinephrine transporter inhibition, σ(1) stimulation, NMDA and PCP antagonism, and possible serotonin 5HT1b/d receptor stimulation. Additional properties for

Functional polymorphisms in the interleukin-6 and serotonin transporter genes, and depression and fatigue induced by interferon-alpha and ribavirin treatment.

LENUS (Irish Health Repository)

Bull, S J

2009-12-01

Depression and fatigue are frequent side effects of interferon-alpha (IFN-alpha) treatment, and there is compelling evidence that the inflammatory response system (including interleukin-6, IL-6) and the serotonergic system is important in the pathophysiology of such symptoms. Functional polymorphisms in the promoter region of the IL-6 gene (rs1800795) and serotonin transporter gene (5-HTTLPR) have been identified as regulating these systems. The present study aimed to determine if these polymorphisms were associated with the development of depression and fatigue during IFN-alpha and ribavirin treatment. Ninety-eight Caucasian patients receiving pegylated IFN-alpha and ribavirin treatment for chronic hepatitis C virus at King\\'s College Hospital, London, and Emory University Hospital, Atlanta, participated in this prospective cohort study. Symptoms of depression and fatigue were measured before treatment and at weeks 4, 8, 12 and 24 during treatment. The \\'low IL-6\\' synthesizing genotype (CC) was associated with significantly fewer symptoms of depression (effect size = 0.7 at week 24; F = 9.4, d.f. = 436, P = 0.002). The \\'high transcription\\' serotonin transporter (5-HTT) genotype (LL) was also associated with significantly fewer symptoms of depression, but with a much smaller effect (effect size = 0.2 at week 24; F = 4.5, d.f. = 436, P = 0.03). Neither polymorphisms were associated with symptoms of fatigue (IL-6: F = 1.2, d.f. = 430, P = 0.2; 5-HTT: F = 0.5, d.f. = 430, P = 0.5). The smaller effects of the 5-HTT polymorphism on depression may be explained by an interaction between the genes (F = 5.0, d.f. = 434, P = 0.02): the \\'protective\\' effect of the 5-HTTLPR polymorphism was evident only in the presence of the \\'low IL-6\\' genotype (F = 5.4, d.f. = 64, P = 0.02), not in the presence of the \\'high IL-6\\' genotype (F = 2.2, d.f. = 369, P = 0.1). The association between the IL-6 polymorphism and reduced risk of depressive symptoms confirms the role

Quantitative fluorescence loss in photobleaching for analysis of protein transport and aggregation

Directory of Open Access Journals (Sweden)

Wüstner Daniel

2012-11-01

Full Text Available Abstract Background Fluorescence loss in photobleaching (FLIP is a widely used imaging technique, which provides information about protein dynamics in various cellular regions. In FLIP, a small cellular region is repeatedly illuminated by an intense laser pulse, while images are taken with reduced laser power with a time lag between the bleaches. Despite its popularity, tools are lacking for quantitative analysis of FLIP experiments. Typically, the user defines regions of interest (ROIs for further analysis which is subjective and does not allow for comparing different cells and experimental settings. Results We present two complementary methods to detect and quantify protein transport and aggregation in living cells from FLIP image series. In the first approach, a stretched exponential (StrExp function is fitted to fluorescence loss (FL inside and outside the bleached region. We show by reaction–diffusion simulations, that the StrExp function can describe both, binding/barrier–limited and diffusion-limited FL kinetics. By pixel-wise regression of that function to FL kinetics of enhanced green fluorescent protein (eGFP, we determined in a user-unbiased manner from which cellular regions eGFP can be replenished in the bleached area. Spatial variation in the parameters calculated from the StrExp function allow for detecting diffusion barriers for eGFP in the nucleus and cytoplasm of living cells. Polyglutamine (polyQ disease proteins like mutant huntingtin (mtHtt can form large aggregates called inclusion bodies (IB’s. The second method combines single particle tracking with multi-compartment modelling of FL kinetics in moving IB’s to determine exchange rates of eGFP-tagged mtHtt protein (eGFP-mtHtt between aggregates and the cytoplasm. This method is self-calibrating since it relates the FL inside and outside the bleached regions. It makes it therefore possible to compare release kinetics of eGFP-mtHtt between different cells and

Genetic variation in the serotonin transporter gene (5-HTTLPR, rs25531 influences the analgesic response to the short acting opioid Remifentanil in humans

Directory of Open Access Journals (Sweden)

Schalling Martin

2009-07-01

Full Text Available Abstract Background There is evidence from animal studies that serotonin (5-HT can influence the antinociceptive effects of opioids at the spinal cord level. Therefore, there could be an influence of genetic polymorphisms in the serotonin system on individual variability in response to opioid treatment of pain. The serotonin transporter (5-HTT is a key regulator of serotonin metabolism and availability and its gene harbors several known polymorphisms that are known to affect 5-HTT expression (e.g. 5-HTTLPR, rs25531. The aim of this study was to investigate if the triallelic 5-HTTLPR influences pain sensitivity or the analgesic effect of opioids in humans. 43 healthy volunteers (12 men, 31 women, mean age 26 years underwent heat pain stimulations before and after intravenous injection of Remifentanil; a rapid and potent opioid drug acting on μ-type receptors. Subjects rated their perceived pain on a visual analogue scale (VAS. All participants were genotyped for the 5-HTTLPR and the rs25531 polymorphism. We recruited by advertising, with no history of drug abuse, chronic pain or psychiatric disorders. Results At baseline, there was no difference in pain ratings for the different triallelic 5-HTTLPR genotype groups. However, the opiod drug had a differential analgesic effect depending on the triallelic 5-HTTLPR genotype. Remifentanil had a significantly better analgesic effect in individuals with a genotype coding for low 5-HTT expression (SA/SA and SA/LG as compared to those with high expression(LA/LA, p Conclusion This is the first report showing an influence of the triallelic 5-HTTLPR on pain sensitivity or the analgesic effect of opioids in humans. Previously the 5-HTTLPR s-allele has been associated with higher risk of developing chronic pain conditions but in this study we show that the genotype coding for low 5-HTT expression is associated with a better analgesic effect of an opioid. The s-allele has been associated with downregulation of

Large normal-range TBP and ATXN7 CAG repeat lengths are associated with increased lifetime risk of depression

DEFF Research Database (Denmark)

Gardiner, S. L.; van Belzen, M. J.; Boogaard, M. W.

2017-01-01

Depression is one of the most prevalent and debilitating psychiatric disorders worldwide. Recently, we showed that both relatively short and relatively long cytosine–adenine–guanine (CAG) repeats in the huntingtin gene (HTT) are associated with an increased risk of lifetime depression. However, t...

Hoare type theory, polymorphism and separation

DEFF Research Database (Denmark)

Nanevski, Alexandar; Morrisett, J. Gregory; Birkedal, Lars

2008-01-01

We consider the problem of reconciling a dependently typed functional language with imperative features such as mutable higher-order state, pointer aliasing, and nontermination. We propose Hoare type theory (HTT), which incorporates Hoare-style specifications into types, making it possible to sta...

Early life adversity and serotonin transporter gene variation interact at the level of the adrenal gland to affect the adult hypothalamo-pituitary-adrenal axis

NARCIS (Netherlands)

Doelen, R.H.A. van der; Deschamps, W.; D'Annibale, C.; Peeters, D.; Wevers, R.A.; Zelena, D.; Homberg, J.R.; Kozicz, L.T.

2014-01-01

The short allelic variant of the serotonin transporter (5-HTT) promoter-linked polymorphic region (5-HTTLPR) has been associated with the etiology of major depression by interaction with early life stress (ELS). Furthermore, 5-HTTLPR has been associated with abnormal functioning of the

Serotonin Transporter Knockout Rats Show Improved Strategy Set-Shifting and Reduced Latent Inhibition

Science.gov (United States)

Nonkes, Lourens J. P.; van de Vondervoort, Ilse I. G. M.; de Leeuw, Mark J. C.; Wijlaars, Linda P.; Maes, Joseph H. R.; Homberg, Judith R.

2012-01-01

Behavioral flexibility is a cognitive process depending on prefrontal areas allowing adaptive responses to environmental changes. Serotonin transporter knockout (5-HTT[superscript -/-]) rodents show improved reversal learning in addition to orbitofrontal cortex changes. Another form of behavioral flexibility, extradimensional strategy set-shifting…

Reversal learning and associative memory impairments in a BACHD rat model for Huntington disease

NARCIS (Netherlands)

Abada, Yah-se K.; Nguyen, Huu Phuc; Ellenbroek, Bart; Schreiber, Rudy

2013-01-01

Chorea and psychiatric symptoms are hallmarks of Huntington disease (HD), a neurodegenerative disorder, genetically characterized by the presence of expanded CAG repeats (>35) in the HUNTINGTIN (HTT) gene. HD patients present psychiatric symptoms prior to the onset of motor symptoms and we recently

Thermal conductivity improvement in carbon nanoparticle doped PAO oil: An experimental study

Science.gov (United States)

Shaikh, S.; Lafdi, K.; Ponnappan, R.

2007-03-01

The present work involves a study on the thermal conductivity of nanoparticle-oil suspensions for three types of nanoparticles, namely, carbon nanotubes (CNTs), exfoliated graphite (EXG), and heat treated nanofibers (HTT) with PAO oil as the base fluid. To accomplish the above task, an experimental analysis is performed using a modern light flash technique (LFA 447) for measuring the thermal conductivity of the three types of nanofluids, for different loading of nanoparticles. The experimental results show a similar trend as observed in literature for nanofluids with a maximum enhancement of approximately 161% obtained for the CNT-PAO oil suspension. The overall percent enhancements for different volume fractions of the nanoparticles are highest for the CNT-based nanofluid, followed by the EXG and the HTT. The findings from this study for the three different types of carbon nanoparticles can have great potential in the field of thermal management.

Insulin and IGF-1 improve mitochondrial function in a PI-3K/Akt-dependent manner and reduce mitochondrial generation of reactive oxygen species in Huntington's disease knock-in striatal cells.

Science.gov (United States)

Ribeiro, Márcio; Rosenstock, Tatiana R; Oliveira, Ana M; Oliveira, Catarina R; Rego, A Cristina

2014-09-01

Oxidative stress and mitochondrial dysfunction have been described in Huntington's disease, a disorder caused by expression of mutant huntingtin (mHtt). IGF-1 was previously shown to protect HD cells, whereas insulin prevented neuronal oxidative stress. In this work we analyzed the role of insulin and IGF-1 in striatal cells derived from HD knock-in mice on mitochondrial production of reactive oxygen species (ROS) and related antioxidant and signaling pathways influencing mitochondrial function. Insulin and IGF-1 decreased mitochondrial ROS induced by mHtt and normalized mitochondrial SOD activity, without affecting intracellular glutathione levels. IGF-1 and insulin promoted Akt phosphorylation without changing the nuclear levels of phosphorylated Nrf2 or Nrf2/ARE activity. Insulin and IGF-1 treatment also decreased mitochondrial Drp1 phosphorylation, suggesting reduced mitochondrial fragmentation, and ameliorated mitochondrial function in HD cells in a PI-3K/Akt-dependent manner. This was accompanied by increased total and phosphorylated Akt, Tfam, and mitochondrial-encoded cytochrome c oxidase II, as well as Tom20 and Tom40 in mitochondria of insulin- and IGF-1-treated mutant striatal cells. Concomitantly, insulin/IGF-1-treated mutant cells showed reduced apoptotic features. Hence, insulin and IGF-1 improve mitochondrial function and reduce mitochondrial ROS caused by mHtt by activating the PI-3K/Akt signaling pathway, in a process independent of Nrf2 transcriptional activity, but involving enhanced mitochondrial levels of Akt and mitochondrial-encoded complex IV subunit. Copyright © 2014 Elsevier Inc. All rights reserved.

Looking on the bright side of serotonin transporter gene variation.

NARCIS (Netherlands)

Homberg, J.R.; Lesch, K.P.

2011-01-01

Converging evidence indicates an association of the short (s), low-expressing variant of the repeat length polymorphism, serotonin transporter-linked polymorphic region (5-HTTLPR), in the human serotonin transporter gene (5-HTT, SERT, SLC6A4) with anxiety-related traits and increased risk for

Experiment list: SRX1084162 [Chip-atlas[Archive

Lifescience Database Archive (English)

Full Text Available 0 GSM1811344: P2 HA ChIPSeq; Drosophila melanogaster; ChIP-Seq source_name=Female whole animal_paraquat || tissue=whole animal || gen...der=female || age=1-3 days || genotype=k6801/k6801;gHA-KDM5 || chip antibody=HA htt

Phenotype abnormality: 251 [Arabidopsis Phenome Database[Archive

Lifescience Database Archive (English)

Full Text Available lant flowering stage in environment of long day length regimen in environment of long day length regimen htt... 251 http://metadb.riken.jp/db/SciNetS_ria224i/cria224u1ria224u757i delayed whole p

Loss aversion and 5HTT gene variants in adolescent anxiety.

Science.gov (United States)

Ernst, Monique; Plate, Rista C; Carlisi, Christina O; Gorodetsky, Elena; Goldman, David; Pine, Daniel S

2014-04-01

Loss aversion, a well-documented behavioral phenomenon, characterizes decisions under risk in adult populations. As such, loss aversion may provide a reliable measure of risky behavior. Surprisingly, little is known about loss aversion in adolescents, a group who manifests risk-taking behavior, or in anxiety disorders, which are associated with risk-avoidance. Finally, loss aversion is expected to be modulated by genotype, particularly the serotonin transporter (SERT) gene variant, based on its role in anxiety and impulsivity. This genetic modulation may also differ between anxious and healthy adolescents, given their distinct propensities for risk taking. The present work examines the modulation of loss aversion, an index of risk-taking, and reaction-time to decision, an index of impulsivity, by the serotonin-transporter-gene-linked polymorphisms (5HTTLPR) in healthy and clinically anxious adolescents. Findings show that loss aversion (1) does manifest in adolescents, (2) does not differ between healthy and clinically anxious participants, and (3), when stratified by SERT genotype, identifies a subset of anxious adolescents who are high SERT-expressers, and show excessively low loss-aversion and high impulsivity. This last finding may serve as preliminary evidence for 5HTTLPR as a risk factor for the development of comorbid disorders associated with risk-taking and impulsivity in clinically anxious adolescents. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

Loss aversion and 5HTT gene variants in adolescent anxiety

Directory of Open Access Journals (Sweden)

Monique Ernst

2014-04-01

Full Text Available Loss aversion, a well-documented behavioral phenomenon, characterizes decisions under risk in adult populations. As such, loss aversion may provide a reliable measure of risky behavior. Surprisingly, little is known about loss aversion in adolescents, a group who manifests risk-taking behavior, or in anxiety disorders, which are associated with risk-avoidance. Finally, loss aversion is expected to be modulated by genotype, particularly the serotonin transporter (SERT gene variant, based on its role in anxiety and impulsivity. This genetic modulation may also differ between anxious and healthy adolescents, given their distinct propensities for risk taking. The present work examines the modulation of loss aversion, an index of risk-taking, and reaction-time to decision, an index of impulsivity, by the serotonin-transporter-gene-linked polymorphisms (5HTTLPR in healthy and clinically anxious adolescents. Findings show that loss aversion (1 does manifest in adolescents, (2 does not differ between healthy and clinically anxious participants, and (3, when stratified by SERT genotype, identifies a subset of anxious adolescents who are high SERT-expressers, and show excessively low loss-aversion and high impulsivity. This last finding may serve as preliminary evidence for 5HTTLPR as a risk factor for the development of comorbid disorders associated with risk-taking and impulsivity in clinically anxious adolescents.

Association between a genetic variant in the serotonin transporter gene (SLC6A4) and suicidal behavior in patients with schizophrenia

DEFF Research Database (Denmark)

Lindholm Carlstrom, Eva; Saetre, Peter; Rosengren, Anders

2012-01-01

ABSTRACT: BACKGROUND: The serotonin (5-hydroxytryptamin; 5-HT) system has a central role in the circuitry of cognition and emotions. Multiple lines of evidence suggest that genetic variation in the serotonin transporter gene (SLC6A4; 5-HTT) is associated with schizophrenia and suicidal behavior. ...

Polymorphisms of genes related to the hypothalamic-pituitary-adrenal axis influence the cortisol awakening response as well as self-perceived stress.

Science.gov (United States)

Li-Tempel, Ting; Larra, Mauro F; Winnikes, Ulrike; Tempel, Tobias; DeRijk, Roel H; Schulz, André; Schächinger, Hartmut; Meyer, Jobst; Schote, Andrea B

2016-09-01

The hypothalamus-pituitary-adrenal (HPA) axis is a crucial endocrine system for coping with stress. A reliable and stable marker for the basal state of that system is the cortisol awakening response (CAR). We examined the influence of variants of four relevant candidate genes; the mineralocorticoid receptor gene (MR), the glucocorticoid receptor gene (GR), the serotonin transporter gene (5-HTT) and the gene encoding the brain-derived neurotrophic factor (BDNF) on CAR and self-perceived stress in 217 healthy subjects. We found that polymorphisms of GR influenced both, the basal state of the HPA axis as well as self-perceived stress. MR only associated with self-perceived stress and 5-HTT only with CAR. BDNF did not affected any of the investigated indices. In summary, we suggest that GR variants together with the CAR and supplemented with self reports on perceived stress might be useful indicators for the basal HPA axis activity. Copyright © 2016 Elsevier B.V. All rights reserved.

Human Neural Stem Cell Transplantation Rescues Functional Deficits in R6/2 and Q140 Huntington's Disease Mice

Directory of Open Access Journals (Sweden)

Jack C. Reidling

2018-01-01

Full Text Available Huntington's disease (HD is an inherited neurodegenerative disorder with no disease-modifying treatment. Expansion of the glutamine-encoding repeat in the Huntingtin (HTT gene causes broad effects that are a challenge for single treatment strategies. Strategies based on human stem cells offer a promising option. We evaluated efficacy of transplanting a good manufacturing practice (GMP-grade human embryonic stem cell-derived neural stem cell (hNSC line into striatum of HD modeled mice. In HD fragment model R6/2 mice, transplants improve motor deficits, rescue synaptic alterations, and are contacted by nerve terminals from mouse cells. Furthermore, implanted hNSCs are electrophysiologically active. hNSCs also improved motor and late-stage cognitive impairment in a second HD model, Q140 knockin mice. Disease-modifying activity is suggested by the reduction of aberrant accumulation of mutant HTT protein and expression of brain-derived neurotrophic factor (BDNF in both models. These findings hold promise for future development of stem cell-based therapies.

Glucose transportation in the brain and its impairment in Huntington disease: one more shade of the energetic metabolism failure?

Science.gov (United States)

Morea, Veronica; Bidollari, Eris; Colotti, Gianni; Fiorillo, Annarita; Rosati, Jessica; De Filippis, Lidia; Squitieri, Ferdinando; Ilari, Andrea

2017-07-01

Huntington's disease (HD) or Huntington's chorea is the most common inherited, dominantly transmitted, neurodegenerative disorder. It is caused by increased CAG repeats number in the gene coding for huntingtin (Htt) and characterized by motor, behaviour and psychiatric symptoms, ultimately leading to death. HD patients also exhibit alterations in glucose and energetic metabolism, which result in pronounced weight loss despite sustained calorie intake. Glucose metabolism decreases in the striatum of all the subjects with mutated Htt, but affects symptom presentation only when it drops below a specific threshold. Recent evidence points at defects in glucose uptake by the brain, and especially by neurons, as a relevant component of central glucose hypometabolism in HD patients. Here we review the main features of glucose metabolism and transport in the brain in physiological conditions and how these processes are impaired in HD, and discuss the potential ability of strategies aimed at increasing intracellular energy levels to counteract neurological and motor degeneration in HD patients.

Widespread AAV1- and AAV2-mediated transgene expression in the nonhuman primate brain: implications for Huntington's disease

Directory of Open Access Journals (Sweden)

Piotr Hadaczek

2016-01-01

Full Text Available Huntington's disease (HD is caused by a toxic gain-of-function associated with the expression of the mutant huntingtin (htt protein. Therefore, the use of RNA interference to inhibit Htt expression could represent a disease-modifying therapy. The potential of two recombinant adeno-associated viral vectors (AAV, AAV1 and AAV2, to transduce the cortico-striatal tissues that are predominantly affected in HD was explored. Green fluorescent protein was used as a reporter in each vector to show that both serotypes were broadly distributed in medium spiny neurons in the striatum and cortico-striatal neurons after infusion into the putamen and caudate nucleus of nonhuman primates (NHP, with AAV1-directed expression being slightly more robust than AAV2-driven expression. This study suggests that both serotypes are capable of targeting neurons that degenerate in HD, and it sets the stage for the advanced preclinical evaluation of an RNAi-based therapy for this disease.

Tics as an initial manifestation of juvenile Huntington's disease: case report and literature review.

Science.gov (United States)

Cui, Shi-Shuang; Ren, Ru-Jing; Wang, Ying; Wang, Gang; Chen, Sheng-Di

2017-08-08

Huntington's disease (HD) is an autosomal dominant disorder, typically characterized by chorea due to a trinucleotide repeat expansion in the HTT gene, although the clinical manifestations of patients with juvenile HD (JHD) are atypical. A 17-year-old boy with initial presentation of tics attended our clinic and his DNA analysis demonstrated mutation in the HTT gene (49 CAG repeats). After treatment, his symptoms improved. Furthermore, we performed literature review through searching the databases and summarized clinical features in 33 JHD patients. The most prevalent symptoms are ataxia, and two cases reported that tics as initial and prominent manifestation in JHD. Among them, 88% patients carried CAG repeats beyond 60 and most of them have family history. This case here illustrates the variable range of clinical symptoms of JHD and the necessity of testing for the HD mutation in young patients with tics with symptoms unable to be explained by Tourette's syndrome (TS).

Enhancing the gene-environment interaction framework through a quasi-experimental research design: evidence from differential responses to September 11.

Science.gov (United States)

Fletcher, Jason M

2014-01-01

This article uses a gene-environment interaction framework to examine the differential responses to an objective external stressor based on genetic variation in the production of depressive symptoms. This article advances the literature by utilizing a quasi-experimental environmental exposure design, as well as a regression discontinuity design, to control for seasonal trends, which limit the potential for gene-environment correlation and allow stronger causal claims. Replications are attempted for two prominent genes (5-HTT and MAOA), and three additional genes are explored (DRD2, DRD4, and DAT1). This article provides evidence of a main effect of 9/11 on reports of feelings of sadness and fails to replicate a common finding of interaction using 5-HTT but does show support for interaction with MAOA in men. It also provides new evidence that variation in the DRD4 gene modifies an individual's response to the exposure, with individuals with no 7-repeats found to have a muted response.

A Study of the Standard Model Higgs Boson Decaying to a Pair of Tau Leptons with the CMS Detector at the LHC

CERN Document Server

AUTHOR|(INSPIRE)INSPIRE-00398807; Smith, Wesley H.; Herndon, Matthew F.

This thesis presents a 5.5 standard deviation observation of the Higgs boson decaying to fermions using the data collected at the LHC at 13\\TeV center-of-mass energy. The studied dataset corresponds to an integrated luminosity of 35.9\\fbinv. The best fit signal strength for the $\\htt$ process is measured to be $\\mu = 1.24 ^{+0.29} _{-0.27}$, consistent with standard model predictions. Unique event categories are used targeting the leading Higgs boson production processes, gluon fusion, vector boson fusion, and associated production. This provides signal regions sensitive to Higgs boson couplings to both fermions and vector bosons. These two Higgs boson couplings are measured and are consistent with standard model predictions within one standard deviation. This 5.5 standard deviation observation of the $\\htt$ process and the consistency of the Higgs boson couplings with the standard model provide confirmation of the Higgs boson Yukawa couplings to fermions. This is evidence that the Higgs field provides mass f...

Genetic variation in the serotonin transporter gene (5-HTTLPR, rs25531) influences the analgesic response to the short acting opioid Remifentanil in humans.

Science.gov (United States)

Kosek, Eva; Jensen, Karin B; Lonsdorf, Tina B; Schalling, Martin; Ingvar, Martin

2009-07-01

There is evidence from animal studies that serotonin (5-HT) can influence the antinociceptive effects of opioids at the spinal cord level. Therefore, there could be an influence of genetic polymorphisms in the serotonin system on individual variability in response to opioid treatment of pain. The serotonin transporter (5-HTT) is a key regulator of serotonin metabolism and availability and its gene harbors several known polymorphisms that are known to affect 5-HTT expression (e.g. 5-HTTLPR, rs25531). The aim of this study was to investigate if the triallelic 5-HTTLPR influences pain sensitivity or the analgesic effect of opioids in humans. 43 healthy volunteers (12 men, 31 women, mean age 26 years) underwent heat pain stimulations before and after intravenous injection of Remifentanil; a rapid and potent opioid drug acting on micro-type receptors. Subjects rated their perceived pain on a visual analogue scale (VAS). All participants were genotyped for the 5-HTTLPR and the rs25531 polymorphism. We recruited by advertising, with no history of drug abuse, chronic pain or psychiatric disorders. At baseline, there was no difference in pain ratings for the different triallelic 5-HTTLPR genotype groups. However, the opiod drug had a differential analgesic effect depending on the triallelic 5-HTTLPR genotype. Remifentanil had a significantly better analgesic effect in individuals with a genotype coding for low 5-HTT expression (SA/SA and SA/LG) as compared to those with high expression(LA/LA), p desensitization of 5-HT1 receptors have an increased analgesic response to opioids during acute pain stimuli, but may still be at increased risk of developing chronic pain conditions.

Architecture of polyglutamine-containing fibrils from time-resolved fluorescence decay.

Science.gov (United States)

Röthlein, Christoph; Miettinen, Markus S; Borwankar, Tejas; Bürger, Jörg; Mielke, Thorsten; Kumke, Michael U; Ignatova, Zoya

2014-09-26

The disease risk and age of onset of Huntington disease (HD) and nine other repeat disorders strongly depend on the expansion of CAG repeats encoding consecutive polyglutamines (polyQ) in the corresponding disease protein. PolyQ length-dependent misfolding and aggregation are the hallmarks of CAG pathologies. Despite intense effort, the overall structure of these aggregates remains poorly understood. Here, we used sensitive time-dependent fluorescent decay measurements to assess the architecture of mature fibrils of huntingtin (Htt) exon 1 implicated in HD pathology. Varying the position of the fluorescent labels in the Htt monomer with expanded 51Q (Htt51Q) and using structural models of putative fibril structures, we generated distance distributions between donors and acceptors covering all possible distances between the monomers or monomer dimensions within the polyQ amyloid fibril. Using Monte Carlo simulations, we systematically scanned all possible monomer conformations that fit the experimentally measured decay times. Monomers with four-stranded 51Q stretches organized into five-layered β-sheets with alternating N termini of the monomers perpendicular to the fibril axis gave the best fit to our data. Alternatively, the core structure of the polyQ fibrils might also be a zipper layer with antiparallel four-stranded stretches as this structure showed the next best fit. All other remaining arrangements are clearly excluded by the data. Furthermore, the assessed dimensions of the polyQ stretch of each monomer provide structural evidence for the observed polyQ length threshold in HD pathology. Our approach can be used to validate the effect of pharmacological substances that inhibit or alter amyloid growth and structure. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Asking for an extra photon in Higgs production at the LHC and beyond

Energy Technology Data Exchange (ETDEWEB)

Gabrielli, Emidio [Dipartimento di Fisica Teorica, Università di Trieste,Strada Costiera 11, I-34151 Trieste (Italy); INFN, Sezione di Trieste,Via Valerio 2, I-34127 Trieste (Italy); National Institute Of Chemical Physics And Biophysics (NICPB),Ravala 10, Tallinn 10143 (Estonia); Mele, Barbara [INFN, Sezione di Roma, c/o Dipartimento di Fisica, “Sapienza' Università di Roma, P.le Aldo Moro 2, I-00185 Rome (Italy); Piccinini, Fulvio [INFN, Sezione di Pavia,Via A. Bassi 6, I-27100 Pavia (Italy); Pittau, Roberto [Departamento de Física Teórica y del Cosmos and CAFPE, Universidad de Granada, Campus Fuentenueva s.n., E-18071 Granada (Spain)

2016-07-01

We study the inclusive production of a Higgs boson in association with a high-p{sub T} photon at the LHC, detailing the leading-order features of the main processes contributing to the Hγ final state. Requiring an extra hard photon in Higgs production upsets the cross-section hierarchy for the dominant channels. The Hγ inclusive production comes mainly from photons radiated in vector-boson fusion (VBF), which accounts for about 2/3 of the total rate, for p{sub T}{sup γ,j}>30 GeV, at leading order. On the other hand, radiating a high-p{sub T} photon in the main top-loop Higgs channel implies an extra parton in the final state, which suppresses the production rate by a further α{sub S} power. As a result, the Hγ production via top loops at the LHC has rates comparable with the ones arising from either the Htt̄ production or the HW(Z)γ associated production. Then, in order of decreasing cross section, comes the single-top-plus-Higgs channel, followed in turn by the heavy-flavor fusion processes bb̄→Hγ and cc̄→Hγ. The Hγ production via electroweak loops has just a minor role. At larger c.m. energies, the Htt̄γ channel surpasses the total contribution of top-loop processes. In particular, requiring p{sub T}{sup γ,j}>30 GeV at √S≃100 TeV, Htt̄γ accounts for about 1/4 of the inclusive Hγ production at leading order, about half of the total being due to VBF production.

Granular model, percolation-resistivity, ESR and elastic modulus of carbonaceous materials application to the babassu endocarp heat treated up to 22000C

International Nuclear Information System (INIS)

Emmerich, F.G.

1987-01-01

A microscopic model (granular model) is presented to study heat treated carbons. A granular structure is defined in the carbon matrix, composed of turbostratic graphite-like microcrystallites, cross-linkings and micropores. A general expression is developed to calculate the volume fraction X of the conducting phase of the granular structure as a function of structural parameters obtained from X-ray diffraction small angle X-ray scattering. The granular model and the percolation theory are used to explain the electrical resistivity behaviour with the heat treatment temperature (HTT), where X is the fundamental parameter. An electron spin resonance (ESR) study of the low and high HTT ranges is presented, including the transition range (700-1300 0 C). The elucitation of the spin center nature in this range and the liking with the two adjacent ranges has been pursued. An expression to calculate the elastic modulus (Young's modulus), based on the microscopic granular model with the fundamental participation of the cross-linkings, is derived to account for the behavior of the modulus with the HTT. The granular model with the expression of X, the percolation-resistivity theory, the ESR study, and the expression of the elastic modulus are applied to the babassu endocarp carbon heat treated up to 2200 0 C. This material can be classified as a tipical non-graphitic carbon, being useful to search the validity of the model and the proposed expressions. It is observed that the theoretical expressions describe with reasonable accuracy the respective experimental behaviours. The measurements of physical and chemical parameters of the babassu endocarp treated up to 2200 0 C area also included. (author) [pt

Gudvin Veliki i Uzhasnõi i Zolushka v odnom litse / Galina Balashova

Index Scriptorium Estoniae

Balashova, Galina

2004-01-01

Vene kunstnikust-kontseptualistist Ilja Kabakovist ja tema loomingust. Ülo Soosteri hea sõber, 1996. a. ilmunud monograafia "Ülo Sooster" autor. Tema tutvuskonda kuulunud eesti kunstnikke. Raul Meele loomingu seotusest Ilja Kabakovi omaga. Ilja ja Emilia Kabakovi projekt "Tühi muuseum" avatakse Tallinna Kunstihoones. Eksponeeritud ka Raul Meele installatsioon "Vita Aboriginum"

Doktoriväitekiri komi keele kohakäänete ruumisemantikast / Galina Nekrassova

Index Scriptorium Estoniae

Nekrassova, Galina

2013-01-01

27. dets. 2012. a. kaitses Nikolay Kuznetsov Tartu ülikooli eesti ja üldkeeleteaduse instituudis doktoriväitekirja "Пространственная семантика местных падежей коми языка (когнитивный анализ)" ("Komi keele kohakäänete ruumisemantika (kognitiivne analüüs)")

Phenotype-gene: 399 [Arabidopsis Phenome Database[Archive

Lifescience Database Archive (English)

Full Text Available rescence for quantity of chlorophyll for AT5G51545 Ma Jinfang et al. 2007 Jun. Plant Cell 19(6):1980-93. htt...p://metadb.riken.jp/db/SciNetS_ria224i/cria224u4ria224u17601825i increased fluorescence for quantity of chloroph

The development of high-temperature reactors in the Federal Republic of Germany

International Nuclear Information System (INIS)

Engelmann, P.; Krings, F.

1980-01-01

The principal features of high-temperature reactors are recalled, then the current state of technology of the line in the Federal Republic of Germany is described. Reference is made to the experience of operating the AVR reactor, the construction of the THTR-300 reactor as well as the HTT and PNP projects [fr

A modifier of Huntington's disease onset at the MLH1 locus.

Science.gov (United States)

Lee, Jong-Min; Chao, Michael J; Harold, Denise; Abu Elneel, Kawther; Gillis, Tammy; Holmans, Peter; Jones, Lesley; Orth, Michael; Myers, Richard H; Kwak, Seung; Wheeler, Vanessa C; MacDonald, Marcy E; Gusella, James F

2017-10-01

Huntington's disease (HD) is a dominantly inherited neurodegenerative disease caused by an expanded CAG repeat in HTT. Many clinical characteristics of HD such as age at motor onset are determined largely by the size of HTT CAG repeat. However, emerging evidence strongly supports a role for other genetic factors in modifying the disease pathogenesis driven by mutant huntingtin. A recent genome-wide association analysis to discover genetic modifiers of HD onset age provided initial evidence for modifier loci on chromosomes 8 and 15 and suggestive evidence for a locus on chromosome 3. Here, genotyping of candidate single nucleotide polymorphisms in a cohort of 3,314 additional HD subjects yields independent confirmation of the former two loci and moves the third to genome-wide significance at MLH1, a locus whose mouse orthologue modifies CAG length-dependent phenotypes in a Htt-knock-in mouse model of HD. Both quantitative and dichotomous association analyses implicate a functional variant on ∼32% of chromosomes with the beneficial modifier effect that delays HD motor onset by 0.7 years/allele. Genomic DNA capture and sequencing of a modifier haplotype localize the functional variation to a 78 kb region spanning the 3'end of MLH1 and the 5'end of the neighboring LRRFIP2, and marked by an isoleucine-valine missense variant in MLH1. Analysis of expression Quantitative Trait Loci (eQTLs) provides modest support for altered regulation of MLH1 and LRRFIP2, raising the possibility that the modifier affects regulation of both genes. Finally, polygenic modification score and heritability analyses suggest the existence of additional genetic modifiers, supporting expanded, comprehensive genetic analysis of larger HD datasets. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Graphitization kinetics of fluidized-bed pyrolytic carbons

International Nuclear Information System (INIS)

Beatty, R.L.

1975-08-01

Graphitization of 12 fluidized-bed pyrocarbons was studied as a function of heat-treatment time and temperature (1350 to 3000 0 C) to investigate the effect of initial microstructure on the graphitization process. The term ''graphitization'' is defined to include any thermally induced structural change, whether or not any layer stacking order is attained. A broad range of CVD microstructures was prepared at temperatures from 1150 to 1900 0 C and various propylene and methane concentrations. The twelve carbons spanned a wide range of graphitizabilities, primarily as a function of deposition temperature. Hydrocarbon concentration was of much less importance except for deposition at 1900 0 C. Hydrogen content of the as-deposited carbons decreased with increasing temperature of deposition, and initial graphitization behavior of the low-temperature carbons appeared to be related to hydrogen content and evolution. Rates of change in the parameters varied widely throughout the range of heat-treatment times (HTt) and temperatures (HTT) for the different carbons showing differences between the more graphitizable or ''soft'' carbons from the nongraphitizing or ''hard'' carbons. ΔH for nongraphitizing carbons was 175 +- 15 kcal below 1950 0 C, 240 +- 35 kcal at 1950 to 2700 0 C, and 330 +- 20 kcal above 2700 0 C. For graphitizing carbons deposited at 1150 0 C, values near 245 kcal were obtained from anti chi data for the HTT range 1350 to 1650 0 C, while densification data yielded values of about 160 kcal in the same range. The behaviors observed for graphitizable carbons above 2000 0 C are consistent with literature. Different kinetic behaviors below 2000 0 C were shown to be due to different initial microstructures as well as to different parameters measured. (U.S.)

Electrochemical performance of DVB-modified SiOC and SiCN polymer-derived negative electrodes for lithium-ion batteries

International Nuclear Information System (INIS)

Liu, Guanwei; Kaspar, Jan; Reinold, Lukas Mirko; Graczyk-Zajac, Magdalena; Riedel, Ralf

2013-01-01

Highlights: • Polymer-derived SiCN and SiOC ceramics are studied as anode for Li-ion batteries. • Ceramic precursors are modified in order to increase the carbon content. • Ceramic matrix stabilizes free carbon phase. • Stabilizing role is lost once the amount of carbon exceeds a threshold value. -- Abstract: Chemical modification of commercially available polyorganosilazane (HTT1800) and polyorganosiloxane (Polyramic RD-684a) with divinylbenzene (DVB) is accomplished via hydrosilylation reaction. The incorporation of DVB leads to an increase of the free carbon amount after pyrolysis within the corresponding SiCN and SiOC ceramics. The modification is carried out with lower, equal and higher stoichiometric ratios of the Si-H to C=C groups present in the Si-based polymer and DVB. FTIR results indicate a complete consumption of the Si-H bonds in the case of the stoichiometric amount of DVB and polymer RD-684a, while for HTT1800 neither the stoichiometric ratio nor DVB excess leads to a complete consumption of the Si-H groups. For both SiCN and SiOC ceramics the carbon content is found to increase with the amount of DVB. However, the most significant increase in free carbon content is registered for SiCN samples, namely of ca. 40%. The carbon content changed from 9.9 wt.% in the pure HTT1800-derived material up to 49.3 wt.% for the SiCN ceramic obtained with the highest amount of DVB addition. Accordingly, Li-ion storage and therefore charge storage capacity are simultaneously increased, for the first cycle from 136 to 574 mAh g −1 , while columbic efficiency is raised by 10% up to 60.4%

A gene-environment investigation on personality traits in two independent clinical sets of adult patients with personality disorder and attention deficit/hyperactive disorder.

Science.gov (United States)

Jacob, Christian P; Nguyen, Thuy Trang; Dempfle, Astrid; Heine, Monika; Windemuth-Kieselbach, Christine; Baumann, Katarina; Jacob, Florian; Prechtl, Julian; Wittlich, Maike; Herrmann, Martin J; Gross-Lesch, Silke; Lesch, Klaus-Peter; Reif, Andreas

2010-06-01

While an interactive effect of genes with adverse life events is increasingly appreciated in current concepts of depression etiology, no data are presently available on interactions between genetic and environmental (G x E) factors with respect to personality and related disorders. The present study therefore aimed to detect main effects as well as interactions of serotonergic candidate genes (coding for the serotonin transporter, 5-HTT; the serotonin autoreceptor, HTR1A; and the enzyme which synthesizes serotonin in the brain, TPH2) with the burden of life events (#LE) in two independent samples consisting of 183 patients suffering from personality disorders and 123 patients suffering from adult attention deficit/hyperactivity disorder (aADHD). Simple analyses ignoring possible G x E interactions revealed no evidence for associations of either #LE or of the considered polymorphisms in 5-HTT and TPH2. Only the G allele of HTR1A rs6295 seemed to increase the risk of emotional-dramatic cluster B personality disorders (p = 0.019, in the personality disorder sample) and to decrease the risk of anxious-fearful cluster C personality disorders (p = 0.016, in the aADHD sample). We extended the initial simple model by taking a G x E interaction term into account, since this approach may better fit the data indicating that the effect of a gene is modified by stressful life events or, vice versa, that stressful life events only have an effect in the presence of a susceptibility genotype. By doing so, we observed nominal evidence for G x E effects as well as main effects of 5-HTT-LPR and the TPH2 SNP rs4570625 on the occurrence of personality disorders. Further replication studies, however, are necessary to validate the apparent complexity of G x E interactions in disorders of human personality.

Characterization of neurophysiological and behavioral changes, MRI brain volumetry and 1H MRS in zQ175 knock-in mouse model of Huntington's disease.

Directory of Open Access Journals (Sweden)

Taneli Heikkinen

Full Text Available Huntington's disease (HD is an autosomal neurodegenerative disorder, characterized by severe behavioral, cognitive, and motor deficits. Since the discovery of the huntingtin gene (HTT mutation that causes the disease, several mouse lines have been developed using different gene constructs of Htt. Recently, a new model, the zQ175 knock-in (KI mouse, was developed (see description by Menalled et al, [1] in an attempt to have the Htt gene in a context and causing a phenotype that more closely mimics HD in humans. Here we confirm the behavioral phenotypes reported by Menalled et al [1], and extend the characterization to include brain volumetry, striatal metabolite concentration, and early neurophysiological changes. The overall reproducibility of the behavioral phenotype across the two independent laboratories demonstrates the utility of this new model. Further, important features reminiscent of human HD pathology are observed in zQ175 mice: compared to wild-type neurons, electrophysiological recordings from acute brain slices reveal that medium spiny neurons from zQ175 mice display a progressive hyperexcitability; glutamatergic transmission in the striatum is severely attenuated; decreased striatal and cortical volumes from 3 and 4 months of age in homo- and heterozygous mice, respectively, with whole brain volumes only decreased in homozygotes. MR spectroscopy reveals decreased concentrations of N-acetylaspartate and increased concentrations of glutamine, taurine and creatine + phosphocreatine in the striatum of 12-month old homozygotes, the latter also measured in 12-month-old heterozygotes. Motor, behavioral, and cognitive deficits in homozygotes occur concurrently with the structural and metabolic changes observed. In sum, the zQ175 KI model has robust behavioral, electrophysiological, and histopathological features that may be valuable in both furthering our understanding of HD-like pathophyisology and the evaluation of potential therapeutic

Dopaminergic, Serotonergic, and Oxytonergic Candidate Genes Associated with Infant Attachment Security and Disorganization? In Search of Main and Interaction Effects

Science.gov (United States)

Luijk, Maartje P. C. M.; Roisman, Glenn I.; Haltigan, John D.; Tiemeier, Henning; Booth-LaForce, Cathryn; van IJzendoorn, Marinus H.; Belsky, Jay; Uitterlinden, Andre G.; Jaddoe, Vincent W. V.; Hofman, Albert; Verhulst, Frank C.; Tharner, Anne; Bakermans-Kranenburg, Marian J.

2011-01-01

Background and methods: In two birth cohort studies with genetic, sensitive parenting, and attachment data of more than 1,000 infants in total, we tested main and interaction effects of candidate genes involved in the dopamine, serotonin, and oxytocin systems ("DRD4", "DRD2", "COMT", "5-HTT", "OXTR") on attachment security and disorganization.…

Phenotype-gene: 454 [Arabidopsis Phenome Database[Archive

Lifescience Database Archive (English)

Full Text Available stance in response to organism biotroph for AT5G60600 Gil M Jos辿 et al. 2005 Oct. Plant J. 44(1):155-66. htt...p://metadb.riken.jp/db/SciNetS_ria224i/cria224u4ria224u16167903i increased resistance in response to organism biotroph

Perceived discrimination, serotonin transporter linked polymorphic region status, and the development of conduct problems.

Science.gov (United States)

Brody, Gene H; Beach, Steven R H; Chen, Yi-Fu; Obasi, Ezemenari; Philibert, Robert A; Kogan, Steven M; Simons, Ronald L

2011-05-01

This study examined the prospective relations of adolescents' perceptions of discrimination and their genetic status with increases in conduct problems. Participants were 461 African American youths residing in rural Georgia (Wave 1 mean age = 15.5 years) who provided three waves of data and a saliva sample from which a polymorphism in the SCL6A4 (serotonin transporter [5-HTT]) gene polymorphism known as the 5-HTT linked promoter region (5-HTTLPR) was genotyped. Data analyses using growth curve modeling indicated that perceived discrimination was significantly related to the slope of conduct problems. As hypothesized, interactions between perceived discrimination and genetic status emerged for male but not female youths. Compared with those carrying two copies of the long allele variant of 5-HTTLPR, male youths carrying one or two copies of its short allele variant evinced higher rates of conduct problems over time when they perceived high levels of racial discrimination. These findings are consistent with resilience and differential susceptibility propositions stating that genes can both foster sensitivity to adverse events and confer protection from those events.

Common variations in 4p locus are related to male completed suicide.

Science.gov (United States)

Must, Anne; Kõks, Sulev; Vasar, Eero; Tasa, Gunnar; Lang, Aavo; Maron, Eduard; Väli, Marika

2009-01-01

Suicidal behavior is a multifactorial phenomenon, with a significant genetic predisposition. To assess the contribution of genes in the 4p region to suicide risk, we genotyped 36 single nucleotide polymorphisms from a 49Mb region on the chromosome arm 4p11-16 in a total of 288 male suicide victims and 327 healthy male volunteers. The nonsynonymous variants rs1383180 in EVC gene, rs6811863 in TBC1D1 gene, rs362272 in HTT gene, and rs734312 in WFS1 gene were associated to the male completed suicide. However, only EVC polymorphism remained significant after correcting for multiple comparisons (P < .05 after 10 K permutations). The function of these genes is not clear yet. WFS1 and HTT are related to the unfolded protein response and endoplasmic reticulum stress, and TBC1D1 is a GTPase activator. EVC is a protein with transmembrane and leucine zipper domains, its function has not been elucidated yet. Further studies are required in order to reveal the role of these four polymorphisms in the pathoetiology of suicide.

Association of Anxiety-Related Polymorphisms with Sports Performance in Chilean Long Distance Triathletes: A Pilot Study.

Science.gov (United States)

Sanhueza, Jorge A; Zambrano, Tomás; Bahamondes-Avila, Carlos; Salazar, Luis A

2016-12-01

Different factors affecting athletic performance are well established: intensity and type of training, anthropometric characteristics as well as an important psychological component. However, the contribution of the genetic background has been less investigated. The aim of the present study was to investigate the influence of polymorphisms within genes associated with stress and anxiety ( 5HTT , CRH2R , ACE , NK1R , 5HT1AR and CRF-BP ) on the physical capability and sports performance in triathletes. One hundred and ninety two (192) unrelated Chilean triathletes who participated in the 2014 70.3 Pucón city triathlon were divided into opposite subgroups of sports performance according to their time results. We identified significant associations for five polymorphisms ( 5HTT 5-HTTLPR, ACE I/D, NK1R rs6715729, 5HT1AR -1019C>G and CRF-BP CRF-BPs11) with athletic performance. Our results indicate that these polymorphisms are associated with differential sports performance in Chilean triathletes, establishing an initial background for better understanding the relationship between physical performance, genetics and anxiety disorders.

Association of Anxiety-Related Polymorphisms with Sports Performance in Chilean Long Distance Triathletes: A Pilot Study

Directory of Open Access Journals (Sweden)

Jorge A. Sanhueza, Tomás Zambrano, Carlos Bahamondes-Avila, Luis A. Salazar

2016-12-01

Full Text Available Different factors affecting athletic performance are well established: intensity and type of training, anthropometric characteristics as well as an important psychological component. However, the contribution of the genetic background has been less investigated. The aim of the present study was to investigate the influence of polymorphisms within genes associated with stress and anxiety (5HTT, CRH2R, ACE, NK1R, 5HT1AR and CRF-BP on the physical capability and sports performance in triathletes. One hundred and ninety two (192 unrelated Chilean triathletes who participated in the 2014 70.3 Pucón city triathlon were divided into opposite subgroups of sports performance according to their time results. We identified significant associations for five polymorphisms (5HTT 5-HTTLPR, ACE I/D, NK1R rs6715729, 5HT1AR -1019C>G and CRF-BP CRF-BPs11 with athletic performance. Our results indicate that these polymorphisms are associated with differential sports performance in Chilean triathletes, establishing an initial background for better understanding the relationship between physical performance, genetics and anxiety disorders.

Potentiometric application of boron- and phosphorus-doped glassy carbon electrodes

Directory of Open Access Journals (Sweden)

ZORAN V. LAUSEVIC

2001-03-01

Full Text Available Acomparative study was carried out of the potentiometric application of boronand phosphorus-doped and undoped glassy carbon samples prepared at the same heat treatment temperature (HTT 1000°C. The electrochemical activities of the obtained electrode materials were investigated on the example of argentometric titrations. It was found that the electrochemical behaviour of the doped glassy carbon samples are very similar to a Sigri (undoped glassy carbon sample (HTT 2400°C. The experiments showed that the potentiometric response depends on the polarization mode, the nature of the sample, the pretreatment of the electrode surface, and the nature of the supporting electrolyte. The amounts of iodide, bromide, and of chloridewere determined to be 1.27 mg, 0.80 mg and 0.54 mg, respectively, with a maximum relative standard deviation of less than 1.1%. The obtained results are in good agreement with the results of comparative potentiometric titrations using a silver indicator electrode. The titrationmethod was applied to the indirect determination of pyridoxine hydrochloride, i.e., vitamin B6.

Locus - ASTRA | LSDB Archive [Life Science Database Archive metadata

Lifescience Database Archive (English)

Full Text Available switchLanguage; BLAST Search Image Search Home About Archive Update History Data ...URL: ftp://ftp.biosciencedbc.jp/archive/astra/LATEST/astra_locus.zip File size: 887 KB Simple search URL htt...icing type (ex. cassette) About This Database Database Description Download License Update History of This Database Site Policy | Contact Us Locus - ASTRA | LSDB Archive ...

Ühine tuberkuloosiprojekt Tallinnas / Rein Rannamäe, Jevgenia Epstein, Galina Kikos...[jt.

Index Scriptorium Estoniae

2001-01-01

Tallinna linnavolikogu toetas 2000. aastal oma eelarvega projekti "Koldekontrolli läbiviimine tuberkuloosi haigestunu koldes ja töökohal, kontaktsete isikute vajaduste välja selgitamine" läbiviimist

Put k sokrovishtsham / Boris Pilar, Jevgeni Rogov, Vladimir Anshon...[jt.] ; interv. Galina Balashova

Index Scriptorium Estoniae

2006-01-01

Pilar ja Rogov kunstiprojektist "Maailma kunstiaarded Tallinnas" ja selle raames toimuvast vene maalikunsti ja Pihkva koolkonna ikoonide näitusest "Pihkva muuseumi aarded" Tallinna Õpetajate majas. Anshon osalemisest projektis ja Dubrovskaja Pihkva muuseumist

Development of an improved species specific PCR test for detection of Haemophilus parasuis

DEFF Research Database (Denmark)

Angen, Øystein; Oliveira, Simone; Ahrens, Peter

2007-01-01

, the present PCR test was found to be 100% species specific for H. parasuis, in contrast to the PCR test of Oliveira et al., which also tested positive for strains belonging to A. indolicus, A. porcinus, and A. minor, species commonly occurring in the upper respiratory tract. However, when the PCR test...... with representatives of H. parasuis. The test was further evaluated on 55 clinical samples from 16 Danish pigs suspected for being infected with H. parasuis, showing polyserositis or septicemia at autopsy as well as on 492 nasal swabs. The test was compared with the performance of a PCR test earlier published...... by Oliveira et al. [Oliveira, S., Galina, L., Pijoan, C., 2001. Development of a PCR test to diagnose Haemophilus parasuis infections. J. Vet. Diagn. Invest. 13, 495-501]. The sensitivity of the present PCR test was found to be slightly lower when applied on clinical samples from diseased pigs and 10-fold...

Contamination of liquid oxygen by pressurized gaseous nitrogen

Science.gov (United States)

Zuckerwar, Allan J.; King, Tracy K.; Ngo, Kim Chi

1989-01-01

The penetration of pressurized gaseous nitrogen (GN2) into liquid oxygen (LOX) was investigated experimentally in the 7-inch High Temperature Tunnel, the pilot tunnel for the 8-foot High Temperature Tunnel (8'HTT) at Langley Research Center. A preliminary test using a nuclear monitor revealed the extent of the liquid nitrogen (LN2) build-up at the LOX interface as a function of GN2 pressure. Then an adaptation of the differential flash vaporization technique was used to determine the binary diffusivity of the LOX-LN2 system at a temperature of 90.2 K. The measured value D equals 0.000086 sq cm/s + or - 25 percent together with two prior measurements at lower temperatures revealed an excellent fit to the Arrhenius equation, yielding a pre-exponential factor D sub 0 equals 0.0452 sq cm/s and an activation enthalpy H equals 1.08 kcal/mol. At a pressure of 1700 psi and holding time of 15 min, the penetration of LN2 into LOX (to a 1 percent contamination level) was found to be 0.9 cm, indicating but minimal impact upon 8'HTT operations.

Early Detection of Apathetic Phenotypes in Huntington's Disease Knock-in Mice Using Open Source Tools.

Science.gov (United States)

Minnig, Shawn; Bragg, Robert M; Tiwana, Hardeep S; Solem, Wes T; Hovander, William S; Vik, Eva-Mari S; Hamilton, Madeline; Legg, Samuel R W; Shuttleworth, Dominic D; Coffey, Sydney R; Cantle, Jeffrey P; Carroll, Jeffrey B

2018-02-02

Apathy is one of the most prevalent and progressive psychiatric symptoms in Huntington's disease (HD) patients. However, preclinical work in HD mouse models tends to focus on molecular and motor, rather than affective, phenotypes. Measuring behavior in mice often produces noisy data and requires large cohorts to detect phenotypic rescue with appropriate power. The operant equipment necessary for measuring affective phenotypes is typically expensive, proprietary to commercial entities, and bulky which can render adequately sized mouse cohorts as cost-prohibitive. Thus, we describe here a home-built, open-source alternative to commercial hardware that is reliable, scalable, and reproducible. Using off-the-shelf hardware, we adapted and built several of the rodent operant buckets (ROBucket) to test Htt Q111/+ mice for attention deficits in fixed ratio (FR) and progressive ratio (PR) tasks. We find that, despite normal performance in reward attainment in the FR task, Htt Q111/+ mice exhibit reduced PR performance at 9-11 months of age, suggesting motivational deficits. We replicated this in two independent cohorts, demonstrating the reliability and utility of both the apathetic phenotype, and these ROBuckets, for preclinical HD studies.

Enhanced Store-Operated Calcium Entry Leads to Striatal Synaptic Loss in a Huntington's Disease Mouse Model.

Science.gov (United States)

Wu, Jun; Ryskamp, Daniel A; Liang, Xia; Egorova, Polina; Zakharova, Olga; Hung, Gene; Bezprozvanny, Ilya

2016-01-06

In Huntington's disease (HD), mutant Huntingtin (mHtt) protein causes striatal neuron dysfunction, synaptic loss, and eventual neurodegeneration. To understand the mechanisms responsible for synaptic loss in HD, we developed a corticostriatal coculture model that features age-dependent dendritic spine loss in striatal medium spiny neurons (MSNs) from YAC128 transgenic HD mice. Age-dependent spine loss was also observed in vivo in YAC128 MSNs. To understand the causes of spine loss in YAC128 MSNs, we performed a series of mechanistic studies. We previously discovered that mHtt protein binds to type 1 inositol (1,4,5)-trisphosphate receptor (InsP3R1) and increases its sensitivity to activation by InsP3. We now report that the resulting increase in steady-state InsP3R1 activity reduces endoplasmic reticulum (ER) Ca(2+) levels. Depletion of ER Ca(2+) leads to overactivation of the neuronal store-operated Ca(2+) entry (nSOC) pathway in YAC128 MSN spines. The synaptic nSOC pathway is controlled by the ER resident protein STIM2. We discovered that STIM2 expression is elevated in aged YAC128 striatal cultures and in YAC128 mouse striatum. Knock-down of InsP3R1 expression by antisense oligonucleotides or knock-down or knock-out of STIM2 resulted in normalization of nSOC and rescue of spine loss in YAC128 MSNs. The selective nSOC inhibitor EVP4593 was identified in our previous studies. We now demonstrate that EVP4593 reduces synaptic nSOC and rescues spine loss in YAC128 MSNs. Intraventricular delivery of EVP4593 in YAC128 mice rescued age-dependent striatal spine loss in vivo. Our results suggest EVP4593 and other inhibitors of the STIM2-dependent nSOC pathway as promising leads for HD therapeutic development. In Huntington's disease (HD) mutant Huntingtin (mHtt) causes early corticostriatal synaptic dysfunction and eventual neurodegeneration of medium spine neurons (MSNs) through poorly understood mechanisms. We report here that corticostriatal cocultures prepared from

2009 Biometrics Conference

Science.gov (United States)

2009-01-28

gov/fpkia/crosscert htm. . . – Verisign – Wells Fargo CSPs on Other Bridges at eAuth-4 (Certipath only today) htt // ti th / ki t htp : www.cer pa .com...Center (TEDAC) provided latent fingerprints recovered from an Improvised Explosive Device (IED) to BFC BFC manually processed latent prints...to original fingerprint. If no match manual review; may not test , . Other action may be taken. Copyright© 2009, Graduate Management Admission

PPARGC1A/PGC-1α, TFEB and enhanced proteostasis in Huntington disease: Defining regulatory linkages between energy production and protein–organelle quality control

OpenAIRE

La Spada, Albert R.

2012-01-01

Huntington disease (HD) results from CAG repeats that encode expanded polyglutamine tracts in the HTT/huntingtin protein. HD belongs to a large category of inherited and sporadic neurodegenerative disorders in which production of a misfolded protein initiates the pathogenic cascade. Previous studies have shown that misfolded proteins become resistant to cellular protein turnover pathways by eluding and disabling the ubiquitin-proteasome system (UPS) and autophagy-lysosome pathway. Based upon ...

Effects of 2450 MHz microwave radiation on meiosis and reproduction in male mice

International Nuclear Information System (INIS)

Manikowska-Czerska, E.; Czerski, P.; Leach, W.M.

1988-01-01

A series of studies to examine effects od continuous wave 2450 MHz radiation on meiosis and on chromosomes of germ cells in male CBA/CAY or ICR mice, by means of the spermatocyte (SCT), heritable translocation (HTT) and dominant lethal (DLT) tests is presented. Animals were exposed in an environmentally controlled waveguide system during two consecutive weeks, 30 minutes daily, six days a week. Specific absorption rates (SAR) were used in the range from 0.05 to 20 W/kg. With the SCT, it was demonstrated that chromosomal translocations can be induced by exposure during the first meiotic prophase, particularly during initial and early pachytene stages. The HTT results demonstrated that balanced translocations may be recovered among offspring of exposed males. The DLT provided confirmatory data on effects during prophase and indicated that chromosomal damage may be also induced by exposure of spermatids, during the maturation stage, and of spermatozoa. No changes were observed in spermatogonia. Thus, the effects of exposure were limited to one spermatogenic cycle. Genetically significant effects were induced at an SAR of 2 W/kg in the testes. For comparison, an SAR of 0.4 W/kg is used commonly as a basis for occupational exposure limits

An experimental investigation into the formation of polycyclic-aromatic hydrocarbons (PAH) from pyrolysis of biomass materials

Energy Technology Data Exchange (ETDEWEB)

McGrath, T.; Sharma, R.; Hajaligol, M. [Philip Morris USA, Richmond, VA (United States). Research Center

2001-10-09

The formation of polycyclic-aromatic hydrocarbons (PAH) from the pyrolysis of cellulose, pectin and chlorogenic acid was studied. The primary product, mostly primary volatile tar, was exposed to a higher thermal severity i.e. high temperatures and long residence times. The reactor setup consisted of a quartz tube with two zones, zone I and II, each heated and controlled separately. Zone I was used to first pyrolyse the substrate at 300{degree}C to produce a low temperature tar (LTT) as well as to pyrolyse the product char at 600{degree}C to produce a high temperature tar (HTT). The LTT and HTT were then subjected to a high thermal severity in the second zone (zone II) where the temperature was varied between 700 and 850{degree}C. The residence time of the volatiles in zone II was varied between ca. 90 and 1400 ms (calculated at 800{degree}C). The results show that the yield of most PAHs increased with temperature, except in a few cases where the yield of two- and three-ring PAHs exhibited a maximum. PAHs yields also generally increased as the residence time was increased from 90 to 1400 ms at 800{degree}C. 19 refs., 9 figs., 2 tabs.

The POLARBEAR Experiment: Design and Characterization

Science.gov (United States)

Kermish, Zigmund David

We present the design and characterization of the POLARBEAR experiment. POLARBEAR is a millimeter-wave polarimeter that will measure the Cosmic Microwave Background (CMB) polarization. It was designed to have both the sensitivity and angular resolution to detect the expected B-mode polarization due to gravitational lensing at small angular scales while still enabling a search for the degree scale B-mode polarization caused by inflationary gravitational waves. The instrument utilizes the Huan Tran Telescope (HTT), a 2.5-meter primary mirror telescope, coupled to a unique focal plane of 1,274 antenna-coupled transition-edge sensor (TES) detectors to achieve unprecedented sensitivity from angular scales of the experiment's 4 arcminute beam to several degrees. This dissertation focuses on the design, integration and characterization of the cryogenic receiver for the POLARBEAR instrument. The receiver cools the ˜20 cm focal plane to 0.25 Kelvin, with detector readout provided by a digital frequency-multiplexed SQUID system. The POLARBEAR receiver was been successfully deployed on the HTT for an engineering run in the Eastern Sierras of California and is currently deployed on Cerro Toco in the Atacama Dessert of Chile. We present results from lab tests done to characterize the instrument, from the engineering run and preliminary results from Chile.

microRNA-128a dysregulation in transgenic Huntington’s disease monkeys

Science.gov (United States)

2014-01-01

Background Huntington’s Disease (HD) is a progressive neurodegenerative disorder with a single causal mutation in the Huntingtin (HTT) gene. MicroRNAs (miRNAs) have recently been implicated as epigenetic regulators of neurological disorders, however, their role in HD pathogenesis is not well defined. Here we study transgenic HD monkeys (HD monkeys) to examine miRNA dysregulation in a primate model of the disease. Results In this report, 11 miRNAs were found to be significantly associated (P value monkeys. We further focused on one of those candidates, miR-128a, due to the corresponding disruption in humans and mice with HD as well as its intriguing lists of gene targets. miR-128a was downregulated in our HD monkey model by the time of birth. We then confirmed that miR-128a was also downregulated in the brains of pre-symptomatic and post-symptomatic HD patients. Additionally, our studies confirmed a panel of canonical HD signaling genes regulated by miR-128a, including HTT and Huntingtin Interaction Protein 1 (HIP1). Conclusion Our studies found that miR-128a may play a critical role in HD and could be a viable candidate as a therapeutic or biomarker of the disease. PMID:24929669

Association study of serotonin transporter and monoamine oxidase A genes polymorphisms with antisocial personality disorder in Han Chinese male%5-羟色胺转运体基因和单胺氧化酶A基因多态性与汉族男性反社会人格障碍患者的关联分析

Institute of Scientific and Technical Information of China (English)

茆正洪; 谭钊安; 柯晓燕; 郑大同; 曾彦英; 张建平; 李树明

2010-01-01

目的 探讨5-羟色胺转运体基因(5-HTT)第2内含子的一个可变数串联重复序列(Stin2.VNTR)和单胺氧化酶A(MAOA)基因14外显子上的一种限制性片段长度多态性(EcoRV-RFLP)与汉族男性反社会人格障碍(APD),尤其是具有高度冲动性APD的遗传易感性的关系.方法 (1)APD组:对南京地区某监狱男性服刑人员进行人格诊断问卷(PDQ-4+)调查,在PDQ得分为阳性的可疑人群中由临床医师以美国精神障碍诊断与统计手册第4版(DSM-Ⅳ)关于APD诊断标准进一步确诊,入组118例;全部进行Barratt冲动量表(BIS-11)评分,以冲动总分中位值为界,划分为高冲动APD组和低冲动APD组.(2)监狱对照组:经PDQ排除人格障碍的250名服刑人员作为监狱内对照.(3)正常对照组:同时期医院健康体检者300名设为正常对照.取所有人员血液标本提取DNA,应用聚合酶链反应(PCR)和限制性片段长度多态性方法,对等位基因频率和基因型频率进行对比分析.结果 (1)APD组与正常对照组比较,5-HTT-VNTR基因型多态、MAOA-EcoRV-RFLP多态差异无统计学意义(x2=2.819,P=0.244;x2=2.347,P=0.126).(2)高冲动APD组与正常对照组比较,5-HTT-VNTR基因型多态差异有统计学意义(x2=7.422,P=0.024),MAOA-EcoRV-RFLP的等位基因频率有统计学意义(x2=5.478,P=0.019).(3)2个位点的联合分析中,APD组和高冲动APD组分别与对照组比较,12/12/-多倍体型的差异均有统计学意义(x2=7.164,P=0.007;x2=9.590,P=0.002);12/10/+仅在高冲动APD组与正常对照组间差异有统计学意义(x2=5.378,P=0.020).结论 5-HTT基因第2内含子VNTR多态、MAOA基因EcoRV-RFLP多态与具有高冲动的APD关联,12/12/-多倍体型与中国汉族男性APD发病风险可能有关.%Objective To investigate whether the 5-HTT-VNTR, the EcoRV polymorphism of MAOA gene was associated with antisocial personality disorder (APD) in Han Chinese male criminal offenders. Method In a prison in Jiangsu, the male

Stemcell Information: SKIP000389 [SKIP Stemcell Database[Archive

Lifescience Database Archive (English)

Full Text Available +5ng/ml human bFGF ... Riken BioResource Center 理化学研究所バイオリソースセンター Riken BioResource Center 理化学...研究所バイオリソースセンター Available Riken BioResource Center 理化学研究所バイオリソースセンター htt

Exploring Anthropology’s Value to Military Strategy Since 2000

Science.gov (United States)

2014-04-01

anthropological study of military culture, MA2 : anthropological study for the military, in endeavors such as the Human Terrain System concept, where teams of...Anthropology The AAA has judged MA2 as the least ethical category of military anthropology by means of its code of ethics, CEAUSSIC reports, and...open debates on its blog. The lighting rod system most associated with MA2 is the Human Terrain Team, (HTT) employed under the Human Terrain System

Mismatch repair genes Mlh1 and Mlh3 modify CAG instability in Huntington's disease mice: genome-wide and candidate approaches.

Science.gov (United States)

Pinto, Ricardo Mouro; Dragileva, Ella; Kirby, Andrew; Lloret, Alejandro; Lopez, Edith; St Claire, Jason; Panigrahi, Gagan B; Hou, Caixia; Holloway, Kim; Gillis, Tammy; Guide, Jolene R; Cohen, Paula E; Li, Guo-Min; Pearson, Christopher E; Daly, Mark J; Wheeler, Vanessa C

2013-10-01

The Huntington's disease gene (HTT) CAG repeat mutation undergoes somatic expansion that correlates with pathogenesis. Modifiers of somatic expansion may therefore provide routes for therapies targeting the underlying mutation, an approach that is likely applicable to other trinucleotide repeat diseases. Huntington's disease Hdh(Q111) mice exhibit higher levels of somatic HTT CAG expansion on a C57BL/6 genetic background (B6.Hdh(Q111) ) than on a 129 background (129.Hdh(Q111) ). Linkage mapping in (B6x129).Hdh(Q111) F2 intercross animals identified a single quantitative trait locus underlying the strain-specific difference in expansion in the striatum, implicating mismatch repair (MMR) gene Mlh1 as the most likely candidate modifier. Crossing B6.Hdh(Q111) mice onto an Mlh1 null background demonstrated that Mlh1 is essential for somatic CAG expansions and that it is an enhancer of nuclear huntingtin accumulation in striatal neurons. Hdh(Q111) somatic expansion was also abolished in mice deficient in the Mlh3 gene, implicating MutLγ (MLH1-MLH3) complex as a key driver of somatic expansion. Strikingly, Mlh1 and Mlh3 genes encoding MMR effector proteins were as critical to somatic expansion as Msh2 and Msh3 genes encoding DNA mismatch recognition complex MutSβ (MSH2-MSH3). The Mlh1 locus is highly polymorphic between B6 and 129 strains. While we were unable to detect any difference in base-base mismatch or short slipped-repeat repair activity between B6 and 129 MLH1 variants, repair efficiency was MLH1 dose-dependent. MLH1 mRNA and protein levels were significantly decreased in 129 mice compared to B6 mice, consistent with a dose-sensitive MLH1-dependent DNA repair mechanism underlying the somatic expansion difference between these strains. Together, these data identify Mlh1 and Mlh3 as novel critical genetic modifiers of HTT CAG instability, point to Mlh1 genetic variation as the likely source of the instability difference in B6 and 129 strains and suggest that MLH1

Mismatch repair genes Mlh1 and Mlh3 modify CAG instability in Huntington's disease mice: genome-wide and candidate approaches.

Directory of Open Access Journals (Sweden)

Ricardo Mouro Pinto

2013-10-01

Full Text Available The Huntington's disease gene (HTT CAG repeat mutation undergoes somatic expansion that correlates with pathogenesis. Modifiers of somatic expansion may therefore provide routes for therapies targeting the underlying mutation, an approach that is likely applicable to other trinucleotide repeat diseases. Huntington's disease Hdh(Q111 mice exhibit higher levels of somatic HTT CAG expansion on a C57BL/6 genetic background (B6.Hdh(Q111 than on a 129 background (129.Hdh(Q111 . Linkage mapping in (B6x129.Hdh(Q111 F2 intercross animals identified a single quantitative trait locus underlying the strain-specific difference in expansion in the striatum, implicating mismatch repair (MMR gene Mlh1 as the most likely candidate modifier. Crossing B6.Hdh(Q111 mice onto an Mlh1 null background demonstrated that Mlh1 is essential for somatic CAG expansions and that it is an enhancer of nuclear huntingtin accumulation in striatal neurons. Hdh(Q111 somatic expansion was also abolished in mice deficient in the Mlh3 gene, implicating MutLγ (MLH1-MLH3 complex as a key driver of somatic expansion. Strikingly, Mlh1 and Mlh3 genes encoding MMR effector proteins were as critical to somatic expansion as Msh2 and Msh3 genes encoding DNA mismatch recognition complex MutSβ (MSH2-MSH3. The Mlh1 locus is highly polymorphic between B6 and 129 strains. While we were unable to detect any difference in base-base mismatch or short slipped-repeat repair activity between B6 and 129 MLH1 variants, repair efficiency was MLH1 dose-dependent. MLH1 mRNA and protein levels were significantly decreased in 129 mice compared to B6 mice, consistent with a dose-sensitive MLH1-dependent DNA repair mechanism underlying the somatic expansion difference between these strains. Together, these data identify Mlh1 and Mlh3 as novel critical genetic modifiers of HTT CAG instability, point to Mlh1 genetic variation as the likely source of the instability difference in B6 and 129 strains and suggest

A new drug design targeting the adenosinergic system for Huntington's disease.

Directory of Open Access Journals (Sweden)

Nai-Kuei Huang

Full Text Available BACKGROUND: Huntington's disease (HD is a neurodegenerative disease caused by a CAG trinucleotide expansion in the Huntingtin (Htt gene. The expanded CAG repeats are translated into polyglutamine (polyQ, causing aberrant functions as well as aggregate formation of mutant Htt. Effective treatments for HD are yet to be developed. METHODOLOGY/PRINCIPAL FINDINGS: Here, we report a novel dual-function compound, N(6-(4-hydroxybenzyladenine riboside (designated T1-11 which activates the A(2AR and a major adenosine transporter (ENT1. T1-11 was originally isolated from a Chinese medicinal herb. Molecular modeling analyses showed that T1-11 binds to the adenosine pockets of the A(2AR and ENT1. Introduction of T1-11 into the striatum significantly enhanced the level of striatal adenosine as determined by a microdialysis technique, demonstrating that T1-11 inhibited adenosine uptake in vivo. A single intraperitoneal injection of T1-11 in wildtype mice, but not in A(2AR knockout mice, increased cAMP level in the brain. Thus, T1-11 enters the brain and elevates cAMP via activation of the A(2AR in vivo. Most importantly, addition of T1-11 (0.05 mg/ml to the drinking water of a transgenic mouse model of HD (R6/2 ameliorated the progressive deterioration in motor coordination, reduced the formation of striatal Htt aggregates, elevated proteasome activity, and increased the level of an important neurotrophic factor (brain derived neurotrophic factor in the brain. These results demonstrate the therapeutic potential of T1-11 for treating HD. CONCLUSIONS/SIGNIFICANCE: The dual functions of T1-11 enable T1-11 to effectively activate the adenosinergic system and subsequently delay the progression of HD. This is a novel therapeutic strategy for HD. Similar dual-function drugs aimed at a particular neurotransmitter system as proposed herein may be applicable to other neurotransmitter systems (e.g., the dopamine receptor/dopamine transporter and the serotonin receptor

Clues to γ-secretase, huntingtin and Hirano body normal function using the model organism Dictyostelium discoideum

Directory of Open Access Journals (Sweden)

Myre Michael A

2012-04-01

Full Text Available Abstract Many neurodegenerative disorders, although related by their destruction of brain function, display remarkable cellular and/or regional pathogenic specificity likely due to a deregulated functionality of the mutant protein. However, neurodegenerative disease genes, for example huntingtin (HTT, the ataxins, the presenilins (PSEN1/PSEN2 are not simply localized to neurons but are ubiquitously expressed throughout peripheral tissues; it is therefore paramount to properly understand the earliest precipitating events leading to neuronal pathogenesis to develop effective long-term therapies. This means, in no unequivocal terms, it is crucial to understand the gene's normal function. Unfortunately, many genes are often essential for embryogenesis which precludes their study in whole organisms. This is true for HTT, the β-amyloid precursor protein (APP and presenilins, responsible for early onset Alzheimer's disease (AD. To better understand neurological disease in humans, many lower and higher eukaryotic models have been established. So the question arises: how reasonable is the use of organisms to study neurological disorders when the model of choice does not contain neurons? Here we will review the surprising, and novel emerging use of the model organism Dictyostelium discoideum, a species of soil-living amoeba, as a valuable biomedical tool to study the normal function of neurodegenerative genes. Historically, the evidence on the usefulness of simple organisms to understand the etiology of cellular pathology cannot be denied. But using an organism without a central nervous system to understand diseases of the brain? We will first introduce the life cycle of Dictyostelium, the presence of many disease genes in the genome and how it has provided unique opportunities to identify mechanisms of disease involving actin pathologies, mitochondrial disease, human lysosomal and trafficking disorders and host-pathogen interactions. Secondly, I will

Oligonucleic Acid Drug List: monrd0010 [Oligonucleic Acid Drug Database[Archive

Lifescience Database Archive (English)

Full Text Available ciparum Malaria has been initiated. ... https://www.clinicaltrialsregister.eu/ctr-se...arch/trial/2004-003813-18/GB, https://www.clinicaltrialsregister.eu/ctr-search/trial/2004-004686-15/DE, https:...//www.clinicaltrialsregister.eu/ctr-search/trial/2004-004684-30/DE, https://www.clinicaltrialsregister.eu/...ctr-search/trial/2007-005389-11/GB, https://www.clinicaltrialsregister.eu/ctr-search/search?query=CpG, htt...ps://www.clinicaltrialsregister.eu/ctr-search/trial/2005-004557-10/results, https:/

Oligonucleic Acid Drug List: monrd0030 [Oligonucleic Acid Drug Database[Archive

Lifescience Database Archive (English)

Full Text Available u/ema/index.jsp?curl=pages/medicines/human/medicines/000711/human_med_000806.jsp&mid=WC0b01ac058001d124, htt...nes/human/medicines/000711/human_med_000806.jsp&mid=WC0b01ac058001d124, http://www.kegg.jp/dbget-bin/www_bget?D05216 ... P10415 1G5M ...c_assessment_report/human/000711/WC500070766.pdf, http://www.ema.europa.eu/ema/index.jsp?curl=pages/medici

[Mari Uusküla. Basic colour terms in Finno-Ugric and Slavonic Languages] / Galina Paramei

Index Scriptorium Estoniae

Paramei, Galina

2010-01-01

Arvustus: Uusküla, Mari. Basic colour terms in Finno-ugric and Slavonic languages: myths and facts. Tartu : Tartu University Press, 2008. Dissertationes linguisticae Universitatis Tartuensis, 1406-5657 ; 9

Effect of flomoxef on blood coagulation and alcohol metabolism.

Science.gov (United States)

Uchida, K; Matsubara, T

1991-01-01

The effect of flomoxef, a newly developed oxacephem antibiotic with an N-hydroxyethyltetrazolethiol (HTT) side chain, on blood coagulation and alcohol metabolism was compared with that of a series of cephalosporin antibiotics with N-methyltetrazolethiol (NMTT), thiadiazolethiol (TDT) or methylthiadiazolethiol (MTDT) side chains in position 3' of the cephalosporin nucleus known to cause hypoprothrombinemia and bleeding in patients who are malnourished, debilitated and/or of high age. A disulfiram-like effect caused by inhibition of aldehyde dehydrogenase was observed for NMTT-containing antibiotics. Studies were carried out on healthy volunteers and on rats. Eight-day treatment with 2 g flomoxef i.v. once or twice daily in five and six healthy male volunteers, respectively, did not cause any significant changes in prothrombin time (PT), coagulation factors II, VII, IX or X, in hepaplastin values or fibrinogen levels, activated partial thromboplastin time (APTT), platelet counts, bleeding time, or collagen- and ADP-induced platelet aggregation. Inhibition of vitamin K epoxide reductase was observed in rats treated with flomoxef, yet to a much lesser extent than observed for cephalosporins with NMTT, TDT or MTDT side chains. This defect was quickly normalized by vitamin K injection. There were no differences between oxacephem (1-O) and cephem (1-S) compounds with respect to effects on blood clotting and platelet aggregation. Flomoxef and its side chain HTT showed no influence on alcohol metbolism.

Testing differential susceptibility: Plasticity genes, the social environment, and their interplay in adolescent response inhibition.

Science.gov (United States)

Richards, Jennifer S; Arias Vásquez, Alejandro; van Rooij, Daan; van der Meer, Dennis; Franke, Barbara; Hoekstra, Pieter J; Heslenfeld, Dirk J; Oosterlaan, Jaap; Faraone, Stephen V; Hartman, Catharina A; Buitelaar, Jan K

2017-06-01

Impaired inhibitory control is a key feature of attention-deficit/hyperactivity disorder (ADHD). We investigated gene-environment interaction (GxE) as a possible contributing factor to response inhibition variation in context of the differential susceptibility theory. This states individuals carrying plasticity gene variants will be more disadvantaged in negative, but more advantaged in positive environments. Behavioural and neural measures of response inhibition were assessed during a Stop-signal task in participants with (N = 197) and without (N = 295) ADHD, from N = 278 families (age M = 17.18, SD =3.65). We examined GxE between candidate plasticity genes (DAT1, 5-HTT, DRD4) and social environments (maternal expressed emotion, peer affiliation). A DRD4 × Positive peer affiliation interaction was found on the right fusiform gyrus (rFG) activation during successful inhibition. Further, 5-HTT short allele carriers showed increased rFG activation during failed inhibitions. Maternal warmth and positive peer affiliation were positively associated with right inferior frontal cortex activation during successful inhibition. Deviant peer affiliation was positively related to the error rate. While a pattern of differential genetic susceptibility was found, more clarity on the role of the FG during response inhibition is warranted before firm conclusions can be made. Positive and negative social environments were related to inhibitory control. This extends previous research emphasizing adverse environments.

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

OpenAIRE

Hensman Moss, Davina J; Pardinas, Antonio; Langbehn, Douglas; Lo, Kitty; Leavitt, Blair R; Roos, Raymund; Durr, Alexandra; Mead, Simon; Holmans, Peter; Jones, Lesley; Tabrizi, Sarah J; Coleman, A; Santos, R Dar; Decolongon, J; Sturrock, A

2017-01-01

Background\\ud \\ud Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure.\\ud \\ud Methods\\ud \\ud We generated a progression score on the basis of principal ...

Human glia can both induce and rescue aspects of disease phenotype in Huntington disease

DEFF Research Database (Denmark)

Benraiss, Abdellatif; Wang, Su; Herrlinger, Stephanie

2016-01-01

The causal contribution of glial pathology to Huntington disease (HD) has not been heavily explored. To define the contribution of glia to HD, we established human HD glial chimeras by neonatally engrafting immunodeficient mice with mutant huntingtin (mHTT)-expressing human glial progenitor cells...... chimeras are hyperexcitable. Conversely, normal glia can ameliorate disease phenotype in transgenic HD mice, as striatal transplantation of normal glia rescues aspects of electrophysiological and behavioural phenotype, restores interstitial potassium homeostasis, slows disease progression and extends...

EMQN/CMGS best practice guidelines for the molecular genetic testing of Huntington disease

OpenAIRE

Losekoot, Monique; van Belzen, Martine J; Seneca, Sara; Bauer, Peter; Stenhouse, Susan A R; Barton, David E

2012-01-01

Huntington disease (HD) is caused by the expansion of an unstable polymorphic trinucleotide (CAG)n repeat in exon 1 of the HTT gene, which translates into an extended polyglutamine tract in the protein. Laboratory diagnosis of HD involves estimation of the number of CAG repeats. Molecular genetic testing for HD is offered in a wide range of laboratories both within and outside the European community. In order to measure the quality and raise the standard of molecular genetic testing in these ...

Experiment list: SRX144528 [Chip-atlas[Archive

Lifescience Database Archive (English)

Full Text Available -Seq source_name=IgG ChIP SFN treated || biomaterial_provider=Coriell; http://ccr....coriell.org/Sections/Search/Search.aspx?PgId=165&q=GM06993 || biomaterial_provider=Coriell; http://ccr.cori...ell.org/Sections/Search/Search.aspx?PgId=165&q=GM07000 || biomaterial_provider=Coriell; http://ccr.coriell.o...rg/Sections/Search/Search.aspx?PgId=165&q=GM11882 || biomaterial_provider=Coriell...; http://ccr.coriell.org/Sections/Search/Search.aspx?PgId=165&q=GM11992 || biomaterial_provider=Coriell; htt

A Qualitative Data Collection Strategy for Africa

Science.gov (United States)

2013-02-01

ini on da ta wo rld wi de an d ha s t hr ee an aly sts de dic ate d t o s ub - Sa ha ra n A fric a. Qu an tita tiv e a nd qu ali tat ive da...Int er sta te an d e xtr as tat e w ar s a nd lin ks to oth er qu an tita tiv e i nte rn ati on al re lat ion s da ta. htt p:/ /w ww

Inhibition of dipeptidyl peptidase-4: The mechanisms of action and clinical use of vildagliptin for the management of type 2 diabetes

Directory of Open Access Journals (Sweden)

Galina Smushkin

2009-06-01

Full Text Available Galina Smushkin, Adrian VellaDivision of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic College of Medicine, Rochester, MN, USAAbstract: Postprandial hyperglycemia in type 2 diabetes is characterized by impaired insulin secretion and action, decreased glucose effectiveness and defective suppression of glucagon secretion. Newly available therapies for type 2 diabetes target the pathway of the incretin hormone glucagon-like peptide-1 (GLP-1. Oral inhibitors of dipeptidyl peptidase-4 (DPP-4 raise the level of endogenous GLP-1 by inhibiting its clearance thereby lowering fasting and postprandial glucose concentrations. Unlike compounds which act as agonists of the GLP-1 receptor, DPP-4 inhibitors are not associated with significant effects on gastrointestinal motility, which led to a controversy around the mechanisms responsible for their glucose-lowering effects. Here we review the evidence in regards to the mechanisms whereby DPP-4 inhibitors lower glucose concentrations. Their effects are most likely mediated by an increase in endogenous GLP-1, although additional mechanisms may be involved. The pharmacology, efficacy and safety of vildagliptin, a novel DPP-4 inhibitor, are also discussed.Keywords: insulin secretion, insulin action, incretin, DPP-4 inhibitor, glucagon-like peptide 1

Xyloketal-derived small molecules show protective effect by decreasing mutant Huntingtin protein aggregates in Caenorhabditis elegans model of Huntington’s disease

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Zeng YX

2016-04-01

Full Text Available Yixuan Zeng,1,2,* Wenyuan Guo,1,* Guangqing Xu,3 Qinmei Wang,4 Luyang Feng,1,2 Simei Long,1 Fengyin Liang,1 Yi Huang,1 Xilin Lu,1 Shichang Li,5 Jiebin Zhou,5 Jean-Marc Burgunder,6 Jiyan Pang,5 Zhong Pei1,2 1Department of Neurology, National Key Clinical Department and Key Discipline of Neurology, Guangdong Key Laboratory for Diagnosis and Treatment of Major Neurological Disease, The First Affiliated Hospital, Sun Yat-sen University, 2Guangzhou Center, Chinese Huntington’s Disease Network, 3Department of Rehabilitation, The First Affiliated Hospital, 4Key laboratory on Assisted Circulation, Ministry of Health, Department of Cardiovascular Medicine of the First Affiliated Hospital, 5School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou, Guangdong, People’s Republic of China; 6Swiss Huntington’s Disease Center, Department of Neurology, University of Bern, Bern, Switzerland *These authors contributed equally to this work Abstract: Huntington’s disease is an autosomal-dominant neurodegenerative disorder, with chorea as the most prominent manifestation. The disease is caused by abnormal expansion of CAG codon repeats in the IT15 gene, which leads to the expression of a glutamine-rich protein named mutant Huntingtin (Htt. Because of its devastating disease burden and lack of valid treatment, development of more effective therapeutics for Huntington’s disease is urgently required. Xyloketal B, a natural product from mangrove fungus, has shown protective effects against toxicity in other neurodegenerative disease models such as Parkinson’s and Alzheimer’s diseases. To identify potential neuroprotective molecules for Huntington’s disease, six derivatives of xyloketal B were screened in a Caenorhabditis elegans Huntington’s disease model; all six compounds showed a protective effect. Molecular docking studies indicated that compound 1 could bind to residues GLN369 and GLN393 of the mutant Htt protein, forming a

Epigenetic and epistatic interactions between serotonin transporter and brain-derived neurotrophic factor genetic polymorphism: insights in depression.

Science.gov (United States)

Ignácio, Z M; Réus, G Z; Abelaira, H M; Quevedo, J

2014-09-05

Epidemiological studies have shown significant results in the interaction between the functions of brain-derived neurotrophic factor (BDNF) and 5-HT in mood disorders, such as major depressive disorder (MDD). The latest research has provided convincing evidence that gene transcription of these molecules is a target for epigenetic changes, triggered by stressful stimuli that starts in early childhood and continues throughout life, which are subsequently translated into structural and functional phenotypes culminating in depressive disorders. The short variants of 5-HTTLPR and BDNF-Met are seen as forms which are predisposed to epigenetic aberrations, which leads individuals to a susceptibility to environmental adversities, especially when subjected to stress in early life. Moreover, the polymorphic variants also feature epistatic interactions in directing the functional mechanisms elicited by stress and underlying the onset of depressive disorders. Also emphasized are works which show some mediators between stress and epigenetic changes of the 5-HTT and BDNF genes, such as the hypothalamic-pituitary-adrenal (HPA) axis and the cAMP response element-binding protein (CREB), which is a cellular transcription factor. Both the HPA axis and CREB are also involved in epistatic interactions between polymorphic variants of 5-HTTLPR and Val66Met. This review highlights some research studying changes in the epigenetic patterns intrinsic to genes of 5-HTT and BDNF, which are related to lifelong environmental adversities, which in turn increases the risks of developing MDD. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

Fission gas behavior during fast thermal transients

International Nuclear Information System (INIS)

Esteves, R.G.

1976-01-01

The behavior of non-equilibrium fission in fuel elements undergoing fast thermal transients is analyzed. To facilitate the analysis, a new variable, the equilibrium variable (EV) is defined. This variable, together with bubble radius, completely specifies a bubble with respect to its size and equilibrium condition. The analysis is coded using a two-variable (radius and EV) multigroup numerical approximation that accepts as input the time-temperature history, the time-fission rate history, and the time-thermal gradient history of the fuel element. Studies were performed to test the code for convergence with respect to the time interval and the number of groups chosen. For a series of transient simulation studies, the measurements obtained at HEDL (microscopic examination of intragranular porosity in oxide fuel transient-tested in TREAT) are used. Two different transient histories were selected; the first, a high-temperature transient (HTT) with a peak at 2477 0 K and the second, a low-temperature transient (LTT) with a peak-temperature at 2000 0 K. The LTT was simulated for three different conditions: Bubbles were allowed to move via (a) only biased migration, (b) via random migration, and (c) via both mechanisms. The HTT was also run for both mechanisms. The agreement with HEDL microscopic observations was fair for bubbles smaller than 964 A in diameter, and poor for larger bubbles. Bubbles that grew during the heat-up part of the transient were frozen at a larger size during the cool down

High Protein Diet and Huntington's Disease

Science.gov (United States)

Wu, Yih-Ru; Chen, Pei; Tsai, Fuu-Jen; Yang, Chueh-Lien; Tsao, Ya-Tzu; Chang, Wen; Hsieh, I-Shan; Chern, Yijuang; Soong, Bing-Wen

2015-01-01

Huntington’s disease (HD) is a neurodegenerative disorder caused by the huntingtin (HTT) gene with expanded CAG repeats. In addition to the apparent brain abnormalities, impairments also occur in peripheral tissues. We previously reported that mutant Huntingtin (mHTT) exists in the liver and causes urea cycle deficiency. A low protein diet (17%) restores urea cycle activity and ameliorates symptoms in HD model mice. It remains unknown whether the dietary protein content should be monitored closely in HD patients because the normal protein consumption is lower in humans (~15% of total calories) than in mice (~22%). We assessed whether dietary protein content affects the urea cycle in HD patients. Thirty HD patients were hospitalized and received a standard protein diet (13.7% protein) for 5 days, followed by a high protein diet (HPD, 26.3% protein) for another 5 days. Urea cycle deficiency was monitored by the blood levels of citrulline and ammonia. HD progression was determined by the Unified Huntington’s Disease Rating Scale (UHDRS). The HPD increased blood citrulline concentration from 15.19 μmol/l to 16.30 μmol/l (p = 0.0378) in HD patients but did not change blood ammonia concentration. A 2-year pilot study of 14 HD patients found no significant correlation between blood citrulline concentration and HD progression. Our results indicated a short period of the HPD did not markedly compromise urea cycle function. Blood citrulline concentration is not a reliable biomarker of HD progression. PMID:25992839

High Protein Diet and Huntington's Disease.

Directory of Open Access Journals (Sweden)

Chiung-Mei Chen

Full Text Available Huntington's disease (HD is a neurodegenerative disorder caused by the huntingtin (HTT gene with expanded CAG repeats. In addition to the apparent brain abnormalities, impairments also occur in peripheral tissues. We previously reported that mutant Huntingtin (mHTT exists in the liver and causes urea cycle deficiency. A low protein diet (17% restores urea cycle activity and ameliorates symptoms in HD model mice. It remains unknown whether the dietary protein content should be monitored closely in HD patients because the normal protein consumption is lower in humans (~15% of total calories than in mice (~22%. We assessed whether dietary protein content affects the urea cycle in HD patients. Thirty HD patients were hospitalized and received a standard protein diet (13.7% protein for 5 days, followed by a high protein diet (HPD, 26.3% protein for another 5 days. Urea cycle deficiency was monitored by the blood levels of citrulline and ammonia. HD progression was determined by the Unified Huntington's Disease Rating Scale (UHDRS. The HPD increased blood citrulline concentration from 15.19 μmol/l to 16.30 μmol/l (p = 0.0378 in HD patients but did not change blood ammonia concentration. A 2-year pilot study of 14 HD patients found no significant correlation between blood citrulline concentration and HD progression. Our results indicated a short period of the HPD did not markedly compromise urea cycle function. Blood citrulline concentration is not a reliable biomarker of HD progression.

Pitfalls in the detection of cholesterol in Huntington’s disease models

Science.gov (United States)

Marullo, Manuela; Valenza, Marta; Leoni, Valerio; Caccia, Claudio; Scarlatti, Chiara; De Mario, Agnese; Zuccato, Chiara; Di Donato, Stefano; Carafoli, Ernesto; Cattaneo, Elena

2012-01-01

Background Abnormalities in brain cholesterol homeostasis have been reported in Huntington’s disease (HD), an adult-onset neurodegenerative disorder caused by an expansion in the number of CAG repeats in the huntingtin (HTT) gene. However, the results have been contradictory with respect to whether cholesterol levels increase or decrease in HD models. Biochemical and mass spectrometry methods show reduced levels of cholesterol precursors and cholesterol in HD cells and in the brains of several HD animal models. Abnormal brain cholesterol homeostasis was also inferred from studies in HD patients. In contrast, colorimetric and enzymatic methods indicate cholesterol accumulation in HD cells and tissues. Here we used several methods to investigate cholesterol levels in cultured cells in the presence or absence of mutant HTT protein. Results Colorimetric and enzymatic methods with low sensitivity gave variable results, whereas results from a sensitive analytical method, gas chromatography-mass spectrometry, were more reliable. Sample preparation, high cell density and cell clonality also influenced the detection of intracellular cholesterol. Conclusions Detection of cholesterol in HD samples by colorimetric and enzymatic assays should be supplemented by detection using more sensitive analytical methods. Care must be taken to prepare the sample appropriately. By evaluating lathosterol levels using isotopic dilution mass spectrometry, we confirmed reduced cholesterol biosynthesis in knock-in cells expressing the polyQ mutation in a constitutive or inducible manner. *Correspondence should be addressed to Elena Cattaneo: elena.cattaneo@unimi.it PMID:23145355

Pitfalls in the detection of cholesterol in Huntington's disease models.

Science.gov (United States)

Marullo, Manuela; Valenza, Marta; Leoni, Valerio; Caccia, Claudio; Scarlatti, Chiara; De Mario, Agnese; Zuccato, Chiara; Di Donato, Stefano; Carafoli, Ernesto; Cattaneo, Elena

2012-10-11

Background Abnormalities in brain cholesterol homeostasis have been reported in Huntington's disease (HD), an adult-onset neurodegenerative disorder caused by an expansion in the number of CAG repeats in the huntingtin (HTT) gene. However, the results have been contradictory with respect to whether cholesterol levels increase or decrease in HD models. Biochemical and mass spectrometry methods show reduced levels of cholesterol precursors and cholesterol in HD cells and in the brains of several HD animal models. Abnormal brain cholesterol homeostasis was also inferred from studies in HD patients. In contrast, colorimetric and enzymatic methods indicate cholesterol accumulation in HD cells and tissues. Here we used several methods to investigate cholesterol levels in cultured cells in the presence or absence of mutant HTT protein. Results Colorimetric and enzymatic methods with low sensitivity gave variable results, whereas results from a sensitive analytical method, gas chromatography-mass spectrometry, were more reliable. Sample preparation, high cell density and cell clonality also influenced the detection of intracellular cholesterol. Conclusions Detection of cholesterol in HD samples by colorimetric and enzymatic assays should be supplemented by detection using more sensitive analytical methods. Care must be taken to prepare the sample appropriately. By evaluating lathosterol levels using isotopic dilution mass spectrometry, we confirmed reduced cholesterol biosynthesis in knock-in cells expressing the polyQ mutation in a constitutive or inducible manner. *Correspondence should be addressed to Elena Cattaneo: elena.cattaneo@unimi.it.

Assessment of motor function, sensory motor gating and recognition memory in a novel BACHD transgenic rat model for huntington disease.

Science.gov (United States)

Abada, Yah-Se K; Nguyen, Huu Phuc; Schreiber, Rudy; Ellenbroek, Bart

2013-01-01

Huntington disease (HD) is frequently first diagnosed by the appearance of motor symptoms; the diagnosis is subsequently confirmed by the presence of expanded CAG repeats (> 35) in the HUNTINGTIN (HTT) gene. A BACHD rat model for HD carrying the human full length mutated HTT with 97 CAG-CAA repeats has been established recently. Behavioral phenotyping of BACHD rats will help to determine the validity of this model and its potential use in preclinical drug discovery studies. The present study seeks to characterize the progressive emergence of motor, sensorimotor and cognitive deficits in BACHD rats. Wild type and transgenic rats were tested from 1 till 12 months of age. Motor tests were selected to measure spontaneous locomotor activity (open field) and gait coordination. Sensorimotor gating was assessed in acoustic startle response paradigms and recognition memory was evaluated in an object recognition test. Transgenic rats showed hyperactivity at 1 month and hypoactivity starting at 4 months of age. Motor coordination imbalance in a Rotarod test was present at 2 months and gait abnormalities were seen in a Catwalk test at 12 months. Subtle sensorimotor changes were observed, whereas object recognition was unimpaired in BACHD rats up to 12 months of age. The current BACHD rat model recapitulates certain symptoms from HD patients, especially the marked motor deficits. A subtle neuropsychological phenotype was found and further studies are needed to fully address the sensorimotor phenotype and the potential use of BACHD rats for drug discovery purposes.

Correlations of Behavioral Deficits with Brain Pathology Assessed through Longitudinal MRI and Histopathology in the HdhQ150/Q150 Mouse Model of Huntington's Disease.

Directory of Open Access Journals (Sweden)

Ivan Rattray

Full Text Available A variety of mouse models have been developed that express mutant huntingtin (mHTT leading to aggregates and inclusions that model the molecular pathology observed in Huntington's disease. Here we show that although homozygous HdhQ150 knock-in mice developed motor impairments (rotarod, locomotor activity, grip strength by 36 weeks of age, cognitive dysfunction (swimming T maze, fear conditioning, odor discrimination, social interaction was not evident by 94 weeks. Concomitant to behavioral assessments, T2-weighted MRI volume measurements indicated a slower striatal growth with a significant difference between wild type (WT and HdhQ150 mice being present even at 15 weeks. Indeed, MRI indicated significant volumetric changes prior to the emergence of the "clinical horizon" of motor impairments at 36 weeks of age. A striatal decrease of 27% was observed over 94 weeks with cortex (12% and hippocampus (21% also indicating significant atrophy. A hypothesis-free analysis using tensor-based morphometry highlighted further regions undergoing atrophy by contrasting brain growth and regional neurodegeneration. Histology revealed the widespread presence of mHTT aggregates and cellular inclusions. However, there was little evidence of correlations between these outcome measures, potentially indicating that other factors are important in the causal cascade linking the molecular pathology to the emergence of behavioral impairments. In conclusion, the HdhQ150 mouse model replicates many aspects of the human condition, including an extended pre-manifest period prior to the emergence of motor impairments.

Genetic Contributors to Intergenerational CAG Repeat Instability in Huntington's Disease Knock-In Mice.

Science.gov (United States)

Neto, João Luís; Lee, Jong-Min; Afridi, Ali; Gillis, Tammy; Guide, Jolene R; Dempsey, Stephani; Lager, Brenda; Alonso, Isabel; Wheeler, Vanessa C; Pinto, Ricardo Mouro

2017-02-01

Huntington's disease (HD) is a neurodegenerative disorder caused by the expansion of a CAG trinucleotide repeat in exon 1 of the HTT gene. Longer repeat sizes are associated with increased disease penetrance and earlier ages of onset. Intergenerationally unstable transmissions are common in HD families, partly underlying the genetic anticipation seen in this disorder. HD CAG knock-in mouse models also exhibit a propensity for intergenerational repeat size changes. In this work, we examine intergenerational instability of the CAG repeat in over 20,000 transmissions in the largest HD knock-in mouse model breeding datasets reported to date. We confirmed previous observations that parental sex drives the relative ratio of expansions and contractions. The large datasets further allowed us to distinguish effects of paternal CAG repeat length on the magnitude and frequency of expansions and contractions, as well as the identification of large repeat size jumps in the knock-in models. Distinct degrees of intergenerational instability were observed between knock-in mice of six background strains, indicating the occurrence of trans-acting genetic modifiers. We also found that lines harboring a neomycin resistance cassette upstream of Htt showed reduced expansion frequency, indicative of a contributing role for sequences in cis, with the expanded repeat as modifiers of intergenerational instability. These results provide a basis for further understanding of the mechanisms underlying intergenerational repeat instability. Copyright © 2017 by the Genetics Society of America.

Vene külaelust XX sajandi lõpus / Galina Ponomarjova ; vene keelest tõlkinud Jaan Isotamm

Index Scriptorium Estoniae

Ponomarjova, Galina, 1954-

2001-01-01

Arvustus: Говорит Ивахново : Наблюдения над процессом выживания псковской деревни в 1996 -1998 гг./ Natalia Baschmakoff, Nina Loimi, Johanna Takala. (Learning by doing : Working papers from the Russian Department University of Joensuu, 1456-0976 ; 2). Joensuu, 2000

CISSP Study Guide

CERN Document Server

Conrad, Eric; Feldman, Joshua

2010-01-01

The CISSP Study Guide is aligned to cover all of the material included in the exam, complete with special attention to recent updates. The 10 domains are covered completely and as concisely as possible with an eye to passing the exam thr first time. Each of the 10 domains has its own chapter that includes specially-designed pedagogy to aid you in passing the exam. Clearly Stated Exam Objectives Unique Terms / Definitions Exam Warnings Helpful Notes Learning By Example Stepped Chapter Ending Questions Self Test Appendix Detailed Glossary Web Site (htt

Taxonomy Icon Data: Ptychodera flava Eschscholtz (Acorn worm) [Taxonomy Icon

Lifescience Database Archive (English)

Full Text Available Ptychodera flava Eschscholtz (Acorn worm) Ptychodera flava Hemichordata Ptychodera_flava_L.png Ptycho...dera_flava_NL.png Ptychodera_flava_S.png Ptychodera_flava_NS.png http://biosciencedbc.jp/t...axonomy_icon/icon.cgi?i=Ptychodera+flava&t=L http://biosciencedbc.jp/taxonomy_icon/icon.cgi?i=Ptychodera+fla...va&t=NL http://biosciencedbc.jp/taxonomy_icon/icon.cgi?i=Ptychodera+flava&t=S htt...p://biosciencedbc.jp/taxonomy_icon/icon.cgi?i=Ptychodera+flava&t=NS http://togodb.biosciencedbc.jp/togodb/view/taxonomy_icon_comment_en?species_id=161 ...

Psychiatric and cognitive symptoms in Huntington's disease are modified by polymorphisms in catecholamine regulating enzyme genes

DEFF Research Database (Denmark)

Vinther-Jensen, T; Nielsen, Troels Tolstrup; Budtz-Jørgensen, E

2016-01-01

Huntington's disease (HD) is an autosomal dominantly inherited neurodegenerative disorder characterized by motor, psychiatric, and cognitive manifestations. HD is caused by a CAG repeat expansion in the Huntingtin (HTT) gene but the exact pathogenesis remains unknown. Dopamine imbalance has......-described cohort of Danish HD gene-expansion carriers. We show that cognitive impairment and psychiatric symptoms in HD are modified by polymorphisms in the monoamine oxidase A (MAOA) and catechol-O-methyltransferase (COMT) genes and by the 4p16.3 B haplotype. These results support the theory of dopamine imbalance...

Taxonomy Icon Data: Anopheles stephensi [Taxonomy Icon

Lifescience Database Archive (English)

Full Text Available Anopheles stephensi Anopheles stephensi Arthropoda Anopheles_stephensi_L.png Anopheles_stephen...si_NL.png Anopheles_stephensi_S.png Anopheles_stephensi_NS.png http://biosciencedbc.jp/taxonomy_i...con/icon.cgi?i=Anopheles+stephensi&t=L http://biosciencedbc.jp/taxonomy_icon/icon.cgi?i=Anopheles+stephensi&...t=NL http://biosciencedbc.jp/taxonomy_icon/icon.cgi?i=Anopheles+stephensi&t=S htt...p://biosciencedbc.jp/taxonomy_icon/icon.cgi?i=Anopheles+stephensi&t=NS http://togodb.biosciencedbc.jp/togodb/view/taxonomy_icon_comment_en?species_id=149 ...

Serotonin transporter evolution and impact of polymorphic transcriptional regulation

DEFF Research Database (Denmark)

Søeby, Karen; Larsen, Svend Ask; Olsen, Line

2005-01-01

The serotonin transporter (SERT) is the primary drug target in the current antidepressant therapy. A functional polymorphism in the 2nd intron of the 5HTT gene encoding the SERT has been identified and associated with susceptibility to affective disorders and treatment response to antidepressants....... This study addresses the possible impact of the variable number of tandem repeats (VNTR) to behavior and disease by examining the evolutionary origin and mechanisms of differential transcriptional regulation of SERT. We trace the evolutionary origin of the VNTR and show that it is present and varies...

Serotonin transporter evolution and impact of polymorphic transcriptional regulation

DEFF Research Database (Denmark)

Søeby, Karen; Larsen, Svend Ask; Olsen, Line

2005-01-01

The serotonin transporter (SERT) is the primary drug target in the current antidepressant therapy. A functional polymorphism in the 2nd intron of the 5HTT gene encoding the SERT has been identified and associated with susceptibility to affective disorders and treatment response to antidepressants...... in the VNTRs of all mammalian SERT genes. The number of these putative binding sites varies proportionally to the length of the VNTR. We propose that the intronic VNTR have been selectively targeted through mammalian evolution to finetune transcriptional regulation of the serotonin expression....

Developmental exposure to terbutaline and chlorpyrifos: pharmacotherapy of preterm labor and an environmental neurotoxicant converge on serotonergic systems in neonatal rat brain regions

International Nuclear Information System (INIS)

Aldridge, Justin E.; Meyer, Armando; Seidler, Frederic J.; Slotkin, Theodore A.

2005-01-01

Developmental exposure to unrelated neurotoxicants can nevertheless produce similar neurobehavioral outcomes. We examined the effects of developmental exposure to terbutaline, a tocolytic β 2 -adrenoceptor agonist used to arrest preterm labor, and chlorpyrifos (CPF), a widely used organophosphate pesticide, on serotonin (5HT) systems. Treatments were chosen to parallel periods typical of human developmental exposures, terbutaline (10 mg/kg) on postnatal days (PN) 2-5 and CPF (5 mg/kg) on PN11-14, with assessments conducted on PN45, comparing each agent alone as well as sequential administration of both. Although neither treatment affected growth or viability, each elicited similar alterations in factors that are critical to the function of the 5HT synapse: 5HT 1A receptors, 5HT 2 receptors, and the presynaptic 5HT transporter (5HTT). Either agent elicited global increases in 5HT receptors and the 5HTT in brain regions possessing 5HT cell bodies (midbrain, brainstem) as well as in the hippocampus, which contains 5HT projections. For both terbutaline and CPF, males were affected more than females, although there were some regional disparities in the sex selectivity between the two agents. Both altered 5HT receptor-mediated cell signaling, suppressing stimulatory effects on adenylyl cyclase and enhancing inhibitory effects. When animals were exposed sequentially to both agents, the outcomes were no more than additive and, for many effects, less than additive, suggesting convergence of the two agents on a common set of developmental mechanisms. Our results indicate that 5HT systems represent a target for otherwise unrelated neuroteratogens

Rejecting probability summation for radial frequency patterns, not so Quick!

Science.gov (United States)

Baldwin, Alex S; Schmidtmann, Gunnar; Kingdom, Frederick A A; Hess, Robert F

2016-05-01

Radial frequency (RF) patterns are used to assess how the visual system processes shape. They are thought to be detected globally. This is supported by studies that have found summation for RF patterns to be greater than what is possible if the parts were being independently detected and performance only then improved with an increasing number of cycles by probability summation between them. However, the model of probability summation employed in these previous studies was based on High Threshold Theory (HTT), rather than Signal Detection Theory (SDT). We conducted rating scale experiments to investigate the receiver operating characteristics. We find these are of the curved form predicted by SDT, rather than the straight lines predicted by HTT. This means that to test probability summation we must use a model based on SDT. We conducted a set of summation experiments finding that thresholds decrease as the number of modulated cycles increases at approximately the same rate as previously found. As this could be consistent with either additive or probability summation, we performed maximum-likelihood fitting of a set of summation models (Matlab code provided in our Supplementary material) and assessed the fits using cross validation. We find we are not able to distinguish whether the responses to the parts of an RF pattern are combined by additive or probability summation, because the predictions are too similar. We present similar results for summation between separate RF patterns, suggesting that the summation process there may be the same as that within a single RF. Copyright © 2016 Elsevier Ltd. All rights reserved.

Generation of induced pluripotent stem cell line, CSSi004-A (2962, from a patient diagnosed with Huntington's disease at the presymptomatic stage

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Eris Bidollari

2018-04-01

Full Text Available Huntington's disease (HD is an incurable, autosomal dominant, hereditary neurodegenerative disorder that typically manifests itself in midlife. This pathology is linked to the deregulation of multiple, as yet unknown, cellular processes starting before HD onset. A human iPS cell line was generated from skin fibroblasts of a subject at the presymptomatic life stage, carrying a polyglutamine expansion in HTT gene codifying Huntingtin protein. The iPSC line contained the expected CAG expansion, expressed the expected pluripotency markers, displayed in vivo differentiation potential to the three germ layers and had a normal karyotype.

Derivation of Huntington Disease affected Genea046 human embryonic stem cell line

Directory of Open Access Journals (Sweden)

Biljana Dumevska

2016-03-01

Full Text Available The Genea046 human embryonic stem cell line was derived from a donated, fully commercially consented ART blastocyst, carrying HTT gene CAG expansion of 45 repeats, indicative of Huntington Disease. Following ICM outgrowth on inactivated human feeders, karyotype was confirmed as 46, XX by CGH and STR analysis demonstrated a female Allele pattern. The hESC line had pluripotent cell morphology, 85% of cells expressed Nanog, 92% Oct4, 75% Tra1–60 and 99% SSEA4 and demonstrated Alkaline Phosphatase activity. The cell line was negative for Mycoplasma and visible contamination.

Analiza wsparcia oczekiwanego z ustaleniem jego dawców w odniesieniu do osób z wyłonioną stomią jelitową = Expected and received support as well as its providers at patients with emerged intestinal stoma

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Szadowska-Szlachetka, Zdzisława; Janczaruk, Marzena; Kijewska, Jadwiga; Starosławska, Elżbieta; Łuczyk Marta

2015-01-01

Szadowska-Szlachetka Zdzisława, Janczaruk Marzena, Kijewska Jadwiga, Starosławska Elżbieta, Łuczyk Marta. Analiza wsparcia oczekiwanego z ustaleniem jego dawców w odniesieniu do osób z wyłonioną stomią jelitową = Expected and received support as well as its providers at patients with emerged intestinal stoma. Journal of Education, Health and Sport. 2015;5(3):91-102. ISSN 2391-8306. DOI: 10.5281/zenodo.16253 http://ojs.ukw.edu.pl/index.php/johs/article/view/2015%3B5%283%29%3A91-102 htt...

Progress and Challenges of Protecting North American Ash Trees from the Emerald Ash Borer Using Biological Control

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Jian J. Duan

2018-03-01

Full Text Available After emerald ash borer (EAB, Agrilus planipennis Fairmaire, was discovered in the United States, a classical biological control program was initiated against this destructive pest of ash trees (Fraxinus spp.. This biocontrol program began in 2007 after federal regulatory agencies and the state of Michigan approved release of three EAB parasitoid species from China: Tetrastichus planipennisi Yang (Eulophidae, Spathius agrili Yang (Braconidae, and Oobius agrili Zhang and Huang (Encyrtidae. A fourth EAB parasitoid, Spathius galinae Belokobylskij (Braconidae from Russia, was approved for release in 2015. We review the rationale and ecological premises of the EAB biocontrol program, and then report on progress in North American ash recovery in southern Michigan, where the parasitoids were first released. We also identify challenges to conserving native Fraxinus using biocontrol in the aftermath of the EAB invasion, and provide suggestions for program improvements as EAB spreads throughout North America. We conclude that more work is needed to: (1 evaluate the establishment and impact of biocontrol agents in different climate zones; (2 determine the combined effect of EAB biocontrol and host plant resistance or tolerance on the regeneration of North American ash species; and (3 expand foreign exploration for EAB natural enemies throughout Asia.

Brain urea increase is an early Huntington's disease pathogenic event observed in a prodromal transgenic sheep model and HD cases.

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Handley, Renee R; Reid, Suzanne J; Brauning, Rudiger; Maclean, Paul; Mears, Emily R; Fourie, Imche; Patassini, Stefano; Cooper, Garth J S; Rudiger, Skye R; McLaughlan, Clive J; Verma, Paul J; Gusella, James F; MacDonald, Marcy E; Waldvogel, Henry J; Bawden, C Simon; Faull, Richard L M; Snell, Russell G

2017-12-26

The neurodegenerative disorder Huntington's disease (HD) is typically characterized by extensive loss of striatal neurons and the midlife onset of debilitating and progressive chorea, dementia, and psychological disturbance. HD is caused by a CAG repeat expansion in the Huntingtin ( HTT ) gene, translating to an elongated glutamine tract in the huntingtin protein. The pathogenic mechanism resulting in cell dysfunction and death beyond the causative mutation is not well defined. To further delineate the early molecular events in HD, we performed RNA-sequencing (RNA-seq) on striatal tissue from a cohort of 5-y-old OVT73 -line sheep expressing a human CAG-expansion HTT cDNA transgene. Our HD OVT73 sheep are a prodromal model and exhibit minimal pathology and no detectable neuronal loss. We identified significantly increased levels of the urea transporter SLC14A1 in the OVT73 striatum, along with other important osmotic regulators. Further investigation revealed elevated levels of the metabolite urea in the OVT73 striatum and cerebellum, consistent with our recently published observation of increased urea in postmortem human brain from HD cases. Extending that finding, we demonstrate that postmortem human brain urea levels are elevated in a larger cohort of HD cases, including those with low-level neuropathology (Vonsattel grade 0/1). This elevation indicates increased protein catabolism, possibly as an alternate energy source given the generalized metabolic defect in HD. Increased urea and ammonia levels due to dysregulation of the urea cycle are known to cause neurologic impairment. Taken together, our findings indicate that aberrant urea metabolism could be the primary biochemical disruption initiating neuropathogenesis in HD.

Proteotoxic stress induces phosphorylation of p62/SQSTM1 by ULK1 to regulate selective autophagic clearance of protein aggregates.

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Junghyun Lim

Full Text Available Disruption of proteostasis, or protein homeostasis, is often associated with aberrant accumulation of misfolded proteins or protein aggregates. Autophagy offers protection to cells by removing toxic protein aggregates and injured organelles in response to proteotoxic stress. However, the exact mechanism whereby autophagy recognizes and degrades misfolded or aggregated proteins has yet to be elucidated. Mounting evidence demonstrates the selectivity of autophagy, which is mediated through autophagy receptor proteins (e.g. p62/SQSTM1 linking autophagy cargos and autophagosomes. Here we report that proteotoxic stress imposed by the proteasome inhibition or expression of polyglutamine expanded huntingtin (polyQ-Htt induces p62 phosphorylation at its ubiquitin-association (UBA domain that regulates its binding to ubiquitinated proteins. We find that autophagy-related kinase ULK1 phosphorylates p62 at a novel phosphorylation site S409 in UBA domain. Interestingly, phosphorylation of p62 by ULK1 does not occur upon nutrient starvation, in spite of its role in canonical autophagy signaling. ULK1 also phosphorylates S405, while S409 phosphorylation critically regulates S405 phosphorylation. We find that S409 phosphorylation destabilizes the UBA dimer interface, and increases binding affinity of p62 to ubiquitin. Furthermore, lack of S409 phosphorylation causes accumulation of p62, aberrant localization of autophagy proteins and inhibition of the clearance of ubiquitinated proteins or polyQ-Htt. Therefore, our data provide mechanistic insights into the regulation of selective autophagy by ULK1 and p62 upon proteotoxic stress. Our study suggests a potential novel drug target in developing autophagy-based therapeutics for the treatment of proteinopathies including Huntington's disease.

JUNCTOPHILIN 3 (JPH3) EXPANSION MUTATIONS CAUSING HUNTINGTON DISEASE LIKE 2 (HDL2) ARE COMMON IN SOUTH AFRICAN PATIENTS WITH AFRICAN ANCESTRY AND A HUNTINGTON DISEASE PHENOTYPE

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Krause, A; Mitchell, CL; Essop, F; Tager, S; Temlett, J; Stevanin, G; Ross, CA; Rudnicki, DD; Margolis, RL

2015-01-01

Huntington disease (HD) is a progressive autosomal dominant neurodegenerative disorder, characterized by abnormal movements, cognitive decline and psychiatric symptoms, caused by a CAG repeat expansion in the huntingtin (HTT) gene on chromosome 4p. A CAG/CTG repeat expansion in the junctophilin-3 (JPH3) gene on chromosome 16q24.2 causes a Huntington disease-like phenotype (HDL2). All patients to date with HDL2 have some African ancestry. The present study aimed to characterize the genetic basis of the Huntington disease phenotype in South Africans and to investigate the possible origin of the JPH3 mutation. In a sample of unrelated South African individuals referred for diagnostic HD testing, 62% (106/171) of white patients compared to only 36% (47/130) of black patients had an expansion in HTT. However, 15% (20/130) of black South African patients and no white patients (0/171) had an expansion in JPH3, confirming the diagnosis of Huntington disease like 2 (HDL2). Individuals with HDL2 share many clinical features with individuals with HD and are clinically indistinguishable in many cases, although the average age of onset and diagnosis in HDL2 is 5 years later than HD and individual clinical features may be more prominent. HDL2 mutations contribute significantly to the HD phenotype in South Africans with African ancestry. JPH3 haplotype studies in 31 families, mainly from South Africa and North America, provide evidence for a founder mutation and support a common African origin for all HDL2 patients. Molecular testing in individuals with an HD phenotype and African ancestry should include testing routinely for JPH3 mutations. PMID:26079385

Ammonium, Nitrate, and Phosphate Sorption to and Solute Leaching from Biochars Prepared from Corn Stover ( L.) and Oak Wood ( spp.).

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Hollister, C Colin; Bisogni, James J; Lehmann, Johannes

2013-01-01

Biochar (BC) was evaluated for nitrogen (N) and phosphorus (P) removal from aqueous solution to quantify its nutrient pollution mitigation potential in agroecosystems. Sorption isotherms were prepared for solutions of ammonium (NH), nitrate (NO), and phosphate (PO-P) using BC of corn ( L.) and oak ( spp.) feedstock, each pyrolyzed at 350 and 550°C highest treatment temperature (HTT). Sorption experiments were performed on original BC as well as on BC that went through a water extraction pretreatment (denoted WX-BC). Ammonium sorption was observed for WX-Oak-BC and WX-Corn-BC, and Freundlich model linearization showed that a 200°C increase in HTT resulted in a 55% decrease in * values for WX-Oak-BC and a 69% decrease in * for WX-Corn-BC. Nitrate sorption was not observed for any BC. Removing metals by water extraction from WX-Oak-350 and WX-Oak-550 resulted in a 25 to 100% decrease in phosphate removal efficiency relative to original Oak-350 and Oak-550, respectively. No PO-P sorption was observed using any Corn-BC. Calcium (Ca) leached from BC produced at 550°C was 63 and 104% higher than from BC produced at 350°C for corn and oak, respectively. Leaching of P was two orders of magnitude lower in WX-Oak-BC than in WX-Corn-BC, concurrent with similar difference in magnesium (Mg). Nitrate and NH leaching from consecutive water extractions of all tested BCs was mostly below detection limits. Copyright © by the American Society of Agronomy, Crop Science Society of America, and Soil Science Society of America, Inc.

Oxidative metabolism and Ca2+ handling in isolated brain mitochondria and striatal neurons from R6/2 mice, a model of Huntington's disease.

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Hamilton, James; Pellman, Jessica J; Brustovetsky, Tatiana; Harris, Robert A; Brustovetsky, Nickolay

2016-07-01

Alterations in oxidative metabolism and defects in mitochondrial Ca 2+ handling have been implicated in the pathology of Huntington's disease (HD), but existing data are contradictory. We investigated the effect of human mHtt fragments on oxidative metabolism and Ca 2+ handling in isolated brain mitochondria and cultured striatal neurons from the R6/2 mouse model of HD. Non-synaptic and synaptic mitochondria isolated from the brains of R6/2 mice had similar respiratory rates and Ca 2+ uptake capacity compared with mitochondria from wild-type (WT) mice. Respiratory activity of cultured striatal neurons measured with Seahorse XF24 flux analyzer revealed unaltered cellular respiration in neurons derived from R6/2 mice compared with neurons from WT animals. Consistent with the lack of respiratory dysfunction, ATP content of cultured striatal neurons from R6/2 and WT mice was similar. Mitochondrial Ca 2+ accumulation was also evaluated in cultured striatal neurons from R6/2 and WT animals. Our data obtained with striatal neurons derived from R6/2 and WT mice show that both glutamate-induced increases in cytosolic Ca 2+ and subsequent carbonilcyanide p-triflouromethoxyphenylhydrazone-induced increases in cytosolic Ca 2+ were similar between WT and R6/2, suggesting that mitochondria in neurons derived from both types of animals accumulated comparable amounts of Ca 2+ Overall, our data argue against respiratory deficiency and impaired Ca 2+ handling induced by human mHtt fragments in both isolated brain mitochondria and cultured striatal neurons from transgenic R6/2 mice. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Analysis list: E2f4 [Chip-atlas[Archive

Lifescience Database Archive (English)

Full Text Available E2f4 Blood,Embryonic fibroblast,Liver,Muscle,Pluripotent stem cell + mm9 http://dba...rchive.biosciencedbc.jp/kyushu-u/mm9/target/E2f4.1.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/E2f4....5.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/E2f4.10.tsv http://dbarchive.biosciencedbc....jp/kyushu-u/mm9/colo/E2f4.Blood.tsv,http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/colo/E2f4....Embryonic_fibroblast.tsv,http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/colo/E2f4.Liver.tsv,htt

Hacia una terapia neuroprotectora con cannabinoides en la enfermedad de Huntington : estudios preclínicos y clínicos

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Valdeolivas Rojas, Sara

2017-01-01

La enfermedad de Huntington (EH) es una enfermedad con herencia autosómica dominante causada por una mutación en el gen IT15, que codifica la proteína huntingtina (HTT). Esta proteína presenta una amplia expresión células de mamíferos y, aunque su función exacta no es totalmente conocida, se sabe que está relacionada con la modulación de procesos celulares tales como transcripción génica, señalización celular, metabolismo energético y neurogénesis. La mutación consiste en una expansión excesi...

Effect of hydrothermal treatment of coal on the oxidation susceptibility and electrical resistivity of HTT coke

Energy Technology Data Exchange (ETDEWEB)

Sarkar, N.B.; Sarkar, P.; Choudhury, A. [Central Fuel Research Institute, P.O. FRI, Dhanbad-828108, Jharkhand (India)

2005-02-25

The influence of hydrothermal treatment of coal prior to carbonization, on the oxidation susceptibility of resultant coke/char, calcined at 1350, 1800 and 2200 {sup o}C has been investigated. The non-isothermal thermogravimetric analysis technique has been employed, and parameters such as onset, DTG peak temperatures, and cumulative oxidation loss (wt.%) at different temperatures have been utilized to compare proneness to oxidation with respective untreated samples apart from electrical resistivity. Data suggest that all the cokes/chars samples produced from hydrothermally treated coals are less reactive and more electrically conductive (less resistive) than their respective untreated counterparts. But the extent of improvement of oxidation resistance and electrical conductivity appears to be coal-specific. The kinetic parameters obtained by non-linear regression analysis on multi-curve reveal that the n{sup th} order reaction model (where 'n' was found to vary from 0.9 to 1.3) is the best-fitted model. The higher activation energy values observed for hydrothermally treated coke samples are in agreement with the observation of TG analysis data. Overall results indicate the importance of introducing a hydrothermal treatment step for the improvement of oxidation resistance as well as electrical conductivity of the coke samples.

Interaction of child maltreatment and 5-HTT polymorphisms: suicidal ideation among children from low-SES backgrounds.

Science.gov (United States)

Cicchetti, Dante; Rogosch, Fred A; Sturge-Apple, Melissa; Toth, Sheree L

2010-06-01

To investigate whether genotypic variation of the serotonin transporter gene-linked promoter region (5-HTTLPR) moderates the effect of maltreatment on suicidal ideation in school-aged children. Eight hundred and fifty low-income children (478 maltreated; 372 non-maltreated) provided DNA samples and self-reported depressive and suicidal symptoms. Genotypes of 5-HTTLPR (s/s or s/l vs. l/l) were determined by fragment analyses. Higher suicidal ideation was found among maltreated than non-maltreated children; the groups did not differ in 5-HTTLPR genotype frequencies. Children with one to two maltreatment subtypes and s/s or s/l genotypes had higher suicidal ideation than those with the l/l genotype; suicidal ideation did not differ in non-maltreated children or children with three to four maltreatment subtypes based on 5-HTTLPR variation. The results were applicable to emotionally maltreated/neglected and to physically/sexually abused children. Gene-environment interaction was not found for depressive symptoms. The protective effect of the 5-HTTLPR l/l genotype on suicidal ideation was limited to maltreated children experiencing fewer subtypes.

[Hepatic transit times and liver elasticity compared with meld in predicting a 1 year adverse clinical outcome of a clinically diagnosed cirrhosis].

Science.gov (United States)

Koller, Tomáš; Piešťanská, Zuzana; Hlavatý, Tibor; Holomáň, Jozef; Glasa, Jozef; Payer, Juraj

Hepatic transit times measured by the contrast enhanced ultrasonography and liver elasticity were found to predict a clinically significant portal hypertension. However, these modalities we not yet sufficiently evaluated in predicting adverse clinical outcome in patients with clinically diagnosed cirrhosis (D´Amico stages > 1), having a clinically significant portal hypertension. The aim of our study was to assess the predictive power of the liver transit times and the liver elasticity on an adverse clinical outcome of clinically diagnosed cirrhosis compared with the MELD score. The study group included 48 consecutive outpatients with cirrhosis in the 2., 3. and 4. DAmico stages. Patients with stage 4 could have jaundice, patients with other complications of portal hypertension were excluded. Transit times were measured from the time of intravenous administration of contrast agent (Sonovue) to a signal appearance in a hepatic vein (hepatic vein arrival time, HVAT) or time difference between the contrast signal in the hepatic artery and hepatic vein (hepatic transit time, HTT) in seconds. Elasticity was measured using the transient elastography (Fibroscan). The transit times and elasticity were measured at baseline and patients were followed for up for 1 year. Adverse outcome of cirrhosis was defined as the appearance of clinically apparent ascites and/or hospitalization for liver disease and/or death within 1 year. The mean age was 61 years, with female/male ratio 23/25. At baseline, the median Child-Pugh score was 5 (IQR 5.0-6.0), MELD 9.5 (IQR 7.6 to 12.1), median HVAT was 22 s (IQR 19-25) and HTT 6 (IQR 5-9). HTT and HVAT negatively correlated with Child-Pugh (-0.351 and -0.441, p = 0.002) and MELD (-0.479 and -0.388, p = 0.006) scores. The adverse outcome at 1-year was observed in 11 cases (22.9 %), including 6 deaths and 5 hospitalizations. Median HVAT in those with/without the adverse outcome was 20 seconds (IQR 19.3-23.5) compared with 22 s (IQR 19-26, p

Морфогенез кісток скелету щурів на тлі тривалого вживання тартразину та можливості його корекції = Morphogenesis bones rats against long tartrazine use and possibilities of its correction = Морфогенез костей скелета крыс на фоне длительного употребления тартразина и возможность его коррекции

OpenAIRE

Lukjantseva, Galina

2016-01-01

Lukjantseva Galina Морфогенез кісток скелету щурів на тлі тривалого вживання тартразину та можливості його корекції = Morphogenesis bones rats against long tartrazine use and possibilities of its correction = Морфогенез костей скелета крыс на фоне длительного употребления тартразина и возможность его коррекции Journal of Education, Health and Sport. 2016;6(10):520-533. eISSN 2391-8306. DOI http://dx.doi.org/10.5281/zenodo.167128 http://ojs.ukw.edu.pl/index.php/johs/article/view/4002 ...

Auguste Baillayre et ses éleves européens

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Stavilă

2017-10-01

Full Text Available Known in the ambiance of the Romanian art of the interwar period as one of the most talented painters, Auguste Baillayre also asserted himself as an excellent professor. His pedagogical activity has known, from the very start, brilliant achievements. Having received European studies, those over 30 students in his studio, whom Auguste Baillayre remembers in 1961, did not return to Bessarabia. Olesi Hršanovschi-Beassley (Olga Olby, Lydia Luzanovsky, Gregoire Michonze, Antoine Irisse and Joseph Bronstein studied in Paris, Felix Roitman, Helen Barlo and Natalia Bragalia – in Brussels, Elisabeth Ivanovsky, Nina Jascinsky and Nicolae Coleadici in Amsterdam. Theodor Kiriacoff worked in Romania, in Iasi and then in Bucharest, where Helen Barlo and Natalia Bragalia return after studying in France, Gheorghe Ceglocoff comes from Dresden and Galina Ceaşcenco creates her works in Prague. These are all remarkable plastic artists who affirmed themselves outside the Bessarabian borders. Their studies at the art academies „La Grand Chaumière”, „École Nationale Supérieure des Arts Décoratifs”, „Académie Julian”, „Académie Ranson” in Paris, „Académie Royale de Beaux-Arts” in Brussels, and „Académie de Beaux-Arts” in Dresden have demonstrated the professional level of Auguste Baillayre’s disciples.

Hope for the best or prepare for the worst? Towards a spatial cognitive bias test for mice.

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Vanessa Kloke

Full Text Available Cognitive bias, the altered information processing resulting from the background emotional state of an individual, has been suggested as a promising new indicator of animal emotion. Comparable to anxious or depressed humans, animals in a putatively negative emotional state are more likely to judge an ambiguous stimulus as if it predicts a negative event, than those in positive states. The present study aimed to establish a cognitive bias test for mice based on a spatial judgment task and to apply it in a pilot study to serotonin transporter (5-HTT knockout mice, a well-established mouse model for the study of anxiety- and depression-related behavior. In a first step, we validated that our setup can assess different expectations about the outcome of an ambiguous stimulus: mice having learned to expect something positive within a maze differed significantly in their behavior towards an unfamiliar location than animals having learned to expect something negative. In a second step, the use of spatial location as a discriminatory stimulus was confirmed by showing that mice interpret an ambiguous stimulus depending on its spatial location, with a position exactly midway between a positive and a negative reference point provoking the highest level of ambiguity. Finally, the anxiety- and depression-like phenotype of the 5-HTT knockout mouse model manifested--comparable to human conditions--in a trend for a negatively distorted interpretation of ambiguous information, albeit this effect was not statistically significant. The results suggest that the present cognitive bias test provides a useful basis to study the emotional state in mice, which may not only increase the translational value of animal models in the study of human affective disorders, but which is also a central objective of animal welfare research.

Serotonin transporter promoter region (5-HTTLPR) polymorphism is associated with the intravaginal ejaculation latency time in Dutch men with lifelong premature ejaculation.

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Janssen, Paddy K C; Bakker, Steven C; Réthelyi, Janos; Zwinderman, Aeilko H; Touw, Daan J; Olivier, Berend; Waldinger, Marcel D

2009-01-01

Lifelong premature ejaculation (LPE) is characterized by persistent intravaginal ejaculation latency times (IELTs) of less than 1 minute, and has been postulated as a neurobiological dysfunction with genetic vulnerability for the short IELTs, related to disturbances of central serotonin (5-hydroxytryptamine [5-HT]) neurotransmission and 5-HT receptor functioning. To investigate the relationship between 5-HT transporter gene-linked polymorphism (5-HTTLPR) and short IELTs in men with lifelong PE. A prospective study was conducted in 89 Dutch Caucasian men with lifelong PE. IELT during coitus was assessed by stopwatch over a 1-month period. Controls consisted of 92 Dutch Caucasian men. All men with LPE were genotyped for a 5-HTT-promoter polymorphism. Allele frequencies and genotypes of short (S) and long (L) variants of 5-HTTLPR polymorphism were compared between patients and controls. Association between LL, SL, and SS genotypes, and the natural logarithm of the IELT in men with LPE was investigated. IELT measured by stopwatch, 5-HTTLPR polymorphism. In men with lifelong PE, the geometric mean, median, and natural mean IELTs were 21, 26, and 32 seconds, respectively. There were no significant differences in the 5-HTT polymorphism alleles and genotypes between 89 Dutch Caucasian men with LPE (S 47%, L 53%/LL 29%, SL 48%, SS 22%) and 92 Dutch Caucasian controls (S 48%, L 52%/LL 29%, SL 45%, SS 26%). In men with lifelong PE there was a statistically significant difference between LL, SL, and SS genotypes in their geometric mean IELT (P IELTs than the SS and SL genotypes. The 5-HTTLPR polymorphism is associated with significant effects on the latency to ejaculate in men with lifelong PE. Men with SS and SL genotypes have 100% and 90% longer ejaculation time, respectively than men with LL genotypes.

Tetrahydrocannabinolic acid is a potent PPARγ agonist with neuroprotective activity.

Science.gov (United States)

Nadal, Xavier; Del Río, Carmen; Casano, Salvatore; Palomares, Belén; Ferreiro-Vera, Carlos; Navarrete, Carmen; Sánchez-Carnerero, Carolina; Cantarero, Irene; Bellido, Maria Luz; Meyer, Stefan; Morello, Gaetano; Appendino, Giovanni; Muñoz, Eduardo

2017-12-01

Phytocannabinoids are produced in Cannabis sativa L. in acidic form and are decarboxylated upon heating, processing and storage. While the biological effects of decarboxylated cannabinoids such as Δ 9 -tetrahydrocannabinol have been extensively investigated, the bioactivity of Δ 9 -tetahydrocannabinol acid (Δ 9 -THCA) is largely unknown, despite its occurrence in different Cannabis preparations. Here we have assessed possible neuroprotective actions of Δ 9 -THCA through modulation of PPARγ pathways. The effects of six phytocannabinoids on PPARγ binding and transcriptional activity were investigated. The effect of Δ 9 -THCA on mitochondrial biogenesis and PPARγ coactivator 1-α expression was investigated in Neuro-2a (N2a) cells. The neuroprotective effect was analysed in STHdh Q111/Q111 cells expressing a mutated form of the huntingtin protein and in N2a cells infected with an adenovirus carrying human huntingtin containing 94 polyQ repeats (mHtt-q94). The in vivo neuroprotective activity of Δ 9 -THCA was investigated in mice intoxicated with the mitochondrial toxin 3-nitropropionic acid (3-NPA). Cannabinoid acids bind and activate PPARγ with higher potency than their decarboxylated products. Δ 9 -THCA increased mitochondrial mass in neuroblastoma N2a cells and prevented cytotoxicity induced by serum deprivation in STHdh Q111/Q111 cells and by mutHtt-q94 in N2a cells. Δ 9 -THCA, through a PPARγ-dependent pathway, was neuroprotective in mice treated with 3-NPA, improving motor deficits and preventing striatal degeneration. In addition, Δ 9 -THCA attenuated microgliosis, astrogliosis and up-regulation of proinflammatory markers induced by 3-NPA. Δ 9 -THCA shows potent neuroprotective activity, which is worth considering for the treatment of Huntington's disease and possibly other neurodegenerative and neuroinflammatory diseases. © 2017 The British Pharmacological Society.

Genetic Moderators of the Impact of Physical Activity on Depressive Symptoms.

Science.gov (United States)

Dotson, V M; Hsu, F C; Langaee, T Y; McDonough, C W; King, A C; Cohen, R A; Newman, A B; Kritchevsky, S B; Myers, V; Manini, T M; Pahor, M

2016-01-01

Converging evidence suggests that physical activity is an effective intervention for both clinical depression and sub-threshold depressive symptoms; however, findings are not always consistent. These mixed results might reflect heterogeneity in response to physical activity, with some subgroups of individuals responding positively, but not others. 1) To examine the impact of genetic variation and sex on changes in depressive symptoms in older adults after a physical activity (PA) intervention, and 2) to determine if PA differentially improves particular symptom dimensions of depression. Randomized controlled trial. Four field centers (Cooper Institute, Stanford University, University of Pittsburgh, and Wake Forest University). 396 community-dwelling adults aged 70-89 years who participated in the Lifestyle Interventions and Independence for Elders Pilot Study (LIFE-P). 12-month PA intervention compared to an education control. Polymorphisms in the serotonin transporter (5-HTT), brain-derived neurotrophic factor (BDNF), and apolipoprotein E (APOE) genes; 12-month change in the Center for Epidemiologic Studies Depression Scale total score, as well as scores on the depressed affect, somatic symptoms, and lack of positive affect subscales. Men randomized to the PA arm showed the greatest decreases in somatic symptoms, with a preferential benefit in male carriers of the BDNF Met allele. Symptoms of lack of positive affect decreased more in men compared to women, particularly in those possessing the 5-HTT L allele, but the effect did not differ by intervention arm. APOE status did not affect change in depressive symptoms. Results of this study suggest that the impact of PA on depressive symptoms varies by genotype and sex, and that PA may mitigate somatic symptoms of depression more than other symptoms. The results suggest that a targeted approach to recommending PA therapy for treatment of depression is viable.

Stress-induced activation of the brainstem Bcl-xL gene expression in rats treated with fluoxetine: correlations with serotonin metabolism and depressive-like behavior.

Science.gov (United States)

Shishkina, Galina T; Kalinina, Tatyana S; Berezova, Inna V; Dygalo, Nikolay N

2012-01-01

Mechanisms underlying stress-induced depression and antidepressant drug action were shown to involve alterations in serotonergic (5-HT) neurotransmission and expression of genes coding for proteins associated with neurotrophic signaling pathways and cell-survival in the hippocampus and cortex. Expression of these genes in the brainstem containing 5-HT neurons may also be related to vulnerability or resilience to stress-related psychopathology. Here we investigated 5-HT markers and expression of genes for Brain-Derived Neurotrophic Factor (BDNF) and apoptotic proteins in the brainstem in relation to swim stress-induced behavioral despair. We found that anti-apoptotic Bcl-xL gene is sensitive to stress during the course of fluoxetine administration. Responsiveness of this gene to stress appeared concomitantly with an antidepressant-like effect of fluoxetine in the forced swim test. Bcl-xL transcript levels showed negative correlations with duration of immobility in the test and 5-HT turnover in the brainstem. In contrast, BDNF and pro-apoptotic protein Bax mRNA levels were unchanged by either fluoxetine or stress, suggesting specificity of Bcl-xL gene responses to these treatments. We also found that the levels of mRNAs for tryptophan hydroxylase-2 (TPH2) and 5-HT transporter (5-HTT) were significantly down-regulated following prolonged treatment with fluoxetine, but were not affected by stress. Unlike TPH2 and 5-HTT, 5-HT1A receptor mRNA levels were not altered by fluoxetine but significantly increased in response to swim stress. These data show that long-term fluoxetine treatment leads to changes in 5-HT and Bcl-xL responses to stress associated with antidepressant-like effects of the drug. This article is part of a Special Issue entitled 'Anxiety and Depression'. Copyright © 2011 Elsevier Ltd. All rights reserved.

Serotonin transporter bi- and triallelic genotypes and their relationship with anxiety and academic performance: a preliminary study.

Science.gov (United States)

Calapoğlu, Mustafa; Sahin-Calapoğlu, Nilufer; Karaçöp, Ataman; Soyöz, Mustafa; Elyıldırım, Umit Y; Avşaroğlu, Selahattin

2011-01-01

Considerable evidence suggests that variation of the serotonin-transporter-linked promoter region (5- HTTLPR) is associated with anxiety-related traits. Academic outcomes are also more closely related to trait anxiety. This preliminary study aimed to explore the association between academic performance and levels of anxiety with respect to the bi- and triallelic classification of 5-HTTLPR polymorphism of the 5-HTT gene in teacher candidates. In our study, Spielberger's State-Trait Anxiety Inventory, the Selection Examination for Professional Posts in Public Organizations (KPSS) and 5-HTTLPR genotypes were used to investigate a group of 94 healthy teacher candidates. Higher anxiety scores were significantly associated with the S'S' genotype. There was no direct, statistically significant association between academic performance and genotypic groups regarding bi- and triallelic classification. However, the students who have L'L' or LL genotypes had the lowest levels of trait anxiety and the poorest academic performance. Additionally, there was a significant positive correlation between academic performance and anxiety levels. These findings support the idea that S and L(G) alleles are associated with anxiety-related traits, and that the S'S' genotype may be a good indicator for anxiety-related traits in a sample from the Turkish population. A specific degree of anxiety is considered to be a motivation for learning and high academic performance. However, 5-HTTLPR polymorphism of the 5-HTT gene may be one of the genetic factors affecting academic performance in connection with anxiety levels. Implications for incorporating anxiety management training in the educational process in terms of both environmental and individual factors will have a very important role in improving effective strategies for student personality services, as well as for development and planning. © 2010 S. Karger AG, Basel.

Hope for the best or prepare for the worst? Towards a spatial cognitive bias test for mice.

Science.gov (United States)

Kloke, Vanessa; Schreiber, Rebecca S; Bodden, Carina; Möllers, Julian; Ruhmann, Hanna; Kaiser, Sylvia; Lesch, Klaus-Peter; Sachser, Norbert; Lewejohann, Lars

2014-01-01

Cognitive bias, the altered information processing resulting from the background emotional state of an individual, has been suggested as a promising new indicator of animal emotion. Comparable to anxious or depressed humans, animals in a putatively negative emotional state are more likely to judge an ambiguous stimulus as if it predicts a negative event, than those in positive states. The present study aimed to establish a cognitive bias test for mice based on a spatial judgment task and to apply it in a pilot study to serotonin transporter (5-HTT) knockout mice, a well-established mouse model for the study of anxiety- and depression-related behavior. In a first step, we validated that our setup can assess different expectations about the outcome of an ambiguous stimulus: mice having learned to expect something positive within a maze differed significantly in their behavior towards an unfamiliar location than animals having learned to expect something negative. In a second step, the use of spatial location as a discriminatory stimulus was confirmed by showing that mice interpret an ambiguous stimulus depending on its spatial location, with a position exactly midway between a positive and a negative reference point provoking the highest level of ambiguity. Finally, the anxiety- and depression-like phenotype of the 5-HTT knockout mouse model manifested--comparable to human conditions--in a trend for a negatively distorted interpretation of ambiguous information, albeit this effect was not statistically significant. The results suggest that the present cognitive bias test provides a useful basis to study the emotional state in mice, which may not only increase the translational value of animal models in the study of human affective disorders, but which is also a central objective of animal welfare research.

Convergent genetic modulation of the endocrine stress response involves polymorphic variations of 5-HTT, COMT and MAOA

NARCIS (Netherlands)

Jabbi, M.; Korf, J.; Kema, I. P.; Hartman, C.; van der Pompe, G.; Minderaa, R. B.; Ormel, J.; den Boer, J. A.

Highly prevalent stress-related disorders such as major depression ( MD) are characterised by a dysregulation of the neuroendocrine system. Although heritability for these disorders is high, the role of genes in the underlying pathophysiology is poorly understood. Here, we show that polymorphic

Design of the ATLAS Phase-II hardware-based tracking processor

CERN Document Server

Poggi, Riccardo; The ATLAS collaboration

2018-01-01

The expected increase in peak luminosity of the upgraded high-luminosity LHC will force the ATLAS experiment to increase early stage trigger selection power. The agreed strategy is to implement precise hardware track reconstruction, through which sharper trigger turn-on curves can be achieved for primary single-lepton selections, while contributing to b-tagging and tau-tagging techniques as well as multi-jet rejection. The hardware-based tracking for the trigger (HTT) will use a combination of Associative Memory ASICs and FPGAs to provide the software-based trigger system with access to tracking information. In this poster, we present the requirements, architecture and projected performance of the system in terms of tracking capability, and trigger selection, based on detailed simulations.

Henkin and Hybrid Logic

DEFF Research Database (Denmark)

Blackburn, Patrick Rowan; Huertas, Antonia; Manzano, Maria

2014-01-01

Leon Henkin was not a modal logician, but there is a branch of modal logic that has been deeply influenced by his work. That branch is hybrid logic, a family of logics that extend orthodox modal logic with special proposition symbols (called nominals) that name worlds. This paper explains why...... Henkin’s techniques are so important in hybrid logic. We do so by proving a completeness result for a hybrid type theory called HTT, probably the strongest hybrid logic that has yet been explored. Our completeness result builds on earlier work with a system called BHTT, or basic hybrid type theory...... is due to the first-order perspective, which lies at the heart of Henin’s best known work and hybrid logic....

A study of chemical equilibrium of tri-component mixtures of hydrogen isotopes

International Nuclear Information System (INIS)

Cristescu, Ioana; Cristescu, I.; Peculea, M.

1998-01-01

In this paper we present a model for computing the equilibrium constants for chemical reactions between hydrogen's isotopes as function of temperature. The equilibrium constants were expressed with the aid of Gibbs potential and the partition function of the mixture. We assessed the partition function for hydrogen's isotopes having in view that some nuclei are fermions and other bosons. As results we plotted the values of equilibrium constants as function of temperature. Knowing these values we determined the deuterium distribution on species (for mixture H 2 -HD-D 2 ) as function of total deuterium concentration and the tritium distribution on species (for mixtures D 2 -DT-T 2 and H 2 -HT-T 2 ) as function of total tritium concentration. (authors)

A step to diagnosis of sleep apnea with next generation sequencing

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Snigdha Pattanaik

2017-12-01

Aberrant respiratory control mechanisms have been implicated in dentofacial deformities, such as long face syndrome or adenoid facies. Obstructive sleep apnea (OSA is a potentially life-threatening condition in which the patient suffers periodic cessation of breathing during sleep and is the most important etiological factor in the long face syndrome. The symptoms include loud snoring, irregular breathing patterns and restless movements during sleep which impairs the quality of life. The aim of this study is to determine the genetic association of obstructive sleep apnea associated genes (ACE, TNF-α, IL-6, 5-HTR2A, 5-HTR2C, 5-HTT, LEPR, PPAR-γ, ADRB, and APOE with specific primers in polymerized chain reaction through an extensive genome search in Odisha population.

A meta-analysis of the effects of the 5-hydroxytryptamine transporter gene-linked promoter region polymorphism on susceptibility to lifelong premature ejaculation.

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Lijie Zhu

Full Text Available OBJECTIVE: Premature ejaculation (PE has been reported as the most common male sexual dysfunction with global prevalence rates estimated at approximately 30%. The neurobiogenesis of ejaculation is very complex and involves the serotoninergic (5-hydroxytryptamine, 5-HT system. Recently, genetic polymorphisms located on SLC6A4 gene codifying for 5-HT transporter (5-HTT, the major regulator of serotonic neurotransmission, have been linked with the pathogenesis and risk of PE. Apparently studies of this type of polymorphism in PE have show conflicting results. METHODS: A meta-analysis was performed that are available in relation with 5-HTT gene-linked promoter region (5-HTTLPR polymorphism and the risk of lifelong PE (LPE in men to clarify this relationship. We searched Pubmed and Embase (last search updated on Aug 2012 using 'premature ejaculation', 'polymorphism or variant', 'genotype', 'ejaculatory function', and 'rapid ejaculation' as keywords and reference lists of studies corresponded to the inclusion criteria for meta-analysis. These studies involved the total number of 481 LPE men and 466 health control men subjects. Odds ratio (OR and 95% confidence intervals (CIs were used to evaluate this relationship. RESULTS: In the overall analysis, significant associations between LPE risk and 5-HTTLPR polymorphism were found (L-allele vs. S-allele OR = 0.86, 95% CI = 0.79-0.95, P = 0.002; LL vs. SS: OR = 0.80, 95% CI = 0.68-0.95, P = 0.009; LS vs. SS: OR = 0.85, 95% CI = 0.76-0.97, P = 0.012 and LL+LS vs. SS: OR = 0.88, 95% CI = 0.81-0.95, P = 0.002. Moreover, in subgroup analysis based on ethnicity, similar significant associations were detected. The Egger's test did not reveal presence of a publication bias. CONCLUSIONS: Our investigations demonstrate that 5-HTTLPR (L>S polymorphism might protect men against LPE risk. Further studies based on larger sample size and gene-environment interactions should

A representative prescription for emotional disease, Ding-Zhi-Xiao-Wan restores 5-HT system deficit through interfering the synthesis and transshipment in chronic mild stress-induced depressive rats.

Science.gov (United States)

Dong, Xian-Zhe; Li, Zhao-Liang; Zheng, Xiao-Li; Mu, Li-Hua; Zhang, Gang-qiang; Liu, Ping

2013-12-12

Ding-Zhi-Xiao-Wan (DZ, also known as Kai-Xin-San) is a famous traditional Chinese medicine used for the treatment of emotional disease. Previously, we have found that in a variety of animal models of depression (such as tail suspension model, model of chronic fatigue and forced swimming model) DZ demonstrated significant antidepressant behavior and promoted the production of 5-hydroxytryptamine (5-HT). However, the mechanisms of 5-HT regulation are still unclear. Therefore, the current study is designed to further investigate the antidepressant effect of DZ by observing its influence on 5-HT synthesis, metabolism, transport and other key links, so as to clarify the molecular mechanism of its 5-HT regulation. Solitary rising combined with the chronic unpredictable mild stress (CMS) was used to establish the rat model of depression. The rats were given DZ for 3 weeks, the behavior change and the following items in hippocampus and prefrontal cortex were detected simultaneously: 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), tryptophan hydroxylase (TPH), aromatic amino acid decarboxylase (AADC), monoamine oxidase (MAO) and 5-HT transporter (5-HTT) were observed. Our results showed that treatment with the DZ significantly improved the behavior and simultaneously increased the 5-HT level in the hippocampus, prefrontal cortex tissues and hippocampus extracellular of depressive rats. In future studies revealed that DZ could significantly increase the protein and mRNA expression of the key enzymes TPH during the 5-HT synthesis process in the hippocampus and prefrontal cortex of the depressed rats, and suppress the expression of 5-HTT protein and mRNA at the same time. But it had no effects on MAO-A and MAO-B activities. We believe that antidepressant effect of DZ is caused by the increase of 5-HT synthesis and reduction of 5-HT re-uptake, and eventually increase the content of 5-HT in the brain and the synaptic gaps. © 2013 Published by Elsevier Ireland Ltd.

Prenatal serotonin reuptake inhibitor (SRI antidepressant exposure and serotonin transporter promoter genotype (SLC6A4 influence executive functions at 6 years of age

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Whitney eWeikum

2013-10-01

Full Text Available Prenatal exposure to serotonin reuptake inhibitor (SRI antidepressants and maternal depression may affect prefrontal cognitive skills (executive functions; EFs including self-control, working memory and cognitive flexibility. We examined long-term effects of prenatal SRI exposure on EFs to determine whether effects are moderated by maternal mood and/or genetic variations in SLC6A4 (a gene that codes for the serotonin transporter [5-HTT] central to the regulation of synaptic serotonin levels and behavior. Children who were exposed to SRIs prenatally (SRI-exposed N=26 and non-exposed (N=38 were studied at age 6 years (M=6.3 SD=0.5 using the Hearts & Flowers task (H&F to assess EFs. Maternal mood was measured during pregnancy (3rd trimester and when the child was age 6 years (Hamilton Depression Scale. Parent reports of child behavior were also obtained (MacArthur Health & Behavior Questionnaire. Parents of prenatally SRI-exposed children reported fewer child externalizing and inattentive (ADHD behaviors. Generalized estimate equation modeling showed a significant 3-way interaction between prenatal SRI exposure, SLC6A4 variant, and maternal mood at the 6-year time-point on H&F accuracy. For prenatally SRI-exposed children, regardless of maternal mood, the H&F accuracy of children with reduced 5HTT expression (a short [S] allele remained stable. Even with increasing maternal depressive symptoms (though all below clinical threshold, EFs of children with at least one short allele were comparable to children with the same genotype whose mothers reported few if any depressive symptoms – in this sense they showed resilience. Children with two long (L alleles were more sensitive to context. When their mothers had few depressive symptoms, LL children showed extremely good EF performance – better than any other group. When their mothers reported more depressive symptoms, LL children’s EF performance was worse than that of any other group.

Orphan drugs in development for Huntington's disease: challenges and progress

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Burgunder JM

2015-02-01

Full Text Available Jean-Marc Burgunder1–4 1Swiss Huntington’s Disease Centre, Department of Neurology, University of Bern, Bern, Switzerland; 2Department of Neurology, West China Hospital, Sichuan University, Chengdu, 3Department of Neurology, Xiangya Hospital, Central South University, Changsha, 4Department of Neurology, Sun Yat-sen University, Guangzhou, People’s Republic of China Abstract: Huntington’s disease is a monogenic disorder encompassing a variable phenotype with progressive cognitive, psychiatric, and movement disorders. Knowledge of the mechanisms involved in this disorder has made substantial advances since the discovery of the gene mutation. The dynamic mutation is the expansion of a CAG (cytosine-adenine-guanine repeat in the huntingtin (HTT gene, which is transcribed into an abnormal protein with an elongated polyglutamine tract. Polyglutamine HTT accumulates and is changed in its function in multifaceted ways related to the numerous roles of the normal protein. The protein is expressed in numerous areas of the brain and also in other organs. The major brain region involved in the disease process is the striatum, but it is clear that other systems are involved as well. This accumulated knowledge has now led to the development of treatment strategies based on specific molecular pathways for symptomatic and disease course-modifying treatment. The most proximal way to handle the disturbed protein is to hinder the gene transcription, translation, and/or to increase protein clearance. Other mechanisms now being approached include modulation of energy and intracellular signaling, induction of factors potentially leading to neuroprotection, as well as modulation of glial function. Several clinical trials based on these approaches are now under way, and it is becoming clear that a future disease-modifying therapy will be a combination of several approaches harmonized with symptomatic treatments. In this review, some of the most promising and

Disease-toxicant interactions in manganese exposed Huntington disease mice: early changes in striatal neuron morphology and dopamine metabolism.

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Jennifer L Madison

Full Text Available YAC128 Huntington's disease (HD transgenic mice accumulate less manganese (Mn in the striatum relative to wild-type (WT littermates. We hypothesized that Mn and mutant Huntingtin (HTT would exhibit gene-environment interactions at the level of neurochemistry and neuronal morphology. Twelve-week-old WT and YAC128 mice were exposed to MnCl(2-4H(2O (50 mg/kg on days 0, 3 and 6. Striatal medium spiny neuron (MSN morphology, as well as levels of dopamine (DA and its metabolites (which are known to be sensitive to Mn-exposure, were analyzed at 13 weeks (7 days from initial exposure and 16 weeks (28 days from initial exposure. No genotype-dependent differences in MSN morphology were apparent at 13 weeks. But at 16 weeks, a genotype effect was observed in YAC128 mice, manifested by an absence of the wild-type age-dependent increase in dendritic length and branching complexity. In addition, genotype-exposure interaction effects were observed for dendritic complexity measures as a function of distance from the soma, where only YAC128 mice were sensitive to Mn exposure. Furthermore, striatal DA levels were unaltered at 13 weeks by genotype or Mn exposure, but at 16 weeks, both Mn exposure and the HD genotype were associated with quantitatively similar reductions in DA and its metabolites. Interestingly, Mn exposure of YAC128 mice did not further decrease DA or its metabolites versus YAC128 vehicle exposed or Mn exposed WT mice. Taken together, these results demonstrate Mn-HD disease-toxicant interactions at the onset of striatal dendritic neuropathology in YAC128 mice. Our results identify the earliest pathological change in striatum of YAC128 mice as being between 13 to 16 weeks. Finally, we show that mutant HTT suppresses some Mn-dependent changes, such as decreased DA levels, while it exacerbates others, such as dendritic pathology.

Setup Accuracy of the Novalis ExacTrac 6DOF System for Frameless Radiosurgery

International Nuclear Information System (INIS)

Gevaert, Thierry; Verellen, Dirk; Tournel, Koen; Linthout, Nadine; Bral, Samuel; Engels, Benedikt; Collen, Christine; Depuydt, Tom; Duchateau, Michael; Reynders, Truus; Storme, Guy; De Ridder, Mark

2012-01-01

Purpose: Stereotactic radiosurgery using frame-based positioning is a well-established technique for the treatment of benign and malignant lesions. By contrast, a new trend toward frameless systems using image-guided positioning techniques is gaining mainstream acceptance. This study was designed to measure the detection and positioning accuracy of the ExacTrac/Novalis Body (ET/NB) for rotations and to compare the accuracy of the frameless with the frame-based radiosurgery technique. Methods and Materials: A program was developed in house to rotate reference computed tomography images. The angles measured by the system were compared with the known rotations. The accuracy of ET/NB was evaluated with a head phantom with seven lead beads inserted, mounted on a treatment couch equipped with a robotic tilt module, and was measured with a digital water level and portal films. Multiple hidden target tests (HTT) were performed to measure the overall accuracy of the different positioning techniques for radiosurgery (i.e., frameless and frame-based with relocatable mask or invasive ring, respectively). Results: The ET/NB system can detect rotational setup errors with an average accuracy of 0.09° (standard deviation [SD] 0.06°), 0.02° (SD 0.07°), and 0.06° (SD 0.14°) for longitudinal, lateral, and vertical rotations, respectively. The average positioning accuracy was 0.06° (SD 0.04°), 0.08° (SD 0.06°), and 0.08° (SD 0.07°) for longitudinal, lateral and vertical rotations, respectively. The results of the HTT showed an overall three-dimensional accuracy of 0.76 mm (SD 0.46 mm) for the frameless technique, 0.87 mm (SD 0.44 mm) for the relocatable mask, and 1.19 mm (SD 0.45 mm) for the frame-based technique. Conclusions: The study showed high detection accuracy and a subdegree positioning accuracy. On the basis of phantom studies, the frameless technique showed comparable accuracy to the frame-based approach.

Functional connectivity of the dorsal and median raphe nuclei at rest

DEFF Research Database (Denmark)

Beliveau, Vincent; Svarer, Claus; Frokjaer, Vibe G

2015-01-01

Serotonin (5-HT) is a neurotransmitter critically involved in a broad range of brain functions and implicated in the pathophysiology of neuropsychiatric illnesses including major depression, anxiety and sleep disorders. Despite being widely distributed throughout the brain, there is limited...... knowledge on the contribution of 5-HT to intrinsic brain activity. The dorsal raphe (DR) and median raphe (MR) nuclei are the source of most serotonergic neurons projecting throughout the brain and thus provide a compelling target for a seed-based probe of resting-state activity related to 5-HT. Here we...... implemented a novel multimodal neuroimaging approach for investigating resting-state functional connectivity (FC) between DR and MR and cortical, subcortical and cerebellar target areas. Using [(11)C]DASB positron emission tomography (PET) images of the brain serotonin transporter (5-HTT) combined...

Comparison of Different Pretreatment Strategies for Ethanol Production of West African Biomass

DEFF Research Database (Denmark)

Thomsen, Sune Tjalfe; Gonzalez Londono, Jorge Enrique; Schmidt, Jens Ejbye

2015-01-01

husks, cocoa pods, maize cobs, maize stalks, rice straw, groundnut straw and oil palm empty fruit bunches. It was found that four biomass’ (plantain peelings, plantain trunks, maize cobs and maize stalks) were most promising for production of cellulosic ethanol with profitable enzymatic conversion......Pretreating lignocellulosic biomass for cellulosic ethanol production in a West African setting requires smaller scale and less capital expenditure compared to current state of the art. In the present study, three low-tech methods applicable for West African conditions, namely Boiling Pretreatment...... (BP), Soaking in Aqueous Ammonia (SAA) and White Rot Fungi pretreatment (WRF), were compared to the high-tech solution of hydrothermal pretreatment (HTT). The pretreatment methods were tested on 11 West African biomasses, i.e. cassava stalks, plantain peelings, plantain trunks, plantain leaves, cocoa...

Magistritöö kaitsmine

Index Scriptorium Estoniae

2001-01-01

18.06.2001 kaitsevad TPÜ kultuuriajaloo magistritööde kaitsmise nõukogus magistritöid Igor Tõnurist "Pillid ja pillimäng eesti külaelus", Tatjana Tšervova "Vene kogukonna ühiskondlikust ja kultuurielust Tallinnas aastatel 1880-1905".19.06. TPÜ sotsiaaltöö magistritööde kaitsmise nõukogus Katrin Raamat "Keskealiste meeste stress tänases Eestis"; Andres Siplane "Bioloogiliste sidemete katkemise seostest hälbiva käitumisega"; Astrid Ojasoon "Kriminaalhooldusaluste sotsiaalteenuste vajadused ja nende rahuldamise võimalused"; Anneli Niinemets "Sotsiaaltöö eriala TPÜs : õppetöö kvaliteet ja lõpetanute kutsekindlus"; Galina Kilk "Kriminaalhooldus ja sotsiaaltöö : alaealiste sotsiaalse rehabilitatsiooni võimalusi"; Orest Kormašov TPÜ kunstiteaduste magistritööde kaitsmise nõukogus "17. saj. ikonostaasid Püha Nikolai kirikus Tallinnas". 20.06. TPÜ organisatsioonikäitumise magistritööde kaitsmise nõukogus Reet Runge "Organisatsiooni radikaalne ümberkorraldamine - protsessid, struktuur, inimesed (AS Eesti Telefon allüksuse televõrgud täiustustegevuse põhjal)"; Tarmo Toiger "Managing knowledge in organizations : creating, gathering and mobilizing knowledge in Estonian Company" (Teadmiste juhtimine organisatsioonis : teadmiste loomine, kogumine ning edastamine Eesti ettevõtetes); Janika Kuusk "Inimressursi juhtimise tulemuslikkuse hindamise meetodid". 20.06. Jaanika Vassiljeva TPÜ kasvatusteaduste (kutseõpetuse ja reaalainete didaktika) magistritööde kaitsmise nõukogus "Eesti keskkooliõpilaste ja üliõpilaste keskkonnateadvus (1989 ja 1999 a. võrdlus). 21.06. Maile Meius TPÜ bioloogia magistritööde kaitsmise nõukogus "Trajektoormeetodi kasutamise võimalused meteoroloogias ja aerobioloogias"

Optimal Time Allocation in Backscatter Assisted Wireless Powered Communication Networks

Science.gov (United States)

Lyu, Bin; Yang, Zhen; Gui, Guan; Sari, Hikmet

2017-01-01

This paper proposes a wireless powered communication network (WPCN) assisted by backscatter communication (BackCom). This model consists of a power station, an information receiver and multiple users that can work in either BackCom mode or harvest-then-transmit (HTT) mode. The time block is mainly divided into two parts corresponding to the data backscattering and transmission periods, respectively. The users first backscatter data to the information receiver in time division multiple access (TDMA) during the data backscattering period. When one user works in the BackCom mode, the other users harvest energy from the power station. During the data transmission period, two schemes, i.e., non-orthogonal multiple access (NOMA) and TDMA, are considered. To maximize the system throughput, the optimal time allocation policies are obtained. Simulation results demonstrate the superiority of the proposed model. PMID:28587171

Changes in 5-HT4 receptor and 5-HT transporter binding in olfactory bulbectomized and glucocorticoid receptor heterozygous mice

DEFF Research Database (Denmark)

Licht, Cecilie L; Kirkegaard, Lisbeth; Zueger, Maha

2010-01-01

. The olfactory bulbectomized mice displayed increased activity in the open field test, a characteristic depression-like feature of this model. After bulbectomy, 5-HT(4) receptor binding was increased in the ventral hippocampus (12%) but unchanged in the dorsal hippocampus, frontal and caudal caudate putamen......]citalopram in two murine models of depression-related states, olfactory bulbectomy and glucocorticoid receptor heterozygous (GR(+/-)) mice. The olfactory bulbectomy model is characterized by 5-HT system changes, while the GR(+/-) mice have a deficit in hypothalamic-pituitary-adrenal (HPA) system control....... Among post hoc analyzed regions, there was a 14% decrease in 5-HT(4) receptor binding in the olfactory tubercles. The 5-HTT binding was unchanged in the hippocampus and caudate putamen of bulbectomized mice but post hoc analysis showed small decreases in lateral septum and lateral globus pallidus...

Pretreatment of the macroalgae Chaetomorpha linum for the production of bioethanol - Comparison of five pretreatment technologies

DEFF Research Database (Denmark)

Schultz-Jensen, Nadja; Thygesen, Anders; Thomsen, Sune Tjalfe

2013-01-01

-assisted pretreatment (PAP) and ball milling (BM), to determine effects of the pretreatment methods on the conversion of C. linum into ethanol by simultaneous saccharification and fermentation (SSF). WO and BM showed the highest ethanol yield of 44. g ethanol/100. g glucan, which was close to the theoretical ethanol......A qualified estimate for pretreatment of the macroalgae Chaetomorpha linum for ethanol production was given, based on the experience of pretreatment of land-based biomass. C. linum was subjected to hydrothermal pretreatment (HTT), wet oxidation (WO), steam explosion (STEX), plasma...... yield of 57. g ethanol/100. g glucan. A 64% higher ethanol yield, based on raw material, was reached after pretreatment with WO and BM compared with unpretreated C. linum, however 50% of the biomass was lost during WO. Results indicated that the right combination of pretreatment and marine macroalgae...

Hydrophobically Modified siRNAs Silence Huntingtin mRNA in Primary Neurons and Mouse Brain

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Julia F Alterman

2015-01-01

Full Text Available Applications of RNA interference for neuroscience research have been limited by a lack of simple and efficient methods to deliver oligonucleotides to primary neurons in culture and to the brain. Here, we show that primary neurons rapidly internalize hydrophobically modified siRNAs (hsiRNAs added directly to the culture medium without lipid formulation. We identify functional hsiRNAs targeting the mRNA of huntingtin, the mutation of which is responsible for Huntington's disease, and show that direct uptake in neurons induces potent and specific silencing in vitro. Moreover, a single injection of unformulated hsiRNA into mouse brain silences Htt mRNA with minimal neuronal toxicity. Thus, hsiRNAs embody a class of therapeutic oligonucleotides that enable simple and straightforward functional studies of genes involved in neuronal biology and neurodegenerative disorders in a native biological context.

The role of the serotonergic system in suicidal behavior

Science.gov (United States)

Sadkowski, Marta; Dennis, Brittany; Clayden, Robert C; ElSheikh, Wala; Rangarajan, Sumathy; DeJesus, Jane; Samaan, Zainab

2013-01-01

Serotonin is a widely investigated neurotransmitter in several psychopathologies, including suicidal behavior (SB); however, its role extends to several physiological functions involving the nervous system, as well as the gastrointestinal and cardiovascular systems. This review summarizes recent research into ten serotonergic genes related to SB. These genes – TPH1, TPH2, SLC6A4, SLC18A2, HTR1A, HTR1B, HTR2A, DDC, MAOA, and MAOB – encode proteins that are vital to serotonergic function: tryptophan hydroxylase; the serotonin transporter 5-HTT; the vesicular transporter VMAT2; the HTR1A, HTR1B, and HTR2A receptors; the L-amino acid decarboxylase; and the monoamine oxidases. This review employed a systematic search strategy and a narrative research methodology to disseminate the current literature investigating the link between SB and serotonin. PMID:24235834

SUMO-1 is associated with a subset of lysosomes in glial protein aggregate diseases.

Science.gov (United States)

Wong, Mathew B; Goodwin, Jacob; Norazit, Anwar; Meedeniya, Adrian C B; Richter-Landsberg, Christiane; Gai, Wei Ping; Pountney, Dean L

2013-01-01

Oligodendroglial inclusion bodies characterize a subset of neurodegenerative diseases. Multiple system atrophy (MSA) is characterized by α-synuclein glial cytoplasmic inclusions and progressive supranuclear palsy (PSP) is associated with glial tau inclusions. The ubiquitin homologue, SUMO-1, has been identified in inclusion bodies in MSA, located in discrete sub-domains in α-synuclein-positive inclusions. We investigated SUMO-1 associated with oligodendroglial inclusion bodies in brain tissue from MSA and PSP and in glial cell models. We examined MSA and PSP cases and compared to age-matched normal controls. Fluorescence immunohistochemistry revealed frequent SUMO-1 sub-domains within and surrounding inclusions bodies in both diseases and showed punctate co-localization of SUMO-1 and the lysosomal marker, cathepsin D, in affected brain regions. Cell counting data revealed that 70-75 % of lysosomes in inclusion body-positive oligodendrocytes were SUMO-1-positive consistently across MSA and PSP cases, compared to 20 % in neighbouring inclusion body negative oligodendrocytes and 10 % in normal brain tissue. Hsp90 co-localized with some SUMO-1 puncta. We examined the SUMO-1 status of lysosomes in 1321N1 human glioma cells over-expressing α-synuclein and in immortalized rat oligodendrocyte cells over-expressing the four repeat form of tau following treatment with the proteasome inhibitor, MG132. We also transfected 1321N1 cells with the inherently aggregation-prone huntingtin exon 1 mutant, HttQ74-GFP. Each cell model showed the association of SUMO-1-positive lysosomes around focal cytoplasmic accumulations of α-synuclein, tau or HttQ74-GFP, respectively. Association of SUMO-1 with lysosomes was also detected in glial cells bearing α-synuclein aggregates in a rotenone-lesioned rat model. SUMO-1 labelling of lysosomes showed a major increase between 24 and 48 h post-incubation of 1321N1 cells with MG132 resulting in an increase in a 90 kDa SUMO-1-positive band

Association of the 5-HTT gene-linked promoter region (5-HTTLPR polymorphism with psychiatric disorders: review of psychopathology and pharmacotherapy

Directory of Open Access Journals (Sweden)

Kenna GA

2012-01-01

Full Text Available George A Kenna1, Nick Roder-Hanna2, Lorenzo Leggio3, William H Zywiak4, James Clifford5, Steven Edwards3, John A Kenna6, Jessica Shoaff1, Robert M Swift11Center for Alcohol and Addiction Studies, Department of Psychiatry and Human Behavior, Brown University, Providence; 2College of Pharmacy, University of Rhode Island, Kingston; 3Center for Alcohol and Addiction Studies, Department of Community Health, Brown University, Providence; 4Butler Hospital, Providence, RI; 5Virginia Institute for Psychiatric and Behavior Genetics, Virginia Commonwealth University, Richmond, VA; 6College of Nursing, University of Rhode Island, Kingston, RI, USAAbstract: Serotonin (5-HT regulates important biological and psychological processes including mood, and may be associated with the development of several psychiatric disorders. An association between psychopathology and genes that regulate 5-HT neurotransmission is a robust area of research. Identification of the genes responsible for the predisposition, development, and pharmacological response of various psychiatric disorders is crucial to the advancement of our understanding of their underlying neurobiology. This review highlights research investigating 5-HT transporter (5-HTTLPR polymorphism, because studies investigating the impact of the 5-HTTLPR polymorphism have demonstrated significant associations with many psychiatric disorders. Decreased transcriptional activity of the S allele (“risk allele” may be associated with a heightened amygdala response leading to anxiety-related personality traits, major depressive disorder, suicide attempts, and bipolar disorder. By contrast, increased transcriptional activity of the L allele is considered protective for depression but is also associated with completed suicide, nicotine dependence, and attention deficit hyperactivity disorder. For some disorders, such as post-traumatic stress disorder and major depressive disorder, the research suggests that treatment response may vary by allele (such as an enhanced response to serotonin specific reuptake inhibitors in patients with major depressive disorder and post-traumatic stress disorder with L alleles, and for alcohol dependence, the association and treatment for S or L alleles may vary with alcoholic subtype. While some studies suggest that 5-HTTLPR polymorphism can moderate the response to pharmacotherapy, the association between 5-HTTLPR alleles and therapeutic outcomes is inconsistent. The discovery of triallelic 5-HTTLPR alleles (LA/LG/S may help to explain some of the conflicting results of many past association studies, while concurrently providing more meaningful data in the future. Studies assessing 5-HTTLPR as the solitary genetic factor contributing to the etiology of psychiatric disorders continue to face the challenges of statistically small effect sizes and limited replication.Keywords: 5-HTTLPR, SCC6A4, 5-HT, serotonin, genetics, alleles, triallele, psychiatric, polymorphisms, pharmacotherapy, psychopathology

Identification of genetic variants associated with Huntington's disease progression

DEFF Research Database (Denmark)

Hensman Moss, Davina J; Pardiñas, Antonio F; Langbehn, Douglas

2017-01-01

indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008-11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers...... in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression......BACKGROUND: Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate...

A Home Away from Home

DEFF Research Database (Denmark)

McIlvenny, Paul

2008-01-01

The House of Tiny Tearaways (HTT) first appeared on British television in May 2005. Over a six-day period, three families are invited to reside in a specially designed house together with a resident clinical psychologist. The house is to be “a home away from home” for the resident families...... in order to analyze excerpts from the program and to explore how the affordances and constraints of the specially designed house—its architecture and spatial configuration, as well as the surveillance technology embedded within its walls—are assembled within particular familial activities, and how...... the relationships between family members are reshaped as a result. The analysis focuses on several key phenomena: 1) practices of video observation in relation to the domestic sphere; 2) use of inscription devices, such as video displays, to capture and visualize behavior and action in the “home;” 3) practicing...

FUNCTIONAL SPECIALIZATION OF DUPLICATED FLAVONOID BIOSYNTHESIS GENES IN WHEAT

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Khlestkina E.

2012-08-01

Full Text Available Gene duplication followed by subfunctionalization and neofunctionalization is of a great evolutionary importance. In plant genomes, duplicated genes may result from either polyploidization (homoeologous genes or segmental chromosome duplications (paralogous genes. In allohexaploid wheat Triticum aestivum L. (2n=6x=42, genome BBAADD, both homoeologous and paralogous copies were found for the regulatory gene Myc encoding MYC-like transcriptional factor in the biosynthesis of flavonoid pigments, anthocyanins, and for the structural gene F3h encoding one of the key enzymes of flavonoid biosynthesis, flavanone 3-hydroxylase. From the 5 copies (3 homoeologous and 2 paralogous of the Myc gene found in T. aestivum, only one plays a regulatory role in anthocyanin biosynthesis, interacting complementary with another transcriptional factor (MYB-like to confer purple pigmentation of grain pericarp in wheat. The role and functionality of the other 4 copies of the Myc gene remain unknown. From the 4 functional copies of the F3h gene in T. aestivum, three homoeologues have similar function. They are expressed in wheat organs colored with anthocyanins or in the endosperm, participating there in biosynthesis of uncolored flavonoid substances. The fourth copy (the B-genomic paralogue is transcribed neither in wheat organs colored with anthocyanins nor in seeds, however, it’s expression has been noticed in roots of aluminium-stressed plants, where the three homoeologous copies are not active. Functional diversification of the duplicated flavonoid biosynthesis genes in wheat may be a reason for maintenance of the duplicated copies and preventing them from pseudogenization.The study was supported by RFBR (11-04-92707. We also thank Ms. Galina Generalova for technical assistance.

The Danish HD Registrya nationwide family registry of HD families in Denmark

DEFF Research Database (Denmark)

Gilling, M.; Budtz-Jorgensen, E.; Boonen, S. E.

2017-01-01

-8:100 000. 1451 individuals in the DHR had the size of the HTT CAG repeat determined of which 975 had 36 CAG repeats or more (mean ± SD: 43,5 ± 4,8). Two unrelated individuals were compound heterozygous for alleles ≥36 CAGs, and 60 individuals from 34 independent families carried an intermediate allele.......The Danish Huntington's Disease Registry (DHR) is a nationwide family registry comprising 14 245 individuals from 445 Huntington's disease (HD) families of which the largest family includes 845 individuals in 8 generations. 1136 DNA and/or blood samples and 18 fibroblast cultures are stored...... in a local biobank. The birthplace of the oldest HD carrier in each of the 261 families of Danish origin was unevenly distributed across Denmark with a high number of families in the middle part of the peninsula Jutland and in Copenhagen, the capital. The prevalence of HD in Denmark was calculated to be 5...

Inspired by CERN

CERN Multimedia

2004-01-01

Art students inspired by CERN will be returning to show their work 9 to 16 October in Building 500, outside the Auditorium. Seventeen art students from around Europe visited CERN last January for a week of introductions to particle physics and astrophysics, and discussions with CERN scientists about their projects. A CERN scientist "adopted"each artist so they could ask questions during and after the visit. Now the seeds planted during their visit have come to fruition in a show using many media and exploring varied concepts, such as how people experience the online world, the sheer scale of CERN's equipment, and the abstractness of the entities scientists are looking for. "The work is so varied, people are going to love some pieces and detest others," says Andrew Charalambous, the project coordinator from University College London who is also curating the exhibition. "It's contemporary modern art, and that's sometimes difficult to take in." For more information on this thought-provoking show, see: htt...

Nonlinear Aeroelastic Analysis of the HIAD TPS Coupon in the NASA 8' High Temperature Tunnel: Theory and Experiment

Science.gov (United States)

Goldman, Benjamin D.; Scott, Robert C,; Dowell, Earl H.

2014-01-01

The purpose of this work is to develop a set of theoretical and experimental techniques to characterize the aeroelasticity of the thermal protection system (TPS) on the NASA Hypersonic Inflatable Aerodynamic Decelerator (HIAD). A square TPS coupon experiences trailing edge oscillatory behavior during experimental testing in the 8' High Temperature Tunnel (HTT), which may indicate the presence of aeroelastic flutter. Several theoretical aeroelastic models have been developed, each corresponding to a different experimental test configuration. Von Karman large deflection theory is used for the plate-like components of the TPS, along with piston theory for the aerodynamics. The constraints between the individual TPS layers and the presence of a unidirectional foundation at the back of the coupon are included by developing the necessary energy expressions and using the Rayleigh Ritz method to derive the nonlinear equations of motion. Free vibrations and limit cycle oscillations are computed and the frequencies and amplitudes are compared with accelerometer and photogrammetry data from the experiments.

Reversal of Phenotypic Abnormalities by CRISPR/Cas9-Mediated Gene Correction in Huntington Disease Patient-Derived Induced Pluripotent Stem Cells

Directory of Open Access Journals (Sweden)

Xiaohong Xu

2017-03-01

Full Text Available Huntington disease (HD is a dominant neurodegenerative disorder caused by a CAG repeat expansion in HTT. Here we report correction of HD human induced pluripotent stem cells (hiPSCs using a CRISPR-Cas9 and piggyBac transposon-based approach. We show that both HD and corrected isogenic hiPSCs can be differentiated into excitable, synaptically active forebrain neurons. We further demonstrate that phenotypic abnormalities in HD hiPSC-derived neural cells, including impaired neural rosette formation, increased susceptibility to growth factor withdrawal, and deficits in mitochondrial respiration, are rescued in isogenic controls. Importantly, using genome-wide expression analysis, we show that a number of apparent gene expression differences detected between HD and non-related healthy control lines are absent between HD and corrected lines, suggesting that these differences are likely related to genetic background rather than HD-specific effects. Our study demonstrates correction of HD hiPSCs and associated phenotypic abnormalities, and the importance of isogenic controls for disease modeling using hiPSCs.

Comparison between subjects with long- and short-allele carriers in the BOLD signal within amygdala during emotional tasks

Science.gov (United States)

Hadi, Shamil; Siadat, Mohamad R.; Babajani-Feremi, Abbas

2012-03-01

Emotional tasks may result in a strong blood oxygen level-dependent (BOLD) signal in the amygdala in 5- HTTLRP short-allele. Reduced anterior cingulate cortex (ACC)-amygdala connectivity in short-allele provides a potential mechanistic account for the observed increase in amygdala activity. In our study, fearful and threatening facial expressions were presented to two groups of 12 subjects with long- and short-allele carriers. The BOLD signals of the left amygdala of each group were averaged to increase the signal-to-noise ratio. A Bayesian approach was used to estimate the model parameters to elucidate the underlying hemodynamic mechanism. Our results showed a positive BOLD signal in the left amygdala for short-allele individuals, and a negative BOLD signal in the same region for long-allele individuals. This is due to the fact that short-allele is associated with lower availability of serotonin transporter (5-HTT) and this leads to an increase of serotonin (5-HT) concentration in the cACC-amygdala synapse.

The Wilson films--Huntington's chorea.

Science.gov (United States)

Klein, Christine

2011-12-01

Wilson's Queen Square Case 9 with Huntington's chorea shows a 68-year-old man with mild to moderate generalized chorea, impaired fixation, and probable cognitive decline in keeping with a diagnosis of Huntington's disease (HD). An age of onset in the late sixties and a negative family history suggest a relatively small expanded trinucleotide repeat in the HTT gene in the patient and reduced penetrance of an even shorter repeat allele in one of his parents. A highly sensitive and specific gene test has been offered worldwide for diagnostic testing of HD for almost two decades. This test, obviously unavailable at Wilson's times, became the historic frontrunner for guidelines of symptomatic, presymptomatic, and prenatal testing for an adult-onset neurodegenerative disorder. Regarding treatment of HD, however, we are still awaiting the successful translation of research results into the development of effective cause-directed, neuropreventive and neurorestaurative therapies. Copyright © 2011 Movement Disorder Society.

NEIGHBORHOOD CRIME AND DEPRESSIVE SYMPTOMS AMONG AFRICAN AMERICAN WOMEN: GENETIC MODERATION AND EPIGENETIC MEDIATOIN OF EFFECTS

Science.gov (United States)

Lei, Man-Kit; Beach, Steven R. H.; Simons, Ronald L.; Philibert, Robert A.

2015-01-01

Introduction Social scientists have long recognized the important role that neighborhood crime can play in stress-related disease, but very little is known about potential biosocial mechanisms that may link the experience of living in high-crime neighborhoods with depression. Objective The current study introduces an integrated model that combines neighborhood, genetic, and epigenetic factors. Methods Hypotheses were tested with a sample of 99 African American women from the Family and Community Health Study (FACHS). Results Allele variants of the serotonin transporter gene (5-HTT) interact with neighborhood crime to predict depressive symptoms in a manner consonant with the differential susceptibility perspective. Furthermore, this association is mediated by DNA methylation of the promoter region of the serotonin transporter gene. Conclusion The findings provide support for an integrated model in which changes in DNA methylation, resulting from neighborhood crime, can result in an increase or decrease in gene activity which, in turn, influences depressive symptoms. PMID:26513121

Neighborhood crime and depressive symptoms among African American women: Genetic moderation and epigenetic mediation of effects.

Science.gov (United States)

Lei, Man-Kit; Beach, Steven R H; Simons, Ronald L; Philibert, Robert A

2015-12-01

Social scientists have long recognized the important role that neighborhood crime can play in stress-related disease, but very little is known about potential biosocial mechanisms that may link the experience of living in high-crime neighborhoods with depression. The current study introduces an integrated model that combines neighborhood, genetic, and epigenetic factors. Hypotheses were tested with a sample of 99 African American women from the Family and Community Health Study (FACHS). Allele variants of the serotonin transporter gene (5-HTT) interact with neighborhood crime to predict depressive symptoms in a manner consonant with the differential susceptibility perspective. Furthermore, this association is mediated by DNA methylation of the promoter region of the serotonin transporter gene. The findings provide support for an integrated model in which changes in DNA methylation, resulting from neighborhood crime, can result in an increase or decrease in gene activity which, in turn, influences depressive symptoms. Copyright © 2015 Elsevier Ltd. All rights reserved.

Exploring Genetic Factors Involved in Huntington Disease Age of Onset

DEFF Research Database (Denmark)

Valcárcel-Ocete, Leire; Alkorta-Aranburu, Gorka; Iriondo, Mikel

2015-01-01

age (motor AO or mAO). Multiple linear regression analyses were performed between genetic variation within 20 candidate genes and eAO or mAO, using DNA and clinical information of 253 HD patients from REGISTRY project. Gene expression analyses were carried out by RT-qPCR with an independent sample......Age of onset (AO) of Huntington disease (HD) is mainly determined by the length of the CAG repeat expansion (CAGexp) in exon 1 of the HTT gene. Additional genetic variation has been suggested to contribute to AO, although the mechanism by which it could affect AO is presently unknown. The aim...... of this study is to explore the contribution of candidate genetic factors to HD AO in order to gain insight into the pathogenic mechanisms underlying this disorder. For that purpose, two AO definitions were used: the earliest age with unequivocal signs of HD (earliest AO or eAO), and the first motor symptoms...

Evaluation of the host specificity of Spathius galinae (Hymenoptera: Braconidae), a larval parasitoid of the emerald ash borer (Coleoptera: Buprestidae) in Northeast Asia

Science.gov (United States)

Host-specificity determination prior to the introduction of non-native natural enemies (predators and parasitoids) is a critical component of the risk assessment for modern classical biological control programs. In the present study, we assessed the host specificity of a newly described parasitoid,...

Serotonin receptor 3A polymorphism c.-42C > T is associated with severe dyspepsia

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Grobbee Diederick E

2011-10-01

Full Text Available Abstract Background The association between anxiety and depression related traits and dyspepsia may reflect a common genetic predisposition. Furthermore, genetic factors may contribute to the risk of having increased visceral sensitivity, which has been implicated in dyspeptic symptom generation. Serotonin (5-HT modulates visceral sensitivity by its action on 5-HT3 receptors. Interestingly, a functional polymorphism in HTR3A, encoding the 5-HT3 receptor A subunit, has been reported to be associated with depression and anxiety related traits. A functional polymorphism in the serotonin transporter (5-HTT, which terminates serotonergic signalling, was also found associated with these psychiatric comorbidities and increased visceral sensitivity in irritable bowel syndrome, which coexistence is associated with higher dyspeptic symptom severity. We investigated the association between these functional polymorphisms and dyspeptic symptom severity. Methods Data from 592 unrelated, Caucasian, primary care patients with dyspepsia participating in a randomised clinical trial comparing step-up and step-down antacid drug treatment (The DIAMOND trial were analysed. Patients were genotyped for HTR3A c.-42C > T SNP and the 44 bp insertion/deletion polymorphism in the 5-HTT promoter (5-HTTLPR. Intensity of 8 dyspeptic symptoms at baseline was assessed using a validated questionnaire (0 = none; 6 = very severe. Sum score ≥20 was defined severe dyspepsia. Results HTR3A c.-42T allele carriers were more prevalent in patients with severe dyspepsia (OR 1.50, 95% CI 1.06-2.20. This association appeared to be stronger in females (OR 2.05, 95% CI 1.25-3.39 and patients homozygous for the long (L variant of the 5-HTTLPR genotype (OR 2.00, 95% CI 1.01-3.94. Females with 5-HTTLPR LL genotype showed the strongest association (OR = 3.50, 95% CI = 1.37-8.90. Conclusions The HTR3A c.-42T allele is associated with severe dyspeptic symptoms. The stronger association among

Efeito da suplementação com L-alanil-L-glutamina sobre a resposta de hipersensibilidade do tipo tardio em ratos submetidos ao treinamento intenso Effect of L-glutamine and L-alanyl-L-glutamine supplementation on the response to delayed-type hypersensitivity test (DTH in rats submitted to intense training

Directory of Open Access Journals (Sweden)

Marcelo Macedo Rogero

2002-12-01

Full Text Available O treinamento intenso e o exercício exaustivo podem ocasionar imunossupressão em atletas por meio da diminuição da concentração plasmática de glutamina. O presente estudo verificou inicialmente o efeito da suplementação com L-glutamina e L-alanilL-glutamina sobre a resposta ao teste de hipersensibilidade do tipo tardio (HTT em ratos submetidos ao treinamento intenso em natação durante seis semanas. Posteriormente, foi avaliado o efeito dessas intervenções nutricionais sobre a contagem total e porcentual de leucócitos e concentração sérica de anticorpos IgG anti-albumina de soro bovino, em animais submetidos ao teste de exaustão e recuperados durante o período de 3 horas. Não houve efeito do treinamento e da suplementação sobre a resposta ao teste de HTT. Animais suplementados apresentaram maior concentração de glutamina no plasma (PIntense training and exhaustive exercise may cause immunesupression in athletes by reducing plasma glutamine concentration. Initially, this study verified the effect of L-glutamine and L-alanyl-L-glutamine supplementation on the response to delayed-type hypersensitivity test (DTH in rats submitted to intense swimming training for six weeks. Later on, we assessed the effect of these nutritional interventions on total and differential white blood cell counts and on concentration of anti-bovine serum albumin IgG antibodies, in animals submitted to exhaustion test and a three-hour recovery period. There was no effect of training and supplementation on the response to DTH. Supplemented animals presented greatest plasma glutamine concentration (p<0.05, though this increase in glutaminemia did not interfere on the serum IgG antibody concentration. The recovery period after intense exercise resulted in decreased glutaminemia as compared with the values obtained immediately after exhaustion test (p<0.05. Increase in corticosterone levels induced by strenuous exercises led to leukocytosis, neutrophilia

GOLIMUMAB SAFETY ACCORDING TO CLINICAL FINDINGS

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G. V. Lukina

2015-01-01

Full Text Available                                                      The review analyzes trials dealing with the safety of golimumab (GLM  used in rheumatology.  This drug was the latest Contact: Galina Lukina;gvl3@yandex.ru Поступила 12.05.14tumor necrosis factor α (TNF-α inhibitor introduced  into clinical practice and therefore the estimation of its tolerability is particularly relevant. The data obtained in large-scale clinical trials suggest that GLM has a good safety profile. The most common  adverse events (AE were infections, more often mild. The rate of infections was higher with the use of GLM 100 mg than with that of 50 mg. The overall cancer rate did not increase during a follow-up of less than 160 weeks. However, the rate of lymphomas in patients receiving GLM 100 mg proved to be higher than in those taking GLM 50 mg, in the general population, and in the placebo group in particular. AE were evenly distributed among patients with rheumatoid  arthritis, psoriatic arthritis, or ankylosing spondylitis. Overall, the findings are in agreement with the data on the safety of previously used TNF-α inhibitors. No fundamentally new AE have been encountered. It is necessary to accumulate  data on the use of GLM in real clinical practice, which will be able to more objectively define its place in the current therapy of rheumatic diseases.

Personal involvement as a special style of Department of Psychology, Lomonosov Moscow State University

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Takhir Yu. Bazarov

2016-09-01

Full Text Available The author, being a former student of the Department of Psychology, Lomonosov Moscow State University, and now is teacher, professor, remembers those who created and maintained such traditions of the Department as depth of knowledge and coherence of ideas, methodological clarity and dialogue, holistic view of the issue and using problem solving in teaching, and also the joint work of professors and students in the way of perceiving the truth. According to the author the 50th anniversary of the Department of Psychology is an occasion to both recall the path members of the Department went over the years, including several epochs, and to outline the prospects for further development. Considerable attention is paid to the personality of G.M. Andreeva, who is a gifted teacher, a brilliant scholar, and one of the founders of social psychology in the Russia. Particular attention is drawn to Galina Andreeva collecting the brightest staff of the Chair of Social Psychology, whose key feature was involvement in both the scientific and also collective life of the Department, which contributed to the development of the new important branch of psychology. The author also singles out the figure of the wonderful teacher L.A. Petrovskaya who encouraged the students to cherish their individuality as she believed it to be the main tool of the professional psychologist. With much gratitude the author recalls tips for organizing the teaching process received from A.U. Kharash. The paper characterizes the current state and the importance of the Department, and outlines the prospects for further development. In particular, the author speaks of the need for developing student personal involvement in professional activities, and also of creating favourable conditions at the Deaprtment for a student successful transition from training to real life.

Polimorfismo del gen del transportador de serotonina (5-HTT y trastorno de depresión mayor en pacientes en Bogotá, Colombia

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Isabel Pérez-Olmos

2016-06-01

Conclusiones. El genotipo SL se asoció con el trastorno de depresión mayor en pacientes de todas las edades. El alelo S se asoció significativamente con el trastorno de depresión mayor en pacientes menores de 37 años al ajustar por trastornos concomitantes de ansiedad.

Crèche and School - Important dates

CERN Multimedia

Staff Association

2018-01-01

Enrolments 2018-2019 Enrolments to the Crèche and School for the school year 2018-2019 will take place on 5, 6 and 7 March 2018 from 10 am to 1 pm at the Crèche and School of the CERN Staff Association. Registration forms will be available from Thursday 1st March 2018. For more information, please visit the website: http://nurseryschool.web.cern.ch/. * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * Saturday 3 March 2018 Open Day at Crèche and School of the CERN Staff Association Are you considering enrolling your child to the Crèche and School of the CERN Staff Association? If you work at CERN, then this event is for you: come visit the school and meet the Management on Saturday 3 March 2018 from 10 to 12 am It will be our pleasure to present to you our structure, its projects and premises, and answer any questions you may have. Please sign up for one of the two sessions via Doodle before Friday 2 March 2018: htt...

Reversal of Phenotypic Abnormalities by CRISPR/Cas9-Mediated Gene Correction in Huntington Disease Patient-Derived Induced Pluripotent Stem Cells.

Science.gov (United States)

Xu, Xiaohong; Tay, Yilin; Sim, Bernice; Yoon, Su-In; Huang, Yihui; Ooi, Jolene; Utami, Kagistia Hana; Ziaei, Amin; Ng, Bryan; Radulescu, Carola; Low, Donovan; Ng, Alvin Yu Jin; Loh, Marie; Venkatesh, Byrappa; Ginhoux, Florent; Augustine, George J; Pouladi, Mahmoud A

2017-03-14

Huntington disease (HD) is a dominant neurodegenerative disorder caused by a CAG repeat expansion in HTT. Here we report correction of HD human induced pluripotent stem cells (hiPSCs) using a CRISPR-Cas9 and piggyBac transposon-based approach. We show that both HD and corrected isogenic hiPSCs can be differentiated into excitable, synaptically active forebrain neurons. We further demonstrate that phenotypic abnormalities in HD hiPSC-derived neural cells, including impaired neural rosette formation, increased susceptibility to growth factor withdrawal, and deficits in mitochondrial respiration, are rescued in isogenic controls. Importantly, using genome-wide expression analysis, we show that a number of apparent gene expression differences detected between HD and non-related healthy control lines are absent between HD and corrected lines, suggesting that these differences are likely related to genetic background rather than HD-specific effects. Our study demonstrates correction of HD hiPSCs and associated phenotypic abnormalities, and the importance of isogenic controls for disease modeling using hiPSCs. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

[Neurogenetics in Peru, example of translational research].

Science.gov (United States)

Mazzetti, Pilar; Inca-Martínez, Miguel; Tirado-Hurtado, Indira; Milla-Neyra, Karina; Silva-Paredes, Gustavo; Vishnevetsky, Anastasia; Cornejo-Olivas, Mario

2015-10-01

Neurogenetics is an emerging discipline in Peru that links basic research with clinical practice. The Neurogenetics Research Center located in Lima, Peru is the only unit dedicated to the specialized care of neurogenetic diseases in the country. From the beginning, neurogenetics research has been closely linked to the study of Huntington’s Disease (HD), from the PCR genotyping of the HTT gene, to the current haplogroup studies in HD. Research in other monogenic diseases led to the implementation of alternative methodologies for the genotyping of Fragile X and Myotonic Dystrophy Type 1. Both, national and international collaborative efforts have facilitated the discovery of new genetic variants in complex multigenic diseases such as Parkinson’s disease and Alzheimer’s disease. Additionally, multidisciplinary education and mentoring have allowed for the training of new neurogenetics specialists, supporting the sustained growth of the discipline in the country. The promotion of research in Peru has spurred the growth of neurogenetics research, although limitations in infrastructure, technology, and education remain a challenge for the further growth of research in this field.

2013 CERN Road Race

CERN Document Server

Klaus Hanke

2013-01-01

The 2013 edition of the annual CERN Road Race will be held on Wednesday 18 September at 18.15.   The 5.5 km race takes place over 3 laps of a 1.8 km circuit in the West Area of the Meyrin site, and is open to everyone working at CERN and their families. There are runners of all speeds, with times ranging from under 17 to over 34 minutes, and the race is run on a handicap basis, by staggering the starting times so that (in theory) all runners finish together. Children (< 15 years) have their own race over 1 lap of 1.8 km. As usual, there will be a “best family” challenge (judged on best parent + best child). Trophies are awarded in the usual men’s, women’s and veterans’ categories, and there is a challenge for the best age/performance. Every adult will receive a souvenir prize, financed by a registration fee of 10 CHF. Children enter free (each child will receive a medal). More information, and the online entry form, can be found at: htt...

Association of polymorphisms in 5-HTT (SLC6A4) and MAOA genes with measures of obesity in young adults of Portuguese origin.

Science.gov (United States)

Dias, Helena; Muc, Magdalena; Padez, Cristina; Manco, Licínio

2016-01-01

To investigate the association of polymorphisms in SLC6A4 and MAOA genes with overweight (including obesity). Young adults (n = 535) of Portuguese origin were genotyped for the SLC6A4 polymorphisms 5-HTTLPR and STin2 and a MAOA VNTR. BMI and body fat percentage were measured and a questionnaire was used to assess individual's sport practicing habits. In whole study sample, haplotype-based analysis revealed significant association with overweight/obesity for the individual 5-HTTLPR/Stin2 haplotype L10 (p = 0.04). In men, the MAOA 3R genotype was nominally associated with body fat (p = 0.04). In inactive individuals, overweight/obesity was found significantly associated with 5-HTTLPR L-allele (p = 0.01) and nominally associated with STin2 10-allele (p = 0.03). A significant association was also found testing for all haplotype effects (χ(2 )= 8.7; p = 0.03). We found some evidences for the association of SLC6A4 and MAOA genes with measures of obesity. Our results suggest physical inactivity accentuates the influence of SLC6A4 polymorphisms on obesity risk.

5-HTTLPR polymorphism impacts task-evoked and resting-state activities of the amygdala in Han Chinese.

Science.gov (United States)

Li, Sufang; Zou, Qihong; Li, Jun; Li, Jin; Wang, Deyi; Yan, Chaogan; Dong, Qi; Zang, Yu-Feng

2012-01-01

Prior research has shown that the amygdala of carriers of the short allele (s) of the serotonin transporter (5-HTT) gene (5-HTTLPR) have a larger response to negative emotional stimuli and higher spontaneous activity during the resting state than non-carriers. However, recent studies have suggested that the effects of 5-HTTLPR may be specific to different ethnic groups. Few studies have been conducted to address this issue. Blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) was conducted on thirty-eight healthy Han Chinese subjects (l/l group, n = 19; s/s group, n = 19) during the resting state and during an emotional processing task. Compared with the s/s group, the l/l group showed significantly increased regional homogeneity or local synchronization in the right amygdala during the resting state (|t|>2.028, pemotional processing task. 5-HTTLPR can alter the spontaneous activity of the amygdala in Han Chinese. However, the effect of 5-HTTLPR on the amygdala both in task state and resting state in Asian population was no similar with Caucasians. They suggest that the effect of 5-HTTLPR on the amygdala may be modulated by ethnic differences.

The Kynurenine Pathway Modulates Neurodegeneration in a Drosophila Model of Huntington’s Disease

Science.gov (United States)

Campesan, Susanna; Green, Edward W.; Breda, Carlo; Sathyasaikumar, Korrapati V.; Muchowski, Paul J.; Schwarcz, Robert; Kyriacou, Charalambos P.; Giorgini, Flaviano

2014-01-01

Summary Neuroactive metabolites of the kynurenine pathway (KP) of tryptophan degradation have been implicated in the pathophysiology of neurodegenerative disorders, including Huntington’s disease (HD) [1]. A central hallmark of HD is neurodegeneration caused by a polyglutamine expansion in the huntingtin (htt) protein [2]. Here we exploit a transgenic Drosophila melanogaster model of HD to interrogate the therapeutic potential of KP manipulation. We observe that genetic and pharmacological inhibition of kynurenine 3-monooxygenase (KMO) increases levels of the neuroprotective metabolite kynurenic acid (KYNA) relative to the neurotoxic metabolite 3-hydroxykynurenine (3-HK) and ameliorates neurodegeneration. We also find that genetic inhibition of tryptophan 2,3-dioxygenase (TDO), the first and rate-limiting step in the pathway, leads to a similar neuroprotective shift toward KYNA synthesis. Importantly, we demonstrate that the feeding of KYNA and 3-HK to HD model flies directly modulates neurodegeneration, underscoring the causative nature of these metabolites. This study provides the first genetic evidence that inhibition of KMO and TDO activity protects against neurodegenerative disease in an animal model, indicating that strategies targeted at two key points within the KP may have therapeutic relevance in HD, and possibly other neurodegenerative disorders. PMID:21636279

Differential susceptibility to maternal expressed emotion in children with ADHD and their siblings? Investigating plasticity genes, prosocial and antisocial behaviour.

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Richards, Jennifer S; Hartman, Catharina A; Franke, Barbara; Hoekstra, Pieter J; Heslenfeld, Dirk J; Oosterlaan, Jaap; Arias Vásquez, Alejandro; Buitelaar, Jan K

2015-02-01

The differential susceptibility theory states that children differ in their susceptibility towards environmental experiences, partially due to plasticity genes. Individuals carrying specific variants in such genes will be more disadvantaged in negative but, conversely, more advantaged in positive environments. Understanding gene-environment interactions may help unravel the causal mechanisms involved in multifactorial psychiatric disorders such as Attention-Deficit/Hyperactivity Disorder (ADHD). The differential susceptibility theory was examined by investigating the presence of interaction effects between maternal expressed emotion (EE; warmth and criticism) and the solitary and combined effects of plasticity genes (DAT1, DRD4, 5-HTT) on prosocial and antisocial behaviour (measured with parent- and self-reports) in children with ADHD and their siblings (N = 366, M = 17.11 years, 74.9% male). Maternal warmth was positively associated with prosocial behaviour and negatively with antisocial behaviour, while maternal criticism was positively associated with antisocial behaviour and negatively with prosocial behaviour. No evidence of differential susceptibility was found. The current study found no evidence for differential susceptibility based on the selected plasticity genes, in spite of strong EE-behaviour associations. It is likely that additional factors play a role in the complex relationship between genes, environment and behaviour.

A combined approach for the assessment of cell viability and cell functionality of human fibrochondrocytes for use in tissue engineering.

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Garzón, Ingrid; Carriel, Victor; Marín-Fernández, Ana Belén; Oliveira, Ana Celeste; Garrido-Gómez, Juan; Campos, Antonio; Sánchez-Quevedo, María Del Carmen; Alaminos, Miguel

2012-01-01

Temporo-mandibular joint disc disorders are highly prevalent in adult populations. Autologous chondrocyte implantation is a well-established method for the treatment of several chondral defects. However, very few studies have been carried out using human fibrous chondrocytes from the temporo-mandibular joint (TMJ). One of the main drawbacks associated to chondrocyte cell culture is the possibility that chondrocyte cells kept in culture tend to de-differentiate and to lose cell viability under in in-vitro conditions. In this work, we have isolated human temporo-mandibular joint fibrochondrocytes (TMJF) from human disc and we have used a highly-sensitive technique to determine cell viability, cell proliferation and gene expression of nine consecutive cell passages to determine the most appropriate cell passage for use in tissue engineering and future clinical use. Our results revealed that the most potentially viable and functional cell passages were P5-P6, in which an adequate equilibrium between cell viability and the capability to synthesize all major extracellular matrix components exists. The combined action of pro-apoptotic (TRAF5, PHLDA1) and anti-apoptotic genes (SON, HTT, FAIM2) may explain the differential cell viability levels that we found in this study. These results suggest that TMJF should be used at P5-P6 for cell therapy protocols.

Control of Huntington’s Disease-Associated Phenotypes by the Striatum-Enriched Transcription Factor Foxp2

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Lea J. Hachigian

2017-12-01

Full Text Available Summary: Alteration of corticostriatal glutamatergic function is an early pathophysiological change associated with Huntington’s disease (HD. The factors that regulate the maintenance of corticostriatal glutamatergic synapses post-developmentally are not well understood. Recently, the striatum-enriched transcription factor Foxp2 was implicated in the development of these synapses. Here, we show that, in mice, overexpression of Foxp2 in the adult striatum of two models of HD leads to rescue of HD-associated behaviors, while knockdown of Foxp2 in wild-type mice leads to development of HD-associated behaviors. We note that Foxp2 encodes the longest polyglutamine repeat protein in the human reference genome, and we show that it can be sequestered into aggregates with polyglutamine-expanded mutant Huntingtin protein (mHTT. Foxp2 overexpression in HD model mice leads to altered expression of several genes associated with synaptic function, genes that present additional targets for normalization of corticostriatal dysfunction in HD. : Hachigian et al. demonstrate that manipulating levels of the striatum-enriched transcription factor Foxp2 can either rescue or mimic HD-associated behaviors in vivo. They link Foxp2 to the post-developmental regulation of the structure and function of the corticostriatal synapse. Keywords: Huntington’s disease, Foxp2, striatum, corticostriatal synapse

The Balloon-Based Manometry Evaluation of Swallowing in Patients with Amyotrophic Lateral Sclerosis

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Jerzy Tomik

2017-03-01

Full Text Available The aim of the study was to analyse the disturbances of the oro-pharyngeal swallowing phase of dysphagia in amyotrophic lateral sclerosis (ALS patients with the use of specific manometric measurements and to evaluate their plausible association with the duration of the disease. Seventeen patients with ALS were evaluated with manometric examinations of the oral and pharyngeal part of the gastrointestinal tract. Tests were carried out by using the oesophageal balloon-based method with four balloon transducers located 5 cm away from each other. The following manometric parameters were analysed: the base of tongue contraction (BTC and the upper oesophageal sphincter pressure (UESP, and the hypopharyngeal suction pump (HSP as well as the oro-pharyngeal, pharyngeal and hypopharyngeal transit time and average pharyngeal bolus velocity (oropharyngeal transit time (OTT, pharyngeal transit time (PTT, hypopharyngeal transit time (HTT and average pharyngeal bolus velocity (APBV, respectively. Manomatric examinations during swallowing in patients with ALS showed significant weakness of BTC, a decrease of HSP and a decrease of the velocity of bolus transit inside the pharynx which were particularly marked between the first and the third examination. Manometric examinations of the oro-pharyngeal part of the gastrointestinal tract are useful and supportive methods in the analysis of swallowing disturbances in ALS patients.

Association between a genetic variant in the serotonin transporter gene (SLC6A4 and suicidal behavior in patients with schizophrenia

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Lindholm Carlström Eva

2012-05-01

Full Text Available Abstract Background The serotonin (5-hydroxytryptamin; 5-HT system has a central role in the circuitry of cognition and emotions. Multiple lines of evidence suggest that genetic variation in the serotonin transporter gene (SLC6A4; 5-HTT is associated with schizophrenia and suicidal behavior. In this study, we wanted to elucidate whether SLC6A4 variations is involved in attempted suicide among patients with schizophrenia in a Scandinavian case–control sample. Methods Patients diagnosed with schizophrenia from three Scandinavian samples were assessed for presence or absence of suicide attempts, based on record reviews and interview data. Seven SLC6A4 single nucleotide polymorphisms (SNPs were genotyped in 837 schizophrenia patients and 1,473 control individuals. Association analyses and statistical evaluations were performed with the program UNPHASED (version 3.0.9. Results We observed an allele association between the SNP rs16965628, located in intron one of SLC6A4, and attempted suicide (adjusted p-value 0.01, among patients with schizophrenia. No association was found to a diagnosis of schizophrenia, when patients were compared to healthy control individuals. Conclusion The gene SLC6A4 appears to be involved in suicidal ideation among patients with schizophrenia. Independent replication is needed before more firm conclusions can be drawn.

Os fatores genéticos da insônia - Uma revisão de literatura

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Guilherme Sousa Ferreira

2017-05-01

Full Text Available A insônia é um dos distúrbios do sono caracterizado pela dificuldade em iniciar ou manter o sono. Isso se reflete em um sono de baixa qualidade que pode causar problemas ao longo do dia, como cansaço e falta de energia. Sob essa condição, estão associados alguns fatores genéticos, entre eles os genes ABCC9, 5-HTT e Clock. A presente revisão de literatura tem por objetivo a explanação acerca dos fatores genéticos relacionados com o distúrbio da insônia. Trata-se de uma revisão de literatura de forma sistemática, realizada por meio de um levantamento bibliográfico que procura reunir os conhecimentos sobre as características da insônia e sua herança gênica. Encontrou-se uma relevância de achados autorais valiosos para a síntese dessa pesquisa. Portanto, a partir do estudo abordado nessa revisão, torna-se evidente a importância do conhecimento das causas genéticas do distúrbio da insônia para a melhor abordagem clínica, haja vista a relevância desse mecanismo biológico.

EMQN/CMGS best practice guidelines for the molecular genetic testing of Huntington disease.

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Losekoot, Monique; van Belzen, Martine J; Seneca, Sara; Bauer, Peter; Stenhouse, Susan A R; Barton, David E

2013-05-01

Huntington disease (HD) is caused by the expansion of an unstable polymorphic trinucleotide (CAG)n repeat in exon 1 of the HTT gene, which translates into an extended polyglutamine tract in the protein. Laboratory diagnosis of HD involves estimation of the number of CAG repeats. Molecular genetic testing for HD is offered in a wide range of laboratories both within and outside the European community. In order to measure the quality and raise the standard of molecular genetic testing in these laboratories, the European Molecular Genetics Quality Network has organized a yearly external quality assessment (EQA) scheme for molecular genetic testing of HD for over 10 years. EQA compares a laboratory's output with a fixed standard both for genotyping and reporting of the results to the referring physicians. In general, the standard of genotyping is very high but the clarity of interpretation and reporting of the test result varies more widely. This emphasizes the need for best practice guidelines for this disorder. We have therefore developed these best practice guidelines for genetic testing for HD to assist in testing and reporting of results. The analytical methods and the potential pitfalls of molecular genetic testing are highlighted and the implications of the different test outcomes for the consultand and his or her family members are discussed.

Genetic contributions of the serotonin transporter to social learning of fear and economic decision making.

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Crişan, Liviu G; Pana, Simona; Vulturar, Romana; Heilman, Renata M; Szekely, Raluca; Druğa, Bogdan; Dragoş, Nicolae; Miu, Andrei C

2009-12-01

Serotonin (5-HT) modulates emotional and cognitive functions such as fear conditioning (FC) and decision making. This study investigated the effects of a functional polymorphism in the regulatory region (5-HTTLPR) of the human 5-HT transporter (5-HTT) gene on observational FC, risk taking and susceptibility to framing in decision making under uncertainty, as well as multidimensional anxiety and autonomic control of the heart in healthy volunteers. The present results indicate that in comparison to the homozygotes for the long (l) version of 5-HTTLPR, the carriers of the short (s) version display enhanced observational FC, reduced financial risk taking and increased susceptibility to framing in economic decision making. We also found that s-carriers have increased trait anxiety due to threat in social evaluation, and ambiguous threat perception. In addition, s-carriers also show reduced autonomic control over the heart, and a pattern of reduced vagal tone and increased sympathetic activity in comparison to l-homozygotes. This is the first genetic study that identifies the association of a functional polymorphism in a key neurotransmitter-related gene with complex social-emotional and cognitive processes. The present set of results suggests an endophenotype of anxiety disorders, characterized by enhanced social learning of fear, impaired decision making and dysfunctional autonomic activity.

Transgenic animal models for study of the pathogenesis of Huntington's disease and therapy.

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Chang, Renbao; Liu, Xudong; Li, Shihua; Li, Xiao-Jiang

2015-01-01

Huntington's disease (HD) is caused by a genetic mutation that results in polyglutamine expansion in the N-terminal regions of huntingtin. As a result, this polyQ expansion leads to the misfolding and aggregation of mutant huntingtin as well as age-dependent neurodegeneration. The genetic mutation in HD allows for generating a variety of animal models that express different forms of mutant huntingtin and show differential pathology. Studies of these animal models have provided an important insight into the pathogenesis of HD. Mouse models of HD include transgenic mice, which express N-terminal or full-length mutant huntingtin ubiquitously or selectively in different cell types, and knock-in mice that express full-length mutant Htt at the endogenous level. Large animals, such as pig, sheep, and monkeys, have also been used to generate animal HD models. This review focuses on the different features of commonly used transgenic HD mouse models as well as transgenic large animal models of HD, and also discusses how to use them to identify potential therapeutics. Since HD shares many pathological features with other neurodegenerative diseases, identification of therapies for HD would also help to develop effective treatment for different neurodegenerative diseases that are also caused by protein misfolding and occur in an age-dependent manner.

Somatic Genetic Variation in Solid Pseudopapillary Tumor of the Pancreas by Whole Exome Sequencing

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Meng Guo

2017-01-01

Full Text Available Solid pseudopapillary tumor of the pancreas (SPT is a rare pancreatic disease with a unique clinical manifestation. Although CTNNB1 gene mutations had been universally reported, genetic variation profiles of SPT are largely unidentified. We conducted whole exome sequencing in nine SPT patients to probe the SPT-specific insertions and deletions (indels and single nucleotide polymorphisms (SNPs. In total, 54 SNPs and 41 indels of prominent variations were demonstrated through parallel exome sequencing. We detected that CTNNB1 mutations presented throughout all patients studied (100%, and a higher count of SNPs was particularly detected in patients with older age, larger tumor, and metastatic disease. By aggregating 95 detected variation events and viewing the interconnections among each of the genes with variations, CTNNB1 was identified as the core portion in the network, which might collaborate with other events such as variations of USP9X, EP400, HTT, MED12, and PKD1 to regulate tumorigenesis. Pathway analysis showed that the events involved in other cancers had the potential to influence the progression of the SNPs count. Our study revealed an insight into the variation of the gene encoding region underlying solid-pseudopapillary neoplasm tumorigenesis. The detection of these variations might partly reflect the potential molecular mechanism.

Gene transfer in rodents and primates as a new tool for modeling diseases in animals and assessing functions by in vivo imaging

Energy Technology Data Exchange (ETDEWEB)

Deglon, N. [Atomic Energy Commission (CEA), Dept. of Medical Research and MIRCen Program, 91 - Orsay (France)

2006-07-01

vector expressing mutant htt in adult rats results in a selective neuro-pathology characterized by a sequential appearance of ubiquitinated htt aggregates, neuronal dysfunction and cell death, typical of HD. Recently, we have scaled-up the approach in non-human primates and assessed the behavioral deficits associated with the striatal pathology. The animals progressively developed spontaneous dys-kinetic movements of the legs, arms and trunk. These symptoms persisted up to 30 weeks, the longest time-point studied. These data constitute a proof of principle for the development of a genetic model of HD in non-human primates and indicate that a local overexpression of Httl7l-82Q in the putamen in non-human primates is sufficient to induce involuntary abnormal movements highly reminiscent of HD. In parallel to the development of these animal models, experimental studies have led to the identification of therapeutic candidates that may interfere with the molecular events mediating neuro-degeneration. Several disease-modifying therapeutic interventions have been identified. Data from pre-clinical studies performed in animal models of Parkinson's disease including the assessment of functional recovery by PET imaging will be presented. (author)

Efecto de cuatro métodos de labranza sobre las propiedades físicas y la pérdida de suelo en la rotación papa-pastos en áreas de ladera en una región alto andina de Colombia Effect of four tillage methods on the physical properties and loss of soil in the potato-grass rotation in hillside areas of a high Andean region in Colombia

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Napoleón Bernal

2008-01-01

Full Text Available Este estudio avaluó la pérdida y los cambios en las propiedades físicas del suelo y la producción de papa amarilla Solanum phureja, como resultado de cuatro sistemas de labranza (Tracción humana, LTH; Tracción animal, LTA; Mecánica, LM; y Mecánica combinada, LMC en Santa Lucía, municipio de Tuluá, región alto andina de Colombia a 2.870 msnm. Los tratamientos se evaluaron usando un diseño de bloques completos al azar con tres repeticiones. La pérdida de suelo se determinó por medio de canaletas de escorrentía. La información se analizó por medio de una matriz de cambio para cada propiedad física. La tracción mecánica afectó negativamente las propiedades físicas del suelo, lo que se evidenció en el incremento de pérdidas por escorrentía. La mayor pérdida de suelo se asoció con el uso de LM y disminuyó hasta el 50% con LTH: (LM 6.12 t ha-1 año-1; LMC 5.0 t ha-1 año-1; LTA 3.7 t ha-1 año-1 and LTH 2.73 t ha-1 año-1. LTA generó la mayor retribución económica y ambiental, porque su producción (13 t/ha fue mayor que el promedio obtenido en los tratamientos (12.4 t/ha y la pérdida de suelo fue menor que la generada por LM y LMC.This study evaluated the loss and the changes in the soil physical properties, and the production of yellow potato Solanum phureja, as a result of four tillage systems (Human traction, THT; Animal traction, ATT; Mechanical, MT; and Mechanical combined, CMT in Santa Lucia, Tuluá municipality, high andean region of Colombia to 2.870 masl. Treatments were evaluated using a completely randomized blocks desing with three replicates, and the data examined by means of a matrix of change for each physical property. Soil loss was determined by the ditch of runoff. Mechanical traction affected the soil physical properties negatively, that became evident in the increment of losses with the runoff. The bigger loss of soil was correlated with MT use and it diminished to the 50 % with HTT: (MT 6.12 tha-1

Gene transfer in rodents and primates as a new tool for modeling diseases in animals and assessing functions by in vivo imaging

International Nuclear Information System (INIS)

Deglon, N.

2006-01-01

expressing mutant htt in adult rats results in a selective neuro-pathology characterized by a sequential appearance of ubiquitinated htt aggregates, neuronal dysfunction and cell death, typical of HD. Recently, we have scaled-up the approach in non-human primates and assessed the behavioral deficits associated with the striatal pathology. The animals progressively developed spontaneous dys-kinetic movements of the legs, arms and trunk. These symptoms persisted up to 30 weeks, the longest time-point studied. These data constitute a proof of principle for the development of a genetic model of HD in non-human primates and indicate that a local overexpression of Httl7l-82Q in the putamen in non-human primates is sufficient to induce involuntary abnormal movements highly reminiscent of HD. In parallel to the development of these animal models, experimental studies have led to the identification of therapeutic candidates that may interfere with the molecular events mediating neuro-degeneration. Several disease-modifying therapeutic interventions have been identified. Data from pre-clinical studies performed in animal models of Parkinson's disease including the assessment of functional recovery by PET imaging will be presented. (author)

A combined approach for the assessment of cell viability and cell functionality of human fibrochondrocytes for use in tissue engineering.

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Ingrid Garzón

Full Text Available Temporo-mandibular joint disc disorders are highly prevalent in adult populations. Autologous chondrocyte implantation is a well-established method for the treatment of several chondral defects. However, very few studies have been carried out using human fibrous chondrocytes from the temporo-mandibular joint (TMJ. One of the main drawbacks associated to chondrocyte cell culture is the possibility that chondrocyte cells kept in culture tend to de-differentiate and to lose cell viability under in in-vitro conditions. In this work, we have isolated human temporo-mandibular joint fibrochondrocytes (TMJF from human disc and we have used a highly-sensitive technique to determine cell viability, cell proliferation and gene expression of nine consecutive cell passages to determine the most appropriate cell passage for use in tissue engineering and future clinical use. Our results revealed that the most potentially viable and functional cell passages were P5-P6, in which an adequate equilibrium between cell viability and the capability to synthesize all major extracellular matrix components exists. The combined action of pro-apoptotic (TRAF5, PHLDA1 and anti-apoptotic genes (SON, HTT, FAIM2 may explain the differential cell viability levels that we found in this study. These results suggest that TMJF should be used at P5-P6 for cell therapy protocols.

The effect of interactions between genetics and cannabis use on neurocognition. A review.

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Cosker, E; Schwitzer, T; Ramoz, N; Ligier, F; Lalanne, L; Gorwood, P; Schwan, R; Laprévote, V

2018-03-02

Cannabis is one of the most widely-used drugs in industrialized countries. It is now well established that cannabis use impacts neurocognition. In the intoxication period time episodic memory, working memory and attention are impacted and impulsivity is increased. The long-term effects of cannabis use tend to be similar. Various internal factors, such as sex differences, modulate this impact. It is unclear whether genetic variations can also influence the impact of cannabis on neurocognition. We set out to examine the impact of genetic variations on neurocognition in cannabis users. We conducted a search via the PubMed, Web of Science, and ScienceDirect databases to identify studies measuring neurocognition and assessing genotypes in the context of cannabis use. We included 13 articles. We found that working memory, verbal and visual memory and sustained attention are more impacted during intoxication in subjects with the Val COMT allele. COMT gene could also modulate sustained attention in regular use. The CNR1, AKT1, DBH and 5-HTT/SLC6A4 genes may also modulate effects. Most of these genes are linked to schizophrenia. A fuller understanding of their impact on the effects of cannabis on neurocognition would thus help elucidate the mechanisms linking cannabis and psychosis. However, evidence is still scant, and more research is needed. Copyright © 2017. Published by Elsevier Inc.

Tritium isolation from lithium inorganic compounds applicable to thermonuclear reactor breeding blanket

International Nuclear Information System (INIS)

Vasil'ev, V.G.; Ershova, Z.V.; Nikiforov, A.S.

1982-01-01

Tritium separation from inorganic lithium compounds: Li 2 O, LiAlO 2 , Li 2 SiO 3 , Li 4 SiO 4 , LiF, LiBeF 3 , Li 2 BeF 4 irradiated with a beam of a gamma facility and a nuclear reactor, has been studied. In the first case the gas phase is absent. In the latter one- the tritium amount in the gas does not exceed 1-2% of its total amount in the salt. Based on the EPR spectra of irradiated salts the concentrations of paramagnetic centres are calculated. It is shown that during thermal annealing the main portion of tritium in the gas phase is in the form of oxide (HTO, T 2 O). Tritium is separated from lithium fluoroberyllates in the form of hydrogen (HT, T 2 ). The kinetics of tritium oxide isolation from irradiated lithium oxide aluminate, metha- and orthosilicates, lithium sulphate has been studied. The activation energies of tritium oxide separation process are presented. A supposition is made that chemical reaction of the HTO (T 2 O) or HT(T 2 ) or HF(TF) formation is a limiting stage. Clarification of the process stage limiting the rate of tritium recovery will permit to evaluate conditions for the optimum work of lithium material in the blanket, lithium zone to select the lithium element structure and temperature regime of irradiation

The role of the serotonergic system in suicidal behavior

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Sadkowski M

2013-11-01

Full Text Available Marta Sadkowski,1,* Brittany Dennis,2–4,* Robert C Clayden,2 Wala ElSheikh,5 Sumathy Rangarajan,5 Jane DeJesus,5 Zainab Samaan3–6 1Arts and Sciences Program, 2Faculty of Health Sciences, 3Department of Clinical Epidemiology and Biostatistics, 4Population Genomics Program, McMaster University, Hamilton, ON, Canada; 5Population Health Research Institute, Hamilton, ON, Canada; 6Department of Psychiatry and Behavioral Neurosciences, McMaster University, Hamilton, ON, Canada *These authors contributed equally to this work Abstract: Serotonin is a widely investigated neurotransmitter in several psychopathologies, including suicidal behavior (SB; however, its role extends to several physiological functions involving the nervous system, as well as the gastrointestinal and cardiovascular systems. This review summarizes recent research into ten serotonergic genes related to SB. These genes – TPH1, TPH2, SLC6A4, SLC18A2, HTR1A, HTR1B, HTR2A, DDC, MAOA, and MAOB – encode proteins that are vital to serotonergic function: tryptophan hydroxylase; the serotonin transporter 5-HTT; the vesicular transporter VMAT2; the HTR1A, HTR1B, and HTR2A receptors; the L-amino acid decarboxylase; and the monoamine oxidases. This review employed a systematic search strategy and a narrative research methodology to disseminate the current literature investigating the link between SB and serotonin. Keywords: serotonin, suicide, genetic

Physical exercise ameliorates mood disorder-like behavior on high fat diet-induced obesity in mice.

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Park, Hye-Sang; Lee, Jae-Min; Cho, Han-Sam; Park, Sang-Seo; Kim, Tae-Woon

2017-04-01

Obesity is associated with mood disorders such as depression and anxiety. The aim of this study was to investigate whether treadmill exercise had any benefits on mood disorder by high fat diet (HFD) induced obesity. Mice were randomly divided into four groups: control, control and exercise, high fat diet (HFD), and HFD and exercise. Obesity was induced by a 20-week HFD (60%). In the exercise groups, exercise was performed 6 times a week for 12 weeks, with the exercise duration and intensity gradually increasing at 4-week intervals. Mice were tested in tail suspension and elevated plus maze tasks in order to verify the mood disorder like behavior such as depression and anxiety on obesity. In the present study, the number of 5-HT- and TPH-positive cells, and expression of 5-HT 1A and 5-HTT protein decreased in dorsal raphe, and depression and anxiety like behavior increased in HFD group compared with the CON group. In contrast, treadmill exercise ameliorated mood disorder like behavior by HFD induced obesity and enhanced expression of the serotonergic system in the dorsal raphe. We concluded that exercise increases the capacity of the serotonergic system in the dorsal raphe, which improves the mood disorders associated with HFD-induced obesity. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Large-scale functional RNAi screen in C. elegans identifies genes that regulate the dysfunction of mutant polyglutamine neurons.

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Lejeune, François-Xavier; Mesrob, Lilia; Parmentier, Frédéric; Bicep, Cedric; Vazquez-Manrique, Rafael P; Parker, J Alex; Vert, Jean-Philippe; Tourette, Cendrine; Neri, Christian

2012-03-13

A central goal in Huntington's disease (HD) research is to identify and prioritize candidate targets for neuroprotective intervention, which requires genome-scale information on the modifiers of early-stage neuron injury in HD. Here, we performed a large-scale RNA interference screen in C. elegans strains that express N-terminal huntingtin (htt) in touch receptor neurons. These neurons control the response to light touch. Their function is strongly impaired by expanded polyglutamines (128Q) as shown by the nearly complete loss of touch response in adult animals, providing an in vivo model in which to manipulate the early phases of expanded-polyQ neurotoxicity. In total, 6034 genes were examined, revealing 662 gene inactivations that either reduce or aggravate defective touch response in 128Q animals. Several genes were previously implicated in HD or neurodegenerative disease, suggesting that this screen has effectively identified candidate targets for HD. Network-based analysis emphasized a subset of high-confidence modifier genes in pathways of interest in HD including metabolic, neurodevelopmental and pro-survival pathways. Finally, 49 modifiers of 128Q-neuron dysfunction that are dysregulated in the striatum of either R/2 or CHL2 HD mice, or both, were identified. Collectively, these results highlight the relevance to HD pathogenesis, providing novel information on the potential therapeutic targets for neuroprotection in HD. © 2012 Lejeune et al; licensee BioMed Central Ltd.

dAdd1 and dXNP prevent genome instability by maintaining HP1a localization at Drosophila telomeres.

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Chavez, Joselyn; Murillo-Maldonado, Juan Manuel; Bahena, Vanessa; Cruz, Ana Karina; Castañeda-Sortibrán, América; Rodriguez-Arnaiz, Rosario; Zurita, Mario; Valadez-Graham, Viviana

2017-12-01

Telomeres are important contributors to genome stability, as they prevent linear chromosome end degradation and contribute to the avoidance of telomeric fusions. An important component of the telomeres is the heterochromatin protein 1a (HP1a). Mutations in Su(var)205, the gene encoding HP1a in Drosophila, result in telomeric fusions, retrotransposon regulation loss and larger telomeres, leading to chromosome instability. Previously, it was found that several proteins physically interact with HP1a, including dXNP and dAdd1 (orthologues to the mammalian ATRX gene). In this study, we found that mutations in the genes encoding the dXNP and dAdd1 proteins affect chromosome stability, causing chromosomal aberrations, including telomeric defects, similar to those observed in Su(var)205 mutants. In somatic cells, we observed that dXNP and dAdd1 participate in the silencing of the telomeric HTT array of retrotransposons, preventing anomalous retrotransposon transcription and integration. Furthermore, the lack of dAdd1 results in the loss of HP1a from the telomeric regions without affecting other chromosomal HP1a binding sites; mutations in dxnp also affected HP1a localization but not at all telomeres, suggesting a specialized role for dAdd1 and dXNP proteins in locating HP1a at the tips of the chromosomes. These results place dAdd1 as an essential regulator of HP1a localization and function in the telomere heterochromatic domain.

Flomoxef, a new oxacephem antibiotic, does not cause hemostatic defects.

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Cazzola, M; Brancaccio, V; De Giglio, C; Paternò, E; Matera, M G; Rossi, F

1993-03-01

Antibiotics of the beta-lactam class may cause coagulation defects and bleeding. It has been suggested that N-methyltetrazolethiol (NMTT), a common side chain group at the 3'-position of the cephem or 1-oxacephem frame, could be responsible for the hypoprothrombinemic effect of the antibiotics and that it could inhibit the liver vitamin K-epoxide reductase activity. Flomoxef (6315-S) is a new oxacephem antibiotic which differs from latamoxef because it has [1-(2-hydroxethyl)-1H-tetrazol-5-yl] thiomethyl (HTT) as a side chain at the 3'-position of cephem group instead of NMTT and an extensive modification of 7 beta-acylamino side chain. The present study was carried out to study its effects on vitamin K-dependent blood coagulation parameters in human volunteers. Ten adult patients (6 men and 4 women), suffering from chronic bronchitis, entered into the study. Each patient received ten 1 g i.m. injections of flomoxef at 12-hourly intervals. Apparently, the treatment with this oxacephem antibiotic had no significant effect. PT, PTT and fibrinogen remained in the normal range in all patients and factors II+VII+X, protein C, protein S and AT III were not depleted. The trend was similar both in men and women. Based on the results of the present study, we conclude that flomoxef is an antibiotic that does not exhibit an effect on blood coagulation, even in males.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative study on biodistribution of domestic and imported 125I-β-CIT

International Nuclear Information System (INIS)

Liu Xingdang; Lin Xiangtong; Fang Ping; Chen Zhengping; Zhou Xiang; Wang Bocheng; Zhang Manda

2003-01-01

Objective: To characterize the kinetics and biodistribution of a domestically synthesized 125 I-2β-carbomethoxy-3β-4-iodopheny1tropane (β-CIT ) and to compare it with that of 125 I-β-CIT imported from RBI company. Methods: 1)The biodistribution of domestic and RBI company produced 125 I-β-CIT in KM mice. Twenty groups of mice (group of 5) were injected into the tail vein with either one of 125 I-β-CIT products. Each group of both products was killed at 5,15,30 and 45 min, and 1, 2, 4, 6, 8 and 24 h. 2)Autoradiography was performed on the brain of SD rats at 2 h after injection. Results: Domestic 125 I-β-CIT was primarily uptaked in the striatum, also in areas rich in 5-HTT such as the brain stem, frontal cortex, parietal cortex, temporal cortex, occipital cortex and hippocampus. Striatal uptake peaked at 2 h postinjection of 125 I-β-CIT. The ratio of specific to nonspecific binding in striatum peaked at 6 h. The highest radioactivity was in the lungs and the less radioactivity was in the liver, kidney, spleen and intestine. Autoradiography confirmed that 125 I-β-CIT primarily bound to striatum and lower room temperature significantly reduced the binding of the agent. Conclusion: The domestic 125 I-β-CIT binds primarily to dopamine transporters in the striatum in mice and rats and the maximum uptake is in the lungs

Whole-exome sequencing and an iPSC-derived cardiomyocyte model provides a powerful platform for gene discovery in left ventricular hypertrophy

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Degui eZhi

2012-05-01

Full Text Available Rationale: Left ventricular hypertrophy (LVH is a heritable predictor of cardiovascular disease, particularly in blacks. Objective: Determine the feasibility of combining evidence from two distinct but complimentary experimental approaches to identify novel genetic predictors of increased LV mass . Methods: Whole exome sequencing (WES was conducted in 7 African American sibling trios ascertained on high average familial LV mass indexed to height (LVMHT. WES identified 31,426 missense or nonsense mutations (MS/NS which were examined for association with LVMHT using linear mixed models adjusted for age, sex, body weight, and family relationship. To functionally assess WES findings, human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM were stimulated to induce hypertrophy; mRNA sequencing was used to determine expression differences associated with hypertrophy onset. Results: After correction for multiple testing, 295 MS/NS variants in 265 genes were associated with LVMHT. We identified 44 of 265 WES genes differentially expressed (P<0.05 in hypertrophied cells. To further prioritize these 44 candidates, 7 supportive statistical and annotation-based criteria were used to evaluate the relevance of these genes. Five genes, HLA-B, HTT, MTSS1, SLC5A12, THBS1, were each supported by 3 criteria. THBS1 encodes an adhesive glycoprotein that promotes matrix preservation in pressure-overload LVH and harbors conserved and predicted damaging variants. Conclusions: Combining evidence from cutting-edge genetic and cellular experiments can enable identification of novel LVH risk loci.

Depression, osteoporosis, serotonin and cell membrane viscosity between biology and philosophical anthropology

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Gabrielli Fabio

2011-03-01

Full Text Available Abstract Due to the relationship between biology and culture, we believe that depression, understood as a cultural and existential phenomenon, has clear markers in molecular biology. We begin from an existential analysis of depression constituting the human condition and then shift to analysis of biological data confirming, according to our judgment, its original (ontological structure. In this way philosophy is involved at the anthropological level, in as much as it detects the underlying meanings of depression in the original biological-cultural horizon of human life. Considering the integration of knowledge it is the task of molecular biology to identify the aforementioned markers, to which the existential aspects of depression are linked to. In particular, recent works show the existence of a link between serotonin and osteoporosis as a result of a modified expression of the low-density lipoprotein receptor-related protein 5 gene. Moreover, it is believed that the hereditary or acquired involvement of tryptophan hydroxylase 2 (Tph2 or 5-hydroxytryptamine transporter (5-HTT is responsible for the reduced concentration of serotonin in the central nervous system, causing depression and affective disorders. This work studies the depression-osteoporosis relationship, with the aim of focusing on depressive disorders that concern the quantitative dynamic of platelet membrane viscosity and interactome cytoskeleton modifications (in particular Tubulin and Gsα protein as a possible condition of the involvement of the serotonin axis (gut, brain and platelet, not only in depression but also in connection with osteoporosis.

Neural network analysis in pharmacogenetics of mood disorders

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Serretti Alessandro

2004-12-01

Full Text Available Abstract Background The increasing number of available genotypes for genetic studies in humans requires more advanced techniques of analysis. We previously reported significant univariate associations between gene polymorphisms and antidepressant response in mood disorders. However the combined analysis of multiple gene polymorphisms and clinical variables requires the use of non linear methods. Methods In the present study we tested a neural network strategy for a combined analysis of two gene polymorphisms. A Multi Layer Perceptron model showed the best performance and was therefore selected over the other networks. One hundred and twenty one depressed inpatients treated with fluvoxamine in the context of previously reported pharmacogenetic studies were included. The polymorphism in the transcriptional control region upstream of the 5HTT coding sequence (SERTPR and in the Tryptophan Hydroxylase (TPH gene were analysed simultaneously. Results A multi layer perceptron network composed by 1 hidden layer with 7 nodes was chosen. 77.5 % of responders and 51.2% of non responders were correctly classified (ROC area = 0.731 – empirical p value = 0.0082. Finally, we performed a comparison with traditional techniques. A discriminant function analysis correctly classified 34.1 % of responders and 68.1 % of non responders (F = 8.16 p = 0.0005. Conclusions Overall, our findings suggest that neural networks may be a valid technique for the analysis of gene polymorphisms in pharmacogenetic studies. The complex interactions modelled through NN may be eventually applied at the clinical level for the individualized therapy.

Effect of four tillage methods on the physical properties and loss of soil in the potato–grass rotation in hillside areas of a high Andean region in Colombia Efecto de cuatro métodos de labranza sobre las propiedades físicas y la pérdida de suelo en la rotación papa–pastos en áreas de ladera en una región alto andina de Colombia

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Ramírez Luís

2008-03-01

Full Text Available This study evaluated the loss and the changes in the soil physical properties, and the production of yellow potato Solanum phureja, as a result of four tillage systems (Human traction, THT; Animal traction, ATT; Mechanical, MT; and Mechanical combined, CMT in Santa Lucia, Tuluá municipality, high andean region of Colombia to 2.870 masl. Treatments were evaluated using a completely randomized blocks desing with three replicates, and the data examined by means of a matrix of change for each physical property. Soil loss was determined by the ditch of runoff. Mechanical traction affected the soil physical properties negatively, that became evident in the increment of losses with the runoff. The bigger loss of soil was correlated with MT use and it diminished to the 50 % with HTT: (MT 6.12 tha^–1 year^–1; CMT 5.0 tha^–1 year^–1; ATT 3.7 tha^–1 year^–1 and HTT 2.73 tha^–1 year^–1. ATT generated the bigger cost–reducing and environmental retribution, because his production (13 tha^–1 was major than the average obtained in the treatments (12.4 tha^–1 and the lost one belonging to ground was minor than the generated for MT and CMT.Este estudio avaluó la pérdida y los cambios en las propiedades físicas del suelo y la producción de papa amarilla Solanum phureja, como resultado de cuatro sistemas de labranza (Tracción humana, LTH; Tracción animal, LTA; Mecánica, LM; y Mecánica combinada, LMC en Santa Lucía, municipio de Tuluá, región alto andina de Colombia a 2.870 msnm. Los tratamientos se evaluaron usando un diseño de bloques completos al azar con tres repeticiones. La pérdida de suelo se determinó por medio de canaletas de escorrentía. La información se analizó por medio de una matriz de cambio para

Developmentally Sensitive Interaction Effects of Genes and the Social Environment on Total and Subcortical Brain Volumes.

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Jennifer S Richards

Full Text Available Smaller total brain and subcortical volumes have been linked to psychopathology including attention-deficit/hyperactivity disorder (ADHD. Identifying mechanisms underlying these alterations, therefore, is of great importance. We investigated the role of gene-environment interactions (GxE in interindividual variability of total gray matter (GM, caudate, and putamen volumes. Brain volumes were derived from structural magnetic resonance imaging scans in participants with (N = 312 and without ADHD (N = 437 from N = 402 families (age M = 17.00, SD = 3.60. GxE effects between DAT1, 5-HTT, and DRD4 and social environments (maternal expressed warmth and criticism; positive and deviant peer affiliation as well as the possible moderating effect of age were examined using linear mixed modeling. We also tested whether findings depended on ADHD severity. Deviant peer affiliation was associated with lower caudate volume. Participants with low deviant peer affiliations had larger total GM volumes with increasing age. Likewise, developmentally sensitive GxE effects were found on total GM and putamen volume. For total GM, differential age effects were found for DAT1 9-repeat and HTTLPR L/L genotypes, depending on the amount of positive peer affiliation. For putamen volume, DRD4 7-repeat carriers and DAT1 10/10 homozygotes showed opposite age relations depending on positive peer affiliation and maternal criticism, respectively. All results were independent of ADHD severity. The presence of differential age-dependent GxE effects might explain the diverse and sometimes opposing results of environmental and genetic effects on brain volumes observed so far.

The influence of genetic and environmental factors among MDMA users in cognitive performance.

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Elisabet Cuyàs

Full Text Available This study is aimed to clarify the association between MDMA cumulative use and cognitive dysfunction, and the potential role of candidate genetic polymorphisms in explaining individual differences in the cognitive effects of MDMA. Gene polymorphisms related to reduced serotonin function, poor competency of executive control and memory consolidation systems, and high enzymatic activity linked to bioactivation of MDMA to neurotoxic metabolites may contribute to explain variations in the cognitive impact of MDMA across regular users of this drug. Sixty ecstasy polydrug users, 110 cannabis users and 93 non-drug users were assessed using cognitive measures of Verbal Memory (California Verbal Learning Test, CVLT, Visual Memory (Rey-Osterrieth Complex Figure Test, ROCFT, Semantic Fluency, and Perceptual Attention (Symbol Digit Modalities Test, SDMT. Participants were also genotyped for polymorphisms within the 5HTT, 5HTR2A, COMT, CYP2D6, BDNF, and GRIN2B genes using polymerase chain reaction and TaqMan polymerase assays. Lifetime cumulative MDMA use was significantly associated with poorer performance on visuospatial memory and perceptual attention. Heavy MDMA users (>100 tablets lifetime use interacted with candidate gene polymorphisms in explaining individual differences in cognitive performance between MDMA users and controls. MDMA users carrying COMT val/val and SERT s/s had poorer performance than paired controls on visuospatial attention and memory, and MDMA users with CYP2D6 ultra-rapid metabolizers performed worse than controls on semantic fluency. Both MDMA lifetime use and gene-related individual differences influence cognitive dysfunction in ecstasy users.

Developmentally Sensitive Interaction Effects of Genes and the Social Environment on Total and Subcortical Brain Volumes.

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Richards, Jennifer S; Arias Vásquez, Alejandro; Franke, Barbara; Hoekstra, Pieter J; Heslenfeld, Dirk J; Oosterlaan, Jaap; Faraone, Stephen V; Buitelaar, Jan K; Hartman, Catharina A

2016-01-01

Smaller total brain and subcortical volumes have been linked to psychopathology including attention-deficit/hyperactivity disorder (ADHD). Identifying mechanisms underlying these alterations, therefore, is of great importance. We investigated the role of gene-environment interactions (GxE) in interindividual variability of total gray matter (GM), caudate, and putamen volumes. Brain volumes were derived from structural magnetic resonance imaging scans in participants with (N = 312) and without ADHD (N = 437) from N = 402 families (age M = 17.00, SD = 3.60). GxE effects between DAT1, 5-HTT, and DRD4 and social environments (maternal expressed warmth and criticism; positive and deviant peer affiliation) as well as the possible moderating effect of age were examined using linear mixed modeling. We also tested whether findings depended on ADHD severity. Deviant peer affiliation was associated with lower caudate volume. Participants with low deviant peer affiliations had larger total GM volumes with increasing age. Likewise, developmentally sensitive GxE effects were found on total GM and putamen volume. For total GM, differential age effects were found for DAT1 9-repeat and HTTLPR L/L genotypes, depending on the amount of positive peer affiliation. For putamen volume, DRD4 7-repeat carriers and DAT1 10/10 homozygotes showed opposite age relations depending on positive peer affiliation and maternal criticism, respectively. All results were independent of ADHD severity. The presence of differential age-dependent GxE effects might explain the diverse and sometimes opposing results of environmental and genetic effects on brain volumes observed so far.

The utility of zebrafish to study the mechanisms by which ethanol affects social behavior and anxiety during early brain development.

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Parker, Matthew O; Annan, Leonette V; Kanellopoulos, Alexandros H; Brock, Alistair J; Combe, Fraser J; Baiamonte, Matteo; Teh, Muy-Teck; Brennan, Caroline H

2014-12-03

Exposure to moderate levels of ethanol during brain development has a number of effects on social behavior but the molecular mechanisms that mediate this are not well understood. Gaining a better understanding of these factors may help to develop therapeutic interventions in the future. Zebrafish offer a potentially useful model in this regard. Here, we introduce a zebrafish model of moderate prenatal ethanol exposure. Embryos were exposed to 20mM ethanol for seven days (48hpf-9dpf) and tested as adults for individual social behavior and shoaling. We also tested their basal anxiety with the novel tank diving test. We found that the ethanol-exposed fish displayed reductions in social approach and shoaling, and an increase in anxiety in the novel tank test. These behavioral differences corresponded to differences in hrt1aa, slc6a4 and oxtr expression. Namely, acute ethanol caused a spike in oxtr and ht1aa mRNA expression, which was followed by down-regulation at 7dpf, and an up-regulation in slc6a4 at 72hpf. This study confirms the utility of zebrafish as a model system for studying the molecular basis of developmental ethanol exposure. Furthermore, it proposes a putative developmental mechanism characterized by ethanol-induced OT inhibition leading to suppression of 5-HT and up-regulation of 5-HT1A, which leads, in turn, to possible homeostatic up-regulation of 5-HTT at 72hpf and subsequent imbalance of the 5-HT system. Copyright © 2014 Elsevier Inc. All rights reserved.

A functional polymorphism in a serotonin transporter gene (5-HTTLPR) interacts with 9/11 to predict gun-carrying behavior.

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Barnes, J C; Beaver, Kevin M; Boutwell, Brian B

2013-01-01

On September 11, 2001, one of the deadliest terrorist attacks in US history took place on American soil and people around the world were impacted in myriad ways. Building on prior literature which suggests individuals are more likely to purchase a gun for self-protection if they are fearful of being victimized, the authors hypothesized that the terrorist attacks of 9/11 would lead to an increase in gun carrying among US residents. At the same time, a line of research has shown that a polymorphism in the 5-HTT gene (i.e., 5-HTTLPR) interacts with environmental stressors to predict a range of psychopathologies and behaviors. Thus, it was hypothesized that 9/11 and 5-HTTLPR would interact to predict gun carrying. The results supported both hypotheses by revealing a positive association between 9/11 and gun carrying (b = .426, odds ratio = 1.531, standard error for b = .194, z = 2.196, p = .028) in the full sample of respondents (n = 15,052) and a statistically significant interaction between 9/11 and 5-HTTLPR in the prediction of gun carrying (b = -1.519, odds ratio = .219, standard error for b = .703, z = -2.161, p = .031) in the genetic subsample of respondents (n = 2,350). This is one of the first studies to find an association between 9/11 and gun carrying and, more importantly, is the first study to report a gene-environment interaction (GxE) between a measured gene and a terrorist attack.

Electrochemical Performance of Electrospun carbon nanofibers as free-standing and binder-free anodes for Sodium-Ion and Lithium-Ion Batteries

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Jin, Juan; Shi, Zhi-qiang; Wang, Cheng-yang

2014-01-01

Highlights: • Electrospun carbon nanofiber webs were prepared by pyrolysis of polyacrylonitrile. • The webs as binder-free and current collector-free electrodes for SIBs and LIBs. • Different layer spacing and pore size for Li and Na lead different electrochemical behavior. • Electrochemical performances of the electrodes were high. - Abstract: A series of hard carbon nanofiber-based electrodes derived from electrospun polyacrylonitrile (PAN) nanofibers (PAN-CNFs) have been fabricated by stabilization in air at about 280 °C and then carbonization in N 2 at heat treatment temperatures (HTT) between 800 and 1500 °C. The electrochemical performances of the binder-free, current collector-free carbon nanofiber-based anodes in lithium-ion batteries and sodium-ion batteries are systematically investigated and compared. We demonstrate the presence of similar alkali metal insertion mechanisms in both cases, but just the differences of the layer spacing and pore size available for lithium and sodium ion lead the discharge capacity delivered at sloping region and plateau region to vary from the kinds of alkali elements. Although the anodes in sodium-ion batteries show poorer rate capability than that in lithium-ion batteries, they still achieve a reversible sodium intercalation capacity of 275 mAh g −1 and similar cycling stability due to the conductive 3-D network, weakly ordered turbostratic structure and a large interlayer spacing between graphene sheets. The feature of high capacity and stable cycling performance makes PAN-CNFs to be promising candidates as electrodes in rechargeable sodium-ion batteries and lithium-ion batteries

Drosophila eye color mutants as therapeutic tools for Huntington disease.

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Green, Edward W; Campesan, Susanna; Breda, Carlo; Sathyasaikumar, Korrapati V; Muchowski, Paul J; Schwarcz, Robert; Kyriacou, Charalambos P; Giorgini, Flaviano

2012-01-01

Huntington disease (HD) is a fatal inherited neurodegenerative disorder caused by a polyglutamine expansion in the huntingtin protein (htt). A pathological hallmark of the disease is the loss of a specific population of striatal neurons, and considerable attention has been paid to the role of the kynurenine pathway (KP) of tryptophan (TRP) degradation in this process. The KP contains three neuroactive metabolites: 3-hydroxykynurenine (3-HK), quinolinic acid (QUIN), and kynurenic acid (KYNA). 3-HK and QUIN are neurotoxic, and are increased in the brains of early stage HD patients, as well as in yeast and mouse models of HD. Conversely, KYNA is neuroprotective and has been shown to be decreased in HD patient brains. We recently used a Drosophila model of HD to measure the neuroprotective effect of genetic and pharmacological inhibition of kynurenine monoxygenase (KMO)-the enzyme catalyzing the formation of 3-HK at a pivotal branch point in the KP. We found that KMO inhibition in Drosophila robustly attenuated neurodegeneration, and that this neuroprotection was correlated with reduced levels of 3-HK relative to KYNA. Importantly, we showed that KP metabolites are causative in this process, as 3-HK and KYNA feeding experiments modulated neurodegeneration. We also found that genetic inhibition of the upstream KP enzyme tryptophan-2,3-dioxygenase (TDO) was neuroprotective in flies. Here, we extend these results by reporting that genetic impairment of KMO or TDO is protective against the eclosion defect in HD model fruit flies. Our results provide further support for the possibility of therapeutic KP interventions in HD.

Neurogenética en el Perú, ejemplo de investigación traslacional

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Pilar Mazzetti

Full Text Available La neurogenética es una disciplina emergente en el Perú que vincula la investigación básica con la práctica clínica. El Centro de Investigación Básica en Neurogenética, es el único centro en el Perú dedicado a la atención especializada de enfermedades neurogenéticas. La investigación en esta área está estrechamente ligada a la enfermedad de Huntington, desde la genotipificación del gen HTT por PCR, hasta los actuales estudios de haplogrupos en esta enfermedad. La investigación en otras enfermedades monogénicas permitió la implementación de metodologías alternativas para la genotipificación del síndrome X frágil y distrofia miotónica tipo 1. Esfuerzos colaborativos nacionales e internacionales han permitido conocer nuevas variantes genéticas en enfermedades complejas, como la enfermedad de Parkinson y Alzheimer. El entrenamiento multidisciplinario y la mentoría fomentan la formación de nuevos especialistas en neurogenética, permitiendo el crecimiento sostenido de esta disciplina en el país. El impulso de la investigación en el Perú ha impulsado el crecimiento de la investigación en neurogenética; sin embargo, las limitaciones en infraestructura, tecnología y capacitación aún son un reto para el crecimiento de investigación en esta disciplina

Proceedings of Patient Reported Outcome Measure’s (PROMs Conference Sheffield 2016: advances in patient reported outcomes research

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Tim Croudace

2016-10-01

Full Text Available Table of contents S1 Using computerized adaptive testing Tim Croudace S2 Well-being: what is it, how does it compare to health and what are the implications of using it to inform health policy John Brazier O1 “Am I going to get better?”—Using PROMs to inform patients about the likely benefit of surgery Nils Gutacker, Andrew Street O2 Identifying Patient Reported Outcome Measures for an electronic Personal Health Record Dan Robotham, Samantha Waterman, Diana Rose, Safarina Satkunanathan, Til Wykes O3 Examining the change process over time qualitatively: transformative learning and response shift Nasrin Nasr, Pamela Enderby O4 Developing a PROM to evaluate self-management in diabetes (HASMID: giving patients a voice Jill Carlton, Donna Rowen, Jackie Elliott, John Brazier, Katherine Stevens, Hasan Basarir, Alex Labeit O5 Development of the Primary Care Outcomes Questionnaire (PCOQ Mairead Murphy, Sandra Hollinghurst, Chris Salisbury O6 Developing the PKEX score- a multimodal assessment tool for patients with shoulder problems Dominic Marley, James Wilson, Amy Barrat, Bibhas Roy O7 Applying multiple imputation to multi-item patient reported outcome measures: advantages and disadvantages of imputing at the item, sub-scale or score level Ines Rombach, Órlaith Burke, Crispin Jenkinson, Alastair Gray, Oliver Rivero-Arias O8 Integrating Patient Reported Outcome Measures (PROMs into routine primary care for patients with multimorbidity: a feasibility study Ian Porter, Jaheeda Gangannagaripalli, Charlotte Bramwell, Jose M. Valderas O9 eRAPID: electronic self-report and management of adverse-events for pelvic radiotherapy (RT patients Patricia Holch, Susan Davidson, Jacki Routledge, Ann Henry, Kevin Franks, Alex Gilbert, Kate Absolom & Galina Velikova O10 Patient reported outcomes (PROMs based recommendation in clinical guidance for the management of chronic conditions in the United Kingdom Ian Porter, Jose M.Valderas O11 Cross-sectional and

Genetic loading on human loving styles.

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Emanuele, Enzo; Brondino, Natascia; Pesenti, Sara; Re, Simona; Geroldi, Diego

2007-12-01

It has been hypothesized that cerebral neurotransmitters such as dopamine and serotonin could play a role in human romantic bonding. However, no data on the genetic basis of human romantic love are currently available. To address this issue, we looked for associations between markers in neurotransmitter genes (the serotonin transporter gene, 5-HTT; the serotonin receptor 2A, 5HT2A; the dopamine D2 receptor gene, DRD2; and the dopamine D4 receptor gene, DRD4) and the six styles of love as conceptualized by Lee (Eros, Ludus, Storge, Pragma, Mania and Agape). A total of 350 healthy young adults (165 males and 185 females, mean age: 24.1+/-3.9 years, range 18-32 years) filled the 24-item Love Attitudes Scale (LAS) and were genotyped for the following six polymorphic markers: the serotonin transporter-linked polymorphic region (5-HTTLPR), the 5HT2A T102C and C516T polymorphisms, the DRD2 TaqI A and TaqI B variants, and the DRD4 exon 3 VNTR polymorphism. Statistical analysis revealed a significant association between the DRD2 TaqI A genotypes and "Eros" (a loving style characterized by a tendency to develop intense emotional experiences based on the physical attraction to the partner), as well as between the C516T 5HT2A polymorphism and "Mania" (a possessive and dependent romantic attachment, characterized by self-defeating emotions). These associations were present in both sexes and remained significant even after adjustment for potential confounders. Our data provide the first evidence of a possible genetic loading on human loving styles.

Muerte fetal en el Hospital Nacional Arzobispo Loayza durante el periodo agosto 2003-noviembre 2004.

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Luis Miguel Milla Vera

2005-10-01

Full Text Available Objetivos: Identificar las causas de los casos de muerte fetal, así como sus características sociodemográficas, clínicas, patológicas, y la tasa. Materiales y métodos: Se realizó un estudio descriptivo. Se buscaron los casos de muerte fetal en el libro de registros del servicio de obstetricia del Hospital Nacional Arzobispo Loayza entre agosto 2003 y noviembre 2004. Se buscaron las historias clínicas e informes anatomopatológicos correspondientes recopilándose los hallazgos. Resultados: Se encontraron 61 casos de muerte fetal, 47 se incluyeron en el estudio. Se registraron 4 524 nacidos vivos. La tasa de muerte fetal fue 13,48 por 1 000 nacidos vivos. Edad gestacional promedio fue de 28,29 semanas y peso promedio de 1 277,86 g. La edad menor a 35 años (76,59%, ausencia de control prenatal o control prenatal inadecuado (66,66%, paridad menor a 4 (86,96%, antecedente de aborto (21,73%, pequeño para edad gestacional (PEG (28,26%, hemorragia del tercer trimestre (HTT (17,39%, preeclampsia (8,69% y hallazgos anormales placentarios (23,28% fueron las características sociodemográficas, clínicas y patológicas más frecuentes. El 59,27% de los casos presentaba informe de patología. No se logró inferir causa alguna en 36,2%. Conclusiones: Los casos de muerte fetal durante el periodo de estudio no contenían los datos tanto clínicos como patológicos suficientes para identificar claramente las causas de muerte fetal. (Rev Med Hered 2005;16:260-265.

Functional convergence of Akt protein with VEGFR-1 in human endothelial progenitor cells exposed to sera from patient with type 2 diabetes mellitus.

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Hassanpour, Mehdi; Rezabakhsh, Aysa; Rahbarghazi, Reza; Nourazarian, Alireza; Nouri, Mohammad; Avci, Çığır Biray; Ghaderi, Shahrooz; Alidadyani, Neda; Bagca, Bakiye Goker; Bagheri, Hesam Saghaei

2017-11-01

Diabetes mellitus type 2 predisposes patients to various microvascular complications. In the current experiment, the potent role of diabetes mellitus was investigated on the content of VEGFR-1, -2, Tie-1 and -2, and Akt in human endothelial progenitor cells. The gene expression profile of mTOR and Hedgehog signaling pathways were measured by PCR array. The possible crosstalk between RTKs, mTOR and Hedgehog signaling was also studied by bioinformatic analysis. Endothelial progenitor cells were incubated with serum from normal and diabetic for 7days. Compared to non-treated cells, diabetic serum-induced cell apoptosis (~2-fold) and prohibited cell migration toward bFGF (p1). ELISA analysis showed that diabetes exposed cells had increased abundance of Tie-1, -2 and VEGFR-2 and reduced amount of VEGFR-1 (p1) in diabetic cells. Western blotting showed a marked reduction in the protein level of Akt after cells exposure to serum from diabetic subjects (p1). PCR array revealed a significant stimulation of both mTOR and Hedgehog signaling pathways in diabetic cells (p1, -2 and Tie-2, but not Tie-1, are master regulators of angiogenesis. There is a crosstalk between RTKs and mTOR signaling by involving P62, GABARAPL1, and HTT genes. It seems that physical interaction and co-expression of Akt decreased the level of VEGFR-1 in diabetic cells. Regarding data from the present experiment, diabetic serum contributed to uncontrolled induction of both mTOR and Hedgehog signaling in endothelial progenitor cells. Diabetes mellitus induces mTOR pathway by involving receptor tyrosine kinases while Hedgehog stimulation is independent of these receptors. Copyright © 2017 Elsevier Inc. All rights reserved.

Identification of extreme motor phenotypes in Huntington's disease.

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Braisch, Ulrike; Hay, Birgit; Muche, Rainer; Rothenbacher, Dietrich; Landwehrmeyer, G Bernhard; Long, Jeffrey D; Orth, Michael

2017-04-01

The manifestation of motor signs in Huntington's disease (HD) has a well-known inverse relationship with HTT CAG repeat length, but the prediction is far from perfect. The probability of finding disease modifiers is enhanced in individuals with extreme HD phenotypes. We aimed to identify extreme HD motor phenotypes conditional on CAG and age, such as patients with very early or very late onset of motor manifestation. Retrospective data were available from 1,218 healthy controls and 9,743 HD participants with CAG repeats ≥40, and a total of about 30,000 visits. Boundaries (2.5% and 97.5% quantiles) for extreme motor phenotypes (UHDRS total motor score (TMS) and motor age-at-onset) were estimated using quantile regression for longitudinal data. More than 15% of HD participants had an extreme TMS phenotype for at least one visit. In contrast, only about 4% of participants were consistent TMS extremes at two or more visits. Data from healthy controls revealed an upper cut-off of 13 for the TMS representing the extreme of motor ratings for a normal aging population. In HD, boundaries of motor age-at-onset based on diagnostic confidence or derived from the TMS data cut-off in controls were similar. In summary, a UHDRS TMS of more than 13 in an individual carrying the HD mutation indicates a high likelihood of motor manifestations of HD irrespective of CAG repeat length or age. The identification of motor phenotype extremes can be useful in the search for disease modifiers, for example, genetic or environmental such as medication. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Characterization and selection of biochar for an efficient retention of tricyclazole in a flooded alluvial paddy soil

International Nuclear Information System (INIS)

García-Jaramillo, Manuel; Cox, Lucía; Knicker, Heike E.; Cornejo, Juan; Spokas, Kurt A.; Hermosín, M.Carmen

2015-01-01

Highlights: • Biochar CEC was inversely correlated with HTT. • Enhanced aromaticity was associated to an improved biochar adsorption of tricyclazole. • The SSA of the biochars was inversely correlated with DOC contents. • Adsorption of tricyclazole was related to high SSA and low DOC content of biochars. • The use of AC and biochar in conjunction provides the slow release of tricyclazole. - Abstract: Biochars, from different organic residues, are increasingly proposed as soil amendments for their agronomic and environmental benefits. A systematic detection method that correlates biochar properties to their abilities to adsorb organic compounds is still lacking. Seven biochars obtained after pyrolysis at different temperatures and from different feedstock (alperujo compost, rice hull, and woody debris), were characterized and tested to reveal potential remedial forms for pesticide capture in flooded soils. Biochar properties were determined by nuclear magnetic resonance (NMR) spectroscopy, Fourier transform infrared spectroscopy, specific surface area (SSA) assessment and scanning electron microscopy. In addition, dissolved organic matter (DOM) from these biochars was extracted and quantified in order to evaluate the effect on pesticide sorption. The biochars from alperujo compost presented very high affinity to the fungicide tricyclazole (55.9, 83.5, and 90.3% for B1, B4, and B5, respectively). This affinity was positively correlated with the pyrolysis temperature, the pH, the increased SSA of the biochars, and the enhanced aromaticity. Sorptive capacities were negatively related to DOM contents. The amendment with a mixture of compost and biochar endows the alluvial soil with high sorptive properties (from K fads(soil) = 9.26 to K fads(mixture) = 17.89) without impeding the slow release of tricyclazole

Transgenic animal models for study of the pathogenesis of Huntington’s disease and therapy

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Chang RB

2015-04-01

Full Text Available Renbao Chang,1 Xudong Liu,1 Shihua Li,2 Xiao-Jiang Li1,2 1State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, People’s Republic of China; 2Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA Abstract: Huntington’s disease (HD is caused by a genetic mutation that results in polyglutamine expansion in the N-terminal regions of huntingtin. As a result, this polyQ expansion leads to the misfolding and aggregation of mutant huntingtin as well as age-dependent neurodegeneration. The genetic mutation in HD allows for generating a variety of animal models that express different forms of mutant huntingtin and show differential pathology. Studies of these animal models have provided an important insight into the pathogenesis of HD. Mouse models of HD include transgenic mice, which express N-terminal or full-length mutant huntingtin ubiquitously or selectively in different cell types, and knock-in mice that express full-length mutant Htt at the endogenous level. Large animals, such as pig, sheep, and monkeys, have also been used to generate animal HD models. This review focuses on the different features of commonly used transgenic HD mouse models as well as transgenic large animal models of HD, and also discusses how to use them to identify potential therapeutics. Since HD shares many pathological features with other neurodegenerative diseases, identification of therapies for HD would also help to develop effective treatment for different neurodegenerative diseases that are also caused by protein misfolding and occur in an age-dependent manner. Keywords: transgenic animal models, Huntington’s disease, pathogenesis, therapy

Neuropathological Comparison of Adult Onset and Juvenile Huntington's Disease with Cerebellar Atrophy: A Report of a Father and Son.

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Latimer, Caitlin S; Flanagan, Margaret E; Cimino, Patrick J; Jayadev, Suman; Davis, Marie; Hoffer, Zachary S; Montine, Thomas J; Gonzalez-Cuyar, Luis F; Bird, Thomas D; Keene, C Dirk

2017-01-01

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a trinucleotide (CAG) repeat expansion in huntingtin (HTT) on chromosome 4. Anticipation can cause longer repeat expansions in children of HD patients. Juvenile Huntington's disease (JHD), defined as HD arising before age 20, accounts for 5-10% of HD cases, with cases arising in the first decade accounting for approximately 1%. Clinically, JHD differs from the predominately choreiform adult onset Huntington's disease (AOHD) with variable presentations, including symptoms such as myoclonus, seizures, Parkinsonism, and cognitive decline. The neuropathologic changes of AOHD are well characterized, but there are fewer reports that describe the neuropathology of JHD. Here we report a case of a six-year-old boy with paternally-inherited JHD caused by 169 CAG trinucleotide repeats who presented at age four with developmental delay, dysarthria, and seizures before dying at age 6. The boy's clinical presentation and neuropathological findings are directly compared to those of his father, who presented with AOHD and 54 repeats. A full autopsy was performed for the JHD case and a brain-only autopsy was performed for the AOHD case. Histochemically- and immunohistochemically-stained slides were prepared from formalin-fixed, paraffin-embedded tissue sections. Both cases had neuropathology corresponding to Vonsattel grade 3. The boy also had cerebellar atrophy with huntingtin-positive inclusions in the cerebellum, findings not present in the father. Autopsies of father and son provide a unique opportunity to compare and contrast the neuropathologic findings of juvenile and adult onset HD while also providing the first immunohistochemical evidence of cerebellar involvement in JHD. Additionally this is the first known report to include findings from peripheral tissue in a case of JHD.

An Ancient Transkingdom Horizontal Transfer of Penelope-Like Retroelements from Arthropods to Conifers.

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Lin, Xuan; Faridi, Nurul; Casola, Claudio

2016-05-02

Comparative genomics analyses empowered by the wealth of sequenced genomes have revealed numerous instances of horizontal DNA transfers between distantly related species. In eukaryotes, repetitive DNA sequences known as transposable elements (TEs) are especially prone to move across species boundaries. Such horizontal transposon transfers, or HTTs, are relatively common within major eukaryotic kingdoms, including animals, plants, and fungi, while rarely occurring across these kingdoms. Here, we describe the first case of HTT from animals to plants, involving TEs known as Penelope-like elements, or PLEs, a group of retrotransposons closely related to eukaryotic telomerases. Using a combination of in situ hybridization on chromosomes, polymerase chain reaction experiments, and computational analyses we show that the predominant PLE lineage, EN(+)PLEs, is highly diversified in loblolly pine and other conifers, but appears to be absent in other gymnosperms. Phylogenetic analyses of both protein and DNA sequences reveal that conifers EN(+)PLEs, or Dryads, form a monophyletic group clustering within a clade of primarily arthropod elements. Additionally, no EN(+)PLEs were detected in 1,928 genome assemblies from 1,029 nonmetazoan and nonconifer genomes from 14 major eukaryotic lineages. These findings indicate that Dryads emerged following an ancient horizontal transfer of EN(+)PLEs from arthropods to a common ancestor of conifers approximately 340 Ma. This represents one of the oldest known interspecific transmissions of TEs, and the most conspicuous case of DNA transfer between animals and plants. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution 2016. This work is written by US Government employees and is in the public domain in the US.

Citalopram for the Treatment of Agitation in Alzheimer Dementia: Genetic Influences.

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Peters, Matthew E; Vaidya, Vijay; Drye, Lea T; Devanand, Davangere P; Mintzer, Jacobo E; Pollock, Bruce G; Porsteinsson, Anton P; Rosenberg, Paul B; Schneider, Lon S; Shade, David M; Weintraub, Daniel; Yesavage, Jerome; Lyketsos, Constantine G; Avramopoulos, Dimitri

2016-03-01

To assess potential genetic influences on citalopram treatment efficacy for agitation in individuals with Alzheimer dementia (AD). Six functional genetic variants were studied in the following genes: serotonin receptor 2A (HTR2A-T102C), serotonin receptor 2C (HTR2C-Cys23Ser), serotonin transporter (5HTT-LPR), brain-derived neurotropic factor (BDNF-Val66Met), apolipoprotein E (ε2, ε3, ε4 variants), and cytochrome P450 (CYP2C19). Treatment response by genotype was measured by (1) the agitation domain of the Neurobehavioral Rating Scale, (2) the modified Alzheimer Disease Cooperative Study-Clinical Global Impression of Change scale (mADCS-CGIC), (3) the agitation domain of the Neuropsychiatric Inventory (NPI), and (4) the Cohen-Mansfield Agitation Inventory. We utilized data from the Citalopram for Agitation in Alzheimer's Disease (CitAD) database. CitAD was a 9-week randomized, double-blind, placebo-controlled multicenter clinical trial showing significant improvement in agitation and caregiver distress in patients treated with citalopram. Proportional odds logistic regression and mixed effects models were used to examine the above-mentioned outcome measures. Significant interactions were noted on the NPI agitation domain for HTR2A (likelihood ratio [LR] = 6.19, df = 2, P = .04) and the mADCS-CGIC for HTR2C (LR = 4.33, df = 2, P = .02) over 9 weeks. Treatment outcomes in CitAD showed modest, although statistically significant, influence of genetic variation at HTR2A and HTR2C loci. Future studies should continue to examine the interaction of known genetic variants with antidepressant treatment in patients with AD having agitation. © The Author(s) 2015.

Characterization and selection of biochar for an efficient retention of tricyclazole in a flooded alluvial paddy soil

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García-Jaramillo, Manuel, E-mail: mgarcia@irnas.csic.es [Instituto de Recursos Naturales y Agrobiología de Sevilla (IRNAS-CSIC), P.O. Box 1052, 41080 Seville (Spain); Cox, Lucía; Knicker, Heike E.; Cornejo, Juan [Instituto de Recursos Naturales y Agrobiología de Sevilla (IRNAS-CSIC), P.O. Box 1052, 41080 Seville (Spain); Spokas, Kurt A. [United States Department of Agriculture–Agricultural Research Service, 1991 Upper Buford Circle, Saint Paul 55108, MN (United States); Hermosín, M.Carmen [Instituto de Recursos Naturales y Agrobiología de Sevilla (IRNAS-CSIC), P.O. Box 1052, 41080 Seville (Spain)

2015-04-09

Highlights: • Biochar CEC was inversely correlated with HTT. • Enhanced aromaticity was associated to an improved biochar adsorption of tricyclazole. • The SSA of the biochars was inversely correlated with DOC contents. • Adsorption of tricyclazole was related to high SSA and low DOC content of biochars. • The use of AC and biochar in conjunction provides the slow release of tricyclazole. - Abstract: Biochars, from different organic residues, are increasingly proposed as soil amendments for their agronomic and environmental benefits. A systematic detection method that correlates biochar properties to their abilities to adsorb organic compounds is still lacking. Seven biochars obtained after pyrolysis at different temperatures and from different feedstock (alperujo compost, rice hull, and woody debris), were characterized and tested to reveal potential remedial forms for pesticide capture in flooded soils. Biochar properties were determined by nuclear magnetic resonance (NMR) spectroscopy, Fourier transform infrared spectroscopy, specific surface area (SSA) assessment and scanning electron microscopy. In addition, dissolved organic matter (DOM) from these biochars was extracted and quantified in order to evaluate the effect on pesticide sorption. The biochars from alperujo compost presented very high affinity to the fungicide tricyclazole (55.9, 83.5, and 90.3% for B1, B4, and B5, respectively). This affinity was positively correlated with the pyrolysis temperature, the pH, the increased SSA of the biochars, and the enhanced aromaticity. Sorptive capacities were negatively related to DOM contents. The amendment with a mixture of compost and biochar endows the alluvial soil with high sorptive properties (from K{sub fads(soil)} = 9.26 to K{sub fads(mixture)} = 17.89) without impeding the slow release of tricyclazole.

Tensor decomposition-based unsupervised feature extraction identifies candidate genes that induce post-traumatic stress disorder-mediated heart diseases.

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Taguchi, Y-H

2017-12-21

Although post-traumatic stress disorder (PTSD) is primarily a mental disorder, it can cause additional symptoms that do not seem to be directly related to the central nervous system, which PTSD is assumed to directly affect. PTSD-mediated heart diseases are some of such secondary disorders. In spite of the significant correlations between PTSD and heart diseases, spatial separation between the heart and brain (where PTSD is primarily active) prevents researchers from elucidating the mechanisms that bridge the two disorders. Our purpose was to identify genes linking PTSD and heart diseases. In this study, gene expression profiles of various murine tissues observed under various types of stress or without stress were analyzed in an integrated manner using tensor decomposition (TD). Based upon the obtained features, ∼ 400 genes were identified as candidate genes that may mediate heart diseases associated with PTSD. Various gene enrichment analyses supported biological reliability of the identified genes. Ten genes encoding protein-, DNA-, or mRNA-interacting proteins-ILF2, ILF3, ESR1, ESR2, RAD21, HTT, ATF2, NR3C1, TP53, and TP63-were found to be likely to regulate expression of most of these ∼ 400 genes and therefore are candidate primary genes that cause PTSD-mediated heart diseases. Approximately 400 genes in the heart were also found to be strongly affected by various drugs whose known adverse effects are related to heart diseases and/or fear memory conditioning; these data support the reliability of our findings. TD-based unsupervised feature extraction turned out to be a useful method for gene selection and successfully identified possible genes causing PTSD-mediated heart diseases.

Binding, internalization and fate of Huntingtin Exon1 fibrillar assemblies in mitotic and nonmitotic neuroblastoma cells.

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Ruiz-Arlandis, G; Pieri, L; Bousset, L; Melki, R

2016-02-01

The aggregation of Huntingtin (HTT) protein and of its moiety encoded by its Exon1 (HTTExon1) into fibrillar structures inside neurons is the molecular hallmark of Huntington's disease. Prion-like transmission of these aggregates between cells has been demonstrated. The cell-to-cell transmission mechanisms of these protein aggregates and the susceptibility of different kinds of neuronal cells to these toxic assemblies still need assessment. Here, we documented the binding to and internalization by differentiated and undifferentiated neuroblastoma cells of exogenous fibrillar HTTExon1 and polyglutamine (polyQ) polypeptides containing the same number of glutamines. We assessed the contribution of endocytosis to fibrillar HTTExon1 uptake, their intracellular localization and fate. We observed that undifferentiated neuroblastoma cells were more susceptible to fibrillar HTTExon1 and polyQ than their differentiated counterparts. Furthermore, we demonstrated that exogenous HTTExon1 aggregates are mainly taken up by endocytosis and directed to lysosomal compartments in both mitotic and quiescent cells. These data suggest that the rates of endocytic processes that differ in mitotic and quiescent cells strongly impact the uptake of exogenous HTTExon1 and polyQ fibrils. This may be either the consequence of distinct metabolisms or distributions of specific protein partners for amyloid-like assemblies at the surface of highly dividing versus quiescent cells. Our results highlight the importance of endocytic processes in the internalization of exogenous HTTExon1 fibrils and suggest that a proportion of those assemblies reach the cytosol where they can amplify by recruiting the endogenous protein after escaping, by yet an unknown process, from the endo-lysosomal compartments. © 2015 British Neuropathological Society.

Genetic influences on attention deficit hyperactivity disorder symptoms from age 2 to 3: A quantitative and molecular genetic investigation

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Saudino Kimberly J

2010-12-01

Full Text Available Abstract Background A twin study design was used to assess the degree to which additive genetic variance influences ADHD symptom scores across two ages during infancy. A further objective in the study was to observe whether genetic association with a number of candidate markers reflects results from the quantitative genetic analysis. Method We have studied 312 twin pairs at two time-points, age 2 and age 3. A composite measure of ADHD symptoms from two parent-rating scales: The Child Behavior Checklist/1.5 - 5 years (CBCL hyperactivity scale and the Revised Rutter Parent Scale for Preschool Children (RRPSPC was used for both quantitative and molecular genetic analyses. Results At ages 2 and 3 ADHD symptoms are highly heritable (h2 = 0.79 and 0.78, respectively with a high level of genetic stability across these ages. However, we also observe a significant level of genetic change from age 2 to age 3. There are modest influences of non-shared environment at each age independently (e2 = 0.22 and 0.21, respectively, with these influences being largely age-specific. In addition, we find modest association signals in DAT1 and NET1 at both ages, along with suggestive specific effects of 5-HTT and DRD4 at age 3. Conclusions ADHD symptoms are heritable at ages 2 and 3. Additive genetic variance is largely shared across these ages, although there are significant new effects emerging at age 3. Results from our genetic association analysis reflect these levels of stability and change and, more generally, suggest a requirement for consideration of age-specific genotypic effects in future molecular studies.

Contextual fear conditioning in virtual reality is affected by 5HTTLPR and NPSR1 polymorphisms: effects on fear-potentiated startle

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Evelyn eGlotzbach-Schoon

2013-04-01

Full Text Available The serotonin (5-HT and neuropeptide S (NPS systems are discussed as important genetic modulators of fear and sustained anxiety contributing to the etiology of anxiety disorders. Sustained anxiety is a crucial characteristic of most anxiety disorders which likely develops through context conditioning. This study investigated if and how genetic alterations of the 5-HT and the NPS systems as well as their interaction modulate contextual fear conditioning; specifically, function polymorphic variants in the genes coding for the 5-HT transporter (5HTT and the NPS receptor (NPSR1 were studied. A large group of healthy volunteers was therefore stratified for 5HTTLPR (S+ vs. LL carriers and NPSR1 rs324981 (T+ vs. AA carriers polymorphisms resulting in four genotype groups (S+/T+, S+/AA, LL/T+, LL/AA of 20 participants each. All participants underwent contextual fear conditioning and extinction using a virtual reality paradigm. During acquisition, one virtual office room (anxiety context, CXT+ was paired with an unpredictable electric stimulus (unconditioned stimulus, US, whereas another virtual office room was not paired with any US (safety context, CXT-. During extinction no US was administered. Anxiety responses were quantified by fear-potentiated startle and ratings. Most importantly, we found a gene × gene interaction on fear-potentiated startle. Only carriers of both risk alleles (S+/T+ exhibited higher startle responses in CXT+ compared to CXT-. In contrast, anxiety ratings were only influenced by the NPSR1 polymorphism with AA carriers showing higher anxiety ratings in CXT+ as compared to CXT-. Our results speak in favor of a two level account of fear conditioning with diverging effects on implicit vs. explicit fear responses. Contextual fear reflected in potentiated startle responses may be an endophenotype for anxiety disorders.

Identification of elevated urea as a severe, ubiquitous metabolic defect in the brain of patients with Huntington's disease.

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Patassini, Stefano; Begley, Paul; Reid, Suzanne J; Xu, Jingshu; Church, Stephanie J; Curtis, Maurice; Dragunow, Mike; Waldvogel, Henry J; Unwin, Richard D; Snell, Russell G; Faull, Richard L M; Cooper, Garth J S

Huntington's disease (HD) is a neurodegenerative disorder wherein the aetiological defect is a mutation in the Huntington's gene (HTT), which alters the structure of the huntingtin protein through the lengthening of a polyglutamine tract and initiates a cascade that ultimately leads to dementia and premature death. However, neurodegeneration typically manifests in HD only in middle age, and processes linking the causative mutation to brain disease are poorly understood. Here, our objective was to elucidate further the processes that cause neurodegeneration in HD, by measuring levels of metabolites in brain regions known to undergo varying degrees of damage. We applied gas-chromatography/mass spectrometry-based metabolomics in a case-control study of eleven brain regions in short post-mortem-delay human tissue from nine well-characterized HD patients and nine controls. Unexpectedly, a single major abnormality was evident in all eleven brain regions studied across the forebrain, midbrain and hindbrain, namely marked elevation of urea, a metabolite formed in the urea cycle by arginase-mediated cleavage of arginine. Urea cycle activity localizes primarily in the liver, where it functions to incorporate protein-derived amine-nitrogen into urea for recycling or urinary excretion. It also occurs in other cell-types, but systemic over-production of urea is not known in HD. These findings are consistent with impaired local urea regulation in brain, by up-regulation of synthesis and/or defective clearance. We hypothesize that defective brain urea metabolism could play a substantive role in the pathogenesis of neurodegeneration, perhaps via defects in osmoregulation or nitrogen metabolism. Brain urea metabolism is therefore a target for generating novel monitoring/imaging strategies and/or therapeutic interventions aimed at ameliorating the impact of HD in patients. Copyright © 2015 Elsevier Inc. All rights reserved.

Natural variation in sensory-motor white matter organization influences manifestations of Huntington's disease.

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Orth, Michael; Gregory, Sarah; Scahill, Rachael I; Mayer, Isabella Sm; Minkova, Lora; Klöppel, Stefan; Seunarine, Kiran K; Boyd, Lara; Borowsky, Beth; Reilmann, Ralf; Bernhard Landwehrmeyer, G; Leavitt, Blair R; Roos, Raymund Ac; Durr, Alexandra; Rees, Geraint; Rothwell, John C; Langbehn, Douglas; Tabrizi, Sarah J

2016-12-01

While the HTT CAG-repeat expansion mutation causing Huntington's disease (HD) is highly correlated with the rate of pathogenesis leading to disease onset, considerable variance in age-at-onset remains unexplained. Therefore, other factors must influence the pathogenic process. We asked whether these factors were related to natural biological variation in the sensory-motor system. In 243 participants (96 premanifest and 35 manifest HD; 112 controls), sensory-motor structural MRI, tractography, resting-state fMRI, electrophysiology (including SEP amplitudes), motor score ratings, and grip force as sensory-motor performance were measured. Following individual modality analyses, we used principal component analysis (PCA) to identify patterns associated with sensory-motor performance, and manifest versus premanifest HD discrimination. We did not detect longitudinal differences over 12 months. PCA showed a pattern of loss of caudate, grey and white matter volume, cortical thickness in premotor and sensory cortex, and disturbed diffusivity in sensory-motor white matter tracts that was connected to CAG repeat length. Two further major principal components appeared in controls and HD individuals indicating that they represent natural biological variation unconnected to the HD mutation. One of these components did not influence HD while the other non-CAG-driven component of axial versus radial diffusivity contrast in white matter tracts were associated with sensory-motor performance and manifest HD. The first component reflects the expected CAG expansion effects on HD pathogenesis. One non-CAG-driven component reveals an independent influence on pathogenesis of biological variation in white matter tracts and merits further investigation to delineate the underlying mechanism and the potential it offers for disease modification. Hum Brain Mapp 37:4615-4628, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Overlap between age-at-onset and disease-progression determinants in Huntington disease.

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Aziz, N Ahmad; van der Burg, Jorien M M; Tabrizi, Sarah J; Landwehrmeyer, G Bernhard

2018-05-09

A fundamental but still unresolved issue regarding Huntington disease (HD) pathogenesis is whether the factors that determine age at onset are the same as those that govern disease progression. Because elucidation of this issue is crucial for the development as well as optimal timing of administration of novel disease-modifying therapies, we aimed to assess the extent of overlap between age-at-onset and disease-progression determinants in HD. Using observational data from Enroll-HD, the largest cohort of patients with HD worldwide, in this study we present, validate, and apply an intuitive method based on linear mixed-effect models to quantify the variability in the rate of disease progression in HD. A total of 3,411 patients with HD met inclusion criteria. We found that (1) about two-thirds of the rate of functional, motor, and cognitive progression in HD is determined by the same factors that also determine age at onset, with CAG repeat-dependent mechanisms having by far the largest effect; (2) although expanded HTT CAG repeat size had a large influence on average body weight, the rate of weight loss was largely independent of factors that determine age at onset in HD; and (3) about one-third of the factors that determine the rate of functional, motor, and cognitive progression are different from those that govern age at onset and need further elucidation. Our findings imply that targeting of CAG repeat-dependent mechanisms, for example through gene-silencing approaches, is likely to affect the rate of functional, motor, and cognitive impairment, but not weight loss, in manifest HD mutation carriers. Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Using a commercially available DNA extraction kit to obtain high quality human genomic DNA suitable for PCR and genotyping from 11-year-old saliva saturated cotton spit wads

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Hudziak James J

2008-12-01

Full Text Available Abstract Background We sought to describe the integrity of human genomic DNA extracted from saliva saturated cotton spit wads stored at -20°C for approximately 11 years. 783 spit wad samples were collected from an ADHD sample population (Vermont Family Study during 1996–2000. Human genomic DNA was extracted from the spit wads using a commercially available kit; QIAamp DNA Blood Midi Kit (Qiagen, Inc., Valencia, CA. with a few modifications. Results The resulting DNA yield was more than adequate for genetic analysis and ranged from approximately 1 μg to a total of 80 μg (mean 17.3 μgs ± 11.9 μgs. A260/A280 ratios for the human genomic DNA extracted from the spit wads was consistently within the generally acceptable values of 1.7–2.0, with the lowest purity being 1.70, and a mean value of 1.937 ± 0.226 for the 783 samples. The DNA also was suitable for PCR reactions as evidenced by the amplification of the serotonin-transporter-linked polymorphic region, 5HTTLPR. 5HTTLPR is a functional polymorphism in the promoter region of the serotonin transporter gene (HTT, SLC6A4, or SERT, consisting of two intensively studied alleles. 770 of the 783 samples (98.3% produced fragments after PCR of the expected size with primers specific for 5HTTLPR. Conclusion High quality and abundant genomic DNA can be successfully retrieved from saliva saturated cotton spit wads using the commercially available kit, QIAamp DNA Blood Midi Kit from Qiagen, Inc. Furthermore, the DNA can be extracted in less than 3 hours and multiple samples can be processed simultaneously thus reducing processing time.

The role of the serotonergic and GABA system in translational approaches in drug discovery for anxiety disorders

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Jocelien DA Olivier

2013-06-01

Full Text Available There is ample evidence that genetic factors play an important role in anxiety disorders. In support, human genome-wide association studies have implicated several novel candidate genes. However, illumination of such genetic factors involved in anxiety disorders has not resulted in novel drugs over the past decades. A complicating factor is the heterogeneous classification of anxiety disorders in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR and diverging operationalization of anxiety used in preclinical and clinical studies. Currently, there is an increasing focus on the gene-environment interaction in anxiety as genes do not operate in isolation and environmental factors have been found to significantly contribute to the development of anxiety disorders in at-risk individuals. Nevertheless, extensive research on gene-environment mechanisms in anxiety has not resulted in major breakthroughs in drug discovery. Modification of individual genes in rodent models has enabled the specific study of anxiety in preclinical studies. In this context, two extensively studied neurotransmitters involved in anxiety are the GABA and 5-HT system. In this review, we illustrate the complex interplay between genes and environment in anxiety processes by reviewing preclinical and clinical studies on the serotonin transporter (5-HTT, 5-HT1A receptor, 5-HT2 receptor and GABAA receptor. Even though targets from the serotonin and GABA system have yielded drugs with known anxiolytic efficacy, the relation between the genetic background of these targets and anxiety symptoms and development of anxiety disorders is largely unknown. The aim of this review is to show the vast complexity of genetic and environmental factors in anxiety disorders. In light of the difficulty with which common genetic variants are identified in anxiety disorders, animal models with translational validity may aid in elucidating the neurobiological background of these genes

Genetics of Lesch's typology of alcoholism.

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Samochowiec, Jerzy; Kucharska-Mazur, Jolanta; Grzywacz, Anna; Pelka-Wysiecka, Justyna; Mak, Monika; Samochowiec, Agnieszka; Bienkowski, Przemyslaw

2008-02-15

It is widely accepted that dopamine and serotonin (5-HT) neurotransmission can be critically involved in the development of alcohol abuse and alcohol dependence. Lesch's typology of alcoholism has been gaining increasing popularity as it qualitatively differentiates patients into different treatment response subgroups. The aim of the present study was to evaluate a possible genetic background of Lesch's typology with special emphasis placed on dopamine- and serotonin-related genes. 122 alcoholics (the mean age: 35+/-9 years) were investigated. According to Lesch's typology, 58 patients were of type I, 36 patients of type II, 11 patients of type III, and 17 patients of type IV. Alcohol drinking and family history was assessed by means of a structured interview, based on the Semi-Structured Assessment for the Genetics of Alcoholism. 150 control subjects without psychiatric disorders were also recruited. The control group was ethnically-, age- and gender-matched to the patients. The DRD2 TaqIA, exon 8, and promoter -141C ins/del polymorphisms as well as COMT Val158Met, 5HTT 44 bp del in promoter, and DAT 40 bp VNTR polymorphisms were detected by means of PCR. No significant differences were observed when the whole group of alcoholics and the controls were compared. Similarly, there were no differences between either the Lesch type I or type II alcoholics and the control subjects. No significant differences were observed between type I and type II alcoholics. Alleles frequencies were not calculated for the Lesch type III and type IV alcoholics since the number of patients was too small. The present results argue against any major role of the investigated polymorphisms in either Lesch type I or type II alcoholism. More comprehensive studies are needed to define the role of the investigated polymorphisms in Lesch type III and type IV alcoholism.

The integrate model of emotion, thinking and self regulation: an application to the "paradox of aging".

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Williams, Leanne M; Gatt, Justine M; Hatch, Ainslie; Palmer, Donna M; Nagy, Marie; Rennie, Christopher; Cooper, Nicholas J; Morris, Charlotte; Grieve, Stuart; Dobson-Stone, Carol; Schofield, Peter; Clark, C Richard; Gordon, Evian; Arns, Martijn; Paul, Robert H

2008-09-01

This study was undertaken using the INTEGRATE Model of brain organization, which is based on a temporal continuum of emotion, thinking and self regulation. In this model, the key organizing principle of self adaption is the motivation to minimize danger and maximize reward. This principle drives brain organization across a temporal continuum spanning milliseconds to seconds, minutes and hours. The INTEGRATE Model comprises three distinct processes across this continuum. Emotion is defined by automatic action tendencies triggered by signals that are significant due to their relevance to minimizing danger-maximizing reward (such as abrupt, high contrast stimuli). Thinking represents cognitive functions and feelings that rely on brain and body feedback emerging from around 200 ms post-stimulus onwards. Self regulation is the modulation of emotion, thinking and feeling over time, according to more abstract adaptions to minimize danger-maximize reward. Here, we examined the impact of dispositional factors, age and genetic variation, on this temporal continuum. Brain Resource methodology provided a standardized platform for acquiring genetic, brain and behavioral data in the same 1000 healthy subjects. Results showed a "paradox" of declining function in the "thinking" time scale over the lifespan (6 to 80+ years), but a corresponding preservation or even increase in automatic functions of "emotion" and "self regulation". This paradox was paralleled by a greater loss of grey matter in cortical association areas (assessed using MRI) over age, but a relative preservation of subcortical grey matter. Genetic polymorphisms associated with both healthy function and susceptibility to disorder (including the BDNFVal(66)Met, COMTVal(158/108)Met, MAOA and DRD4 tandem repeat and 5HTT-LPR polymorphisms) made specific contributions to emotion, thinking and self regulatory functions, which also varied according to age.

Genetics Modulate Gray Matter Variation Beyond Disease Burden in Prodromal Huntington’s Disease

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Jingyu Liu

2018-03-01

Full Text Available Huntington’s disease (HD is a neurodegenerative disorder caused by an expansion mutation of the cytosine–adenine–guanine (CAG trinucleotide in the HTT gene. Decline in cognitive and motor functioning during the prodromal phase has been reported, and understanding genetic influences on prodromal disease progression beyond CAG will benefit intervention therapies. From a prodromal HD cohort (N = 715, we extracted gray matter (GM components through independent component analysis and tested them for associations with cognitive and motor functioning that cannot be accounted for by CAG-induced disease burden (cumulative effects of CAG expansion and age. Furthermore, we examined genetic associations (at the genomic, HD pathway, and candidate region levels with the GM components that were related to functional decline. After accounting for disease burden, GM in a component containing cuneus, lingual, and middle occipital regions was positively associated with attention and working memory performance, and the effect size was about a tenth of that of disease burden. Prodromal participants with at least one dystonia sign also had significantly lower GM volume in a bilateral inferior parietal component than participants without dystonia, after controlling for the disease burden. Two single-nucleotide polymorphisms (SNPs: rs71358386 in NCOR1 and rs71358386 in ADORA2B in the HD pathway were significantly associated with GM volume in the cuneus component, with minor alleles being linked to reduced GM volume. Additionally, homozygous minor allele carriers of SNPs in a candidate region of ch15q13.3 had significantly higher GM volume in the inferior parietal component, and one minor allele copy was associated with a total motor score decrease of 0.14 U. Our findings depict an early genetical GM reduction in prodromal HD that occurs irrespective of disease burden and affects regions important for cognitive and motor functioning.

Experimental validation of new empirical models of the thermal properties of food products for safe shipping

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Hamid, Hanan H.; Mitchell, Mark; Jahangiri, Amirreza; Thiel, David V.

2018-04-01

Temperature controlled food transport is essential for human safety and to minimise food waste. The thermal properties of food are important for determining the heat transfer during the transient stages of transportation (door opening during loading and unloading processes). For example, the temperature of most dairy products must be confined to a very narrow range (3-7 °C). If a predefined critical temperature is exceeded, the food is defined as spoiled and unfit for human consumption. An improved empirical model for the thermal conductivity and specific heat capacity of a wide range of food products was derived based on the food composition (moisture, fat, protein, carbohydrate and ash). The models that developed using linear regression analysis were compared with the published measured parameters in addition to previously published theoretical and empirical models. It was found that the maximum variation in the predicated thermal properties leads to less than 0.3 °C temperature change. The correlation coefficient for these models was 0.96. The t-Stat test ( P-value >0.99) demonstrated that the model results are an improvement on previous works. The transient heat transfer based on the food composition and the temperature boundary conditions was found for a Camembert cheese (short cylindrical shape) using a multiple dimension finite difference method code. The result was verified using the heat transfer today (HTT) educational software which is based on finite volume method. The core temperature rises from the initial temperature (2.7 °C) to the maximum safe temperature in ambient air (20.24 °C) was predicted to within about 35.4 ± 0.5 min. The simulation results agree very well ( +0.2 °C) with the measured temperature data. This improved model impacts on temperature estimation during loading and unloading the trucks and provides a clear direction for temperature control in all refrigerated transport applications.

Evidence for single nucleotide polymorphisms and their association with bipolar disorder

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Szczepankiewicz A

2013-10-01

Full Text Available Aleksandra Szczepankiewicz1,21Laboratory of Molecular and Cell Biology, 2Department of Psychiatric Genetics, Poznan University of Medical Sciences, Poznan, PolandAbstract: Bipolar disorder (BD is a complex disorder with a number of susceptibility genes and environmental risk factors involved in its pathogenesis. In recent years, huge progress has been made in molecular techniques for genetic studies, which have enabled identification of numerous genomic regions and genetic variants implicated in BD across populations. Despite the abundance of genetic findings, the results have often been inconsistent and not replicated for many candidate genes/single nucleotide polymorphisms (SNPs. Therefore, the aim of the review presented here is to summarize the most important data reported so far in candidate gene and genome-wide association studies. Taking into account the abundance of association data, this review focuses on the most extensively studied genes and polymorphisms reported so far for BD to present the most promising genomic regions/SNPs involved in BD. The review of association data reveals evidence for several genes (SLC6A4/5-HTT [serotonin transporter gene], BDNF [brain-derived neurotrophic factor], DAOA [D-amino acid oxidase activator], DTNBP1 [dysbindin], NRG1 [neuregulin 1], DISC1 [disrupted in schizophrenia 1] to be crucial candidates in BD, whereas numerous genome-wide association studies conducted in BD indicate polymorphisms in two genes (CACNA1C [calcium channel, voltage-dependent, L type, alpha 1C subunit], ANK3 [ankyrin 3] replicated for association with BD in most of these studies. Nevertheless, further studies focusing on interactions between multiple candidate genes/SNPs, as well as systems biology and pathway analyses are necessary to integrate and improve the way we analyze the currently available association data.Keywords: candidate gene, genome-wide association study, SLC6A4, BDNF, DAOA, DTNBP1, NRG1, DISC1

Characterization of somatostatin receptors and associated signaling pathways in pancreas of R6/2 transgenic mice.

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Somvanshi, Rishi K; Jhajj, Amrit; Heer, Michael; Kumar, Ujendra

2018-02-01

The present study describes the status of somatostatin receptors (SSTRs) and their colocalization with insulin (β), glucagon (α) and somatostatin (δ) producing cells in the pancreatic islets of 11weeks old R6/2 Huntington's Disease transgenic (HD tg) and age-matched wild type (wt) mice. We also determined expression of tyrosine hydroxylase (TH), glutamic acid decarboxylase (GAD) and presynaptic marker synaptophysin (SYP) in addition to signal transduction pathways associated with diabetes. In R6/2 mice, islets are relatively smaller in size, exhibit enhanced expression and nuclear inclusion of mHtt along with the loss of insulin, glucagon and somatostatin expression. In comparison to wt, R6/2 mice display enhanced mRNA for all SSTRs except SSTR2. In the pancreatic lysate, SSTR1, 4 and 5 immunoreactivity decreases whereas SSTR3 immunoreactivity increases with no discernible changes in SSTR2 immunoreactivity. Furthermore, at the cellular level, R6/2 mice exhibit a receptor specific distributional pattern of SSTRs like immunoreactivity and colocalization with β, α and δ cells. While GAD expression is increased, TH and SYP immunoreactivity was decreased in R6/2 mice, anticipating a cross-talk between the CNS and pancreas in diabetes pathophysiology. We also dissected out the changes in signaling pathway and found decreased activation and expression of PKA, AKT, ERK1/2 and STAT3 in R6/2 mice pancreas. These findings suggest that the impaired organization of SSTRs within islets may lead to perturbed hormonal regulation and signaling. These interconnected complex events might shed new light on the pathogenesis of diabetes in neurodegenerative diseases and the role of SSTRs in potential therapeutic intervention. Copyright © 2017 Elsevier B.V. All rights reserved.

FOXOs modulate proteasome activity in human-induced pluripotent stem cells of Huntington's disease and their derived neural cells.

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Liu, Yanying; Qiao, Fangfang; Leiferman, Patricia C; Ross, Alan; Schlenker, Evelyn H; Wang, Hongmin

2017-11-15

Although it has been speculated that proteasome dysfunction may contribute to the pathogenesis of Huntington's disease (HD), a devastating neurodegenerative disorder, how proteasome activity is regulated in HD affected stem cells and somatic cells remains largely unclear. To better understand the pathogenesis of HD, we analyzed proteasome activity and the expression of FOXO transcription factors in three wild-type (WT) and three HD induced-pluripotent stem cell (iPSC) lines. HD iPSCs exhibited elevated proteasome activity and higher levels of FOXO1 and FOXO4 proteins. Knockdown of FOXO4 but not FOXO1 expression decreased proteasome activity. Following neural differentiation, the HD-iPSC-derived neural progenitor cells (NPCs) demonstrated lower levels of proteasome activity and FOXO expressions than their WT counterparts. More importantly, overexpression of FOXO4 but not FOXO1 in HD NPCs dramatically enhanced proteasome activity. When HD NPCs were further differentiated into DARPP32-positive neurons, these HD neurons were more susceptible to death than WT neurons and formed Htt aggregates under the condition of oxidative stress. Similar to HD NPCs, HD-iPSC-derived neurons showed reduced proteasome activity and diminished FOXO4 expression compared to WT-iPSC-derived neurons. Furthermore, HD iPSCs had lower AKT activities than WT iPSCs, whereas the neurons derived from HD iPSC had higher AKT activities than their WT counterparts. Inhibiting AKT activity increased both FOXO4 level and proteasome activity, indicating a potential role of AKT in regulating FOXO levels. These data suggest that FOXOs modulate proteasome activity, and thus represents a potentially valuable therapeutic target for HD. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Suitability of marginal biomass-derived biochars for soil amendment

Energy Technology Data Exchange (ETDEWEB)

Buss, Wolfram [UK Biochar Research Centre, School of Geosciences, University of Edinburgh, Crew Building, Alexander Crum Brown Road, Edinburgh EH9 3FF (United Kingdom); Graham, Margaret C. [School of Geosciences, University of Edinburgh, Crew Building, Alexander Crum Brown Road, Edinburgh EH9 3FF (United Kingdom); Shepherd, Jessica G. [UK Biochar Research Centre, School of Geosciences, University of Edinburgh, Crew Building, Alexander Crum Brown Road, Edinburgh EH9 3FF (United Kingdom); School of Geosciences, University of Edinburgh, Crew Building, Alexander Crum Brown Road, Edinburgh EH9 3FF (United Kingdom); Mašek, Ondřej, E-mail: ondrej.masek@ed.ac.uk [UK Biochar Research Centre, School of Geosciences, University of Edinburgh, Crew Building, Alexander Crum Brown Road, Edinburgh EH9 3FF (United Kingdom)

2016-03-15

The term “marginal biomass” is used here to describe materials of little or no economic value, e.g. plants grown on contaminated land, food waste or demolition wood. In this study 10 marginal biomass-derived feedstocks were converted into 19 biochars at different highest treatment temperatures (HTT) using a continuous screw-pyrolysis unit. The aim was to investigate suitability of the resulting biochars for land application, judged on the basis of potentially toxic element (PTE) concentration, nutrient content and basic biochar properties (pH, EC, ash, fixed carbon). It was shown that under typical biochar production conditions the percentage content of several PTEs (As, Al, Zn) and nutrients (Ca, Mg) were reduced to some extent, but also that biochar can be contaminated by Cr and Ni during the pyrolysis process due to erosion of stainless steel reactor parts (average + 82.8% Cr, + 226.0% Ni). This can occur to such an extent that the resulting biochar is rendered unsuitable for soil application (maximum addition + 22.5 mg Cr kg{sup −1} biochar and + 44.4 mg Ni kg{sup −1} biochar). Biomass grown on land heavily contaminated with PTEs yielded biochars with PTE concentrations above recommended threshold values for soil amendments. Cd and Zn were of particular concern, exceeding the lowest threshold values by 31-fold and 7-fold respectively, despite some losses into the gas phase. However, thermal conversion of plants from less severely contaminated soils, demolition wood and food waste anaerobic digestate (AD) into biochar proved to be promising for land application. In particular, food waste AD biochar contained very high nutrient concentrations, making it interesting for use as fertiliser. - Highlights: • Marginal biomass feedstocks are materials of little economic value. • Biochar from biomass grown on PTE-rich soils tends to exceed guideline values. • Biochar from biomass with high mineral content can be a beneficial nutrient source. • Cr and Ni

Carbonated soft drinks induce oxidative stress and alter the expression of certain genes in the brains of Wistar rats.

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El-Terras, Adel; Soliman, Mohamed Mohamed; Alkhedaide, Adel; Attia, Hossam Fouad; Alharthy, Abdullah; Banaja, Abdel Elah

2016-04-01

In Saudi Arabia, the consumption of carbonated soft drinks is common and often occurs with each meal. Carbonated soft drink consumption has been shown to exhibit effects on the liver, kidney and bone. However, the effects of these soft drinks on brain activity have not been widely examined, particularly at the gene level. Therefore, the current study was conducted with the aim of evaluating the effects of chronic carbonated soft drink consumption on oxidative stress, brain gene biomarkers associated with aggression and brain histology. In total, 40 male Wistar rats were divided into four groups: Group 1 served as a control and was provided access to food and water ad libitum; and groups 2‑4 were given free access to food and carbonated soft drinks only (Cola for group 2, Pepsi for group 3 and 7‑UP for group 4). Animals were maintained on these diets for 3 consecutive months. Upon completion of the experimental period, animals were sacrificed and serological and histopathological analyses were performed on blood and tissues samples. Reverse transcription‑polymerase chain reaction was used to analyze alterations in gene expression levels. Results revealed that carbonated soft drinks increased the serum levels of malondialdehyde (MDA). Carbonated soft drinks were also observed to downregulate the expression of antioxidants glutathione reductase (GR), catalase and glutathione peroxidase (GPx) in the brain when compared with that in the control rats. Rats administered carbonated soft drinks also exhibited decreased monoamine oxidase A (MAO‑A) and acetylcholine esterase (AChE) serum and mRNA levels in the brain. In addition, soft drink consumption upregulated mRNA expression of dopamine D2 receptor (DD2R), while 5-hydroxytryptamine transporter (5‑HTT) expression was decreased. However, following histological examination, all rats had a normal brain structure. The results of this study demonstrated that that carbonated soft drinks induced oxidative stress and

Distributed Framework for Dynamic Telescope and Instrument Control

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Ames, Troy J.; Case, Lynne

2002-01-01

Traditionally, instrument command and control systems have been developed specifically for a single instrument. Such solutions are frequently expensive and are inflexible to support the next instrument development effort. NASA Goddard Space Flight Center is developing an extensible framework, known as Instrument Remote Control (IRC) that applies to any kind of instrument that can be controlled by a computer. IRC combines the platform independent processing capabilities of Java with the power of the Extensible Markup Language (XML). A key aspect of the architecture is software that is driven by an instrument description, written using the Instrument Markup Language (IML). IML is an XML dialect used to describe graphical user interfaces to control and monitor the instrument, command sets and command formats, data streams, communication mechanisms, and data processing algorithms. The IRC framework provides the ability to communicate to components anywhere on a network using the JXTA protocol for dynamic discovery of distributed components. JXTA (see httD://www.jxta.org,) is a generalized protocol that allows any devices connected by a network to communicate in a peer-to-peer manner. IRC uses JXTA to advertise a device's IML and discover devices of interest on the network. Devices can join or leave the network and thus join or leave the instrument control environment of IRC. Currently, several astronomical instruments are working with the IRC development team to develop custom components for IRC to control their instruments. These instruments include: High resolution Airborne Wideband Camera (HAWC), a first light instrument for the Stratospheric Observatory for Infrared Astronomy (SOFIA); Submillimeter And Far Infrared Experiment (SAFIRE), a Principal Investigator instrument for SOFIA; and Fabry-Perot Interferometer Bolometer Research Experiment (FIBRE), a prototype of the SAFIRE instrument, used at the Caltech Submillimeter Observatory (CSO). Most recently, we have

miR-16 and Fluoxetine Both Reverse Autophagic and Apoptotic Change in Chronic Unpredictable Mild Stress Model Rats

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Yang Yang

2017-07-01

Full Text Available In the clinic selective serotonin reuptake inhibitors (SSRIs, like Fluoxetine, remain the primary treatment for major depression. It has been suggested that miR-16 regulates serotonin transporters (SERT via raphe nuclei and hippocampal responses to antidepressants. However, the underlying mechanism and regulatory pathways are still obtuse. Here, a chronic unpredicted mild stress (CUMS depression model in rats was established, and then raphe nuclei miR-16 and intragastric Fluoxetine injections were administered for a duration of 3 weeks. An open field test and sucrose preference quantification displayed a significant decrease in the CUMS groups when compare to the control groups, however these changes were attenuated by both miR-16 and Fluoxetine treatments. A dual-luciferase reporter assay system verified that hsa-miR-16 inhibitory effects involve the targeting of 3′UTR on the 5-HTT gene. Expression levels of miR-16 and BDNF in the hippocampus were examined with RT-PCR, and it was found that increased 5-HT2a receptor expression induced by CUMS can be decreased by miR-16 and Fluoxetine administration. Immunofluorescence showed that expression levels of neuron NeuN and MAP-2 in CUMS rats were lower. Apoptosis and autophagy levels were evaluated separately through relative expression of Bcl-2, Caspase-3, Beclin-1, and LC3II. Furthermore, CUMS was found to decrease levels of hippocampal mTOR, PI3K, and AKT. These findings indicate that apoptosis and autophagy related pathways could be involved in the effectiveness of antidepressants, in which miR-16 participates in the regulation of, and is likely to help integrate rapid therapeutic strategies to alleviate depression clinically. These findings indicate that miR-16 participates in the regulation of apoptosis and autophagy and could account for some part of the therapeutic effect of SSRIs. This discovery has the potential to further the understanding of SSRIs and accelerate the development of new

Suitability of marginal biomass-derived biochars for soil amendment

International Nuclear Information System (INIS)

Buss, Wolfram; Graham, Margaret C.; Shepherd, Jessica G.; Mašek, Ondřej

2016-01-01

The term “marginal biomass” is used here to describe materials of little or no economic value, e.g. plants grown on contaminated land, food waste or demolition wood. In this study 10 marginal biomass-derived feedstocks were converted into 19 biochars at different highest treatment temperatures (HTT) using a continuous screw-pyrolysis unit. The aim was to investigate suitability of the resulting biochars for land application, judged on the basis of potentially toxic element (PTE) concentration, nutrient content and basic biochar properties (pH, EC, ash, fixed carbon). It was shown that under typical biochar production conditions the percentage content of several PTEs (As, Al, Zn) and nutrients (Ca, Mg) were reduced to some extent, but also that biochar can be contaminated by Cr and Ni during the pyrolysis process due to erosion of stainless steel reactor parts (average + 82.8% Cr, + 226.0% Ni). This can occur to such an extent that the resulting biochar is rendered unsuitable for soil application (maximum addition + 22.5 mg Cr kg −1 biochar and + 44.4 mg Ni kg −1 biochar). Biomass grown on land heavily contaminated with PTEs yielded biochars with PTE concentrations above recommended threshold values for soil amendments. Cd and Zn were of particular concern, exceeding the lowest threshold values by 31-fold and 7-fold respectively, despite some losses into the gas phase. However, thermal conversion of plants from less severely contaminated soils, demolition wood and food waste anaerobic digestate (AD) into biochar proved to be promising for land application. In particular, food waste AD biochar contained very high nutrient concentrations, making it interesting for use as fertiliser. - Highlights: • Marginal biomass feedstocks are materials of little economic value. • Biochar from biomass grown on PTE-rich soils tends to exceed guideline values. • Biochar from biomass with high mineral content can be a beneficial nutrient source. • Cr and Ni from the

Genetic association studies of suicidal behaviour: A review of the past 10 years, progress, limitations and future directions.

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BOJAN MIRKOVIC

2016-09-01

Full Text Available Suicidal behaviours, which range from suicidal ideation to suicide attempts and completed suicide, represent a fatal dimension of mental ill-health. The involvement of genetic risk factors in suicidal behaviour is supported by family, twin, and adoption studies. The aim of this paper is to review recent genetic association studies in suicidal behaviours including (i case-control studies, (ii family-based association studies and (iii genome-wide association studies (GWAS. Various studies on genetic associations have tended to suggest that a number of genes (e.g., tryptophan hydroxylase, serotonin receptors and transporters or brain-derived neurotrophic factors are linked to suicidal behaviours, but these findings are not consistently supported by the results obtained. Although the candidate-gene approach is useful, it is hampered by the present state of knowledge concerning the pathophysiology of diseases. Interpretations of GWAS results are mostly hindered by a lack of annotation describing the functions of most variation throughout the genome.Association studies have addressed a wide range of SNPs in numerous genes. We have included 104 such studies, of which 10 are family-based association studies and 11 are GWAS studies. Numerous meta-analyses of case-control studies have shown significant associations of suicidal behaviour with variants in the serotonin transporter gene (5-HTT or SLC6A4 and the tryptophane hydroxylase1 gene (TPH1, but others report contradictory results. The gene encoding brain-derived neurotrophic factor (BDNF and its receptor (NTRK2 are also promising candidates. Only two of the GWAS studies showed any significant associations. Several pathways are mentioned in an attempt to understand the lack of reproducibility and the disappointing results. Consequently, we review and discuss here the following aspects: (i sample characteristics and confounding factors; (ii statistical limits; (iii gene-gene interactions; (iv gene

HdhQ111 Mice Exhibit Tissue Specific Metabolite Profiles that Include Striatal Lipid Accumulation

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Carroll, Jeffrey B.; Deik, Amy; Fossale, Elisa; Weston, Rory M.; Guide, Jolene R.; Arjomand, Jamshid; Kwak, Seung; Clish, Clary B.; MacDonald, Marcy E.

2015-01-01

The HTT CAG expansion mutation causes Huntington’s Disease and is associated with a wide range of cellular consequences, including altered metabolism. The mutant allele is expressed widely, in all tissues, but the striatum and cortex are especially vulnerable to its effects. To more fully understand this tissue-specificity, early in the disease process, we asked whether the metabolic impact of the mutant CAG expanded allele in heterozygous B6.HdhQ111/+ mice would be common across tissues, or whether tissues would have tissue-specific responses and whether such changes may be affected by diet. Specifically, we cross-sectionally examined steady state metabolite concentrations from a range of tissues (plasma, brown adipose tissue, cerebellum, striatum, liver, white adipose tissue), using an established liquid chromatography-mass spectrometry pipeline, from cohorts of 8 month old mutant and wild-type littermate mice that were fed one of two different high-fat diets. The differential response to diet highlighted a proportion of metabolites in all tissues, ranging from 3% (7/219) in the striatum to 12% (25/212) in white adipose tissue. By contrast, the mutant CAG-expanded allele primarily affected brain metabolites, with 14% (30/219) of metabolites significantly altered, compared to wild-type, in striatum and 11% (25/224) in the cerebellum. In general, diet and the CAG-expanded allele both elicited metabolite changes that were predominantly tissue-specific and non-overlapping, with evidence for mutation-by-diet interaction in peripheral tissues most affected by diet. Machine-learning approaches highlighted the accumulation of diverse lipid species as the most genotype-predictive metabolite changes in the striatum. Validation experiments in cell culture demonstrated that lipid accumulation was also a defining feature of mutant HdhQ111 striatal progenitor cells. Thus, metabolite-level responses to the CAG expansion mutation in vivo were tissue specific and most evident

HdhQ111 Mice Exhibit Tissue Specific Metabolite Profiles that Include Striatal Lipid Accumulation.

Directory of Open Access Journals (Sweden)

Jeffrey B Carroll

Full Text Available The HTT CAG expansion mutation causes Huntington's Disease and is associated with a wide range of cellular consequences, including altered metabolism. The mutant allele is expressed widely, in all tissues, but the striatum and cortex are especially vulnerable to its effects. To more fully understand this tissue-specificity, early in the disease process, we asked whether the metabolic impact of the mutant CAG expanded allele in heterozygous B6.HdhQ111/+ mice would be common across tissues, or whether tissues would have tissue-specific responses and whether such changes may be affected by diet. Specifically, we cross-sectionally examined steady state metabolite concentrations from a range of tissues (plasma, brown adipose tissue, cerebellum, striatum, liver, white adipose tissue, using an established liquid chromatography-mass spectrometry pipeline, from cohorts of 8 month old mutant and wild-type littermate mice that were fed one of two different high-fat diets. The differential response to diet highlighted a proportion of metabolites in all tissues, ranging from 3% (7/219 in the striatum to 12% (25/212 in white adipose tissue. By contrast, the mutant CAG-expanded allele primarily affected brain metabolites, with 14% (30/219 of metabolites significantly altered, compared to wild-type, in striatum and 11% (25/224 in the cerebellum. In general, diet and the CAG-expanded allele both elicited metabolite changes that were predominantly tissue-specific and non-overlapping, with evidence for mutation-by-diet interaction in peripheral tissues most affected by diet. Machine-learning approaches highlighted the accumulation of diverse lipid species as the most genotype-predictive metabolite changes in the striatum. Validation experiments in cell culture demonstrated that lipid accumulation was also a defining feature of mutant HdhQ111 striatal progenitor cells. Thus, metabolite-level responses to the CAG expansion mutation in vivo were tissue specific and

A High-Resolution In Vivo Atlas of the Human Brain's Serotonin System.

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Beliveau, Vincent; Ganz, Melanie; Feng, Ling; Ozenne, Brice; Højgaard, Liselotte; Fisher, Patrick M; Svarer, Claus; Greve, Douglas N; Knudsen, Gitte M

2017-01-04

The serotonin (5-hydroxytryptamine, 5-HT) system modulates many important brain functions and is critically involved in many neuropsychiatric disorders. Here, we present a high-resolution, multidimensional, in vivo atlas of four of the human brain's 5-HT receptors (5-HT 1A , 5-HT 1B , 5-HT 2A , and 5-HT 4 ) and the 5-HT transporter (5-HTT). The atlas is created from molecular and structural high-resolution neuroimaging data consisting of positron emission tomography (PET) and magnetic resonance imaging (MRI) scans acquired in a total of 210 healthy individuals. Comparison of the regional PET binding measures with postmortem human brain autoradiography outcomes showed a high correlation for the five 5-HT targets and this enabled us to transform the atlas to represent protein densities (in picomoles per milliliter). We also assessed the regional association between protein concentration and mRNA expression in the human brain by comparing the 5-HT density across the atlas with data from the Allen Human Brain atlas and identified receptor- and transporter-specific associations that show the regional relation between the two measures. Together, these data provide unparalleled insight into the serotonin system of the human brain. We present a high-resolution positron emission tomography (PET)- and magnetic resonance imaging-based human brain atlas of important serotonin receptors and the transporter. The regional PET-derived binding measures correlate strongly with the corresponding autoradiography protein levels. The strong correlation enables the transformation of the PET-derived human brain atlas into a protein density map of the serotonin (5-hydroxytryptamine, 5-HT) system. Next, we compared the regional receptor/transporter protein densities with mRNA levels and uncovered unique associations between protein expression and density at high detail. This new in vivo neuroimaging atlas of the 5-HT system not only provides insight in the human brain's regional protein

Genetic sensitivity to the caregiving context: The influence of 5httlpr and BDNF val66met on indiscriminate social behavior

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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

Association Between Human SLC6A4 Gene Promoter Polymorphism and the Chinese People with Antisocial Personality Disorder%中国汉族反社会人格障碍人群SLC6A基因启动子区基因多态性的分析

Institute of Scientific and Technical Information of China (English)

谭钊安; 张建平; 曾彦英; 茆正红; 朱晓静; 张慧林; 朱进

2004-01-01

目的:探讨中国汉族人群SLC6A4基因启动子区基因多态性与反社会人格障碍的关系.方法:反社会人格障碍人群来自江苏省少年劳教所的被劳教人员,经人格诊断问卷(PDQ-4)筛查,符合美国精神病协会精神疾病诊断方法(DSM-Ⅳ)关于反社会人格障碍的诊断标准;对照组来自健康体检人群,经PDQ-4排除反社会人格障碍和重型精神病.全部对象取血液标本提取DNA,用PCR方法扩增SLC6A4基因(5-羟色氨转移蛋白基因,5-HTT)启动子区序列片断,部分PCR产物行测序验证.对等位基因频率和基因型频率进行对比分析.结果:符合DSM-Ⅳ反社会人格障碍诊断标准者共90例,对照组140例,PCR产物电泳及测序比对,共获得3种等位基因条带L、S和XL,片断长度各相差44个碱基,分别组成4种基因型LL、LS、SS和XLL.反社会人格障碍人群S等位基因频率和SS基因型频率分别为61.80%和37.08%,与对照组比较,差异有极显著性意义(P＜0.005).结论:S等位基因频率和SS基因型频率与中国汉族人群反社会人格障碍的遗传易感性相关.

Deriving a preference-based utility measure for cancer patients from the European Organisation for the Research and Treatment of Cancer's Quality of Life Questionnaire C30: a confirmatory versus exploratory approach

Directory of Open Access Journals (Sweden)

Costa DSJ

2014-11-01

Full Text Available Daniel SJ Costa,1 Neil K Aaronson,2 Peter M Fayers,3,4 Peter S Grimison,5,6 Monika Janda,7 Julie F Pallant,8 Donna Rowen,9 Galina Velikova,10 Rosalie Viney,11 Tracey A Young,9 Madeleine T King1On behalf of the MAUCa Consortium1Psycho-oncology Co-operative Research Group, University of Sydney, Sydney, NSW, Australia; 2Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; 3Institute of Applied Health Sciences, University of Aberdeen, Aberdeen, UK; 4Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway; 5Chris O'Brien Lifehouse, 6Sydney Medical School, University of Sydney, Sydney, NSW, 7School of Public Health, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, 8Rural Health Academic Centre, University of Melbourne, Shepparton, VIC, Australia; 9School of Health and Related Research, University of Sheffield, Sheffield; 10University of Leeds, St James's Institute of Oncology, Leeds, UK; 11Centre for Health Economics Research and Evaluation, University of Technology, Sydney, NSW, AustraliaBackground: Multi attribute utility instruments (MAUIs are preference-based measures that comprise a health state classification system (HSCS and a scoring algorithm that assigns a utility value to each health state in the HSCS. When developing a MAUI from a health-related quality of life (HRQOL questionnaire, first a HSCS must be derived. This typically involves selecting a subset of domains and items because HRQOL questionnaires typically have too many items to be amendable to the valuation task required to develop the scoring algorithm for a MAUI. Currently, exploratory factor analysis (EFA followed by Rasch analysis is recommended for deriving a MAUI from a HRQOL measure.Aim: To determine whether confirmatory factor analysis (CFA is more appropriate and efficient than EFA to derive a HSCS

Histone deacetylase (HDAC) inhibitors targeting HDAC3 and HDAC1 ameliorate polyglutamine-elicited phenotypes in model systems of Huntington's disease

Science.gov (United States)

Jia, Haiqun; Pallos, Judit; Jacques, Vincent; Lau, Alice; Tang, Bin; Cooper, Andrew; Syed, Adeela; Purcell, Judith; Chen, Yi; Sharma, Shefali; Sangrey, Gavin R.; Darnell, Shayna B.; Plasterer, Heather; Sadri-Vakili, Ghazaleh; Gottesfeld, Joel M.; Thompson, Leslie M.; Rusche, James R.; Marsh, J. Lawrence; Thomas, Elizabeth A.

2012-01-01

We have previously demonstrated amelioration of Huntington's disease (HD)-related phenotypes in R6/2 transgenic mice in response to treatment with the novel histone deacetylase (HDAC) inhibitor 4b. Here we have measured the selectivity profiles of 4b and related compounds against class I and class II HDACs and have tested their ability to restore altered expression of genes related to HD pathology in mice and to rescue disease effects in cell culture and Drosophila models of HD. R6/2 transgenic and wild-type (wt) mice received daily injections of HDAC inhibitors for 3 days followed by real-time PCR analysis to detect expression differences for 13 HD-related genes. We find that HDACi 4b and 136, two compounds showing high potency for inhibiting HDAC3 were most effective in reversing the expression of genes relevant to HD, including Ppp1r1b, which encodes DARPP-32, a marker for medium spiny striatal neurons. In contrast, compounds targeting HDAC1 were less effective at correcting gene expression abnormalities in R6/2 transgenic mice, but did cause significant increases in the expression of selected genes. An additional panel of 4b-related compounds was tested in a Drosophila model of HD and in STHdhQ111 striatal cells to further distinguish HDAC selectivity. Significant improvement in huntingtin-elicited Drosophila eye neurodegeneration in the fly was observed in response to treatment with compounds targeting human HDAC1 and/or HDAC3. In STHdhQ111 striatal cells, the ability of HDAC inhibitors to improve Htt-elicited metabolic deficits correlated with the potency at inhibiting HDAC1 and HDAC3, although the IC50 values for HDAC1 inhibition were typically 10-fold higher than for inhibition of HDAC3. Assessment of HDAC protein localization in brain tissue by Western blot analysis revealed accumulation of HDAC1 and HDAC3 in the nucleus of HD transgenic mice compared to wt mice, with a concurrent decrease in cytoplasmic localization, suggesting that these HDACs contribute

Epigone migraine vertigo (EMV): a late migraine equivalent.

Science.gov (United States)

Pagnini, P; Vannucchi, P; Giannoni, B; Pecci, R

2014-02-01

Migrainous headache is determined by pathogenetic mechanisms that are also able to affect the peripheral and/or central vestibular system, so that vestibular symptoms may substitute and/or present with headache. We are convinced that there can be many different manifestations of vestibular disorders in migrainous patients, representing true different clinical entities due to their different characteristics and temporal relashionship with headache. Based on such considerations, we proposed a classification of vertigo and other vestibular disorders related to migraine, and believe that a particular variant of migraine-related vertigo should be introduced, namely "epigone migraine vertigo" (EMV): this could be a kind of late migraine equivalent, i.e. a kind of vertigo, migrainous in origin, starting late in the lifetime that substitutes, as an equivalent, pre-existing migraine headache. To clarify this particular clinical picture, we report three illustrative clinical cases among 28 patients collected during an observation period of 13 years (November 1991 - November 2004). For all patients, we collected complete personal clinical history. All patients underwent standard neurotological examination, looking for spontaneous-positional, gaze-evoked and caloric induced nystagmus, using an infrared video camera. We also performed a head shaking test (HST) and an head thrust test (HTT). Ocular motility was tested looking at saccades and smooth pursuit. To exclude other significant neurological pathologies, a brain magnetic resonance imaging (MRI) with gadolinium was performed. During the three months after the first visit, patients were invited to keep a diary noting frequency, intensity and duration of vertigo attacks. After that period, we suggested that they use prophylactic treatment with flunarizine (5 mg per day) and/or acetylsalicylic acid (100 mg per day), or propranolol (40 mg twice a day). All patients were again recommended to note in their diary the frequency

BACHD rats expressing full-length mutant huntingtin exhibit differences in social behavior compared to wild-type littermates.

Directory of Open Access Journals (Sweden)

Giuseppe Manfré

Full Text Available Huntington disease (HD is a devastating inherited neurodegenerative disorder characterized by progressive motor, cognitive, and psychiatric symptoms without any cure to slow down or stop the progress of the disease. The BACHD rat model for HD carrying the human full-length mutant huntingtin protein (mHTT with 97 polyQ repeats has been recently established as a promising model which reproduces several HD-like features. While motor and cognitive functions have been characterized in BACHD rats, little is known about their social phenotype.This study focuses especially on social behavior since evidence for social disturbances exists in human patients. Our objective was to compare social behavior in BACHD and wild-type (WT rats at different ages, using two different measures of sociability.Animals were tested longitudinally at the age of 2, 4 and 8 months in the social interaction test to examine different parameters of sociability. A separate cohort of 7 month old rats was tested in the three chamber social test to measure both sociability and social novelty. Gene expression analyses in 8 months old animals were performed by real time qRT-PCR to evaluate a potential involvement of D1 and D2 dopaminergic receptors and the contribution of Brain-derived neurotrophic factor (BDNF to the observed behavioral alterations.In the social interaction test, BACHD rats showed age-dependent changes in behaviour when they were-re introduced to their cagemate after a 24 hours-period of individual housing. The time spent on nape attacks increased with aging. Furthermore, a significant higher level of pinning at 2 months of age was shown in the BACHD rats compared to wild-types, followed by a reduction at 4 and 8 months. On the other hand, BACHD rats exhibited a decreased active social behaviour compared to wild-types, reflected by genotype-effects on approaching, following and social nose contact. In the three chamber social test, BACHD rats seemed to show a mild

'Smoking genes': a genetic association study.

Directory of Open Access Journals (Sweden)

Zoraida Verde

Full Text Available Some controversy exists on the specific genetic variants that are associated with nicotine dependence and smoking-related phenotypes. The purpose of this study was to analyse the association of smoking status and smoking-related phenotypes (included nicotine dependence with 17 candidate genetic variants: CYP2A6*1×2, CYP2A6*2 (1799T>A [rs1801272], CYP2A6*9 (-48T>G [rs28399433], CYP2A6*12, CYP2A13*2 (3375C>T [rs8192789], CYP2A13*3 (7520C>G, CYP2A13*4 (579G>A, CYP2A13*7 (578C>T [rs72552266], CYP2B6*4 (785A>G, CYP2B6*9 (516G>T, CHRNA3 546C>T [rs578776], CHRNA5 1192G>A [rs16969968], CNR1 3764C>G [rs6928499], DRD2-ANKK1 2137G>A (Taq1A [rs1800497], 5HTT LPR, HTR2A -1438A>G [rs6311] and OPRM1 118A>G [rs1799971]. We studied the genotypes of the aforementioned polymorphisms in a cohort of Spanish smokers (cases, N = 126 and ethnically matched never smokers (controls, N = 80. The results showed significant between-group differences for CYP2A6*2 and CYP2A6*12 (both PA (Taq1A polymorphisms was 3.60 (95%CI: 1.75, 7.44 and 2.63 (95%CI: 1.41, 4.89 respectively. Compared with the wild-type genotype, the OR for being a non-smoker in carriers of the minor CYP2A6*2 allele was 1.80 (95%CI: 1.24, 2.65. We found a significant genotype effect (all P≤0.017 for the following smoking-related phenotypes: (i cigarettes smoked per day and CYP2A13*3; (ii pack years smoked and CYP2A6*2, CYP2A6*1×2, CYP2A13*7, CYP2B6*4 and DRD2-ANKK1 2137G>A (Taq1A; (iii nicotine dependence (assessed with the Fagestrom test and CYP2A6*9. Overall, our results suggest that genetic variants potentially involved in nicotine metabolization (mainly, CYP2A6 polymorphisms are those showing the strongest association with smoking-related phenotypes, as opposed to genetic variants influencing the brain effects of nicotine, e.g., through nicotinic acetylcholine (CHRNA5, serotoninergic (HTR2A, opioid (OPRM1 or cannabinoid receptors (CNR1.

Survival End Points for Huntington Disease Trials Prior to a Motor Diagnosis.

Science.gov (United States)

Long, Jeffrey D; Mills, James A; Leavitt, Blair R; Durr, Alexandra; Roos, Raymund A; Stout, Julie C; Reilmann, Ralf; Landwehrmeyer, Bernhard; Gregory, Sarah; Scahill, Rachael I; Langbehn, Douglas R; Tabrizi, Sarah J

2017-11-01

Predictive genetic testing in Huntington disease (HD) enables therapeutic trials in HTT gene expansion mutation carriers prior to a motor diagnosis. Progression-free survival (PFS) is the composite of a motor diagnosis or a progression event, whichever comes first. To determine if PFS provides feasible sample sizes for trials with mutation carriers who have not yet received a motor diagnosis. This study uses data from the 2-phase, longitudinal cohort studies called Track and from a longitudinal cohort study called the Cooperative Huntington Observational Research Trial (COHORT). Track had 167 prediagnosis mutation carriers and 156 noncarriers, whereas COHORT had 366 prediagnosis mutation carriers and noncarriers. Track studies were conducted at 4 sites in 4 countries (Canada, France, England, and the Netherlands) from which data were collected from January 17, 2008, through November 17, 2014. The COHORT was conducted at 38 sites in 3 countries (Australia, Canada, and the United States) from which data were collected from February 14, 2006, through December 31, 2009. Results from the Track data were externally validated with data from the COHORT. The required sample size was estimated for a 2-arm prediagnosis clinical trial. Data analysis took place from May 1, 2016, to June 10, 2017. The primary end point is PFS. Huntington disease progression events are defined for the Unified Huntington's Disease Rating Scale total motor score, total functional capacity, symbol digit modalities test, and Stroop word test. Of Track's 167 prediagnosis mutation carriers, 93 (55.6%) were women, and the mean (SD) age was 40.06 (8.92) years; of the 156 noncarriers, 87 (55.7%) were women, and the mean (SD) age was 45.58 (10.30) years. Of the 366 COHORT participants, 229 (62.5%) were women and the mean (SD) age was 42.21 (12.48) years. The PFS curves of the Track mutation carriers showed good external validity with the COHORT mutation carriers after adjusting for initial progression. For

BACHD rats expressing full-length mutant huntingtin exhibit differences in social behavior compared to wild-type littermates.

Science.gov (United States)

Manfré, Giuseppe; Novati, Arianna; Faccini, Ilaria; Rossetti, Andrea C; Bosch, Kari; Molteni, Raffaella; Riva, Marco A; Van der Harst, Johanneke E; Nguyen, Huu Phuc; Homberg, Judith R

2018-01-01

Huntington disease (HD) is a devastating inherited neurodegenerative disorder characterized by progressive motor, cognitive, and psychiatric symptoms without any cure to slow down or stop the progress of the disease. The BACHD rat model for HD carrying the human full-length mutant huntingtin protein (mHTT) with 97 polyQ repeats has been recently established as a promising model which reproduces several HD-like features. While motor and cognitive functions have been characterized in BACHD rats, little is known about their social phenotype. This study focuses especially on social behavior since evidence for social disturbances exists in human patients. Our objective was to compare social behavior in BACHD and wild-type (WT) rats at different ages, using two different measures of sociability. Animals were tested longitudinally at the age of 2, 4 and 8 months in the social interaction test to examine different parameters of sociability. A separate cohort of 7 month old rats was tested in the three chamber social test to measure both sociability and social novelty. Gene expression analyses in 8 months old animals were performed by real time qRT-PCR to evaluate a potential involvement of D1 and D2 dopaminergic receptors and the contribution of Brain-derived neurotrophic factor (BDNF) to the observed behavioral alterations. In the social interaction test, BACHD rats showed age-dependent changes in behaviour when they were-re introduced to their cagemate after a 24 hours-period of individual housing. The time spent on nape attacks increased with aging. Furthermore, a significant higher level of pinning at 2 months of age was shown in the BACHD rats compared to wild-types, followed by a reduction at 4 and 8 months. On the other hand, BACHD rats exhibited a decreased active social behaviour compared to wild-types, reflected by genotype-effects on approaching, following and social nose contact. In the three chamber social test, BACHD rats seemed to show a mild deficit in

Establishing a learned-helplessness effect paradigm in C57BL/6 mice: behavioural evidence for emotional, motivational and cognitive effects of aversive uncontrollability per se.

Science.gov (United States)

Pryce, Christopher R; Azzinnari, Damiano; Sigrist, Hannes; Gschwind, Tilo; Lesch, Klaus-Peter; Seifritz, Erich

2012-01-01

learning curve for escapes at escape test, consistent with a cognitive deficit. When a tone CS was used to predict e-shock, IS mice exhibited increased reactivity to the CS, consistent with hyper-emotionality. There was no ES-IS difference in pain sensitivity. Mice heterozygous knockout for the 5-HTT gene exhibited an increased LH effect relative to wildtype mice. This mouse model will allow for the detailed molecular study of the aetiology, psychology, neurobiology and neuropharmacology of uncontrollability of aversive stimuli, a potential major aetiological factor and state marker in depression. This article is part of a Special Issue entitled 'Anxiety and Depression'. Copyright © 2011 Elsevier Ltd. All rights reserved.

BACHD rats expressing full-length mutant huntingtin exhibit differences in social behavior compared to wild-type littermates

Science.gov (United States)

Manfré, Giuseppe; Novati, Arianna; Faccini, Ilaria; Rossetti, Andrea C.; Bosch, Kari; Molteni, Raffaella; Riva, Marco A.; Van der Harst, Johanneke E.; Homberg, Judith R.

2018-01-01

Background Huntington disease (HD) is a devastating inherited neurodegenerative disorder characterized by progressive motor, cognitive, and psychiatric symptoms without any cure to slow down or stop the progress of the disease. The BACHD rat model for HD carrying the human full-length mutant huntingtin protein (mHTT) with 97 polyQ repeats has been recently established as a promising model which reproduces several HD-like features. While motor and cognitive functions have been characterized in BACHD rats, little is known about their social phenotype. Objective This study focuses especially on social behavior since evidence for social disturbances exists in human patients. Our objective was to compare social behavior in BACHD and wild-type (WT) rats at different ages, using two different measures of sociability. Methods Animals were tested longitudinally at the age of 2, 4 and 8 months in the social interaction test to examine different parameters of sociability. A separate cohort of 7 month old rats was tested in the three chamber social test to measure both sociability and social novelty. Gene expression analyses in 8 months old animals were performed by real time qRT-PCR to evaluate a potential involvement of D1 and D2 dopaminergic receptors and the contribution of Brain-derived neurotrophic factor (BDNF) to the observed behavioral alterations. Results In the social interaction test, BACHD rats showed age-dependent changes in behaviour when they were-re introduced to their cagemate after a 24 hours-period of individual housing. The time spent on nape attacks increased with aging. Furthermore, a significant higher level of pinning at 2 months of age was shown in the BACHD rats compared to wild-types, followed by a reduction at 4 and 8 months. On the other hand, BACHD rats exhibited a decreased active social behaviour compared to wild-types, reflected by genotype-effects on approaching, following and social nose contact. In the three chamber social test, BACHD rats

How much personality is genetic-determined? The known evidence and future directions%人格有多少是遗传的:已有的证据与未来的取向

Institute of Scientific and Technical Information of China (English)

周明洁; 陈杰; 王力; 张建新

2016-01-01

It is well known that human personality has an important biological basis.Many personality psychologists have committed themselves to answering the question of "how much human personality is genetic-determined".Since the "Big Five" personality structure (Extraversion,Emotional Stability,Agreeableness,Conscientiousness,and Openness to Experience) has been proved to be of universal,studied on the heredity of Big Five personality become popular,in which focus has been moved to the molecular genetic approach from the quantitative genetic approach.The quantitative genetic approach advocates estimating the heritability,the contribution rate of heredity,to the variance of big five personality in a population by means of some behavior genetic study designs such as twin study and family study.The results from twin and family studies showed that the heritability of the Big Five personality is about 31％-41％ and the average heritability of Big Five personality is about 37％.The molecular genetic approach aims to identify specific genes and examine the effects of them on the personality traits at DNA level.In this area,some specific genes have been found to be associated with the Big Five personality,such as the associations of Neuroticism and CNR1,5-HTTLPR,SLC6A4,BDNF,DAT1,DRD4;Extraversion and ADH4,BDNF,COMT,DRD4,mitochondrial gene;Agreeableness and CNR1,ADH4,SLC6A4,MAOA;Conscientiousness and ADH4,MAOA,DRD4,KATNAL2;Openess and 5-HTT,RASA1.Some other researches also found the effects of gene-gene interactions on personality traits,such as that of the interaciton among MAOA,COMT,DRD3 on agreebleness.In addition to the gene polymorphism,DNA Copy number variation has also been found to be associated with personality trait.However,these results of molecular genetic analyzes showed that genes explain much less personality variance,even the genome-wide association study (GWAS) on the five personality factors is not that much impressed.So the specific genes associating with the

ASSOCIATION STUDY OF 5-HTR2A-1438A/G,COMTVAL158MET,MAOA-LPR,DATVNTR AND 5-HTTVNTR POLYMORPHISMS WITH COOCCURRENCE HEROIN DEPENDENCE AND ANTISOCIAL PERSONALITY DISORDERS IN MALES%5-HTR2A-1438A/G、COMTVal158Met、MAOA-LPR、5-HTTVNTR 、DATVNTR与男性海洛因依赖共患反社会性人格障碍的关联研究*

Institute of Scientific and Technical Information of China (English)

杨梅; 郝伟; 邬志美; 王文甫; 周旭辉; 姜国清; 汤美云; 黄健

2010-01-01

目的:探讨5-HTR2A受体基因(5-hydroxytryptamine receptor 2A gene,5-HTR2A)-1438A/G多态性(5-HTR2A-1438A/G,rs6311)、儿茶酚-O-甲基转移酶基因(catechol-O-methyltransferase gene,COMT)Val158Met多态性(COMTVal158Met,rs4680)、单胺氧化酶A基因(monoamine oxidase A gene,MAOA)启动子区可变数目串联重复序列(variable number of tandem repeats,VNTR) 多态性(称为MAOA多型变异区段,MAOA-linked polymorphic region,MAOA-LPR))、多巴胺转运体基因(dopamine transporter gene,DAT)外显子15靠近3′端的可变数目串联重复序列多态性(DATVNTR)、5-HT转运体基因(5-hydroxytryptamine transporter gene,5-HTT)内含子2内可变数目串联重复序列多态性(5-HTTVNTR)及以上各位点之间的交互作用与男性海洛因依赖共患反社会性人格障碍有无关联.方法:采用病历对照关联分析,应用聚合酶链式反应和连接酶检测反应(polymerase chain reaction-ligase detection reaction,PCR-LDR)技术检测588例男性海洛因依赖者(其中共患反社会性人格障碍者311例,不共患反社会性人格障碍者277例)和194例健康男性5-HTR2A-1438A/G、COMTVal158Met、MAOA-LPR、DATVNTR、5-HTTVNTR多态性的基因型,对各位点的基因型频率、等位基因频率及各位点之间的交互作用进行疾病关联分析.结果:共患反社会性人格障碍的男性海洛因依赖者与健康男性间,共患与不共患反社会性人格障碍的男性海洛因依赖者间在5-HTTVNTR的基因型和等位基因频率上均有统计学差异,携带10次重复序列(10-repeats,10R)等位基因的个体共患海洛因依赖和反社会性人格障碍风险相对较大.经MDR分析,在男性海洛因依赖者中,HTTVNTR与DATVNTR的二因模型子对反社会性人格障碍的预测准确度最大,符号检验有统计学差异,校正后P值为0.067,接近显著性差异.携带5-HTTVNTR等位基因10R和/或携带DATVNTR等位基因9R的个体共患反社会性人格�

Foreword

Directory of Open Access Journals (Sweden)

Kristina HMELJAK SANGAWA

2012-12-01

Full Text Available Having received a lively response to our call for papers on the lexicography of Japanese as a second language, the editorial board decided to dedicate two issues of this year's ALA to this theme, and I am happy to introduce the second round of papers, after the first thematic issue published in October this year. This issue is again divided into two parts. The first two papers offer analyses of two aspects of existing dictionaries from the point of view of Japanese language learners, while the following four papers present particular lexicographic projects for learners of Japanese as a foreign language. The first paper, by Kanako Maebo, entitled A survey of register labelling in Japanese dictionaries - Towards the labelling of words in dictionaries for learners of Japanese, analyses register labelling in existing dictionaries of Japanese, both in those expressly intended for learners of Japanese as a second language and those intended for native speakers, pointing out how register information provided by such dictionaries is not sufficient for L2 language production. After stressing the usefulness of usage examples for learners trying to write in Japanese, she offers an example of a corpus-based register analysis and proposes a typology of labels to be assigned to dictionary entries, calling for the development of corpora of different genres to be used for lexical analysis. In the second paper, An analysis of the efficiency of existing kanji indexes and development of a coding-based index, Galina N. Vorobеva and Victor M. Vorobеv tackle one of the most time-consuming tasks learners of Japanese are confronted with: looking up unknown Chinese characters. After a comprehensive description of existing indexes, including less known indexing systems developed by Japanese, Chinese, Russian and German researchers, they compare the efficiency of these systems using the concept of selectivity, and propose their own coding-based system. Although

Polymer-derived microporous ceramics for membranes and sensors for high temperature hydrogen purification and sensing

Energy Technology Data Exchange (ETDEWEB)

Prasad, Ravi Mohan

2012-06-11

activated and Knudsen diffusion. The stability and sensing characteristics of SnO{sub 2} sensors coated with amorphous microporous SiBCN layers have been studied in oxygen-free atmospheres. The SiBCN layers coated on SnO{sub 2} sensors are amorphous, crack-free and microporous. The diameter of micropores (about 0.70 nm) is larger than the kinetic diameter of H{sub 2} (0.289 nm) and CO (0.376 nm) molecules, allowing in this way their diffusion towards the bottom SnO{sub 2} sensing layer. Transient response characteristics and sensor signals of uncoated SnO{sub 2}, three-fold and five-fold SiBCN-coated SnO{sub 2} sensors exposed to CO (10, 20 and 120 ppm) and H{sub 2} (40, 400 and 900 ppm) in nitrogen at 350 and 530 C are obtained. Uncoated SnO{sub 2} sensor is reduced at 530 C in H{sub 2} to tin while SiBCN-coated SnO{sub 2} sensors show reversible resistance changes while exposed to CO and H{sub 2}. Si{sub 3}N{sub 4}-ceramics have been synthesized via a dry ammonia pyrolysis of commercially available polysilazane (KiON HTT 1800). Amorphous microporous-Si{sub 3}N{sub 4} ceramic layers deposited on the top of GaN sensing layer followed by dry ammonia treatment leads to the improved H{sub 2} to CO selectivity of Si{sub 3}N{sub 4}/GaN sensors in the oxygen-free atmosphere. Transient response of the uncoated-, three-fold Si{sub 3}N{sub 4} coated- and ammonia treated-GaN sensors exposed to CO (10, 20 and 120 ppm) and H{sub 2} (40, 400 and 900 ppm) in pure nitrogen at 350 and 530 C are investigated. The results indicate that uncoated-GaN sensor shows high response towards both CO and H{sub 2} whereas for microporous Si{sub 3}N{sub 4} coated- and ammonia treated-GaN gas sensors the sensitivity towards the interfering gas CO is significantly reduced. High-surface area micro- and mesoporous carbon-rich SiCN ceramics have been obtained by controlled thermolysis of a carbon-rich poly(diphenylsilylcarbodiimide) precursor under argon. The formation of porous SiCN ceramics is due to the