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Sample records for kritische anlage zum htr

  1. Benign anlage tumour: a very unusual neck mass.

    PubMed

    Parihar, Shivani; Gohil, Rohit; Oparka, Richie; Kennedy, Ceilidh

    2016-01-01

    A 44-year-old woman presented with a slow-growing asymptomatic neck swelling at the left medial clavicle. Haematological and biochemical work up was normal and an ultrasound confirmed the swelling, but needle aspiration was non-diagnostic. As lymphoma was the main differential diagnosis, the swelling was completely excised. Immunohistochemistry yielded a rare lesion, suspected to represent a myoepithelial/mixed cellularity tumour of soft tissue. The extreme rarity of these tumours required a confirmatory secondary opinion, which ultimately led to it being identified as a benign anlage tumour (previously known as an ectopic hamartomatous thymoma) This case highlights the fact that thorough assessment of patients with neck swellings should be undertaken to rule out sinister causes-keeping in mind more rare differentials-helping to guide final management. PMID:27194678

  2. HTR1B and HTR2C in autism spectrum disorders in Brazilian families.

    PubMed

    Orabona, G M; Griesi-Oliveira, K; Vadasz, E; Bulcão, V L S; Takahashi, V N V O; Moreira, E S; Furia-Silva, M; Ros-Melo, A M S; Dourado, F; Matioli, S R; Matioli, R; Otto, P; Passos-Bueno, M R

    2009-01-23

    Autism spectrum disorders (ASD) is a group of behaviorally defined neurodevelopmental disabilities characterized by multiple genetic etiologies and a complex presentation. Several studies suggest the involvement of the serotonin system in the development of ASD, but only few have investigated serotonin receptors. We have performed a case-control and a family-based study with 9 polymorphisms mapped to two serotonin receptor genes (HTR1B and HTR2C) in 252 Brazilian male ASD patients of European ancestry. These analyses showed evidence of undertransmission of the HTR1B haplotypes containing alleles -161G and -261A at HTR1B gene to ASD (P=0.003), but no involvement of HTR2C to the predisposition to this disease. Considering the relatively low level of statistical significance and the power of our sample, further studies are required to confirm the association of these serotonin-related genes and ASD. PMID:19038234

  3. Postirradiation examination of HTR fuel

    SciTech Connect

    Nabielek, H.; Reitsamer, G.; Kania, M.J.

    1986-01-01

    Fuel for the High Temperature Reactor (HTR) consists of 1 mm diameter coated particles uniformly distributed in a graphite matrix within a cold-molded 60 mm diameter spherical fuel element. Fuel performance demonstrations under simulated normal operation conditions are conducted in accelerated neutron environments available in Material Test Reactors and in real-time environments such as the Arbeitsgemeinschaft Versuchsreaktor (AVR) Juelich. Postirradiation examinations are then used to assess fuel element behavior and the detailed performance of the coated particles. The emphasis in postirradiation examination and accident testing is on assessment of the capability for fuel elements and individual coated particles to retain fission products and actinide fuel materials. To accomplish this task, techniques have been developed which measures fission product and fuel material distributions within or exterior to the particle: Hot Gas Chlorination - provides an accurate method to measure total fuel material concentration outside intact particles; Profile Electrolytic Deconsolidation - permits determination of fission product distribution along fuel element diameter and retrieval of fuel particles from positions within element; Gamma Spectrometry - provides nondestructive method to measure defect particle fractions based on retention of volatile metallic fission products; Particle Cracking - permits a measure of the partitioning of fission products between fuel kernel and particle coatings, and the derivation of diffusion parameters in fuel materials; Micro Gas Analysis - provides gaseous fission product and reactive gas inventory within free volume of single particles; and Mass-spectrometric Burnup Determination - utilizes isotope dilution for the measurement of heavy metal isotope abundances.

  4. HTR7 mediates serotonergic acute and chronic itch

    PubMed Central

    Morita, Takeshi; McClain, Shannan P.; Batia, Lyn M.; Pellegrino, Maurizio; Wilson, Sarah R.; Kienzler, Michael A.; Lyman, Kyle; Olsen, Anne Sofie Braun; Wong, Justin F.; Stucky, Cheryl L.; Brem, Rachel B.; Bautista, Diana M.

    2015-01-01

    SUMMARY Chronic itch is a prevalent and debilitating condition for which few effective therapies are available. We harnessed the natural variation across genetically distinct mouse strains to identify transcripts co-regulated with itch behavior. This survey led to the discovery of the serotonin receptor, HTR7, as a key mediator of serotonergic itch. Activation of HTR7 promoted opening of the ion channel TRPA1, which in turn triggered itch behaviors. In addition, acute itch triggered by serotonin or a selective serotonin reuptake inhibitor required both HTR7 and TRPA1. Aberrant serotonin signaling has long been linked to a variety of human chronic itch conditions, including atopic dermatitis. In a mouse model of atopic dermatitis, mice lacking HTR7 or TRPA1 displayed reduced scratching and skin lesion severity. These data highlight a role for HTR7 in acute and chronic itch, and suggest that HTR7 antagonists may be useful for treating a variety of pathological itch conditions. PMID:26074006

  5. Experimental evidence for the ectodermal origin of the epithelial anlage of the chicken bursa of Fabricius.

    PubMed

    Nagy, Nándor; Oláh, Imre

    2010-09-01

    The bursa of Fabricius (BF) is a central lymphoid organ of birds responsible for B-cell maturation within bursal follicles of epithelial origin. Despite the fundamental importance of the BF to the birth of B lymphocytes in the immune system, the embryological origin of the epithelial component of the BF remains unknown. The BF arises in the tail bud, caudal to the cloaca and in close association with the cloacal membrane, where the anal invagination (anal sinus) of ectoderm and the caudal endodermal wall of the cloaca are juxtaposed. Serial semi-thin sections of the tail bud show that the anal sinus gradually transforms into the bursal duct and proctodeum, which joins the distal part of the cloaca during late embryogenesis. These anatomical findings raise the possibility that the ectoderm may contribute to the epithelial anlage of the BF. The expression of sonic hedgehog and its receptor in the embryonic gut, but not in the BF, further supports an ectodermal origin for the bursal rudiment. Using chick-quail chimeras, quail tail bud ectoderm was homotopically transplanted into ectoderm-ablated chick, resulting in quail-derived bursal follicle formation. Chimeric bursal anlagen were generated in vitro by recombining chick bursal mesenchyme with quail ectoderm or endoderm and grafting the recombination into the chick coelomic cavity. After hematopoietic cell colonization, bursal follicles formed only in grafts containing BF mesenchyme and tail bud ectoderm. These results strongly support the central role of the ectoderm in the development of the bursal epithelium and hence in the maturation of B lymphocytes. PMID:20702559

  6. Graphite Oxidation Simulation in HTR Accident Conditions

    SciTech Connect

    El-Genk, Mohamed

    2012-10-19

    Massive air and water ingress, following a pipe break or leak in steam-generator tubes, is a design-basis accident for high-temperature reactors (HTRs). Analysis of these accidents in both prismatic and pebble bed HTRs requires state-of-the-art capability for predictions of: 1) oxidation kinetics, 2) air helium gas mixture stratification and diffusion into the core following the depressurization, 3) transport of multi-species gas mixture, and 4) graphite corrosion. This project will develop a multi-dimensional, comprehensive oxidation kinetics model of graphite in HTRs, with diverse capabilities for handling different flow regimes. The chemical kinetics/multi-species transport model for graphite burning and oxidation will account for temperature-related changes in the properties of graphite, oxidants (O2, H2O, CO), reaction products (CO, CO2, H2, CH4) and other gases in the mixture (He and N2). The model will treat the oxidation and corrosion of graphite in geometries representative of HTR core component at temperatures of 900°C or higher. The developed chemical reaction kinetics model will be user-friendly for coupling to full core analysis codes such as MELCOR and RELAP, as well as computational fluid dynamics (CFD) codes such as CD-adapco. The research team will solve governing equations for the multi-dimensional flow and the chemical reactions and kinetics using Simulink, an extension of the MATLAB solver, and will validate and benchmark the model's predictions using reported experimental data. Researchers will develop an interface to couple the validated model to a commercially available CFD fluid flow and thermal-hydraulic model of the reactor , and will perform a simulation of a pipe break in a prismatic core HTR, with the potential for future application to a pebble-bed type HTR.

  7. 5-HTR1A and 5-HTR2A genetic polymorphisms and SSRI antidepressant response in depressive Chinese patients

    PubMed Central

    Dong, Zai-Quan; Li, Xi-Rong; He, Lin; He, Guang; Yu, Tao; Sun, Xue-Li

    2016-01-01

    Objective Genetic variabilities within the serotoninergic system may predict response or remission to antidepressant drugs. Several serotonin receptor (5-HTR) gene polymorphisms have been associated with susceptibility to psychiatric diseases. In this study, we analyzed the correlation between 5-HTR1A and 5-HTR2A polymorphisms and response or remission to selective serotonin reuptake inhibitors (SSRIs) drugs. Methods Two hundred and ninety patients who met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for major depressive disorder were involved in this study. SSRIs (fluoxetine, paroxetine, citalopram, or sertraline) were selected randomly for treatment. The Hamilton Rating Scale for Depression was used to evaluate the antidepressant effect. To assess 5-HTR gene variabilities, two single-nucleotide polymorphisms in 5-HTR1A (rs1364043 and rs10042486) and three in 5-HTR2A (rs6311, rs6313, and rs17289304) were genotyped by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry using the Sequenom MassARRAY Analyzer 4 system. Results There were 220 responders and 70 nonresponders (120 remissioners and 170 nonremissioners) after 6 weeks of treatment. We found no association between any of the five 5-HTR1A and 5-HTR2A gene polymorphisms and antidepressant drug response or remission (P>0.05). It is worth mentioning that TT genotype frequency of rs10042486 was significantly different from the CT genotype frequency between responders and nonresponders, although the significance was not maintained after correcting for multiple testing. Conclusion Thus, 5-HTR1A and 5-HTR2A gene polymorphisms may not play an important role in antidepressant drug response or remission. PMID:27445478

  8. The salt-sensitive structure and zinc inhibition of Borrelia burgdorferi protease BbHtrA.

    PubMed

    Russell, Theresa M; Tang, Xiaoling; Goldstein, Jason M; Bagarozzi, Dennis; Johnson, Barbara J B

    2016-02-01

    HtrA serine proteases are highly conserved and essential ATP-independent proteases with chaperone activity. Bacteria express a variable number of HtrA homologues that contribute to the virulence and pathogenicity of bacterial pathogens. Lyme disease spirochetes possess a single HtrA protease homologue, Borrelia burgdorferi HtrA (BbHtrA). Previous studies established that, like the human orthologue HtrA1, BbHtrA is proteolytically active against numerous extracellular proteins in vitro. In this study, we utilized size exclusion chromatography and blue native polyacrylamide gel electrophoresis (BN-PAGE) to demonstrate BbHtrA oligomeric structures that were substrate independent and salt sensitive. Examination of the influence of transition metals on the activity of BbHtrA revealed that this protease is inhibited by Zn(2+) > Cu(2+) > Mn(2+). Extending this analysis to two other HtrA proteases, E. coli DegP and HtrA1, revealed that all three HtrA proteases were reversibly inhibited by ZnCl2 at all micro molar concentrations examined. Commercial inhibitors for HtrA proteases are not available and physiologic HtrA inhibitors are unknown. Our observation of conserved zinc inhibition of HtrA proteases will facilitate structural and functional studies of additional members of this important class of proteases. PMID:26480895

  9. Structural and functional analysis of human HtrA3 protease and its subdomains

    SciTech Connect

    Glaza, Przemyslaw; Osipiuk, Jerzy; Wenta, Tomasz; Zurawa-Janicka, Dorota; Jarzab, Miroslaw; Lesner, Adam; Banecki, Bogdan; Skorko-Glonek, Joanna; Joachimiak, Andrzej; Lipinska, Barbara; van Raaij, Mark J.

    2015-06-25

    Human HtrA3 protease, which induces mitochondria-mediated apoptosis, can be a tumor suppressor and a potential therapeutic target in the treatment of cancer. However, there is little information about its structure and biochemical properties. HtrA3 is composed of an N-terminal domain not required for proteolytic activity, a central serine protease domain and a C-terminal PDZ domain. HtrA3S, its short natural isoform, lacks the PDZ domain which is substituted by a stretch of 7 C-terminal amino acid residues, unique for this isoform. This paper presents the crystal structure of the HtrA3 protease domain together with the PDZ domain (ΔN-HtrA3), showing that the protein forms a trimer whose protease domains are similar to those of human HtrA1 and HtrA2. The ΔN-HtrA3 PDZ domains are placed in a position intermediate between that in the flat saucer-like HtrA1 SAXS structure and the compact pyramidal HtrA2 X-ray structure. The PDZ domain interacts closely with the LB loop of the protease domain in a way not found in other human HtrAs. ΔN-HtrA3 with the PDZ removed (ΔN-HtrA3-ΔPDZ) and an N-terminally truncated HtrA3S (ΔN-HtrA3S) were fully active at a wide range of temperatures and their substrate affinity was not impaired. This indicates that the PDZ domain is dispensable for HtrA3 activity. As determined by size exclusion chromatography, ΔN-HtrA3 formed stable trimers while both ΔN-HtrA3-ΔPDZ and ΔN-HtrA3S were monomeric. This suggests that the presence of the PDZ domain, unlike in HtrA1 and HtrA2, influences HtrA3 trimer formation. The unique C-terminal sequence of ΔN-HtrA3S appeared to have little effect on activity and oligomerization. Additionally, we examined the cleavage specificity of ΔN-HtrA3. Results reported in this paper provide new insights into the structure and function of ΔN-HtrA3, which seems to have a unique combination of features among human HtrA proteases.

  10. Structural and functional analysis of human HtrA3 protease and its subdomains

    DOE PAGESBeta

    Glaza, Przemyslaw; Osipiuk, Jerzy; Wenta, Tomasz; Zurawa-Janicka, Dorota; Jarzab, Miroslaw; Lesner, Adam; Banecki, Bogdan; Skorko-Glonek, Joanna; Joachimiak, Andrzej; Lipinska, Barbara; et al

    2015-06-25

    Human HtrA3 protease, which induces mitochondria-mediated apoptosis, can be a tumor suppressor and a potential therapeutic target in the treatment of cancer. However, there is little information about its structure and biochemical properties. HtrA3 is composed of an N-terminal domain not required for proteolytic activity, a central serine protease domain and a C-terminal PDZ domain. HtrA3S, its short natural isoform, lacks the PDZ domain which is substituted by a stretch of 7 C-terminal amino acid residues, unique for this isoform. This paper presents the crystal structure of the HtrA3 protease domain together with the PDZ domain (ΔN-HtrA3), showing that themore » protein forms a trimer whose protease domains are similar to those of human HtrA1 and HtrA2. The ΔN-HtrA3 PDZ domains are placed in a position intermediate between that in the flat saucer-like HtrA1 SAXS structure and the compact pyramidal HtrA2 X-ray structure. The PDZ domain interacts closely with the LB loop of the protease domain in a way not found in other human HtrAs. ΔN-HtrA3 with the PDZ removed (ΔN-HtrA3-ΔPDZ) and an N-terminally truncated HtrA3S (ΔN-HtrA3S) were fully active at a wide range of temperatures and their substrate affinity was not impaired. This indicates that the PDZ domain is dispensable for HtrA3 activity. As determined by size exclusion chromatography, ΔN-HtrA3 formed stable trimers while both ΔN-HtrA3-ΔPDZ and ΔN-HtrA3S were monomeric. This suggests that the presence of the PDZ domain, unlike in HtrA1 and HtrA2, influences HtrA3 trimer formation. The unique C-terminal sequence of ΔN-HtrA3S appeared to have little effect on activity and oligomerization. Additionally, we examined the cleavage specificity of ΔN-HtrA3. Results reported in this paper provide new insights into the structure and function of ΔN-HtrA3, which seems to have a unique combination of features among human HtrA proteases.« less

  11. Activity-Modulating Monoclonal Antibodies to the Human Serine Protease HtrA3 Provide Novel Insights into Regulating HtrA Proteolytic Activities

    PubMed Central

    Singh, Harmeet; Nero, Tracy L.; Wang, Yao; Parker, Michael W.; Nie, Guiying

    2014-01-01

    Mammalian HtrA (high temperature requirement factor A) proteases, comprising 4 multi-domain members HtrA1-4, play important roles in a number of normal cellular processes as well as pathological conditions such as cancer, arthritis, neurodegenerative diseases and pregnancy disorders. However, how HtrA activities are regulated is not well understood, and to date no inhibitors specific to individual HtrA proteins have been identified. Here we investigated five HtrA3 monoclonal antibodies (mAbs) that we have previously produced, and demonstrated that two of them regulated HtrA3 activity in an opposing fashion: one inhibited while the other stimulated. The inhibitory mAb also blocked HtrA3 activity in trophoblast cells and enhanced migration and invasion, confirming its potential in vivo utility. To understand how the binding of these mAbs modulated HtrA3 protease activity, their epitopes were visualized in relation to a 3-dimensional HtrA3 homology model. This model suggests that the inhibitory HtrA3 mAb blocks substrate access to the protease catalytic site, whereas the stimulatory mAb may bind to the PDZ domain alone or in combination with the N-terminal and protease domains. Since HtrA1, HtrA3 and HtrA4 share identical domain organization, our results establish important foundations for developing potential therapeutics to target these HtrA proteins specifically for the treatment of a number of diseases, including cancer and pregnancy disorders. PMID:25248123

  12. Design and synthesis of new substrates of HtrA2 protease.

    PubMed

    Wysocka, Magdalena; Wojtysiak, Anna; Okońska, Małgorzata; Gruba, Natalia; Jarząb, Mirosław; Wenta, Tomasz; Lipińska, Barbara; Grzywa, Reneta; Sieńczyk, Marcin; Rolka, Krzysztof; Lesner, Adam

    2015-04-15

    HtrA2 belongs to the HtrA (high temperature requirement A) family of ATP-independent serine proteases. The primary function of HtrA2 includes maintaining the mitochondria homeostasis, cell death (by apoptosis, necrosis, or anoikis), and contribution to the cell signaling. Several recent reports have shown involvement of HtrA2 in development of cancer and neurodegenerative disorders. Here, we describe the profiling of HtrA2 protease substrate specificity via the combinatorial chemistry approach that led to the selection of novel intramolecularly quenched substrates. For all synthesized compounds, the highest HtrA2-mediated hydrolysis efficiency and selectivity among tested HtrA family members was observed for ABZ-Ile-Met-Thr-Abu-Tyr-Met-Phe-Tyr(3-NO2)-NH2, which displayed a specificity constant kcat/KM value of 14,535M(-1)s(-1). PMID:25640585

  13. Expression and Functional Significance of HtrA1 Loss in Endometrial Cancer

    PubMed Central

    Mullany, Sally A.; Moslemi-Kebria, Mehdi; Rattan, Ramandeep; Khurana, Ashwani; Clayton, Amy; Ota, Takayo; Mariani, Andrea; Podratz, Karl C.; Chien, Jeremy; Shridhar, Viji

    2010-01-01

    Purpose The purpose of this study was to determine if loss of serine protease HtrA1 in endometrial cancer will promote the invasive potential of EC cell lines. Experimental design Western blot analysis and immunohistochemistry methods were used to determine HtrA1 expression in EC cell lines and primary tumors, respectively. Migration, invasion assays and in vivo xenograft experiment were performed to compare the extent of metastasis between HtrA1 expressing and HtrA-1 knocked down clones. Results Western blot analysis of HtrA1 in 13 EC cell lines revealed complete loss of HtrA1 expression in all 7 papillary serous EC cell lines. Downregulation of HtrA1 in Hec1A and Hec1B cell lines resulted in a 3-4 fold increase in the invasive potential. Exogenous expression of HtrA1 in Ark 1 and Ark 2 cells resulted in 3-4 fold decrease in both invasive and migration potential of these cells. There was an increased rate of metastasis to the lungs associated with HtrA1 downregulation in Hec1B cells compared to control cells with endogenous HtrA1 expression. Enhanced expression of HtrA1 in Ark 2 cells resulted in significantly less tumor nodules metastasizing to the lungs compared to parental or protease deficient (SA mutant) Ark 2 cells. Immunohistochemical (IHC) analysis showed 57% (105/184) of primary EC tumors had low HtrA1 expression. The association of low HtrA1 expression with high-grade endometrioid tumors was statistically significant (p=0.016). Conclusions Collectively, these data indicate loss of HtrA1 may contribute to the aggressiveness and metastatic ability of endometrial tumors. PMID:21098697

  14. Reactor Physics Characterization of the HTR Module with UCO Fuel

    SciTech Connect

    Gerhard Strydom

    2011-01-01

    ABSTRACT The HTR Module [1] is a graphite-moderated, helium cooled pebble bed High Temperature Reactor (HTR) design that has been extensively used as a reference template for the former South African and current Chinese HTR [2] programs. This design utilized spherical fuel elements packed into a dynamic pebble bed, consisting of TRISO coated uranium oxide (UO2) fuel kernels with a U-235 enrichment of 7.8% and a Heavy Metal loading of 7 grams per pebble. The main objective of this study is to compare several important reactor physics and core design parameters for the HTR Module and an identical design utilizing UCO fuel kernels. Fuel kernels of this type are currently being tested in the Idaho National Laboratory’s (INL) Advanced Test Reactor (ATR) as part of the larger Next Generation Nuclear Plant (NGNP) project. The PEBBED-THERMIX [3] code, which was developed specifically for the analysis of pebble bed HTRs, was used to compare the coupled neutronic and thermal fluid performance of the two designs.

  15. Protoporphyrins Enhance Oligomerization and Enzymatic Activity of HtrA1 Serine Protease

    PubMed Central

    Jo, Hakryul; Patterson, Victoria; Stoessel, Sean; Kuan, Chia-Yi; Hoh, Josephine

    2014-01-01

    High temperature requirement protein A1 (HtrA1), a secreted serine protease of the HtrA family, is associated with a multitude of human diseases. However, the exact functions of HtrA1 in these diseases remain poorly understood. We seek to unravel the mechanisms of HtrA1 by elucidating its interactions with chemical or biological modulators. To this end, we screened a small molecule library of 500 bioactive compounds to identify those that alter the formation of extracellular HtrA1 complexes in the cell culture medium. An initial characterization of two novel hits from this screen showed that protoporphyrin IX (PPP-IX), a precursor in the heme biosynthetic pathway, and its metalloporphyrin (MPP) derivatives fostered the oligomerization of HtrA1 by binding to the protease domain. As a result of the interaction with MPPs, the proteolytic activity of HtrA1 against Fibulin-5, a specific HtrA1 substrate in age-related macular degeneration (AMD), was increased. This physical interaction could be abolished by the missense mutations of HtrA1 found in patients with cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). Furthermore, knockdown of HtrA1 attenuated apoptosis induced by PPP-IX. These results suggest that PPP-IX, or its derivatives, and HtrA1 may function as co-factors whereby porphyrins enhance oligomerization and the protease activity of HtrA1, while active HtrA1 elevates the pro-apoptotic actions of porphyrin derivatives. Further analysis of this interplay may shed insights into the pathogenesis of diseases such as AMD, CARASIL and protoporphyria, as well as effective therapeutic development. PMID:25506911

  16. Characterisation of worldwide Helicobacter pylori strains reveals genetic conservation and essentiality of serine protease HtrA.

    PubMed

    Tegtmeyer, Nicole; Moodley, Yoshan; Yamaoka, Yoshio; Pernitzsch, Sandy Ramona; Schmidt, Vanessa; Traverso, Francisco Rivas; Schmidt, Thomas P; Rad, Roland; Yeoh, Khay Guan; Bow, Ho; Torres, Javier; Gerhard, Markus; Schneider, Gisbert; Wessler, Silja; Backert, Steffen

    2016-03-01

    HtrA proteases and chaperones exhibit important roles in periplasmic protein quality control and stress responses. The genetic inactivation of htrA has been described for many bacterial pathogens. However, in some cases such as the gastric pathogen Helicobacter pylori, HtrA is secreted where it cleaves the tumour-suppressor E-cadherin interfering with gastric disease development, but the generation of htrA mutants is still lacking. Here, we show that the htrA gene locus is highly conserved in worldwide strains. HtrA presence was confirmed in 992 H. pylori isolates in gastric biopsy material from infected patients. Differential RNA-sequencing (dRNA-seq) indicated that htrA is encoded in an operon with two subsequent genes, HP1020 and HP1021. Genetic mutagenesis and complementation studies revealed that HP1020 and HP1021, but not htrA, can be mutated. In addition, we demonstrate that suppression of HtrA proteolytic activity with a newly developed inhibitor is sufficient to effectively kill H. pylori, but not other bacteria. We show that Helicobacter htrA is an essential bifunctional gene with crucial intracellular and extracellular functions. Thus, we describe here the first microbe in which htrA is an indispensable gene, a situation unique in the bacterial kingdom. HtrA can therefore be considered a promising new target for anti-bacterial therapy. PMID:26568477

  17. Characterisation of worldwide Helicobacter pylori strains reveals genetic conservation and essentiality of serine protease HtrA

    PubMed Central

    Tegtmeyer, Nicole; Moodley, Yoshan; Yamaoka, Yoshio; Pernitzsch, Sandy Ramona; Schmidt, Vanessa; Traverso, Francisco Rivas; Schmidt, Thomas P.; Rad, Roland; Yeoh, Khay Guan; Bow, Ho; Torres, Javier; Gerhard, Markus; Schneider, Gisbert; Wessler, Silja

    2015-01-01

    Summary HtrA proteases and chaperones exhibit important roles in periplasmic protein quality control and stress responses. The genetic inactivation of htrA has been described for many bacterial pathogens. However, in some cases such as the gastric pathogen H elicobacter pylori, HtrA is secreted where it cleaves the tumour‐suppressor E‐cadherin interfering with gastric disease development, but the generation of htrA mutants is still lacking. Here, we show that the htrA gene locus is highly conserved in worldwide strains. HtrA presence was confirmed in 992 H . pylori isolates in gastric biopsy material from infected patients. Differential RNA‐sequencing (dRNA‐seq) indicated that htrA is encoded in an operon with two subsequent genes, HP1020 and HP1021. Genetic mutagenesis and complementation studies revealed that HP1020 and HP1021, but not htrA, can be mutated. In addition, we demonstrate that suppression of HtrA proteolytic activity with a newly developed inhibitor is sufficient to effectively kill H . pylori, but not other bacteria. We show that H elicobacter  htrA is an essential bifunctional gene with crucial intracellular and extracellular functions. Thus, we describe here the first microbe in which htrA is an indispensable gene, a situation unique in the bacterial kingdom. HtrA can therefore be considered a promising new target for anti‐bacterial therapy. PMID:26568477

  18. HtrA Is Important for Stress Resistance and Virulence in Haemophilus parasuis.

    PubMed

    Zhang, Luhua; Li, Ying; Wen, Yiping; Lau, Gee W; Huang, Xiaobo; Wu, Rui; Yan, Qigui; Huang, Yong; Zhao, Qin; Ma, Xiaoping; Wen, Xintian; Cao, Sanjie

    2016-08-01

    Haemophilus parasuis is an opportunistic pathogen that causes Glässer's disease in swine, with polyserositis, meningitis, and arthritis. The high-temperature requirement A (HtrA)-like protease, which is involved in protein quality control, has been reported to be a virulence factor in many pathogens. In this study, we showed that HtrA of H. parasuis (HpHtrA) exhibited both chaperone and protease activities. Finally, nickel import ATP-binding protein (NikE), periplasmic dipeptide transport protein (DppA), and outer membrane protein A (OmpA) were identified as proteolytic substrates for HpHtrA. The protease activity reached its maximum at 40°C in a time-dependent manner. Disruption of the htrA gene from strain SC1401 affected tolerance to temperature stress and resistance to complement-mediated killing. Furthermore, increased autoagglutination and biofilm formation were detected in the htrA mutant. In addition, the htrA mutant was significantly attenuated in virulence in the murine model of infection. Together, these data demonstrate that HpHtrA plays an important role in the virulence of H. parasuis. PMID:27217419

  19. DNA Methylation Analysis of HTR2A Regulatory Region in Leukocytes of Autistic Subjects.

    PubMed

    Hranilovic, Dubravka; Blazevic, Sofia; Stefulj, Jasminka; Zill, Peter

    2016-02-01

    Disturbed brain and peripheral serotonin homeostasis is often found in subjects with autism spectrum disorder (ASD). The role of the serotonin receptor 2A (HTR2A) in the regulation of central and peripheral serotonin homeostasis, as well as its altered expression in autistic subjects, have implicated the HTR2A gene as a major candidate for the serotonin disturbance seen in autism. Several studies, yielding so far inconclusive results, have attempted to associate autism with a functional SNP -1438 G/A (rs6311) in the HTR2A promoter region, while possible contribution of epigenetic mechanisms, such as DNA methylation, to HTR2A dysregulation in autism has not yet been investigated. In this study, we compared the mean DNA methylation within the regulatory region of the HTR2A gene between autistic and control subjects. DNA methylation was analysed in peripheral blood leukocytes using bisulfite conversion and sequencing of the HTR2A region containing rs6311 polymorphism. Autistic subjects of rs6311 AG genotype displayed higher mean methylation levels within the analysed region than the corresponding controls (P < 0.05), while there was no statistically significant difference for AA and GG carriers. Our study provides preliminary evidence for increased HTR2A promoter methylation in leukocytes of a portion of adult autistic subjects, indicating that epigenetic mechanisms might contribute to HTR2A dysregulation observed in individuals with ASD. PMID:26149086

  20. HtrA chaperone activity contributes to host cell binding in Campylobacter jejuni

    PubMed Central

    2011-01-01

    Background Acute gastroenteritis caused by the food-borne pathogen Campylobacter jejuni is associated with attachment of bacteria to the intestinal epithelium and subsequent invasion of epithelial cells. In C. jejuni, the periplasmic protein HtrA is required for efficient binding to epithelial cells. HtrA has both protease and chaperone activity, and is important for virulence of several bacterial pathogens. Results The aim of this study was to determine the role of the dual activities of HtrA in host cell interaction of C. jejuni by comparing an htrA mutant lacking protease activity, but retaining chaperone activity, with a ΔhtrA mutant and the wild type strain. Binding of C. jejuni to both epithelial cells and macrophages was facilitated mainly by HtrA chaperone activity that may be involved in folding of outer membrane adhesins. In contrast, HtrA protease activity played only a minor role in interaction with host cells. Conclusion We show that HtrA protease and chaperone activities contribute differently to C. jejuni's interaction with mammalian host cells, with the chaperone activity playing the major role in host cell binding. PMID:21939552

  1. HtrA Is Important for Stress Resistance and Virulence in Haemophilus parasuis

    PubMed Central

    Zhang, Luhua; Li, Ying; Wen, Yiping; Lau, Gee W.; Huang, Xiaobo; Wu, Rui; Yan, Qigui; Huang, Yong; Zhao, Qin; Ma, Xiaoping

    2016-01-01

    Haemophilus parasuis is an opportunistic pathogen that causes Glässer's disease in swine, with polyserositis, meningitis, and arthritis. The high-temperature requirement A (HtrA)-like protease, which is involved in protein quality control, has been reported to be a virulence factor in many pathogens. In this study, we showed that HtrA of H. parasuis (HpHtrA) exhibited both chaperone and protease activities. Finally, nickel import ATP-binding protein (NikE), periplasmic dipeptide transport protein (DppA), and outer membrane protein A (OmpA) were identified as proteolytic substrates for HpHtrA. The protease activity reached its maximum at 40°C in a time-dependent manner. Disruption of the htrA gene from strain SC1401 affected tolerance to temperature stress and resistance to complement-mediated killing. Furthermore, increased autoagglutination and biofilm formation were detected in the htrA mutant. In addition, the htrA mutant was significantly attenuated in virulence in the murine model of infection. Together, these data demonstrate that HpHtrA plays an important role in the virulence of H. parasuis. PMID:27217419

  2. Evolution of mitochondrial cell death pathway: Proapoptotic role of HtrA2/Omi in Drosophila

    SciTech Connect

    Igaki, Tatsushi; Suzuki, Yasuyuki; Tokushige, Naoko; Aonuma, Hiroka; Takahashi, Ryosuke . E-mail: ryosuket@kuhp.kyoto-u.ac.jp; Miura, Masayuki . E-mail: miura@mol.f.u-tokyo.ac.jp

    2007-05-18

    Despite the essential role of mitochondria in a variety of mammalian cell death processes, the involvement of mitochondrial pathway in Drosophila cell death has remained unclear. To address this, we cloned and characterized DmHtrA2, a Drosophila homolog of a mitochondrial serine protease HtrA2/Omi. We show that DmHtrA2 normally resides in mitochondria and is up-regulated by UV-irradiation. Upon receipt of apoptotic stimuli, DmHtrA2 is translocated to extramitochondrial compartment; however, unlike its mammalian counterpart, the extramitochondrial DmHtrA2 does not diffuse throughout the cytosol but stays near the mitochondria. RNAi-mediated knock-down of DmHtrA2 in larvae or adult flies results in a resistance to stress stimuli. DmHtrA2 specifically cleaves Drosophila inhibitor-of-apoptosis protein 1 (DIAP1), a cellular caspase inhibitor, and induces cell death both in vitro and in vivo as potent as other fly cell death proteins. Our observations suggest that DmHtrA2 promotes cell death through a cleavage of DIAP1 in the vicinity of mitochondria, which may represent a prototype of mitochondrial cell death pathway in evolution.

  3. The HtrA-Like Protease CD3284 Modulates Virulence of Clostridium difficile

    PubMed Central

    Bakker, Dennis; Buckley, Anthony M.; de Jong, Anne; van Winden, Vincent J. C.; Verhoeks, Joost P. A.; Kuipers, Oscar P.; Douce, Gillian R.; Kuijper, Ed J.

    2014-01-01

    In the past decade, Clostridium difficile has emerged as an important gut pathogen. Symptoms of C. difficile infection range from mild diarrhea to pseudomembranous colitis. Besides the two main virulence factors toxin A and toxin B, other virulence factors are likely to play a role in the pathogenesis of the disease. In other Gram-positive and Gram-negative pathogenic bacteria, conserved high-temperature requirement A (HtrA)-like proteases have been shown to have a role in protein homeostasis and quality control. This affects the functionality of virulence factors and the resistance of bacteria to (host-induced) environmental stresses. We found that the C. difficile 630 genome encodes a single HtrA-like protease (CD3284; HtrA) and have analyzed its role in vivo and in vitro through the creation of an isogenic ClosTron-based htrA mutant of C. difficile strain 630Δerm (wild type). In contrast to the attenuated phenotype seen with htrA deletion in other pathogens, this mutant showed enhanced virulence in the Golden Syrian hamster model of acute C. difficile infection. Microarray data analysis showed a pleiotropic effect of htrA on the transcriptome of C. difficile, including upregulation of the toxin A gene. In addition, the htrA mutant showed reduced spore formation and adherence to colonic cells. Together, our data show that htrA can modulate virulence in C. difficile. PMID:25047848

  4. In-111 chelate conjugates of human transferrin (HTr) and mouse monoclonal anti human transferrin receptor antibody (. cap alpha. HTrR MoAb) for tumor imaging

    SciTech Connect

    Goodwin, D.A.; Meares, C.F.; Diamanti, C.I.; McCall, M.; McTigue, M.; Torti, F.; Martin, B.

    1984-01-01

    At least one of the major pathways of uptake of the commonly used tumor scanning agent Ga-67 is via the transferrin receptor. This suggested the use of stably radio-labeled HTr, and ..cap alpha..HTrR MoAb for tumor imaging in humans. HTr and mouse ..cap alpha..HTrR MoAb were alkylated with 1-(parabromacetamidobenzyl)-EDTA. The mM Alkylproteins, approx. =1 chelate/molecule were labeled with 1-3 mCi In-111 citrate pH/sub 5/ (Sp Act approx. = 100-300 Ci/m mole). Images were made 24 hours after 1 mCi IV and in some patients blood levels, urine excretion and digitized whole body scans were obtained at 1, 24,48 and 96 hours post injection. Ten patients with biopsy proven prostate cancer were studied with In-111 HTr, and four with In-111 ..cap alpha.. HTrR MoAb; all had positive mets on bone scan. In-111 HTr persisted in the circulation with a T1/2 of approx. = four days, approx. = 5%/day being excreted in the urine, to a total of approx. = 60% in 21 days. Nine of ten scans were false negative due to the high blood background. In-111 ..cap alpha..HTrR disappeared rapidly from the blood; with most in the bone marrow at 24 hours. ROI analysis of three patients showed whole body 94% at 24 hours, 89% at 48 hours, and 82% at 96 hours (T1/2 = 10.7 days); liver 19% at 1 hour, 25% at 24 hours, and 21% at 96 hours; spleen 3% at 1 hour, 8% at 24 hours, 7.3% at 48 hours, and 3% at 96 hours. The high bone marrow background allowed only a few of the bone mets seen as bone scan to be visualized. Other tumor types not located in bone may be more easily seen.

  5. Down-Regulation of HtrA1 Activates the Epithelial-Mesenchymal Transition and ATM DNA Damage Response Pathways

    PubMed Central

    Wang, Ning; Eckert, Kristin A.; Zomorrodi, Ali R.; Xin, Ping; Pan, Weihua; Shearer, Debra A.; Weisz, Judith; Maranus, Costas D.; Clawson, Gary A.

    2012-01-01

    Expression of the serine protease HtrA1 is decreased or abrogated in a variety of human primary cancers, and higher levels of HtrA1 expression are directly related to better response to chemotherapeutics. However, the precise mechanisms leading to HtrA1 down regulation during malignant transformation are unclear. To investigate HtrA1 gene regulation in breast cancer, we characterized expression in primary breast tissues and seven human breast epithelial cell lines, including two non-tumorigenic cell lines. In human breast tissues, HtrA1 expression was prominent in normal ductal glands. In DCIS and in invasive cancers, HtrA1 expression was greatly reduced or lost entirely. HtrA1 staining was also reduced in all of the human breast cancer cell lines, compared with the normal tissue and non-tumorigenic cell line controls. Loss of HtrA1 gene expression was attributable primarily to epigenetic silencing mechanisms, with different mechanisms operative in the various cell lines. To mechanistically examine the functional consequences of HtrA1 loss, we stably reduced and/or overexpressed HtrA1 in the non-tumorigenic MCF10A cell line. Reduction of HtrA1 levels resulted in the epithelial-to-mesenchymal transition with acquisition of mesenchymal phenotypic characteristics, including increased growth rate, migration, and invasion, as well as expression of mesenchymal biomarkers. A concomitant decrease in expression of epithelial biomarkers and all microRNA 200 family members was also observed. Moreover, reduction of HtrA1 expression resulted in activation of the ATM and DNA damage response, whereas overexpression of HtrA1 prevented this activation. Collectively, these results suggest that HtrA1 may function as a tumor suppressor by controlling the epithelial-to-mesenchymal transition, and may function in chemotherapeutic responsiveness by mediating DNA damage response pathways. PMID:22761798

  6. The developmental basis of epigenetic regulation of HTR2A and psychiatric outcomes.

    PubMed

    Paquette, Alison G; Marsit, Carmen J

    2014-12-01

    The serotonin receptor 5-HT2A (encoded by HTR2A) is an important regulator of fetal brain development and adult cognitive function. Environmental signals that induce epigenetic changes of serotonin response genes, including HTR2A, have been implicated in adverse mental health outcomes. The objective of this perspective article is to address the medical implications of HTR2A epigenetic regulation, which has been associated with both infant neurobehavioral outcomes and adult mental health. Ongoing research has identified a region of the HTR2A promoter that has been associated with a number of medical outcomes in adults and infants, including bipolar disorder, schizophrenia, chronic fatigue syndrome, borderline personality disorder, suicidality, and neurobehavioral outcomes. Epigenetic regulation of HTR2A has been studied in several different types of tissues, including the placenta. The placenta is an important source of serotonin during fetal neurodevelopment, and placental epigenetic variation of HTR2A has been associated with infant neurobehavioral outcomes, which may represent the basis of adult mental health disorders. Further analysis is needed to identify intrinsic and extrinsic factors that modulate HTR2A methylation, and the mechanism by which this epigenetic variation influences fetal growth and leads to altered brain development, manifesting in psychiatric disorders. PMID:25043477

  7. Insights into the Cyanobacterial Deg/HtrA Proteases

    PubMed Central

    Cheregi, Otilia; Wagner, Raik; Funk, Christiane

    2016-01-01

    Proteins are the main machinery for all living processes in a cell; they provide structural elements, regulate biochemical reactions as enzymes, and are the interface to the outside as receptors and transporters. Like any other machinery proteins have to be assembled correctly and need maintenance after damage, e.g., caused by changes in environmental conditions, genetic mutations, and limitations in the availability of cofactors. Proteases and chaperones help in repair, assembly, and folding of damaged and misfolded protein complexes cost-effective, with low energy investment compared with neo-synthesis. Despite their importance for viability, the specific biological role of most proteases in vivo is largely unknown. Deg/HtrA proteases, a family of serine-type ATP-independent proteases, have been shown in higher plants to be involved in the degradation of the Photosystem II reaction center protein D1. The objective of this review is to highlight the structure and function of their cyanobacterial orthologs. Homology modeling was used to find specific features of the SynDeg/HtrA proteases of Synechocystis sp. PCC 6803. Based on the available data concerning their location and their physiological substrates we conclude that these Deg proteases not only have important housekeeping and chaperone functions within the cell, but also are needed for remodeling the cell exterior. PMID:27252714

  8. Association of Polymorphisms within the Serotonin Receptor Genes 5-HTR1A, 5-HTR1B, 5-HTR2A and 5-HTR2C and Migraine Susceptibility in a Turkish Population

    PubMed Central

    Yücel, Yavuz; Coşkun, Salih; Cengiz, Beyhan; Özdemir, Hasan H.; Uzar, Ertuğrul; Çim, Abdullah; Camkurt, M. Akif; Aluclu, M. Ufuk

    2016-01-01

    Objective Migraine, a highly prevelant headache disorder, is regarded as a polygenic multifactorial disease. Serotonin (5-HT) and their respective receptors have been implicated in the patogenesis. Methods We investigated the 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT2C receptor gene polymorphisms and their association with migraine in Turkish patients. The rs6295, rs1300060, rs1228814, rs6311, rs6313, rs6314, rs6318, rs3813929 (−759C/T) and rs518147 polymorphisms were analyzed in 135 patients with migraine and 139 healthy subjects, using a BioMark 96.96 dynamic array system. Results We found no difference in the frequency of the analyzed eight out of nine polymorpisms between migraine and control groups. However, a significant association was found between the rs3813929 polymorphism in the promoter region of 5-HTR2C gene and migraine. Also, the allele of rs3813929 was more common in the migraine group. Conclusion This result suggests that the 5-HTR2C rs3813929 polymorphism can be a genetic risk factor for migraine in a Turkish population. PMID:27489378

  9. Improved Neutronics Treatment of Burnable Poisons for the Prismatic HTR

    SciTech Connect

    Y. Wang; A. A. Bingham; J. Ortensi; C. J. Permann

    2012-10-01

    In prismatic block High Temperature Reactors (HTR), highly absorbing material such a burnable poison (BP) cause local flux depressions and large gradients in the flux across the blocks which can be a challenge to capture accurately with traditional homogenization methods. The purpose of this paper is to quantify the error associated with spatial homogenization, spectral condensation and discretization and to highlight what is needed for improved neutronics treatments of burnable poisons for the prismatic HTR. A new triangular based mesh is designed to separate the BP regions from the fuel assembly. A set of packages including Serpent (Monte Carlo), Xuthos (1storder Sn), Pronghorn (diffusion), INSTANT (Pn) and RattleSnake (2ndorder Sn) is used for this study. The results from the deterministic calculations show that the cross sections generated directly in Serpent are not sufficient to accurately reproduce the reference Monte Carlo solution in all cases. The BP treatment produces good results, but this is mainly due to error cancellation. However, the Super Cell (SC) approach yields cross sections that are consistent with cross sections prepared on an “exact” full core calculation. In addition, very good agreement exists between the various deterministic transport and diffusion codes in both eigenvalue and power distributions. Future research will focus on improving the cross sections and quantifying the error cancellation.

  10. [Experience with the clinical use of HTR (hard tissue replacement) polymer. Sinus elevation, human histological studies].

    PubMed

    Suba, Z; Szabó, G; Haris, A; Divinyi, T; Martonffy, K

    1991-03-01

    The HTR polymer was employed under clinical circumstances. Results supported that the HTR polymer may well be employed for bone replacement. The forming of the support tissue between the plastic granulums has been accompanied with biopsies. Though in some cases giant cell reaction of alien body type have been observed, yet this has never been of such degree that it would have impeded the reception of the stuff. According to the authors opinion after reinforcement of the lower wall of the facial cavity with HTR polymert in 8 to 10 months an enduring suitable support tissue is formed. PMID:1855596

  11. Evaluation of Borrelia burgdorferi BbHtrA Protease as a Vaccine Candidate for Lyme Borreliosis in Mice

    PubMed Central

    Ullmann, Amy J.; Russell, Theresa M.; Dolan, Marc C.; Williams, Martin; Hojgaard, Andrias; Weiner, Zachary P.; Johnson, Barbara J. B.

    2015-01-01

    Borrelia burgdorferi synthesizes an HtrA protease (BbHtrA) which is a surface-exposed, conserved protein within Lyme disease spirochetes with activity toward CheX and BmpD of Borrelia spp, as well as aggrecan, fibronectin and proteoglycans found in skin, joints and neural tissues of vertebrates. An antibody response against BbHtrA is observed in Lyme disease patients and in experimentally infected laboratory mice and rabbits. Given the surface location of BbHtrA on B. burgdorferi and its ability to elicit an antibody response in infected hosts, we explored recombinant BbHtrA as a potential vaccine candidate in a mouse model of tick-transmitted Lyme disease. We immunized mice with two forms of BbHtrA: the proteolytically active native form and BbHtrA ablated of activity by a serine to alanine mutation at amino acid 226 (BbHtrAS226A). Although inoculation with either BbHtrA or BbHtrAS226A produced high-titer antibody responses in C3H/HeJ mice, neither antigen was successful in protecting mice from B. burgdorferi challenge. These results indicate that the search for novel vaccine candidates against Lyme borreliosis remains a challenge. PMID:26076465

  12. HtrA1 sensitizes ovarian cancer cells to cisplatin-induced cytotoxicity by targeting XIAP for degradation

    PubMed Central

    He, Xiaoping; Khurana, Ashwani; Maguire, Jacie L

    2011-01-01

    HtrA1, a member of serine protease family, has been previously found to be involved in resistance to chemotherapy in ovarian cancer although the underlying mechanism is not clear. Using mixture-based oriented peptide library approach, we previously identified X-linked inhibitor of apoptosis protein (XIAP), a member of the inhibitor of apoptosis proteins (IAPs) family as a potential substrate of HtrA1. The aim of this work is to investigate the link between HtrA1 and XIAP proteins and their relationships with chemoresistance in ovarian cancer. Our results showed that recombinant XIAP was degraded by purified wild type HtrA1 but not mutant HtrA1 in vitro. Consistent with the in vitro data, co-immunoprecipitation assays showed that HtrA1 and XIAP formed a protein complex in vivo. Ectopic expression of HtrA1 led to decreased level of XIAP in OV167 and OV202 ovarian cancer cells, while knockdown of HtrA1 resulted in increased level of XIAP in SKOV3 ovarian cancer cells. Furthermore, over-expression of HtrA1 in OV202 cells promoted cell sensitivity to cisplatin-induced apoptosis which could be reversed by increased expression of XIAP. The cleavage of XIAP induced by HtrA1 was enhanced by cisplatin treatment. Taken together, our experiments have identified XIAP as a novel substrate of HtrA1 and the degradation of XIAP by HtrA1 contributes to cell response to chemotherapy, suggesting that restoring the expression of HtrA1 may be a promising treatment strategy for ovarian cancer. PMID:21387310

  13. Stress Conditions Increase Vimentin Cleavage by Omi/HtrA2 Protease in Human Primary Neurons and Differentiated Neuroblastoma Cells.

    PubMed

    Lucotte, Bérangère; Tajhizi, Mehdi; Alkhatib, Dareen; Samuelsson, Eva-Britt; Wiehager, Birgitta; Schedin-Weiss, Sophia; Sundström, Erik; Winblad, Bengt; Tjernberg, Lars O; Behbahani, Homira

    2015-12-01

    Dysfunctional Omi/HtrA2, a mitochondrial serine protease, has been implicated in various neurodegenerative disorders. Despite the wealth of evidence on the roles of Omi/HtrA2 in apoptosis, little is known about its cytosolic targets, the cleavage of which could account for the observed morphological changes such as cytoskeletal reorganizations in axons. By proteomic analysis, vimentin was identified as a substrate for Omi/HtrA2 and we have reported increased Omi/HtrA2 protease activity in Alzheimer disease (AD) brain. Here, we investigated a possible link between Omi/HtrA2 and vimentin cleavage, and consequence of this cleavage on mitochondrial distribution in neurons. In vitro protease assays showed vimentin to be cleaved by Omi/HtrA2 protease, and proximity ligation assay demonstrated an increased interaction between Omi/HtrA2 and vimentin in human primary neurons upon stress stimuli. Using differentiated neuroblastoma SH-SY5Y cells, we showed that Omi/HtrA2 under several different stress conditions induces cleavage of vimentin in wild-type as well as SH-SY5Y cells transfected with amyloid precursor protein with the Alzheimer disease-associated Swedish mutation. After stress treatment, inhibition of Omi/HtrA2 protease activity by the Omi/HtrA2 specific inhibitor, Ucf-101, reduced the cleavage of vimentin in wild-type cells. Following altered vimentin filaments integrity by stress stimuli, mitochondria was redistributed in differentiated SH-SY5Y cells and human primary neurons. In summary, the findings outlined in this paper suggest a role of Omi/HtrA2 in modulation of vimentin filamentous structure in neurons. Our results provide important findings for understanding the biological role of Omi/HtrA2 activity during stress conditions, and give knowledge of interplay between Omi/HtrA2 and vimentin which might affect mitochondrial distribution in neurons. PMID:25288153

  14. HTR-100 industrial nuclear power plant for generation of heat and electricity

    SciTech Connect

    Brandes, S.; Kohl, W.

    1987-11-01

    Based on their proven high-temperature reactor (HTR) with pebble-bed core, Brown, Boveri and Cie/Hochtemperatur-Reaktorbau have developed an HTR-100 plant that combines favorable capital costs and high availability. Due to the high HTR-specific standards and passive safety features, this plant is especially well suited for siting near the end user. The safety concept permits further operation of the plant or decay heat removal via the operational heat sinks in the event of maloperation and design basis accidents having a higher probability of occurrence. In the event of hypothetical accidents, the decay heat is removed from the reactor pressure vessel by radiation, conduction, and convection to a concrete cooling system operating in natural convection. As an example of the new HTR-100 plant concept, a twin-block plant design for extraction of industrial steam is presented.

  15. Relaxin has anti-apoptotic effects on human trophoblast-derived HTR-8/SV neo cells.

    PubMed

    Lodhi, Romana S Z; Nakabayashi, Koji; Suzuki, Kaho; Yamada, Ai Y; Hazama, Rhoichi; Ebina, Yasuhiko; Yamada, Hideto

    2013-12-01

    The study was conducted to evaluate the effects of human relaxin on apoptosis in the human trophoblast derived HTR-8/SV neo cell line, which is a possible model of human extravillous trophoblasts (EVTs). HTR-8/SV neo cells, cultured in phenol red free RPMI1640 medium, were treated with different doses of human recombinant (rH2) relaxin in serum-deprived conditions. RT-PCR was used for evaluating relaxin receptor: RXFP1 and RXFP2 expression in HTR-8/SV neo cells. The cell death was examined by TUNEL assay. Furthermore, we investigated caspase-3, cleaved PARP and Bcl-2 expressions by Western blot analysis to recognize the translational effects of anti-apoptotic and pro-apoptotic proteins. RXFP1 and RXFP2 mRNA expression was observed in HTR-8/SV neo cells. Compared with untreated control cultures, treatment with rH2 relaxin, decreased TUNEL-positive rate in HTR-8/SV neo cells was observed. Western blot analysis revealed that treatment with rH2 relaxin decreased the expression of caspase-3 and cleaved PARP, but in contrast increased Bcl-2 expression in those cells. These results suggest that rH2 relaxin has anti-apoptotic effects on HTR8/SV neo cells by decreasing pro-apoptotic caspase-3 and cleaved PARP expression and up-regulating anti-apoptotic Bcl-2 expression. PMID:24070111

  16. Induced rates of mitotic crossing over and possible mitotic gene conversion per wing anlage cell in Drosophila melanogaster by X rays and fission neutrons

    SciTech Connect

    Ayaki, T.; Fujikawa, K.; Ryo, H.; Itoh, T.; Kondo, S. )

    1990-09-01

    As a model for chromosome aberrations, radiation-induced mitotic recombination of mwh and flr genes in Drosophila melanogaster strain (mwh +/+ flr) was quantitatively studied. Fission neutrons were five to six times more effective than X rays per unit dose in producing either crossover-mwh/flr twins and mwh singles-or flr singles, indicating that common processes are involved in the production of crossover and flr singles. The X-ray-induced rate/wing anlage cell/Gy for flr singles was 1 X 10(-5), whereas that of crossover was 2 x 10(-4); the former and the latter rate are of the same order of magnitude as those of gene conversion and crossover in yeast, respectively. Thus, we conclude that proximal-marker flr singles induced in the transheterozygote are gene convertants. Using the model based on yeast that recombination events result from repair of double-strand breaks or gaps, we propose that mitotic recombination in the fly is a secondary result of recombinational DNA repair. Evidence for recombinational misrepair in the fly is given. The relative ratio of radiation-induced mitotic crossover to spontaneous meiotic crossover is one order of magnitude higher in the fly than in yeast and humans.

  17. Physik gestern und heute Von der Metallstange zum Hochenergielaser

    NASA Astrophysics Data System (ADS)

    Heering, Peter

    2002-05-01

    Im Mai 1752 wurde in Marly bei Paris auf Anregung des amerikanischen Forschers und Politikers Benjamin Franklin erstmals die elektrische Natur des Blitzes nachgewiesen. Damals beschrieb Franklin auch eine technische Vorrichtung, die als Schutz von Gebäuden vor Blitzschlägen dienen sollte: den Blitzableiter. Diese aus heutiger Sicht scheinbar triviale Vorrichtung wurde aber keineswegs unmittelbar akzeptiert. Und bis heute ist die Forschung zum Schutz von Einrichtungen vor Blitzschlägen nicht abgeschlossen.

  18. HTR4 gene structure and altered expression in the developing lung

    PubMed Central

    2013-01-01

    Background Meta-analyses of genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) spanning the 5-hydroxytryptamine receptor 4 (5-HT4R) gene (HTR4) associated with lung function. The aims of this study were to i) investigate the expression profile of HTR4 in adult and fetal lung tissue and cultured airway cells, ii) further define HTR4 gene structure and iii) explore the potential functional implications of key SNPs using a bioinformatic approach. Methods Following reverse transcription (RT)-PCR in human brain, 5′ rapid amplification of cDNA ends (5′ RACE) was used to examine the exonic structure of HTR4 at the 5′ end. Quantitative (Q)-PCR was used to quantify HTR4 mRNA expression in total RNA from cultured airway cells and whole lung tissue. Publically available gene microarray data on fetal samples of estimated gestational age 7–22 weeks were mined for HTR4 expression. Immunohistochemistry (IHC; in adult and fetal lung tissue) and a radioligand binding assay (in cultured airway cells) were used to analyze 5­HT4R protein expression. Results IHC in adult lung, irrespective of the presence of chronic obstructive pulmonary disease (COPD), suggested low level expression of 5-HT4R protein, which was most prominent in alveolar pneumocytes. There was evidence of differential 5-HT4R protein levels during gestation in fetal lung, which was also evident in gene expression microarray data. HTR4 mRNA expression, assessed by Q-PCR, was <0.5% relative to brain in total adult lung tissue and in human airway smooth muscle (HASM) and bronchial epithelial cells (HBEC) derived from adult donors. Radioligand binding experiments also indicated that HBEC and HASM cells did not express a significant 5-HT4R population. 5′ RACE in brain identified a novel N-terminal variant, containing an extended N-terminal sequence. The functional significance of key HTR4 SNPs was investigated using the encyclopedia of DNA elements consortium (ENCODE

  19. Benchmark Evaluation of HTR-PROTEUS Pebble Bed Experimental Program

    SciTech Connect

    Bess, John D.; Montierth, Leland; Köberl, Oliver; Snoj, Luka

    2014-10-09

    Benchmark models were developed to evaluate 11 critical core configurations of the HTR-PROTEUS pebble bed experimental program. Various additional reactor physics measurements were performed as part of this program; currently only a total of 37 absorber rod worth measurements have been evaluated as acceptable benchmark experiments for Cores 4, 9, and 10. Dominant uncertainties in the experimental keff for all core configurations come from uncertainties in the ²³⁵U enrichment of the fuel, impurities in the moderator pebbles, and the density and impurity content of the radial reflector. Calculations of keff with MCNP5 and ENDF/B-VII.0 neutron nuclear data are greater than the benchmark values but within 1% and also within the 3σ uncertainty, except for Core 4, which is the only randomly packed pebble configuration. Repeated calculations of keff with MCNP6.1 and ENDF/B-VII.1 are lower than the benchmark values and within 1% (~3σ) except for Cores 5 and 9, which calculate lower than the benchmark eigenvalues within 4σ. The primary difference between the two nuclear data libraries is the adjustment of the absorption cross section of graphite. Simulations of the absorber rod worth measurements are within 3σ of the benchmark experiment values. The complete benchmark evaluation details are available in the 2014 edition of the International Handbook of Evaluated Reactor Physics Benchmark Experiments.

  20. Benchmark Evaluation of HTR-PROTEUS Pebble Bed Experimental Program

    DOE PAGESBeta

    Bess, John D.; Montierth, Leland; Köberl, Oliver; Snoj, Luka

    2014-10-09

    Benchmark models were developed to evaluate 11 critical core configurations of the HTR-PROTEUS pebble bed experimental program. Various additional reactor physics measurements were performed as part of this program; currently only a total of 37 absorber rod worth measurements have been evaluated as acceptable benchmark experiments for Cores 4, 9, and 10. Dominant uncertainties in the experimental keff for all core configurations come from uncertainties in the ²³⁵U enrichment of the fuel, impurities in the moderator pebbles, and the density and impurity content of the radial reflector. Calculations of keff with MCNP5 and ENDF/B-VII.0 neutron nuclear data are greatermore » than the benchmark values but within 1% and also within the 3σ uncertainty, except for Core 4, which is the only randomly packed pebble configuration. Repeated calculations of keff with MCNP6.1 and ENDF/B-VII.1 are lower than the benchmark values and within 1% (~3σ) except for Cores 5 and 9, which calculate lower than the benchmark eigenvalues within 4σ. The primary difference between the two nuclear data libraries is the adjustment of the absorption cross section of graphite. Simulations of the absorber rod worth measurements are within 3σ of the benchmark experiment values. The complete benchmark evaluation details are available in the 2014 edition of the International Handbook of Evaluated Reactor Physics Benchmark Experiments.« less

  1. Knockdown of Litopenaeus vannamei HtrA2, an up-regulated gene in response to WSSV infection, leading to delayed shrimp mortality.

    PubMed

    Peepim, Termsri; Phiwsaiya, Kornsunee; Charoensapsri, Walaiporn; Khunrae, Pongsak; Senapin, Saengchan; Rattanarojpong, Triwit

    2016-02-10

    HtrA2 is an apoptosis-activating gene that enhances the apoptotic process by preventing the formation of the IAP-caspase complex, thereby freeing caspase to trigger the apoptosis pathway. In this study, we presented the full-length cDNA sequence of HtrA2 from Litopenaeus vannamei (LvHtrA2). The full-length LvHtrA2 was 1335 bp, encoding 444 amino acids. This deduced amino acid sequence contained five conserved domains: a mitochondrial targeting signal (MTS), a transmembrane (TM) domain, an IAP-binding motif (IBM), a trimerization motif, a serine protease domain, and a PDZ domain normally found in the HtrA2 proteins of other organisms. A phylogenetic analysis revealed that LvHtrA2 clustered with the HtrA2 from other invertebrates and was closely related to Penaeus monodon HtrA2 (PmHtrA2). RT-PCR with RNA extracts from L. vannamei revealed that LvHtrA2 expression was found in several tissues, including the lymphoid organs, the haemocytes, the hepatopancreas, the gill, and the stomach, with different expression levels. When determining the role of LvHtrA2 in WSSV infection, it was found that LvHtrA2 transcription was early up-regulated in the WSSV-infected shrimp at 8h post-infection (p.i.) and expression still remained high at 48 h p.i.. It also demonstrated that dsRNA specific to LvHtrA2 reduced the cumulative mortality in the WSSV-infected shrimp compared with the control group. Additionally, depletion of the LvHtrA2 transcripts reduced expression levels for caspase-3 (Cap-3) gene in shrimp. This result could suggest that LvHtrA2 may involved in apoptosis mediated mortality rather than providing immune protection during WSSV infection. PMID:26712477

  2. A POPULATION-SPECIFIC HTR2B STOP CODON PREDISPOSES TO SEVERE IMPULSIVITY

    PubMed Central

    Bevilacqua, Laura; Doly, Stéphane; Kaprio, Jaakko; Yuan, Qiaoping; Tikkanen, Roope; Paunio, Tiina; Zhou, Zhifeng; Wedenoja, Juho; Maroteaux, Luc; Diaz, Silvina; Belmer, Arnaud; Hodgkinson, Colin A.; Dell’Osso, Liliana; Suvisaari, Jaana; Coccaro, Emil; Rose, Richard J; Peltonen, Leena; Virkkunen, Matti; Goldman, David

    2011-01-01

    SUMMARY Impulsivity, describing action without foresight, is an important feature of several psychiatric diseases, suicidality and violent behavior. The complex origins of impulsivity hinder identification of the genes influencing both it and diseases with which it is associated. We performed exon-centric sequencing of impulsive individuals in a founder population, targeting fourteen genes belonging to the serotonin and dopamine domain. A stop codon in HTR2B that is common (MAF >1%) but exclusive to Finns was identified. Expression of the gene in the human brain was assessed, as well as the molecular functionality of the stop codon that was associated with psychiatric diseases marked by impulsivity in both population and family-based analyses. Knockout of Htr2b increased impulsive behaviors in mice, indicative of predictive validity. Our study shows the potential for identifying and tracing effects of rare alleles in complex behavioral phenotypes using founder populations, and suggests a role for HTR2B in impulsivity. PMID:21179162

  3. Evaluation of the HTR-10 Reactor as a Benchmark for Physics Code QA

    SciTech Connect

    William K. Terry; Soon Sam Kim; Leland M. Montierth; Joshua J. Cogliati; Abderrafi M. Ougouag

    2006-09-01

    The HTR-10 is a small (10 MWt) pebble-bed research reactor intended to develop pebble-bed reactor (PBR) technology in China. It will be used to test and develop fuel, verify PBR safety features, demonstrate combined electricity production and co-generation of heat, and provide experience in PBR design, operation, and construction. As the only currently operating PBR in the world, the HTR-10 can provide data of great interest to everyone involved in PBR technology. In particular, if it yields data of sufficient quality, it can be used as a benchmark for assessing the accuracy of computer codes proposed for use in PBR analysis. This paper summarizes the evaluation for the International Reactor Physics Experiment Evaluation Project (IRPhEP) of data obtained in measurements of the HTR-10’s initial criticality experiment for use as benchmarks for reactor physics codes.

  4. Mitochondrial defects and neurodegeneration in mice overexpressing wild-type or G399S mutant HtrA2.

    PubMed

    Casadei, Nicolas; Sood, Poonam; Ulrich, Thomas; Fallier-Becker, Petra; Kieper, Nicole; Helling, Stefan; May, Caroline; Glaab, Enrico; Chen, Jing; Nuber, Silke; Marcus, Katrin; Rapaport, Doron; Ott, Thomas; Riess, Olaf; Krüger, Rejko; Fitzgerald, Julia C

    2016-02-01

    The protease HtrA2 has a protective role inside mitochondria, but promotes apoptosis under stress. We previously identified the G399S HtrA2 mutation in Parkinson's disease (PD) patients and reported mitochondrial dysfunction in vitro. Mitochondrial dysfunction is a common feature of PD and related to neurodegeneration. Complete loss of HtrA2 has been shown to cause neurodegeneration in mice. However, the full impact of HtrA2 overexpression or the G399S mutation is still to be determined in vivo. Here, we report the first HtrA2 G399S transgenic mouse model. Our data suggest that the mutation has a dominant-negative effect. We also describe a toxic effect of wild-type (WT) HtrA2 overexpression. Only low overexpression of the G399S mutation allowed viable animals and we suggest that the mutant protein is likely unstable. This is accompanied by reduced mitochondrial respiratory capacity and sensitivity to apoptotic cell death. Mice overexpressing WT HtrA2 were viable, yet these animals have inhibited mitochondrial respiration and significant induction of apoptosis in the brain leading to motor dysfunction, highlighting the opposing roles of HtrA2. Our data further underscore the importance of HtrA2 as a key mediator of mitochondrial function and its fine regulatory role in cell fate. The location and abundance of HtrA2 is tightly controlled and, therefore, human mutations leading to gain- or loss of function could provide significant risk for PD-related neurodegeneration. PMID:26604148

  5. HtrA1 Proteolysis of ApoE In Vitro Is Allele Selective.

    PubMed

    Chu, Qian; Diedrich, Jolene K; Vaughan, Joan M; Donaldson, Cynthia J; Nunn, Michael F; Lee, Kuo-Fen; Saghatelian, Alan

    2016-08-01

    Apolipoprotein E (ApoE) belongs to a large class of proteins that solubilize lipids for physiological transport. Humans have three different APOE alleles, APOE ε2, APOE ε3, and APOE ε4, and genetic studies identified ApoE4 as the strongest genetic risk factor for Alzheimer's disease (AD). People who are homozygous for ApoE4 (i.e., ApoE4/E4) are an order of magnitude more likely to develop late-onset AD (LOAD) than ApoE3/E3 carriers. Several differences between ApoE3 and ApoE4 may contribute to AD including the observation that ApoE4 is degraded to a greater extent than ApoE3 in the human brain. Experiments with high-temperature requirement serine peptidase A1 (HtrA1), which is found in the nervous system, demonstrate that HtrA1 is an allele-selective ApoE-degrading enzyme that degrades ApoE4 more quickly than ApoE3. This activity is specific to HtrA1, as similar assays with HtrA2 showed minimal ApoE4 proteolysis and trypsin had no preference between ApoE4 and ApoE3. HtrA1 has also been reported to cleave the tau protein (Tau) and the amyloid protein precursor (APP) to hinder the formation of toxic amyloid deposits associated with AD. Competition assays with ApoE4, ApoE3, and Tau revealed that ApoE4 inhibits Tau degradation. Thus, the identification of ApoE4 as an in vitro HtrA1 substrate suggests a potential biochemical mechanism that links ApoE4 regulation of AD proteins such as Tau. PMID:27379525

  6. Development of a Reliable Fuel Depletion Methodology for the HTR-10 Spent Fuel Analysis

    SciTech Connect

    Chung, Kiwhan; Beddingfield, David H.; Geist, William H.; Lee, Sang-Yoon

    2012-07-03

    A technical working group formed in 2007 between NNSA and CAEA to develop a reliable fuel depletion method for HTR-10 based on MCNPX and to analyze the isotopic inventory and radiation source terms of the HTR-10 spent fuel. Conclusions of this presentation are: (1) Established a fuel depletion methodology and demonstrated its safeguards application; (2) Proliferation resistant at high discharge burnup ({approx}80 GWD/MtHM) - Unfavorable isotopics, high number of pebbles needed, harder to reprocess pebbles; (3) SF should remain under safeguards comparable to that of LWR; and (4) Diversion scenarios not considered, but can be performed.

  7. Campylobacter jejuni serine protease HtrA plays an important role in heat tolerance, oxygen resistance, host cell adhesion, invasion, and transmigration

    PubMed Central

    Lind, Judith; Backert, Steffen; Tegtmeyer, Nicole

    2015-01-01

    Campylobacter jejuni is an important pathogen of foodborne illness. Transmigration across the intestinal epithelial barrier and invasion are considered as primary reasons for tissue damage triggered by C. jejuni. Using knockout mutants, it was shown that the serine protease HtrA may be important for stress tolerance and physiology of C. jejuni. HtrA is also secreted in the extra­cellular environment, where it can cleave junctional host cell proteins such as E-cadherin. Aim of the present study was to establish a genetic complementation system in two C. jejuni strains in order to introduce the wild-type htrA gene in trans, test known htrA phenotypes, and provide the basis to perform further mutagenesis. We confirm that reexpression of the htrA wild-type gene in ΔhtrA mutants restored the following phenotypes: 1) C. jejuni growth at high temperature (44 °C), 2) growth under high oxygen stress conditions, 3) expression of proteolytically active HtrA oligomers, 4) secretion of HtrA into the supernatant, 5) cell attachment and invasion, and 6) transmigration across polarized epithelial cells. These results establish a genetic complementation system for htrA in C. jejuni, exclude polar effects in the ΔhtrA mutants, confirm important HtrA properties, and permit the discovery and dissection of new functions. PMID:25883795

  8. The HtrA protease of Borrelia burgdorferi degrades outer membrane protein BmpD and chemotaxis phosphatase CheX

    PubMed Central

    Coleman, James L; Crowley, Jameson T; Toledo, Alvaro M; Benach, Jorge L

    2013-01-01

    Borrelia burgdorferi, the spirochaetal agent of Lyme disease, codes for a single HtrA protein, HtrABb (BB0104) that is homologous to DegP of Escherichia coli (41% amino acid identity). HtrABb shows physical and biochemical similarities to DegP in that it has the trimer as its fundamental unit and can degrade casein via its catalytic serine. Recombinant HtrABb exhibits proteolytic activity in vitro, while a mutant (HtrABbS198A) does not. However, HtrABb and DegP have some important differences as well. Native HtrABb occurs in both membrane-bound and soluble forms. Despite its homology to DegP, HtrABb could not complement an E. coli DegP deletion mutant. Late stage Lyme disease patients, as well as infected mice and rabbits developed a robust antibody response to HtrABb, indicating that it is a B-cell antigen. In co-immunoprecipitation studies, a number of potential binding partners for HtrABb were identified, as well as two specific proteolytic substrates, basic membrane protein D (BmpD/BB0385) and chemotaxis signal transduction phosphatase CheX (BB0671). HtrABb may function in regulating outer membrane lipoproteins and in modulating the chemotactic response of B. burgdorferi. PMID:23565798

  9. Identification of E-cadherin signature motifs functioning as cleavage sites for Helicobacter pylori HtrA.

    PubMed

    Schmidt, Thomas P; Perna, Anna M; Fugmann, Tim; Böhm, Manja; Jan Hiss; Haller, Sarah; Götz, Camilla; Tegtmeyer, Nicole; Hoy, Benjamin; Rau, Tilman T; Neri, Dario; Backert, Steffen; Schneider, Gisbert; Wessler, Silja

    2016-01-01

    The cell adhesion protein and tumour suppressor E-cadherin exhibits important functions in the prevention of gastric cancer. As a class-I carcinogen, Helicobacter pylori (H. pylori) has developed a unique strategy to interfere with E-cadherin functions. In previous studies, we have demonstrated that H. pylori secretes the protease high temperature requirement A (HtrA) which cleaves off the E-cadherin ectodomain (NTF) on epithelial cells. This opens cell-to-cell junctions, allowing bacterial transmigration across the polarised epithelium. Here, we investigated the molecular mechanism of the HtrA-E-cadherin interaction and identified E-cadherin cleavage sites for HtrA. Mass-spectrometry-based proteomics and Edman degradation revealed three signature motifs containing the [VITA]-[VITA]-x-x-D-[DN] sequence pattern, which were preferentially cleaved by HtrA. Based on these sites, we developed a substrate-derived peptide inhibitor that selectively bound and inhibited HtrA, thereby blocking transmigration of H. pylori. The discovery of HtrA-targeted signature sites might further explain why we detected a stable 90 kDa NTF fragment during H. pylori infection, but also additional E-cadherin fragments ranging from 105 kDa to 48 kDa in in vitro cleavage experiments. In conclusion, HtrA targets E-cadherin signature sites that are accessible in in vitro reactions, but might be partially masked on epithelial cells through functional homophilic E-cadherin interactions. PMID:26983597

  10. Identification of E-cadherin signature motifs functioning as cleavage sites for Helicobacter pylori HtrA

    PubMed Central

    Schmidt, Thomas P.; Perna, Anna M.; Fugmann, Tim; Böhm, Manja; Jan Hiss; Haller, Sarah; Götz, Camilla; Tegtmeyer, Nicole; Hoy, Benjamin; Rau, Tilman T.; Neri, Dario; Backert, Steffen; Schneider, Gisbert; Wessler, Silja

    2016-01-01

    The cell adhesion protein and tumour suppressor E-cadherin exhibits important functions in the prevention of gastric cancer. As a class-I carcinogen, Helicobacter pylori (H. pylori) has developed a unique strategy to interfere with E-cadherin functions. In previous studies, we have demonstrated that H. pylori secretes the protease high temperature requirement A (HtrA) which cleaves off the E-cadherin ectodomain (NTF) on epithelial cells. This opens cell-to-cell junctions, allowing bacterial transmigration across the polarised epithelium. Here, we investigated the molecular mechanism of the HtrA-E-cadherin interaction and identified E-cadherin cleavage sites for HtrA. Mass-spectrometry-based proteomics and Edman degradation revealed three signature motifs containing the [VITA]-[VITA]-x-x-D-[DN] sequence pattern, which were preferentially cleaved by HtrA. Based on these sites, we developed a substrate-derived peptide inhibitor that selectively bound and inhibited HtrA, thereby blocking transmigration of H. pylori. The discovery of HtrA-targeted signature sites might further explain why we detected a stable 90 kDa NTF fragment during H. pylori infection, but also additional E-cadherin fragments ranging from 105 kDa to 48 kDa in in vitro cleavage experiments. In conclusion, HtrA targets E-cadherin signature sites that are accessible in in vitro reactions, but might be partially masked on epithelial cells through functional homophilic E-cadherin interactions. PMID:26983597

  11. Genomic imprinting of the human serotonin-receptor (HTR2) gene involved in development of retinoblastoma

    SciTech Connect

    Kato, Mitsuo V.; Nagayoshi, Mariko; Shimuzu, Takashi

    1996-11-01

    Epidemiological and genetic studies of retinoblastoma (RB) suggested that imprinted genes might be genetically linked to the RB gene. In this study, we found that the human serotonin-receptor, HTR2, gene, which had been mapped nearby the RB gene on chromosome 13, was expressed only in human fibroblasts with a maternal allele and not in cells without a maternal allele. The 5{prime} genomic region of the human HTR2 gene was cloned by PCR-mediated method. Only the 5{prime} region of the gene was methylated in cells with the maternal gene, and it was not methylated in cells without the maternal gene. A polymorphism of PvuII site of the gene was also found and useful for the segregation analysis in a family of an RB patient and for analysis of loss of heterozygosity on chromosome 13 in tumor and its parental origin. These results suggest that the human HTR2 gene might be affected by genomic imprinting and that exclusive expression of the maternal HTR2 gene may be associated with the delayed occurrence of RB, which had lost the maternal chromosome 13. 33 refs., 5 figs., 2 tabs.

  12. Role of group A Streptococcus HtrA in the maturation of SpeB protease.

    PubMed

    Cole, Jason N; Aquilina, John A; Hains, Peter G; Henningham, Anna; Sriprakash, Kadaba S; Caparon, Michael G; Nizet, Victor; Kotb, Malak; Cordwell, Stuart J; Djordjevic, Steven P; Walker, Mark J

    2007-12-01

    The serine protease high-temperature requirement A (HtrA) (DegP) of the human pathogen Streptococcus pyogenes (group A Streptococcus; GAS) is localized to the ExPortal secretory microdomain and is reportedly essential for the maturation of cysteine protease streptococcal pyrogenic exotoxin B (SpeB). Here, we utilize HSC5 (M5 serotype) and the in-frame isogenic mutant HSC5DeltahtrA to determine whether HtrA contributes to the maturation of other GAS virulence determinants. Mutanolysin cell wall extracts and secreted proteins were arrayed by 2-DE and identified by MALDI-TOF PMF analysis. HSC5DeltahtrA had elevated levels of cell wall-associated M protein, whilst the supernatant had higher concentrations of M protein fragments and a reduced amount of mature SpeB protease, compared to wild-type (WT). Western blot analysis and protease assays revealed a delay in the maturation of SpeB in the HSC5DeltahtrA supernatant. HtrA was unable to directly process SpeB zymogen (proSpeB) to the active form in vitro. We therefore conclude that HtrA plays an indirect role in the maturation of cysteine protease SpeB. PMID:18072207

  13. Association of frailty with the serine protease HtrA1 in older adults.

    PubMed

    Lorenzi, Maria; Lorenzi, Teresa; Marzetti, Emanuele; Landi, Francesco; Vetrano, Davide L; Settanni, Silvana; Antocicco, Manuela; Bonassi, Stefano; Valdiglesias, Vanessa; Bernabei, Roberto; Onder, Graziano

    2016-08-01

    Frailty is a geriatric syndrome characterized by multi system dysregulation. It has been suggested that chronic inflammation may be involved in the pathogenesis of frailty. No study so far has identified accurate, specific and sensitive molecular biomarkers for frailty. High-temperature requirement serine protease A1 (HtrA1) is a secreted multidomain serine protease implicated in the inhibition of signaling of active transforming growth factor-β (TGF-β)1, a cytokine which has an important anti-inflammation role. The aim of the present study was to investigate the association of circulating levels of HtrA1 with frailty in a sample of older adults. The study was performed in 120 older adults aged >65years and admitted to a geriatric outpatient clinic. The frailty status of participants was assessed by both the Fried's criteria (physical frailty, PF) and a modified Rockwood's frailty index (FI). Plasma HtrA1 concentration was measured using commercial ELISA kit. Frailty was identified in 61/120 participants (50.8%) using PF, and in 60/118 subjects (50.8%) using FI. Plasma levels of HtrA1 were significantly higher in individuals classified as frail according to PF (75.9ng/mL, 95% CI 67.4-85.6) as compared with non-frail participants (48.4ng/mL, 95% CI 42.5-54.6, p<0.001). A significant association was also observed between frailty, assessed by FI, and HtrA1 levels (72.2ng/mL, 95% CI 63.4-82.3, vs. 50.4ng/mL, 95% CI 44.3-58.0, p<0.001). These associations were confirmed after adjusting for potential confounders. This study demonstrates for the first time the association of plasma levels of HtrA1 with frailty status. Future investigations are needed to validate the potential value of HtrA1 as possible biomarker for frailty. PMID:27058767

  14. Distinct 3D Architecture and Dynamics of the Human HtrA2(Omi) Protease and Its Mutated Variants.

    PubMed

    Gieldon, Artur; Zurawa-Janicka, Dorota; Jarzab, Miroslaw; Wenta, Tomasz; Golik, Przemyslaw; Dubin, Grzegorz; Lipinska, Barbara; Ciarkowski, Jerzy

    2016-01-01

    HtrA2(Omi) protease controls protein quality in mitochondria and plays a major role in apoptosis. Its HtrA2S306A mutant (with the catalytic serine routinely disabled for an X-ray study to avoid self-degradation) is a homotrimer whose subunits contain the serine protease domain (PD) and the regulatory PDZ domain. In the inactive state, a tight interdomain interface limits penetration of both PDZ-activating ligands and PD substrates into their respective target sites. We successfully crystalized HtrA2V226K/S306A, whose active counterpart HtrA2V226K has had higher proteolytic activity, suggesting higher propensity to opening the PD-PDZ interface than that of the wild type HtrA2. Yet, the crystal structure revealed the HtrA2V226K/S306A architecture typical of the inactive protein. To get a consistent interpretation of crystallographic data in the light of kinetic results, we employed molecular dynamics (MD). V325D inactivating mutant was used as a reference. Our simulations demonstrated that upon binding of a specific peptide ligand NH2-GWTMFWV-COOH, the PDZ domains open more dynamically in the wild type protease compared to the V226K mutant, whereas the movement is not observed in the V325D mutant. The movement relies on a PDZ vs. PD rotation which opens the PD-PDZ interface in a lid-like (budding flower-like in trimer) fashion. The noncovalent hinges A and B are provided by two clusters of interfacing residues, harboring V325D and V226K in the C- and N-terminal PD barrels, respectively. The opening of the subunit interfaces progresses in a sequential manner during the 50 ns MD simulation. In the systems without the ligand only minor PDZ shifts relative to PD are observed, but the interface does not open. Further activation-associated events, e.g. PDZ-L3 positional swap seen in any active HtrA protein (vs. HtrA2), were not observed. In summary, this study provides hints on the mechanism of activation of wtHtrA2, the dynamics of the inactive HtrA2V325D, but does not

  15. Distinct 3D Architecture and Dynamics of the Human HtrA2(Omi) Protease and Its Mutated Variants

    PubMed Central

    Gieldon, Artur; Zurawa-Janicka, Dorota; Jarzab, Miroslaw; Wenta, Tomasz; Golik, Przemyslaw; Dubin, Grzegorz; Lipinska, Barbara; Ciarkowski, Jerzy

    2016-01-01

    HtrA2(Omi) protease controls protein quality in mitochondria and plays a major role in apoptosis. Its HtrA2S306A mutant (with the catalytic serine routinely disabled for an X-ray study to avoid self-degradation) is a homotrimer whose subunits contain the serine protease domain (PD) and the regulatory PDZ domain. In the inactive state, a tight interdomain interface limits penetration of both PDZ-activating ligands and PD substrates into their respective target sites. We successfully crystalized HtrA2V226K/S306A, whose active counterpart HtrA2V226K has had higher proteolytic activity, suggesting higher propensity to opening the PD-PDZ interface than that of the wild type HtrA2. Yet, the crystal structure revealed the HtrA2V226K/S306A architecture typical of the inactive protein. To get a consistent interpretation of crystallographic data in the light of kinetic results, we employed molecular dynamics (MD). V325D inactivating mutant was used as a reference. Our simulations demonstrated that upon binding of a specific peptide ligand NH2-GWTMFWV-COOH, the PDZ domains open more dynamically in the wild type protease compared to the V226K mutant, whereas the movement is not observed in the V325D mutant. The movement relies on a PDZ vs. PD rotation which opens the PD-PDZ interface in a lid-like (budding flower-like in trimer) fashion. The noncovalent hinges A and B are provided by two clusters of interfacing residues, harboring V325D and V226K in the C- and N-terminal PD barrels, respectively. The opening of the subunit interfaces progresses in a sequential manner during the 50 ns MD simulation. In the systems without the ligand only minor PDZ shifts relative to PD are observed, but the interface does not open. Further activation-associated events, e.g. PDZ-L3 positional swap seen in any active HtrA protein (vs. HtrA2), were not observed. In summary, this study provides hints on the mechanism of activation of wtHtrA2, the dynamics of the inactive HtrA2V325D, but does not

  16. Unique Residues Involved in Activation of the Multitasking Protease/Chaperone HtrA from Chlamydia trachomatis

    PubMed Central

    Huston, Wilhelmina M.; Tyndall, Joel D. A.; Lott, William B.; Stansfield, Scott H.; Timms, Peter

    2011-01-01

    DegP, a member of the HtrA family of proteins, conducts critical bacterial protein quality control by both chaperone and proteolysis activities. The regulatory mechanisms controlling these two distinct activities, however, are unknown. DegP activation is known to involve a unique mechanism of allosteric binding, conformational changes and oligomer formation. We have uncovered a novel role for the residues at the PDZ1:protease interface in oligomer formation specifically for chaperone substrates of Chlamydia trachomatis HtrA (DegP homolog). We have demonstrated that CtHtrA proteolysis could be activated by allosteric binding and oligomer formation. The PDZ1 activator cleft was required for the activation and oligomer formation. However, unique to CtHtrA was the critical role for residues at the PDZ1:protease interface in oligomer formation when the activator was an in vitro chaperone substrate. Furthermore, a potential in vivo chaperone substrate, the major outer membrane protein (MOMP) from Chlamydia, was able to activate CtHtrA and induce oligomer formation. Therefore, we have revealed novel residues involved in the activation of CtHtrA which are likely to have important in vivo implications for outer membrane protein assembly. PMID:21931748

  17. Unique residues involved in activation of the multitasking protease/chaperone HtrA from Chlamydia trachomatis.

    PubMed

    Huston, Wilhelmina M; Tyndall, Joel D A; Lott, William B; Stansfield, Scott H; Timms, Peter

    2011-01-01

    DegP, a member of the HtrA family of proteins, conducts critical bacterial protein quality control by both chaperone and proteolysis activities. The regulatory mechanisms controlling these two distinct activities, however, are unknown. DegP activation is known to involve a unique mechanism of allosteric binding, conformational changes and oligomer formation. We have uncovered a novel role for the residues at the PDZ1:protease interface in oligomer formation specifically for chaperone substrates of Chlamydia trachomatis HtrA (DegP homolog). We have demonstrated that CtHtrA proteolysis could be activated by allosteric binding and oligomer formation. The PDZ1 activator cleft was required for the activation and oligomer formation. However, unique to CtHtrA was the critical role for residues at the PDZ1:protease interface in oligomer formation when the activator was an in vitro chaperone substrate. Furthermore, a potential in vivo chaperone substrate, the major outer membrane protein (MOMP) from Chlamydia, was able to activate CtHtrA and induce oligomer formation. Therefore, we have revealed novel residues involved in the activation of CtHtrA which are likely to have important in vivo implications for outer membrane protein assembly. PMID:21931748

  18. Human telomerase reverse transcriptase binds to a pre-organized hTR in vivo exposing its template.

    PubMed

    Zemora, Georgeta; Handl, Stefan; Waldsich, Christina

    2016-01-01

    Telomerase is a specialized reverse transcriptase that is responsible for telomere length maintenance. As in other organisms, the minimal components required for an active human telomerase are the template-providing telomerase RNA (hTR) and the enzymatic entity telomerase reverse transcriptase (hTERT). Here, we explored the structure of hTR and the hTERT-induced conformational changes within hTR in living cells. By employing an in vivo DMS chemical probing technique, we showed that the pseudoknot and associated triple helical scaffold form stably in vivo independently of hTERT. In fact, the dimethyl-sulfate (DMS) modification pattern suggests that hTR alone is capable of adopting a conformation that is suited to interact with hTERT. However, in the absence of hTERT the template region of hTR is only weakly accessible to DMS-modifications. The predominant change after binding of hTERT to hTR is the exposure of the template region. PMID:26481359

  19. Role for Serine Protease HtrA (DegP) of Streptococcus pyogenes in the Biogenesis of Virulence Factors SpeB and the Hemolysin Streptolysin S

    PubMed Central

    Lyon, William R.; Caparon, Michael G.

    2004-01-01

    The serine protease HtrA is involved in the folding and maturation of secreted proteins, as well as in the degradation of proteins that misfold during secretion. Depletion of HtrA has been shown to affect the sensitivity of many organisms to thermal and environmental stresses, as well as being essential for virulence in many pathogens. In the present study, we compared the behaviors of several different HtrA mutants of the gram-positive pathogen Streptococcus pyogenes (group A streptococcus). Consistent with prior reports, insertional inactivation of htrA, the gene that encodes HtrA, resulted in a mutant that grew poorly at 37°C. However, an identical phenotype was observed when a similar polar insertion was placed immediately downstream of htrA in the streptococcal chromosome, suggesting that the growth defect of the insertion mutant was not a direct result of insertional inactivation of htrA. This conclusion was supported by the observation that a nonpolar deletion mutation of htrA did not produce the growth defect. However, this mutation did affect the production of several secreted virulence factors whose biogenesis requires extensive processing. For the SpeB cysteine protease, the loss of HtrA was associated with a failure to proteolytically process the zymogen to an active protease. For the streptolysin S hemolysin, a dramatic increase in hemolytic activity resulted from the depletion of HtrA. Interestingly, HtrA-deficient mutants were not attenuated in a murine model of subcutaneous infection. These data add to the growing body of information that implies an important role for HtrA in the biogenesis of secreted proteins in gram-positive bacteria. PMID:14977969

  20. Role for serine protease HtrA (DegP) of Streptococcus pyogenes in the biogenesis of virulence factors SpeB and the hemolysin streptolysin S.

    PubMed

    Lyon, William R; Caparon, Michael G

    2004-03-01

    The serine protease HtrA is involved in the folding and maturation of secreted proteins, as well as in the degradation of proteins that misfold during secretion. Depletion of HtrA has been shown to affect the sensitivity of many organisms to thermal and environmental stresses, as well as being essential for virulence in many pathogens. In the present study, we compared the behaviors of several different HtrA mutants of the gram-positive pathogen Streptococcus pyogenes (group A streptococcus). Consistent with prior reports, insertional inactivation of htrA, the gene that encodes HtrA, resulted in a mutant that grew poorly at 37 degrees C. However, an identical phenotype was observed when a similar polar insertion was placed immediately downstream of htrA in the streptococcal chromosome, suggesting that the growth defect of the insertion mutant was not a direct result of insertional inactivation of htrA. This conclusion was supported by the observation that a nonpolar deletion mutation of htrA did not produce the growth defect. However, this mutation did affect the production of several secreted virulence factors whose biogenesis requires extensive processing. For the SpeB cysteine protease, the loss of HtrA was associated with a failure to proteolytically process the zymogen to an active protease. For the streptolysin S hemolysin, a dramatic increase in hemolytic activity resulted from the depletion of HtrA. Interestingly, HtrA-deficient mutants were not attenuated in a murine model of subcutaneous infection. These data add to the growing body of information that implies an important role for HtrA in the biogenesis of secreted proteins in gram-positive bacteria. PMID:14977969

  1. Use of HTR synthetic bone grafts in conjunction with immediate dental implants.

    PubMed

    Yukna, Raymond A; Sayed-Suleyman, Amer; Finley, James M; Hochstedler, J; Mayer, Elizabeth T

    2003-09-01

    Immediate placement of dental implants in fresh extraction sockets is associated with remaining voids around the implants and often a partial dehiscence or thinning of the facial alveolar plate. Nine patients had Bioplant HTR synthetic bone used as a ridge preservation/augmentation material in conjunction with immediate placement of 10 implants. Hard tissue replacement (HTR) was used to fill the remaining socket void and enhance the facial ridge width, and the wound closed as completely as possible. Dental implants were uncovered at approximately 6 months. Measurements taken of the internal socket width and total ridge width at the implant placement and uncovering showed the mean internal socket width was maintained (7.2 mm vs 6.9 mm), and the total ridge width exhibited a mean change from 9.6 mm to 8.8 mm. Of the 10 implant sites, 7 showed a net increase, 2 no change, and 1 a decrease in overall ridge width. All 10 implants were restored for at least 6 months. These clinical results suggest that HTR is a useful adjunct in the placement of immediate dental implants for the preservation of ridge width and provides a good base for functional and esthetic prosthetic reconstruction. PMID:14596206

  2. HtrA1: Its future potential as a novel biomarker for cancer

    PubMed Central

    ALTOBELLI, EMMA; MARZIONI, DANIELA; LATTANZI, AMEDEO; ANGELETTI, PAOLO MATTEO

    2015-01-01

    HtrA1 appears to be involved in several physiological processes as well as in the pathogenesis of conditions such as Alzheimer’s disease and osteoarthritis. It has also been hypothesized to play a role as a tumor suppressor. This manuscript reviews the current cancer-related HtrA1 research from the methodological and clinical standpoints including studies regarding its potential role as a tumor marker and/or prognostic factor. PRISMA method was used for study selection. The articles thus collected were examined and selected by two independent reviewers; any disagreement was resolved by a methodologist. A laboratory researcher reviewed the methods and laboratory techniques. Fifteen studies met the inclusion criteria and concerned the following cancer sites: the nervous system, bladder, breast, esophagus, stomach, liver, endometrium, thyroid, ovaries, pleura, lung and skin. Most articles described in vivo studies using a morphological approach and immunohistochemistry, whereas protein expression was quantified as staining intensity scored by two raters. Often the results were not comparable due to the different rating scales and study design. Current research on HtrA1 does not conclusively support its role as a tumor suppressor. PMID:26035313

  3. HtrA1: Its future potential as a novel biomarker for cancer.

    PubMed

    Altobelli, Emma; Marzioni, Daniela; Lattanzi, Amedeo; Angeletti, Paolo Matteo

    2015-08-01

    HtrA1 appears to be involved in several physiological processes as well as in the pathogenesis of conditions such as Alzheimer's disease and osteoarthritis. It has also been hypothesized to play a role as a tumor suppressor. This manuscript reviews the current cancer-related HtrA1 research from the methodological and clinical standpoints including studies regarding its potential role as a tumor marker and/or prognostic factor. PRISMA method was used for study selection. The articles thus collected were examined and selected by two independent reviewers; any disagreement was resolved by a methodologist. A laboratory researcher reviewed the methods and laboratory techniques. Fifteen studies met the inclusion criteria and concerned the following cancer sites: the nervous system, bladder, breast, esophagus, stomach, liver, endometrium, thyroid, ovaries, pleura, lung and skin. Most articles described in vivo studies using a morphological approach and immunohistochemistry, whereas protein expression was quantified as staining intensity scored by two raters. Often the results were not comparable due to the different rating scales and study design. Current research on HtrA1 does not conclusively support its role as a tumor suppressor. PMID:26035313

  4. Htr2a expression responds rapidly to environmental stimuli in an Egr3-dependent manner

    PubMed Central

    Maple, Amanda M.; Zhao, Xiuli; Elizalde, Diana I.; McBride, Andrew K.; Gallitano, Amelia L

    2015-01-01

    Pharmacologic and genetic findings have implicated the serotonin 2A receptor (5-HT2AR) in the etiology of schizophrenia. Recent studies have shown reduced 5-HT2AR levels in schizophrenia patients, yet the cause of this difference is unknown. Environmental factors, such as stress, also influence schizophrenia risk, yet little is known about how environment may affect this receptor. To determine if acute stress alters 5-HT2AR expression, we examined the effect of sleep deprivation on cortical Htr2a mRNA in mice. We found that 6 hours of sleep deprivation induces a 2-fold increase in Htr2a mRNA, a more rapid effect than has been previously reported. This effect requires the immediate early gene early growth response 3 (Egr3), as sleep deprivation failed to induce Htr2a expression in Egr3−/− mice. These findings provide a functional link between two schizophrenia candidate genes and an explanation of how environment may influence a genetic predisposition for schizophrenia. PMID:25857407

  5. Idebenone and Resveratrol Extend Lifespan and Improve Motor Function of HtrA2 Knockout Mice

    PubMed Central

    Szegő, Éva M.; Moisoi, Nicoleta; Martins, L. Miguel; Outeiro, Tiago F.; Kermer, Pawel

    2011-01-01

    Heterozygous loss-of-function mutation of the human gene for the mitochondrial protease HtrA2 has been associated with increased risk to develop mitochondrial dysfunction, a process known to contribute to neurodegenerative disorders such as Huntington's disease (HD) and Parkinson's disease (PD). Knockout of HtrA2 in mice also leads to mitochondrial dysfunction and to phenotypes that resemble those found in neurodegenerative disorders and, ultimately, lead to death of animals around postnatal day 30. Here, we show that Idebenone, a synthetic antioxidant of the coenzyme Q family, and Resveratrol, a bioactive compound extracted from grapes, are both able to ameliorate this phenotype. Feeding HtrA2 knockout mice with either compound extends lifespan and delays worsening of the motor phenotype. Experiments conducted in cell culture and on brain tissue of mice revealed that each compound has a different mechanism of action. While Idebenone acts by downregulating the integrated stress response, Resveratrol acts by attenuating apoptosis at the level of Bax. These activities can account for the delay in neuronal degeneration in the striata of these mice and illustrate the potential of these compounds as effective therapeutic approaches against neurodegenerative disorders such as HD or PD. PMID:22205977

  6. A population-specific HTR2B stop codon predisposes to severe impulsivity.

    PubMed

    Bevilacqua, Laura; Doly, Stéphane; Kaprio, Jaakko; Yuan, Qiaoping; Tikkanen, Roope; Paunio, Tiina; Zhou, Zhifeng; Wedenoja, Juho; Maroteaux, Luc; Diaz, Silvina; Belmer, Arnaud; Hodgkinson, Colin A; Dell'osso, Liliana; Suvisaari, Jaana; Coccaro, Emil; Rose, Richard J; Peltonen, Leena; Virkkunen, Matti; Goldman, David

    2010-12-23

    Impulsivity, describing action without foresight, is an important feature of several psychiatric diseases, suicidality and violent behaviour. The complex origins of impulsivity hinder identification of the genes influencing it and the diseases with which it is associated. Here we perform exon-focused sequencing of impulsive individuals in a founder population, targeting fourteen genes belonging to the serotonin and dopamine domain. A stop codon in HTR2B was identified that is common (minor allele frequency > 1%) but exclusive to Finnish people. Expression of the gene in the human brain was assessed, as well as the molecular functionality of the stop codon, which was associated with psychiatric diseases marked by impulsivity in both population and family-based analyses. Knockout of Htr2b increased impulsive behaviours in mice, indicative of predictive validity. Our study shows the potential for identifying and tracing effects of rare alleles in complex behavioural phenotypes using founder populations, and indicates a role for HTR2B in impulsivity. PMID:21179162

  7. Different Roles of COMT and HTR2A Genotypes in Working Memory Subprocesses

    PubMed Central

    Kondo, Hirohito M.; Nomura, Michio; Kashino, Makio

    2015-01-01

    Working memory is linked to the functions of the frontal areas, in which neural activity is mediated by dopaminergic and serotonergic tones. However, there is no consensus regarding how the dopaminergic and serotonergic systems influence working memory subprocesses. The present study used an imaging genetics approach to examine the interaction between neurochemical functions and working memory performance. We focused on functional polymorphisms of the catechol-O-methyltransferase (COMT) Val158Met and serotonin 2A receptor (HTR2A) -1438G/A genes, and devised a delayed recognition task to isolate the encoding, retention, and retrieval processes for visual information. The COMT genotypes affected recognition accuracy, whereas the HTR2A genotypes were associated with recognition response times. Activations specifically related to working memory were found in the right frontal and parietal areas, such as the middle frontal gyrus (MFG), inferior frontal gyrus (IFG), anterior cingulate cortex (ACC), and inferior parietal lobule (IPL). MFG and ACC/IPL activations were sensitive to differences between the COMT genotypes and between the HTR2A genotypes, respectively. Structural equation modeling demonstrated that stronger connectivity in the ACC-MFG and ACC-IFG networks is related to better task performance. The behavioral and fMRI results suggest that the dopaminergic and serotonergic systems play different roles in the working memory subprocesses and modulate closer cooperation between lateral and medial frontal activations. PMID:25974269

  8. Testing of HTR UO2 TRISO fuels in AVR and in material test reactors

    NASA Astrophysics Data System (ADS)

    Kania, Michael J.; Nabielek, Heinz; Verfondern, Karl; Allelein, Hans-Josef

    2013-10-01

    The German High Temperature Reactor Fuel Development Program successfully developed, licensed and manufactured many thousands of spherical fuel elements that were used to power the experimental AVR reactor and the commercial THTR reactor. In the 1970s, this program extended the performance envelope of HTR fuels by developing and qualifying the TRISO-coated particle system. Irradiation testing in real-time AVR tests and accelerated MTR tests demonstrated the superior manufacturing process of this fuel and its irradiation performance. In the 1980s, another program direction change was made to a low enriched UO2 TRISO-coated particle system coupled with high-quality manufacturing specifications designed to meet new HTR plant design needs. These needs included requirements for inherent safety under normal operation and accident conditions. Again, the German fuel development program met and exceeded these challenges by manufacturing and qualifying the low-enriched UO2 TRISO-fuel system for HTR systems with steam generation, gas-turbine systems and very high temperature process heat applications. Fuel elements were manufactured in production scale facilities that contained near defect free UO2 TRISO coated particles, homogeneously distributed within a graphite matrix with very low levels of uranium contamination. Good irradiation performance for these elements was demonstrated under normal operating conditions to 12% FIMA and under accident conditions not exceeding 1600 °C.

  9. 5-HTTLPR, HTR1A, and HTR2A cumulative genetic score interacts with mood reactivity to predict mood-congruent gaze bias.

    PubMed

    Disner, Seth G; McGeary, John E; Wells, Tony T; Ellis, Alissa J; Beevers, Christopher G

    2014-12-01

    Genetic variation within the serotonin system has been associated with biased attention for affective stimuli and, less consistently, with vulnerability for major depressive disorder. In particular, 5-HTTLPR, HTR1A (rs6295), and HTR2A (rs6311) polymorphisms have been linked with biased cognition. The present study developed a serotonergic cumulative genetic score (CGS) that quantified the number of risk alleles associated with these candidate polymorphisms to yield a single CGS. The CGS was then used to model genetic influence on the relationship between reactivity to a negative mood induction and negatively biased cognition. A passive-viewing eye-tracking task was administered to 170 healthy volunteers to assess sustained attention for positive, dysphoric, neutral, and threatening scenes. Participants were then induced into a sad mood and readministered the passive-viewing task. Change in gaze bias, as a function of reactivity to mood induction, was the primary measure of cognitive vulnerability. Results suggest that, although none of the individual genes interacted with mood reactivity to predict change in gaze bias, individuals with higher serotonin CGS were significantly more likely to look toward dysphoric images and away from positive images as mood reactivity increased. These findings suggest that a CGS approach may better capture genetic influences on cognitive vulnerability and reaffirm the need to examine multilocus approaches in genomic research. PMID:24643765

  10. Zum Stellenwert der Unterdruck-Instillationstherapie in der Dermatologie.

    PubMed

    Müller, Cornelia Sigrid Lissi; Burgard, Barbara; Zimmerman, Monika; Vogt, Thomas; Pföhler, Claudia

    2016-08-01

    Die Methoden zur Behandlung akuter und chronischer Wunden unterliegen einer steten Weiterentwicklung, Reevaluierung und Anwendung innovativer Therapieformen. Die Vakuumtherapie zur Wundbehandlung gehört zu den etablierten Behandlungsmodalitäten. Ein innovatives Verfahren kombiniert die Vakuumtherapie mit der automatisierten, kontrollierten Zufuhr und Drainage wirkstoffhaltiger Lösungen zur topischen Wundbehandlung im Wundbett und auch wirkstofffrei durch Instillation physiologischer Kochsalzlösung (Unterdruck-Instillationstherapie). Hierdurch können die Effekte der konventionellen Vakuumtherapie mit denen der lokalen Antisepsis kombiniert werden. Hierdurch kommt es zu einer Reduktion der Wundfläche, einer Induktion von Granulationsgewebe sowie einer Reduktion der Keimbesiedelung der Wunden. Bisher publizierte Studien konzentrieren sich auf die Anwendung dieses Therapieverfahrens zur Behandlung orthopädisch-chirurgischer Krankheiten. Die Datenlage bezüglich der Vakuum-Instillationstherapie in der Dermatochirurgie beschränkt sich derzeit auf Fallberichte und Einzelfallerfahrungen. Randomisierte, prospektive Studien zum Vergleich der Vakuum-Instillationstherapie zur Behandlung dermatologischer Krankheitsbilder existieren bislang nicht. Ziele des vorliegenden Artikels sind die Vorstellung der Vakuumtherapie mit Instillation einschließlich ihres Wirkprinzips, deren mögliche Komplikationen, die Diskussion erdenklicher Kontraindikationen sowie eine Übersicht über die aktuell verfügbare Datenlage. Zusammenfassend scheint sich die Evidenz zu verdichten, dass mittels Unterdruck-Instillationstherapie sowohl einfache als auch komplizierte Wunden effizient behandelt werden können, was sich in einer deutlichen Beschleunigung der Wundgranulation mit konsekutiv früher möglichem Defektverschluss äußert. PMID:27509413

  11. High Temperature Reactor (HTR) Deep Burn Core and Fuel Analysis: Design Selection for the Prismatic Block Reactor

    SciTech Connect

    Francesco Venneri; Chang-Keun Jo; Jae-Man Noh; Yonghee Kim; Claudio Filippone; Jonghwa Chang; Chris Hamilton; Young-Min Kim; Ji-Su Jun; Moon-Sung Cho; Hong-Sik Lim; MIchael A. Pope; Abderrafi M. Ougouag; Vincent Descotes; Brian Boer

    2010-09-01

    The Deep Burn (DB) Project is a U.S. Department of Energy sponsored feasibility study of Transuranic Management using high burnup fuel in the high temperature helium cooled reactor (HTR). The DB Project consists of seven tasks: project management, core and fuel analysis, spent fuel management, fuel cycle integration, TRU fuel modeling, TRU fuel qualification, and HTR fuel recycle. In the Phase II of the Project, we conducted nuclear analysis of TRU destruction/utilization in the HTR prismatic block design (Task 2.1), deep burn fuel/TRISO microanalysis (Task 2.3), and synergy with fast reactors (Task 4.2). The Task 2.1 covers the core physics design, thermo-hydraulic CFD analysis, and the thermofluid and safety analysis (low pressure conduction cooling, LPCC) of the HTR prismatic block design. The Task 2.3 covers the analysis of the structural behavior of TRISO fuel containing TRU at very high burnup level, i.e. exceeding 50% of FIMA. The Task 4.2 includes the self-cleaning HTR based on recycle of HTR-generated TRU in the same HTR. Chapter IV contains the design and analysis results of the 600MWth DB-HTR core physics with the cycle length, the average discharged burnup, heavy metal and plutonium consumptions, radial and axial power distributions, temperature reactivity coefficients. Also, it contains the analysis results of the 450MWth DB-HTR core physics and the analysis of the decay heat of a TRU loaded DB-HTR core. The evaluation of the hot spot fuel temperature of the fuel block in the DB-HTR (Deep-Burn High Temperature Reactor) core under full operating power conditions are described in Chapter V. The investigated designs are the 600MWth and 460MWth DB-HTRs. In Chapter VI, the thermo-fluid and safety of the 600MWth DB-HTRs has been analyzed to investigate a thermal-fluid design performance at the steady state and a passive safety performance during an LPCC event. Chapter VII describes the analysis results of the TRISO fuel microanalysis of the 600MWth and 450

  12. Hepatitis B virus X protein modifies invasion, proliferation and the inflammatory response in an HTR-8/SVneo cell model.

    PubMed

    Cui, Hong; Li, Qiu-Ling; Chen, Jing; Na, Quan; Liu, Cai-Xia

    2015-10-01

    Mother-to-infant transmission of hepatitis B virus (HBV) can occur as an intrauterine, intrapartum or postpartum infection. In the present study, we induced a multifunctional viral regulator of HBV gene products, HBx, and its different fragments to overexpress in a tropho-blast cell line, HTR-8/SVneo. We then identified the biological effects of HBx on HTR-8/SVneo cells. Our results indicated that HBx inhibited apoptosis and induced invasion as detected using Annexin V/propidium iodide (PI) double staining and Transwell assay, respectively. Furthermore, we carried out western blot analysis to analyze the possible related signaling pathway. We confirmed that HBx and its different fragments can activate the Smad signaling pathway, accompanied by downregulation of E-cadherin, and upregulation of vimentin and N-cadherin. TGF‑β1 was used as a control to activate the Smad signaling pathway in HTR-8/SVneo cells. HBx activated the Smad signaling pathway in the HTR-8/SVneo cells. After the signaling pathway was activated, reduced apoptosis, higher invasive ability and enhanced inflammatory response were observed in the HTR-8/SVneo cells. PMID:26251950

  13. Human recombinant H2 relaxin induces AKT and GSK3β phosphorylation and HTR-8/SVneo cell proliferation.

    PubMed

    Astuti, Yoni; Nakabayashi, Koji; Deguchi, Masashi; Ebina, Yasuhiko; Yamada, Hideto

    2015-01-01

    Relaxin is essential for trophoblast development during pregnancy. Evidence shows that relaxin increases trophoblast cell migration capacity. Here, we show the effect of relaxin on protein kinase B (AKT) activation and glycogen synthase kinase 3-beta (GSK3β) inactivation as well as on the proliferation of HTR-8/SVneo cells, a model of human extravillous trophoblast (EVT). HTR-8/SVneo cells were treated with different doses of human recombinant (rH2) relaxin in serum-deprived conditions and treated for increasing time with 1 ng/mL of rH2 relaxin. Western blot analysis was performed to detect pAKT, AKT, pGSK3β, GSK3β, and actin expression. Proliferation of HTR-8/SVneo cells was analyzed by MTS assay. rH2 relaxin treatment increased the ratio of pAKT/AKT, pGSK3β/GSK3β, and proliferation in HTR-8/SVneo cells. Furthermore, AKT and GSK3β activation by rH2 relaxin was inhibited by a phosphoinositide 3-kinase (PI3K) inhibitor. This study suggests that rH2 relaxin induces AKT and GSK3β phosphorylation as well as proliferation in HTR-8/SVneo cells. PMID:25868609

  14. Analysis of the link between the redox state and enzymatic activity of the HtrA (DegP) protein from Escherichia coli.

    PubMed

    Koper, Tomasz; Polit, Agnieszka; Sobiecka-Szkatula, Anna; Wegrzyn, Katarzyna; Scire, Andrea; Figaj, Donata; Kadzinski, Leszek; Zarzecka, Urszula; Zurawa-Janicka, Dorota; Banecki, Bogdan; Lesner, Adam; Tanfani, Fabio; Lipinska, Barbara; Skorko-Glonek, Joanna

    2015-01-01

    Bacterial HtrAs are proteases engaged in extracytoplasmic activities during stressful conditions and pathogenesis. A model prokaryotic HtrA (HtrA/DegP from Escherichia coli) requires activation to cleave its substrates efficiently. In the inactive state of the enzyme, one of the regulatory loops, termed LA, forms inhibitory contacts in the area of the active center. Reduction of the disulfide bond located in the middle of LA stimulates HtrA activity in vivo suggesting that this S-S bond may play a regulatory role, although the mechanism of this stimulation is not known. Here, we show that HtrA lacking an S-S bridge cleaved a model peptide substrate more efficiently and exhibited a higher affinity for a protein substrate. An LA loop lacking the disulfide was more exposed to the solvent; hence, at least some of the interactions involving this loop must have been disturbed. The protein without S-S bonds demonstrated lower thermal stability and was more easily converted to a dodecameric active oligomeric form. Thus, the lack of the disulfide within LA affected the stability and the overall structure of the HtrA molecule. In this study, we have also demonstrated that in vitro human thioredoxin 1 is able to reduce HtrA; thus, reduction of HtrA can be performed enzymatically. PMID:25710793

  15. Analysis of the Link between the Redox State and Enzymatic Activity of the HtrA (DegP) Protein from Escherichia coli

    PubMed Central

    Koper, Tomasz; Polit, Agnieszka; Sobiecka-Szkatula, Anna; Wegrzyn, Katarzyna; Scire, Andrea; Figaj, Donata; Kadzinski, Leszek; Zarzecka, Urszula; Zurawa-Janicka, Dorota; Banecki, Bogdan; Lesner, Adam; Tanfani, Fabio; Lipinska, Barbara; Skorko-Glonek, Joanna

    2015-01-01

    Bacterial HtrAs are proteases engaged in extracytoplasmic activities during stressful conditions and pathogenesis. A model prokaryotic HtrA (HtrA/DegP from Escherichia coli) requires activation to cleave its substrates efficiently. In the inactive state of the enzyme, one of the regulatory loops, termed LA, forms inhibitory contacts in the area of the active center. Reduction of the disulfide bond located in the middle of LA stimulates HtrA activity in vivo suggesting that this S-S bond may play a regulatory role, although the mechanism of this stimulation is not known. Here, we show that HtrA lacking an S-S bridge cleaved a model peptide substrate more efficiently and exhibited a higher affinity for a protein substrate. An LA loop lacking the disulfide was more exposed to the solvent; hence, at least some of the interactions involving this loop must have been disturbed. The protein without S-S bonds demonstrated lower thermal stability and was more easily converted to a dodecameric active oligomeric form. Thus, the lack of the disulfide within LA affected the stability and the overall structure of the HtrA molecule. In this study, we have also demonstrated that in vitro human thioredoxin 1 is able to reduce HtrA; thus, reduction of HtrA can be performed enzymatically. PMID:25710793

  16. Modulation of mitochondrial function and morphology by interaction of Omi/HtrA2 with the mitochondrial fusion factor OPA1

    SciTech Connect

    Kieper, Nicole; Holmstroem, Kira M.; Ciceri, Dalila; Fiesel, Fabienne C.; Wolburg, Hartwig; Ziviani, Elena; Whitworth, Alexander J.; Martins, L. Miguel; Kahle, Philipp J.; Krueger, Rejko

    2010-04-15

    Loss of Omi/HtrA2 function leads to nerve cell loss in mouse models and has been linked to neurodegeneration in Parkinson's and Huntington's disease. Omi/HtrA2 is a serine protease released as a pro-apoptotic factor from the mitochondrial intermembrane space into the cytosol. Under physiological conditions, Omi/HtrA2 is thought to be involved in protection against cellular stress, but the cytological and molecular mechanisms are not clear. Omi/HtrA2 deficiency caused an accumulation of reactive oxygen species and reduced mitochondrial membrane potential. In Omi/HtrA2 knockout mouse embryonic fibroblasts, as well as in Omi/HtrA2 silenced human HeLa cells and Drosophila S2R+ cells, we found elongated mitochondria by live cell imaging. Electron microscopy confirmed the mitochondrial morphology alterations and showed abnormal cristae structure. Examining the levels of proteins involved in mitochondrial fusion, we found a selective up-regulation of more soluble OPA1 protein. Complementation of knockout cells with wild-type Omi/HtrA2 but not with the protease mutant [S306A]Omi/HtrA2 reversed the mitochondrial elongation phenotype and OPA1 alterations. Finally, co-immunoprecipitation showed direct interaction of Omi/HtrA2 with endogenous OPA1. Thus, we show for the first time a direct effect of loss of Omi/HtrA2 on mitochondrial morphology and demonstrate a novel role of this mitochondrial serine protease in the modulation of OPA1. Our results underscore a critical role of impaired mitochondrial dynamics in neurodegenerative disorders.

  17. Common variants of HTR3 genes are associated with obsessive-compulsive disorder and its phenotypic expression.

    PubMed

    Kim, Hae Won; Kang, Jee In; Lee, Sang-Hyuk; An, Suk Kyoon; Sohn, Sung Yun; Hwang, Eun Hee; Lee, Su Young; Kim, Se Joo

    2016-01-01

    Evidence from literature supports the existence of associations between serotonin-related genetic variants and obsessive-compulsive disorder (OCD), but few studies have explored the involvement of serotonin receptor type 3 genes (HTR3) in OCD. To identify whether HTR3 variability affects an individual's susceptibility to OCD, we examined 10 HTR3 variants in 596 individuals with OCD and 599 controls. A significant difference existed in the genotypic distribution of the HTR3B variant rs1176744 between individuals with OCD and controls (odds ratio [OR] = 0.74, 95% confidence interval [CI] = 0.60-0.91, P = 0.0043). A protective haplotype in HTR3B was also associated with OCD (OR = 0.77, CI = 0.63-0.95, permutated P = 0.0179). Analyses of OCD sub-phenotypes demonstrated significant associations between rs3758987 and early onset OCD in male subjects (OR = 0.49, CI = 0.31-0.79, P = 0.0031) and among rs6766410, rs6443930, and the cleaning dimension in female subjects (OR = 0.36, CI = 0.18-0.69, P = 0.0016 and OR = 0.47, CI = 0.29-0.79, P = 0.0030, respectively). Additionally, rs6766410 was related to contamination-based disgust in OCD (P = 0.0044). These results support that common HTR3 variants are involved in OCD and some of its clinical phenotypes. PMID:27616601

  18. EVALUATION OF THE INITIAL CRITICAL CONFIGURATION OF THE HTR-10 PEBBLE-BED REACTOR

    SciTech Connect

    William K. Terry

    2005-11-01

    This report describes the evaluation of data from the initial criticality measurement of the HTR-10 pebble-bed reactor at the Institute of Nuclear Energy Technology in China to determine whether the data are of sufficient quality to use as benchmarks for reactor physics computer codes intended for pebble-bed reactor analysis. The evaluation applied the INL pebble-bed reactor physics code PEBBED to perform an uncertainty analysis on the core critical height. The overall uncertainty in k-effective was slightly over 0.5%, which is considered adequate for an experimental benchmark.

  19. Archivalische Quellen zum Leben und Werk von Franz Xaver von Zach.

    NASA Astrophysics Data System (ADS)

    Wattenberg, D.; Brosche, P.

    Franz Xaver von Zach (1754 - 1832) gehörte um die Wende vom 18. zum 19. Jahrhundert zu den angesehensten und profiliertesten Astronomen. Anliegen dieser Untersuchung ist es, handschriftliche Quellen von Zachs nachzuweisen - auch wenn Vollständigkeit vorläufig nicht erreicht werden kann.

  20. Nonsynonymous HTR2C polymorphism predicts cortisol response to psychosocial stress II: Evidence from two samples.

    PubMed

    Way, Baldwin M; Brown, Kirk Warren; Quaglia, Jordan; McCain, Nancy; Taylor, Shelley E

    2016-08-01

    The 5-HT2C receptor is the primary serotonin receptor located in the corticotrophin releasing hormone (CRH) neurons of the hypothalamus. These neurons initiate the signaling cascade that culminates in cortisol release. Therefore, genetic variation in the 5-HT2C receptor gene (HTR2C) is a prime candidate for affecting cortisol reactivity to stress. Accordingly, we examined the association of a nonsynonymous polymorphism (Cys23Ser; rs6318) in HTR2C with stress reactivity in two Trier Social Stress Tests conducted at separate sites. In both Study 1 (N=128) and Study 2 (N=185), Cys23 homozygous females and hemizygous males had greater cortisol reactivity. There was no relation between this polymorphism and self-reported affective response (Studies 1 and 2) or cardiovascular reactivity (Study 2). Additionally, the short/short genotype of a polymorphism (5-HTTLPR) in the serotonin transporter gene was associated with greater cortisol reactivity in Study 1 as well as in Study 2 (previously reported). The Cys23Ser polymorphism and the 5-HTTLPR were independently associated with cortisol reactivity in both studies. These findings emphasize the important role of genetic variation in the serotonin system on regulating cortisol reactivity to social evaluative stress. Comparison of the present associations with those of prior studies underscores the likely importance of situational and psychological factors in determining the direction and magnitude of the association between genotype and phenotype. PMID:27211696

  1. Chlamydia Serine Protease Inhibitor, targeting HtrA, as a New Treatment for Koala Chlamydia infection

    PubMed Central

    Lawrence, Amba; Fraser, Tamieka; Gillett, Amber; Tyndall, Joel D. A.; Timms, Peter; Polkinghorne, Adam; Huston, Wilhelmina M.

    2016-01-01

    The koala, an iconic marsupial native to Australia, is a threatened species in many parts of the country. One major factor in the decline is disease caused by infection with Chlamydia. Current therapeutic strategies to treat chlamydiosis in the koala are limited. This study examines the effectiveness of an inhibitor, JO146, which targets the HtrA serine protease for treatment of C. pecorum and C. pneumoniae in vitro and ex vivo with the aim of developing a novel therapeutic for koala Chlamydia infections. Clinical isolates from koalas were examined for their susceptibility to JO146. In vitro studies demonstrated that treatment with JO146 during the mid-replicative phase of C. pecorum or C. pneumoniae infections resulted in a significant loss of infectious progeny. Ex vivo primary koala tissue cultures were used to demonstrate the efficacy of JO146 and the non-toxic nature of this compound on peripheral blood mononuclear cells and primary cell lines established from koala tissues collected at necropsy. Our results suggest that inhibition of the serine protease HtrA could be a novel treatment strategy for chlamydiosis in koalas. PMID:27530689

  2. GABA A receptor π subunit promotes apoptosis of HTR-8/SVneo trophoblastic cells: Implications in preeclampsia.

    PubMed

    Lu, Junjie; Zhang, Qian; Tan, Dongmei; Luo, Wenping; Zhao, Hai; Ma, Jing; Liang, Hao; Tan, Yi

    2016-07-01

    Gamma-aminobutyric acid (GABA) functions primarily as an inhibitory neurotransmitter through its receptors in the mature central nervous system. The GABA type A receptor π subunit (GABRP) has been identified in the tissues of the reproductive system, particularly in the uterus. In addition, we have previously detected GABRP expression in both human and mouse placentas. To examine the role of GABRP in trophoblastic cell invasion, we constructed a pIRES2-GABRP-EGFP plasmid which was used for the transfection of a human placental cell line derived from first trimester extravillous trophoblasts (HTR-8/SVneo). The number of invaded cells was decreased by GABRP overexpression. Notably, the decrease in the invasive cell number may be due to the increased apoptosis of the HTR-8/SVneo cells following GABRP transfection, which was further confirmed by flow cytometry, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis. Based on the increased apoptosis of trophoblastic cells in pregnancies complicated by preeclampsia (PE) and the fact that GABRP promotes the apoptosis of trophoblastic cells, we hypothesized that GABRP expression is increased in the placental tissues from patients with PE compared with that in the normal groups and this hypothesis was confirmed by RT-qPCR and immunohistochemical analysis. Taken together, these findings imply that GABRP plays an important role in placentation and this pathway may be a promising molecular target for the development of novel therapeutic strategies for PE. PMID:27221053

  3. A conserved activation cluster is required for allosteric communication in HtrA-family proteases.

    PubMed

    de Regt, Anna K; Kim, Seokhee; Sohn, Jungsan; Grant, Robert A; Baker, Tania A; Sauer, Robert T

    2015-03-01

    In E. coli, outer-membrane stress causes a transcriptional response through a signaling cascade initiated by DegS cleavage of a transmembrane antisigma factor. Each subunit of DegS, an HtrA-family protease, contains a protease domain and a PDZ domain. The trimeric protease domain is autoinhibited by the unliganded PDZ domains. Allosteric activation requires binding of unassembled outer-membrane proteins (OMPs) to the PDZ domains and protein substrate binding. Here, we identify a set of DegS residues that cluster together at subunit-subunit interfaces in the trimer, link the active sites and substrate binding sites, and are crucial for stabilizing the active enzyme conformation in response to OMP signaling. These residues are conserved across the HtrA-protease family, including orthologs linked to human disease, supporting a common mechanism of allosteric activation. Indeed, mutation of residues at homologous positions in the DegP quality-control protease also eliminates allosteric activation. PMID:25703375

  4. Chlamydia Serine Protease Inhibitor, targeting HtrA, as a New Treatment for Koala Chlamydia infection.

    PubMed

    Lawrence, Amba; Fraser, Tamieka; Gillett, Amber; Tyndall, Joel D A; Timms, Peter; Polkinghorne, Adam; Huston, Wilhelmina M

    2016-01-01

    The koala, an iconic marsupial native to Australia, is a threatened species in many parts of the country. One major factor in the decline is disease caused by infection with Chlamydia. Current therapeutic strategies to treat chlamydiosis in the koala are limited. This study examines the effectiveness of an inhibitor, JO146, which targets the HtrA serine protease for treatment of C. pecorum and C. pneumoniae in vitro and ex vivo with the aim of developing a novel therapeutic for koala Chlamydia infections. Clinical isolates from koalas were examined for their susceptibility to JO146. In vitro studies demonstrated that treatment with JO146 during the mid-replicative phase of C. pecorum or C. pneumoniae infections resulted in a significant loss of infectious progeny. Ex vivo primary koala tissue cultures were used to demonstrate the efficacy of JO146 and the non-toxic nature of this compound on peripheral blood mononuclear cells and primary cell lines established from koala tissues collected at necropsy. Our results suggest that inhibition of the serine protease HtrA could be a novel treatment strategy for chlamydiosis in koalas. PMID:27530689

  5. GABA A receptor π subunit promotes apoptosis of HTR-8/SVneo trophoblastic cells: Implications in preeclampsia

    PubMed Central

    LU, JUNJIE; ZHANG, QIAN; TAN, DONGMEI; LUO, WENPING; ZHAO, HAI; MA, JING; LIANG, HAO; TAN, YI

    2016-01-01

    Gamma-aminobutyric acid (GABA) functions primarily as an inhibitory neurotransmitter through its receptors in the mature central nervous system. The GABA type A receptor π subunit (GABRP) has been identified in the tissues of the reproductive system, particularly in the uterus. In addition, we have previously detected GABRP expression in both human and mouse placentas. To examine the role of GABRP in trophoblastic cell invasion, we constructed a pIRES2-GABRP-EGFP plasmid which was used for the transfection of a human placental cell line derived from first trimester extravillous trophoblasts (HTR-8/SVneo). The number of invaded cells was decreased by GABRP overexpression. Notably, the decrease in the invasive cell number may be due to the increased apoptosis of the HTR-8/SVneo cells following GABRP transfection, which was further confirmed by flow cytometry, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis. Based on the increased apoptosis of trophoblastic cells in pregnancies complicated by preeclampsia (PE) and the fact that GABRP promotes the apoptosis of trophoblastic cells, we hypothesized that GABRP expression is increased in the placental tissues from patients with PE compared with that in the normal groups and this hypothesis was confirmed by RT-qPCR and immunohistochemical analysis. Taken together, these findings imply that GABRP plays an important role in placentation and this pathway may be a promising molecular target for the development of novel therapeutic strategies for PE. PMID:27221053

  6. Phototaxis of Halobacterium salinarium requires a signalling complex of sensory rhodopsin I and its methyl-accepting transducer HtrI.

    PubMed Central

    Krah, M; Marwan, W; Verméglio, A; Oesterhelt, D

    1994-01-01

    Sensory rhodopsin I (SRI) is a photoreceptor that mediates phototaxis in the archaeon Halobacterium salinarium. Receptor excitation is relayed to the motility system of the cell by the methyl-accepting transducer protein HtrI. In membranes prepared from cells that lack HtrI the absorbance difference maximum of SRI was shifted from 587 to 565 nm. The thermal decay of the metastable photocycle intermediate SRI373 was measured as time-dependent recovery of the absorbance at 590 nm. In the absence of HtrI the decay was slowed down by two orders of magnitude. When SRI was overproduced in cells that contained normal levels of HtrI, the decay of SRI373 was biexponential indicating two kinetically distinct species. Spectroscopic measurements on intact cells revealed the same effect of HtrI on SRI photocycling as found in isolated membranes. By transient exposure of membranes from wild-type cells to low ionic strength, the decay of SR373 was slowed to the same value found for untreated membranes in the absence of HtrI. In parallel, the absorbance difference maximum was shifted to 565 nm indicating that a physical interaction of HtrI and SRI had been irreversibly destroyed. Overproduction of SRI in the presence of wild-type amounts of HtrI did not increase the light sensitivity of the cells to orange light step down stimulation. It is concluded that SRI and HtrI form a stable complex in the cell membrane that signals to the flagellar motor and defines absorbance maximum, photocycling rate and photochemical efficiency of SRI. PMID:8187768

  7. The NG2 Proteoglycan Protects Oligodendrocyte Precursor Cells against Oxidative Stress via Interaction with OMI/HtrA2

    PubMed Central

    Maus, Frank; Sakry, Dominik; Binamé, Fabien; Karram, Khalad; Rajalingam, Krishnaraj; Watts, Colin; Heywood, Richard; Krüger, Rejko; Stegmüller, Judith; Werner, Hauke B.; Nave, Klaus-Armin; Krämer-Albers, Eva-Maria; Trotter, Jacqueline

    2015-01-01

    The NG2 proteoglycan is characteristically expressed by oligodendrocyte progenitor cells (OPC) and also by aggressive brain tumours highly resistant to chemo- and radiation therapy. Oligodendrocyte-lineage cells are particularly sensitive to stress resulting in cell death in white matter after hypoxic or ischemic insults of premature infants and destruction of OPC in some types of Multiple Sclerosis lesions. Here we show that the NG2 proteoglycan binds OMI/HtrA2, a mitochondrial serine protease which is released from damaged mitochondria into the cytosol in response to stress. In the cytosol, OMI/HtrA2 initiates apoptosis by proteolytic degradation of anti-apoptotic factors. OPC in which NG2 has been downregulated by siRNA, or OPC from the NG2-knockout mouse show an increased sensitivity to oxidative stress evidenced by increased cell death. The proapoptotic protease activity of OMI/HtrA2 in the cytosol can be reduced by the interaction with NG2. Human glioma expressing high levels of NG2 are less sensitive to oxidative stress than those with lower NG2 expression and reducing NG2 expression by siRNA increases cell death in response to oxidative stress. Binding of NG2 to OMI/HtrA2 may thus help protect cells against oxidative stress-induced cell death. This interaction is likely to contribute to the high chemo- and radioresistance of glioma. PMID:26340347

  8. HTR1A Polymorphisms and Clinical Efficacy of Antipsychotic Drug Treatment in Schizophrenia: A Meta-Analysis

    PubMed Central

    Fabbri, Chiara; Kato, Masaki; Koshikawa, Yosuke; Tajika, Aran; Kinoshita, Toshihiko; Serretti, Alessandro

    2016-01-01

    Background: This meta-analysis was conducted to evaluate whether HTR1A gene polymorphisms impact the efficacy of antipsychotic drugs in patients with schizophrenia. Methods: Candidate gene studies that were published in English up to August 6, 2015 were identified by a literature search of PubMed, Web of Science, and Google scholar. Data were pooled from individual clinical trials considering overall symptoms, positive symptoms and negative symptoms, and standard mean differences were calculated by applying a random-effects model. Results: The present meta-analysis included a total of 1281 patients from 10 studies. Three polymorphisms of HTR1A (rs6295, rs878567, and rs1423691) were selected for the analysis. In the pooled data from all studies, none of these HTR1A polymorphisms correlated significantly with either overall symptoms or positive symptoms. However, C allele carriers of the rs6295 polymorphism showed a significantly greater negative symptoms improvement than G allele carriers (P=.04, standardized mean difference =-0.14, 95%CI = 0.01 to 0.28). Conclusions: The results of our present analysis indicate that the HTR1A rs6295 polymorphism may impact negative symptoms improvement but not on either overall symptoms or positive symptoms improvement. However, this meta-analysis was based on a small number of studies and patients, and the effect size on negative symptoms was small. Given this limitation, the results should be confirmed by further investigations. PMID:26568455

  9. Serotonin receptor gene (HTR2A) T102C polymorphism modulates individuals’ perspective taking ability and autistic-like traits

    PubMed Central

    Gong, Pingyuan; Liu, Jinting; Blue, Philip R.; Li, She; Zhou, Xiaolin

    2015-01-01

    Previous studies have indicated that empathic traits, such as perspective taking, are associated with the levels of serotonin in the brain and with autism spectrum conditions. Inspired by the finding that the serotonin receptor 2A gene (HTR2A) modulates the availability of serotonin, this study investigated to what extent HTR2A modulates individuals’ perspective taking ability and autistic-like traits. To examine the associations of the functional HTR2A polymorphism T102C (rs6313) with individuals’ perspective taking abilities and autistic-like traits, we differentiated individuals according to this polymorphism and measured empathic and autistic-like traits with Interpersonal Reactivity Index (IRI) and Autism-Spectrum Quotient (AQ) scale in 523 Chinese people. The results indicated that this polymorphism was significantly associated with the scores on Perspective Taking and Personal Distress subscales of IRI, and Communication subscale of AQ. Individuals with a greater number of the C alleles were less likely to spontaneously adopt the point of view of others, more likely to be anxious when observing the pain endured by others, and more likely to have communication problems. Moreover, the genotype effect on communication problems was mediated by individuals’ perspective taking ability. These findings provide evidence that the HTR2A T102C polymorphism is a predictor of individual differences in empathic and autistic-like traits and highlight the role of the gene in the connection between perspective taking and autistic-like traits. PMID:26557070

  10. The structures of Arabidopsis Deg5 and Deg8 reveal new insights into HtrA proteases

    SciTech Connect

    Sun, Wei; Gao, Feng; Fan, Haitian; Shan, Xiaoyue; Sun, Renhua; Liu, Lin; Gong, Weimin

    2013-05-01

    The crystal structures of Arabidopsis Deg5 and Deg8 have been determined to resolutions of 2.6 and 2.0 Å, respectively, revealing novel structural features of HtrA proteases. Plant Deg5 and Deg8 are two members of the HtrA proteases, a family of oligomeric serine endopeptidases that are involved in a variety of protein quality-control processes. These two HtrA proteases are located in the thylakoid lumen and participate in high-light stress responses by collaborating with other chloroplast proteins. Deg5 and Deg8 degrade photodamaged D1 protein of the photosystem II reaction centre, allowing its in situ replacement. Here, the crystal structures of Arabidopsis thaliana Deg5 (S266A) and Deg8 (S292A) are reported at 2.6 and 2.0 Å resolution, respectively. The Deg5 trimer contains two calcium ions in a central channel, suggesting a link between photodamage control and calcium ions in chloroplasts. Previous structures of HtrA proteases have indicated that their regulation usually requires C-terminal PDZ domain(s). Deg5 is unique in that it contains no PDZ domain and the trimeric structure of Deg5 (S266A) reveals a novel catalytic triad conformation. A similar triad conformation is observed in the hexameric structure of the single PDZ-domain-containing Deg8 (S292A). These findings suggest a novel activation mechanism for plant HtrA proteases and provide structural clues to their function in light-stress response.

  11. The roles of CC2D1A and HTR1A gene expressions in autism spectrum disorders.

    PubMed

    Sener, Elif Funda; Cıkılı Uytun, Merve; Korkmaz Bayramov, Keziban; Zararsiz, Gokmen; Oztop, Didem Behice; Canatan, Halit; Ozkul, Yusuf

    2016-06-01

    Classical autism belongs to a group of heterogeneous disorders known as autism spectrum disorders (ASD). Autism is defined as a neurodevelopmental disorder, characterized by repetitive stereotypic behaviors or restricted interests, social withdrawal, and communication deficits. Numerous susceptibility genes and chromosomal abnormalities have been reported in association with autism but the etiology of this disorder is unknown in many cases. CC2D1A gene has been linked to mental retardation (MR) in a family with a large deletion before. Intellectual disability (ID) is a common feature of autistic cases. Therefore we aimed to investigate the expressions of CC2D1A and HTR1A genes with the diagnosis of autism in Turkey. Forty-four autistic patients (35 boys, 9 girls) and 27 controls were enrolled and obtained whole blood samples to isolate RNA samples from each participant. CC2D1A and HTR1A gene expressions were assessed by quantitative Real-Time PCR (qRT-PCR) in Genome and Stem Cell Center, Erciyes University. Both expressions of CC2D1A and HTR1A genes studied on ASD cases and controls were significantly different (p < 0.001). The expression of HTR1A was undetectable in the ASD samples. Comparison of ID and CC2D1A gene expression was also found statistically significant (p = 0.028). CC2D1A gene expression may be used as a candidate gene for ASD cases with ID. Further studies are needed to investigate the potential roles of these CC2D1A and HTR1A genes in their related pathways in ASD. PMID:26782176

  12. Assignment of a human homolog of the mouse Htr3 receptor gene to chromosome 11q23.1-q23.2

    SciTech Connect

    Weiss, B.; Mertz, A.; Rappold, G.

    1995-09-01

    Serotonin or 5-hydroxytryptamine (5-HT) represents a family of neurotransmitters acting through the 5-HT neuroreceptors. One of these receptors, HTR3, belongs to the family of ligand gated ion channels. Activation of the HTR3 receptor mediates a variety of physiological effects in central and peripheral neurons such as cytotoxic drug-evoked emesis and nociception and is believed to influence behavior relevant to anxiety and cognitive disorders. 16 refs., 1 fig.

  13. PDZ domains determine the native oligomeric structure of the DegP (HtrA) protease.

    PubMed

    Sassoon, N; Arié, J P; Betton, J M

    1999-08-01

    DegP (HtrA) is a periplasmic heat shock serine protease of Escherichia coli that degrades misfolded proteins at high temperatures. Biochemical and biophysical experiments have indicated that the purified DegP exists as a hexamer. To examine whether the PDZ domains of DegP were required for oligomerization, we constructed a DegP variant lacking both PDZ domains. This truncated variant, DegPDelta, exhibited no proteolytic activity but exerted a dominant-negative effect on growth at high temperatures by interfering with the functional assembly of oligomeric DegP. Thus, the PDZ domains contain information necessary for proper assembly of the functional hexameric structure of DegP. PMID:10417648

  14. Preliminary analysis of graphite dust releasing behavior in accident for HTR

    SciTech Connect

    Peng, W.; Yang, X. Y.; Yu, S. Y.; Wang, J.

    2012-07-01

    The behavior of the graphite dust is important to the safety of High Temperature Gas-cooled Reactors. This study investigated the flow of graphite dust in helium mainstream. The analysis of the stresses acting on the graphite dust indicated that gas drag played the absolute leading role. Based on the understanding of the importance of gas drag, an experimental system is set up for the research of dust releasing behavior in accident. Air driven by centrifugal fan is used as the working fluid instead of helium because helium is expensive, easy to leak which make it difficult to seal. The graphite particles, with the size distribution same as in HTR, are added to the experiment loop. The graphite dust releasing behavior at the loss-of-coolant accident will be investigated by a sonic nozzle. (authors)

  15. Graphite corrosion and hydrogen release from HTR fuel elements in Q-brine

    SciTech Connect

    Fachinger, J.; Zhang, Z.X.; Brodda, B.G.

    1995-12-31

    Industrial reprocessing for High Temperature Reactors (HTR) fuel elements has never been installed in Germany. The spent fuel elements are being considered for final disposal in a rock salt repository in the deep geologic underground. Safety analysis requires the assumption of an accidental water ingress into the repository, resulting in the formation of a concentrated salt solution with the typical composition of a quinary brine. After corrosive penetration of the container walls, the brine may finally contact the fuel elements directly and mobilize radionuclides. Duve et al. investigated the leaching of the fission products and actinides from HTR fuel elements in Q-brine. The mobilization of {sup 14}C by graphite corrosion is one of the last data bases required as a source term for the release estimation of radionuclides in the final safety analysis. The evaluation of the hydrogen release was prescribed by the licensing board, because an excessive gas pressure may affect the overall integrity of the geological barrier. {sup 14}C occurs as dissolved organic and inorganic compounds in the brine. The leaching rate or organic {sup 14}C decreases from about 80 Bq to 1 Bq. The amount of organic {sup 14}C decreases from about 80 Bq to 1 Bq during leaching. The release of inorganic {sup 14}C ceases within 4 months. About 100 ppm of the total {sup 14}C inventory was released during leaching. Gaseous {sup 14}C has never been detected. The gas formation is based on the radiolytic degradation of water, with a formation rate of 0.04 to 0.11 ml/d. Gas chromatographic analysis of the gas proved that hydrogen is the main component of the released gas. Tritium and {sup 85}Kr were detected as traces with radio gas chromatography.

  16. Next-Generation Bacillus anthracis Live Attenuated Spore Vaccine Based on the htrA- (High Temperature Requirement A) Sterne Strain

    PubMed Central

    Chitlaru, Theodor; Israeli, Ma’ayan; Bar-Haim, Erez; Elia, Uri; Rotem, Shahar; Ehrlich, Sharon; Cohen, Ofer; Shafferman, Avigdor

    2016-01-01

    Anthrax is a lethal disease caused by the gram-positive spore-producing bacterium Bacillus anthracis. Live attenuated vaccines, such as the nonencapsulated Sterne strain, do not meet the safety standards mandated for human use in the Western world and are approved for veterinary purposes only. Here we demonstrate that disrupting the htrA gene, encoding the chaperone/protease HtrA (High Temperature Requirement A), in the virulent Bacillus anthracis Vollum strain results in significant virulence attenuation in guinea pigs, rabbits and mice, underlying the universality of the attenuated phenotype associated with htrA knockout. Accordingly, htrA disruption was implemented for the development of a Sterne-derived safe live vaccine compatible with human use. The novel B. anthracis SterneΔhtrA strain secretes functional anthrax toxins but is 10–104-fold less virulent than the Sterne vaccine strain depending on animal model (mice, guinea pigs, or rabbits). In spite of this attenuation, double or even single immunization with SterneΔhtrA spores elicits immune responses which target toxaemia and bacteremia resulting in protection from subcutaneous or respiratory lethal challenge with a virulent strain in guinea pigs and rabbits. The efficacy of the immune-protective response in guinea pigs was maintained for at least 50 weeks after a single immunization. PMID:26732659

  17. Distinct roles of secreted HtrA proteases from gram-negative pathogens in cleaving the junctional protein and tumor suppressor E-cadherin.

    PubMed

    Hoy, Benjamin; Geppert, Tim; Boehm, Manja; Reisen, Felix; Plattner, Patrick; Gadermaier, Gabriele; Sewald, Norbert; Ferreira, Fatima; Briza, Peter; Schneider, Gisbert; Backert, Steffen; Wessler, Silja

    2012-03-23

    The periplasmic chaperone and serine protease HtrA is important for bacterial stress responses and protein quality control. Recently, we discovered that HtrA from Helicobacter pylori is secreted and cleaves E-cadherin to disrupt the epithelial barrier, but it remained unknown whether this maybe a general virulence mechanism. Here, we show that important other pathogens including enteropathogenic Escherichia coli, Shigella flexneri, and Campylobacter jejuni, but not Neisseria gonorrhoeae, cleaved E-cadherin on host cells. HtrA deletion in C. jejuni led to severe defects in E-cadherin cleavage, loss of cell adherence, paracellular transmigration, and basolateral invasion. Computational modeling of HtrAs revealed a conserved pocket in the active center exhibiting pronounced proteolytic activity. Differential E-cadherin cleavage was determined by an alanine-to-glutamine exchange in the active center of neisserial HtrA. These data suggest that HtrA-mediated E-cadherin cleavage is a prevalent pathogenic mechanism of multiple gram-negative bacteria representing an attractive novel target for therapeutic intervention to combat bacterial infections. PMID:22337879

  18. The protease inhibitor JO146 demonstrates a critical role for CtHtrA for Chlamydia trachomatis reversion from penicillin persistence

    PubMed Central

    Ong, Vanissa A.; Marsh, James W.; Lawrence, Amba; Allan, John A.; Timms, Peter; Huston, Wilhelmina M.

    2013-01-01

    The Chlamydia trachomatis serine protease HtrA (CtHtrA) has recently been demonstrated to be essential during the replicative phase of the chlamydial developmental cycle. A chemical inhibition strategy (serine protease inhibitor JO146) was used to demonstrate this essential role and it was found that the chlamydial inclusions diminish in size and are lost from the cell after CtHtrA inhibition without formation of viable elementary bodies. The inhibitor (JO146) was used in this study to investigate the role of CtHtrA for penicillin persistence and heat stress conditions for Chlamydia trachomatis. JO146 addition during penicillin persistence resulted in only minor reductions (~1 log) in the final viable infectious yield after persistent Chlamydia were reverted from persistence. However, JO146 treatment during the reversion and recovery from penicillin persistence was completely lethal for Chlamydia trachomatis. JO146 was completely lethal when added either during heat stress conditions, or during the recovery from heat stress conditions. These data together indicate that CtHtrA has essential roles during some stress environments (heat shock), recovery from stress environments (heat shock and penicillin persistence), as well as the previously characterized essential role during the replicative phase of the chlamydial developmental cycle. Thus, CtHtrA is an essential protease with both replicative phase and stress condition functions for Chlamydia trachomatis. PMID:24392355

  19. Benzo(a)pyrene inhibits migration and invasion of extravillous trophoblast HTR-8/SVneo cells via activation of the ERK and JNK pathway.

    PubMed

    Liu, Liyuan; Wang, Yingxiong; Shen, Cha; He, Junlin; Liu, Xueqing; Ding, Yubin; Gao, Rufei; Chen, Xuemei

    2016-07-01

    Benzo(a)pyrene (BaP) is a persistent organic pollutant (POP) that is a serious threat to human health. Numerous studies have shown that BaP causes adverse effects in pregnancy, but the mechanism remains unclear. The moderate invasion of trophoblast cells into the endometrium is an important factor during successful embryo implantation. The aim of this study was to investigate the effect and mechanism of BaP on the invasion and migration of trophoblast cells. HTR-8/SVneo cells were treated with different concentrations (1, 5, 10, 25, 50 and 100 μM) of BaP. The invasion and migration of HTR-8/SVneo cells were observed after BaP treatment. The protein levels related to migration and invasion was detected by Western blot. The results confirmed that BaP inhibits the migration and invasion of extravillous trophoblast HTR-8/SVneo cells. Further investigations indicated that the protein levels of MMP-2, MMP-9 and E-cadherin in HTR-8/SVneo cells were changed by BaP treatment. Moreover, the data demonstrated that BaP activated the MAPK signaling pathway. Pretreatment with specific inhibitors of MAPK rescued BaP-induced change in the migration and invasion of HTR-8/SVneo cells. Taken together, our results indicated that BaP inhibits invasion and the migration of HTR-8/SVneo cells, which might cause a failure in early pregnancy. Copyright © 2015 John Wiley & Sons, Ltd. PMID:26359795

  20. Next-Generation Bacillus anthracis Live Attenuated Spore Vaccine Based on the htrA(-) (High Temperature Requirement A) Sterne Strain.

    PubMed

    Chitlaru, Theodor; Israeli, Ma'ayan; Bar-Haim, Erez; Elia, Uri; Rotem, Shahar; Ehrlich, Sharon; Cohen, Ofer; Shafferman, Avigdor

    2016-01-01

    Anthrax is a lethal disease caused by the gram-positive spore-producing bacterium Bacillus anthracis. Live attenuated vaccines, such as the nonencapsulated Sterne strain, do not meet the safety standards mandated for human use in the Western world and are approved for veterinary purposes only. Here we demonstrate that disrupting the htrA gene, encoding the chaperone/protease HtrA (High Temperature Requirement A), in the virulent Bacillus anthracis Vollum strain results in significant virulence attenuation in guinea pigs, rabbits and mice, underlying the universality of the attenuated phenotype associated with htrA knockout. Accordingly, htrA disruption was implemented for the development of a Sterne-derived safe live vaccine compatible with human use. The novel B. anthracis SterneΔhtrA strain secretes functional anthrax toxins but is 10-10(4)-fold less virulent than the Sterne vaccine strain depending on animal model (mice, guinea pigs, or rabbits). In spite of this attenuation, double or even single immunization with SterneΔhtrA spores elicits immune responses which target toxaemia and bacteremia resulting in protection from subcutaneous or respiratory lethal challenge with a virulent strain in guinea pigs and rabbits. The efficacy of the immune-protective response in guinea pigs was maintained for at least 50 weeks after a single immunization. PMID:26732659

  1. HtrA3 is regulated by 15-deoxy-{Delta}12,14-prostaglandin J2 independently of PPAR{gamma} in clear cell renal cell carcinomas

    SciTech Connect

    Theoleyre, Sandrine; Mottier, Stephanie; Masson, Damien; Denis, Marc G.

    2010-04-09

    Peroxisome proliferator-activated receptor gamma (PPAR{gamma}) ligands have been shown to possess anti-proliferative effects in many types of cancer. In clear cell renal cell carcinoma (CCRCC), the targets involved in these effects are not known. In this study, we demonstrated that, in CCRCC cell lines, the endogenous PPAR{gamma} ligand 15-deoxy-{Delta}12,14-prostaglandin J2 (15dPGJ2) induces the expression, both at the mRNA and the protein levels, of the HtrA3 gene. This gene belongs to the High-Temperature Requirement Factor A family of serine proteases that repress signaling by TGF-{beta} family members and inhibit cell migration. Rosiglitazone or ciglitazone, synthetic PPAR{gamma} agonists, did not induce HtrA3 expression, and the PPAR{gamma} antagonist GW9662 did not prevent 15dPGJ2 induction, suggesting that the up-regulation of HtrA3 by 15dPGJ2 is independent of PPAR{gamma}. The MEK/ERK inhibitor PD98059 dramatically repressed HtrA3 induction. Altogether, these data indicate that 15dPGJ2 is able to stimulate the expression of HtrA3 through an indirect mechanism involving the MEK/ERK pathway but independent of PPAR{gamma}. Our results provide a better understanding of the mechanisms involved in the regulation of HtrA3, a potential tumor suppressor gene.

  2. HtrA stress protein is involved in intramacrophagic replication of adherent and invasive Escherichia coli strain LF82 isolated from a patient with Crohn's disease.

    PubMed

    Bringer, Marie-Agnès; Barnich, Nicolas; Glasser, Anne-Lise; Bardot, Olivier; Darfeuille-Michaud, Arlette

    2005-02-01

    Adherent and invasive Escherichia coli (AIEC) bacteria isolated from Crohn's disease patients are able to greatly replicate within macrophages without escaping from the phagosome and without inducing macrophage death. In the present study, evidence is provided that in AIEC strain LF82 the htrA gene encoding the stress protein HtrA is essential for intracellular replication within J774-A1 macrophages. Deletion of the htrA gene in strain LF82 induced increased sensitivity of the isogenic mutant to oxidative stress caused by hydrogen peroxide and a reduced rate of growth in an acid and nutrient-poor medium partly reproducing the microenvironment of the phagosome. In vitro experiments using an LF82 htrA gene promoter fusion with the lacZ gene revealed a 38-fold activation of the promoter in AIEC LF82 intramacrophagic bacteria. The CpxRA two-component signaling pathway was not involved in this activation. In addition, the activation of the LF82 htrA gene promoter was not observed in the nonpathogenic E. coli K-12 intramacrophagic bacteria, indicating that the AIEC LF82 genetic background is crucial for induction of htrA gene transcription during phagocytosis. PMID:15664909

  3. Relationship between genetic polymorphisms in the HTR1A gene and paranoid schizophrenia in a northern Han Chinese population.

    PubMed

    Zhou, Xue; Ding, Mei; Ding, Chunli; Yao, Jun; Pang, Hao; Xing, Jiaxin; Xuan, Jinfeng; Wang, Baojie

    2013-03-01

    The hypothesis for the etiology of schizophrenia involves various neurotransmitters, including 5-HT. Metabolic disorder of 5-HT is an important underlying neurobiochemical cause leading to the development of mental illness. Abnormality in the receptors involved in 5-HT synthesis and metabolism may affect the functioning of 5-HT in the central nervous system. There are seven types of 5-HT receptor families, with a total of 15 corresponding subtypes. HTR1A is the most abundantly expressed 5-HT receptor subtype in the mammalian brain. SNPs in HTR1A enhance or weaken the functioning of 5-HT by affecting HTR1A expression levels or ligand-binding activity, thereby placing HTR1A in an important role in the study of diseases of the nervous system. This study employed DNA sequencing to investigate HTR1A fragment lengths, including complete exons as well as 5' FR and 3' FR segments, for a total of 2,718 bp. Seven SNP loci (ss212928868, rs6295, rs6294, ss218178047, rs34118353, rs6449693, and rs878567) were found in 182 healthy volunteers and 161 patients. Among them, two SNP loci had not been reported in the National Center for Biotechnology Information (NCBI) database, promoter locus ss212928868 and exon locus ss218178047, which now have been approved by the NCBI database and assigned rs numbers, rs113195492 and rs112846276, respectively. ss212928868 and rs6294 were statistically different between control and paranoid schizophrenic women (P < 0.05), and both loci were in a state of linkage disequilibrium. However, statistical significance was lost after Bonferroni correction. Compared with the GG genotype, the GA + AA genotype had a decreased disease risk (odds ratio(GA + AA) = 0.3529, 95 % confidence interval = 0.1319-0.9444). The data showed that changes in SNP loci of HTR1A were different between paranoid schizophrenic and control group women. Although such differences were lost after statistical correction, studies with larger sample sizes have not been

  4. CVD 908, CVD 908-htrA, and CVD 909 live oral typhoid vaccines: a logical progression.

    PubMed

    Tacket, Carol O; Levine, Myron M

    2007-07-15

    Typhoid fever remains an important public health problem in many parts of the world. Despite the availability of oral Ty21a (Vivotif; Berna Biotech) and parenteral Vi polysaccharide vaccine (Typhim Vi; Aventis Pasteur), improved typhoid fever vaccines have been sought. These include a series of vaccine candidates developed at the Center for Vaccine Development, University of Maryland, based on attenuation of Salmonella enterica serovar Typhi by deletions in the aroC, aroD, and htrA genes. These vaccine candidates, designated "CVD 908," "CVD 908-htrA," and "CVD 909," have been developed and tested in volunteers with variable success. This review summarizes the clinical data that directed the logical progression of this vaccine development strategy. PMID:17582563

  5. HtrC Is Involved in Proteolysis of YpeB during Germination of Bacillus anthracis and Bacillus subtilis Spores

    PubMed Central

    Bernhards, Casey B.; Chen, Yan; Toutkoushian, Hannah

    2014-01-01

    Bacterial endospores can remain dormant for decades yet can respond to nutrients, germinate, and resume growth within minutes. An essential step in the germination process is degradation of the spore cortex peptidoglycan wall, and the SleB protein in Bacillus species plays a key role in this process. Stable incorporation of SleB into the spore requires the YpeB protein, and some evidence suggests that the two proteins interact within the dormant spore. Early during germination, YpeB is proteolytically processed to a stable fragment. In this work, the primary sites of YpeB cleavage were identified in Bacillus anthracis, and it was shown that the stable products are comprised of the C-terminal domain of YpeB. Modification of the predominant YpeB cleavage sites reduced proteolysis, but cleavage at other sites still resulted in loss of full-length YpeB. A B. anthracis strain lacking the HtrC protease did not generate the same stable YpeB products. In B. anthracis and Bacillus subtilis htrC mutants, YpeB was partially stabilized during germination but was still degraded at a reduced rate by other, unidentified proteases. Purified HtrC cleaved YpeB to a fragment similar to that observed in vivo, and this cleavage was stimulated by Mn2+ or Ca2+ ions. A lack of HtrC did not stabilize YpeB or SleB during spore formation in the absence of the partner protein, indicating other proteases are involved in their degradation during sporulation. PMID:25384476

  6. Significant association between rare IPO11-HTR1A variants and attention deficit hyperactivity disorder in Caucasians.

    PubMed

    Zuo, Lingjun; Saba, Laura; Lin, Xiandong; Tan, Yunlong; Wang, Kesheng; Krystal, John H; Tabakoff, Boris; Luo, Xingguang

    2015-10-01

    We comprehensively examined the rare variants in the IPO11-HTR1A region to explore their roles in neuropsychiatric disorders. Five hundred seventy-three to 1,181 rare SNPs in subjects of European descent and 1,234-2,529 SNPs in subjects of African descent (0 < minor allele frequency (MAF) < 0.05) were analyzed in a total of 49,268 subjects in 21 independent cohorts with 11 different neuropsychiatric disorders. Associations between rare variant constellations and diseases and associations between individual rare variants and diseases were tested. RNA expression changes of this region were also explored. We identified a rare variant constellation across the entire IPO11-HTR1A region that was associated with attention deficit hyperactivity disorder (ADHD) in Caucasians (T5: P = 7.9 × 10(-31) ; Fp: P = 1.3 × 10(-32) ), but not with any other disorder examined; association signals mainly came from IPO11 (T5: P = 3.6 × 10(-10) ; Fp: P = 3.2 × 1 0(-10) ) and the intergenic region between IPO11 and HTR1A (T5: P = 4.1 × 10(-30) ; Fp: P = 5.4 × 10(-32) ). One association between ADHD and an intergenic rare variant, i.e., rs10042956, exhibited region- and cohort-wide significance (P = 5.2 × 10(-6) ) and survived correction for false discovery rate (q = 0.006). Cis-eQTL analysis showed that, 29 among the 41 SNPs within or around IPO11 had replicable significant regulatory effects on IPO11 exon expression (1.5 × 10(-17) ≤P < 0.002) in human brain or peripheral blood mononuclear cell tissues. We concluded that IPO11-HTR1A was a significant risk gene region for ADHD in Caucasians. PMID:26079129

  7. Significant association between rare IPO11-HTR1A variants and attention deficit hyperactivity disorder in Caucasians

    PubMed Central

    Zuo, Lingjun; Saba, Laura; Lin, Xiandong; Tan, Yunlong; Wang, Kesheng; Krystal, John H.; Tabakoff, Boris; Luo, Xingguang

    2016-01-01

    Objective We comprehensively examined the rare variants in the IPO11-HTR1A region to explore their roles in neuropsychiatric disorders. Method Five hundred seventy-three to 1,181 rare SNPs in subjects of European descent and 1,234-2,529 SNPs in subjects of African descent (0 < minor allele frequency (MAF) < 0.05) were analyzed in a total of 49,268 subjects in 21 independent cohorts with 11 different neuropsychiatric disorders. Associations between rare variant constellations and diseases and associations between individual rare variants and diseases were tested. RNA expression changes of this region were also explored. Results We identified a rare variant constellation across the entire IPO11-HTR1A region that was associated with attention deficit hyperactivity disorder (ADHD) in Caucasians (T5: p=7.9×10−31; Fp: p=1.3×10−32), but not with any other disorder examined; association signals mainly came from IPO11 (T5: p=3.6×10−10; Fp: p=3.2×10−10) and the intergenic region between IPO11 and HTR1A (T5: p=4.1×10−30; Fp: p=5.4×10−32). One association between ADHD and an intergenic rare variant, i.e., rs10042956, exhibited region- and cohort-wide significance (p=5.2×10−6) and survived correction for false discovery rate (q=0.006). Cis-eQTL analysis showed that, 29 among the 41 SNPs within or around IPO11 had replicable significant regulatory effects on IPO11 exon expression (1.5×10−17≤p<0.002) in human brain or peripheral blood mononuclear cell tissues. Conclusion We concluded that IPO11-HTR1A was a significant risk gene region for ADHD in Caucasians. PMID:26079129

  8. Evidence for the effect of serotonin receptor 1A gene (HTR1A) polymorphism on tractability in Thoroughbred horses.

    PubMed

    Hori, Y; Tozaki, T; Nambo, Y; Sato, F; Ishimaru, M; Inoue-Murayama, M; Fujita, K

    2016-02-01

    Tractability, or how easily animals can be trained and controlled, is an important behavioural trait for the management and training of domestic animals, but its genetic basis remains unclear. Polymorphisms in the serotonin receptor 1A gene (HTR1A) have been associated with individual variability in anxiety-related traits in several species. In this study, we examined the association between HTR1A polymorphisms and tractability in Thoroughbred horses. We assessed the tractability of 167 one-year-old horses reared at a training centre for racehorses using a questionnaire consisting of 17 items. A principal components analysis of answers contracted the data to five principal component (PC) scores. We genotyped two non-synonymous single nucleotide polymorphisms (SNPs) in the horse HTR1A coding region. We found that one of the two SNPs, c.709G>A, which causes an amino acid change at the intracellular region of the receptor, was significantly associated with scores of four of five PCs in fillies (all Ps < 0.05) and one PC in colts (P < 0.01). Horses carrying an A allele at c.709G>A showed lower tractability. This result provides the first evidence that a polymorphism in a serotonin-related gene may affect tractability in horses with the effect partially different depending on sex. PMID:26763159

  9. Association and CpG SNP analysis of HTR4 polymorphisms with suicidal behavior in subjects with schizophrenia.

    PubMed

    Polsinelli, Gina; Zai, Clement C; Strauss, John; Kennedy, James L; De Luca, Vincenzo

    2013-02-01

    Suicide is a major contributor to the morbidity and mortality rates in schizophrenia. Genetic and epigenetic factors have been reported to modulate the risk for suicide although the precise mechanism and magnitude of these contributions is unknown. Previous research indicates that suicide attempters present abnormalities in the serotonergic system. The present study aimed to identify genetic and epigenetic risk variants of the serotonin 5-HT₄ receptor gene (HTR4) for suicidal behavior. We included 234 subjects diagnosed with schizophrenia. For this purpose, we analyzed 11 markers across HTR4 and performed genotype, haplotype and potential methylation analyses, correcting for clinical covariates and ethnic stratification. Three blocks were revealed from the LD analysis. Haplotypes in Block 3 were significantly associated with suicide attempt. The potential methylation analysis was not significant. Our results suggest that HTR4 polymorphisms may not play a major role in the susceptibility for suicidal behavior in subjects with schizophrenia. Moreover, although not significant, the CpG SNP potential methylation analysis would be informative for future methylation analysis on this gene. PMID:22842674

  10. The autolysis of human HtrA1 is governed by the redox state of its N-terminal domain.

    PubMed

    Risør, Michael W; Poulsen, Ebbe Toftgaard; Thomsen, Line R; Dyrlund, Thomas F; Nielsen, Tania A; Nielsen, Niels Chr; Sanggaard, Kristian W; Enghild, Jan J

    2014-06-17

    Human HtrA1 (high-temperature requirement protein A1) belongs to a conserved family of serine proteases involved in protein quality control and cell fate. The homotrimeric ubiquitously expressed protease has chymotrypsin-like specificity and primarily targets hydrophobic stretches in selected or misfolded substrate proteins. In addition, the enzyme is capable of exerting autolytic activity by removing the N-terminal insulin-like growth factor binding protein (IGFBP)/Kazal-like tandem motif without affecting the protease activity. In this study, we have addressed the mechanism governing the autolytic activity and find that it depends on the integrity of the disulfide bonds in the N-terminal IGFBP/Kazal-like domain. The specificity of the autolytic cleavage reveals a strong preference for cysteine in the P1 position of HtrA1, explaining the lack of autolysis prior to disulfide reduction. Significantly, the disulfides were reduced by thioredoxin, suggesting that autolysis of HtrA1 in vivo is linked to the endogenous redox balance and that the N-terminal domain acts as a redox-sensing switch. PMID:24846539

  11. Up-regulation of lymphocyte antigen 6 complex expression in side-population cells derived from a human trophoblast cell line HTR-8/SVneo.

    PubMed

    Inagaki, Tetsunori; Kusunoki, Soshi; Tabu, Kouichi; Okabe, Hitomi; Yamada, Izumi; Taga, Tetsuya; Matsumoto, Akemi; Makino, Shintaro; Takeda, Satoru; Kato, Kiyoko

    2016-01-01

    The continual proliferation and differentiation of trophoblasts are critical for the maintenance of pregnancy. It is well known that the tissue stem cells are associated with the development of tissues and pathologies. It has been demonstrated that side-population (SP) cells identified by fluorescence-activated cell sorting (FACS) are enriched with stem cells. The SP cells in HTR-8/SVneo cells derived from human primary trophoblast cells were isolated by FACS. HTR-8/SVneo-SP cell cultures generated both SP and non-SP (NSP) subpopulations. In contrast, NSP cell cultures produced NSP cells and failed to produce SP cells. These SP cells showed self-renewal capability by serial colony-forming assay. Microarray expression analysis using a set of HTR-8/SVneo-SP and -NSP cells revealed that SP cells overexpressed several stemness genes including caudal type homeobox2 (CDX2) and bone morphogenic proteins (BMPs), and lymphocyte antigen 6 complex locus D (LY6D) gene was the most highly up-regulated in HTR-8/SVneo-SP cells. LY6D gene reduced its expression in the course of a 7-day cultivation in differentiation medium. SP cells tended to reduce its fraction by treatment of LY6D siRNA indicating that LY6D had potential to maintain cell proliferation of HTR-8/SVneo-SP cells. On ontology analysis, epithelial-mesenchymal transition (EMT) pathway was involved in the up-regulated genes on microarray analysis. HTR-SVneo-SP cells showed enhanced migration. This is the first report that LY6D was important for the maintenance of HTR-8/SVneo-SP cells. EMT was associated with the phenotype of these SP cells. PMID:26223706

  12. Laser-Induced Transient Grating Analysis of Dynamics of Interaction between Sensory Rhodopsin II D75N and the HtrII Transducer

    PubMed Central

    Inoue, Keiichi; Sasaki, Jun; Spudich, John L.; Terazima, Masahide

    2007-01-01

    The interaction between sensory rhodopsin II (SRII) and its transducer HtrII was studied by the time-resolved laser-induced transient grating method using the D75N mutant of SRII, which exhibits minimal visible light absorption changes during its photocycle, but mediates normal phototaxis responses. Flash-induced transient absorption spectra of transducer-free D75N and D75N joined to 120 amino-acid residues of the N-terminal part of the SRII transducer protein HtrII (ΔHtrII) showed only one spectrally distinct K-like intermediate in their photocycles, but the transient grating method resolved four intermediates (K1–K4) distinct in their volumes. D75N bound to HtrII exhibited one additional slower kinetic species, which persists after complete recovery of the initial state as assessed by absorption changes in the UV-visible region. The kinetics indicate a conformationally changed form of the transducer portion (designated Tr*), which persists after the photoreceptor returns to the unphotolyzed state. The largest conformational change in the ΔHtrII portion was found to cause a ΔHtrII-dependent increase in volume rising in 8 μs in the K4 state and a drastic decrease in the diffusion coefficient (D) of K4 relatively to those of the unphotolyzed state and Tr*. The magnitude of the decrease in D indicates a large structural change, presumably in the solvent-exposed HAMP domain of ΔHtrII, where rearrangement of interacting molecules in the solvent would substantially change friction between the protein and the solvent. PMID:17189313

  13. Cloning and sequence analysis of partial genomic DNA coding for HtrA-type serine protease of Wolbachia from human lymphatic filarial parasite, Wuchereria bancrofti

    PubMed Central

    Dhamodharan, R; Hoti, SL; Sivapragasam, G; Das, MK

    2011-01-01

    Background: Periplasmic serine proteases of HtrA type of Wolbachia have been shown to play a role in the pathogenesis of filarial disease. Aims: This study was aimed to sequence Wb-HtrA serine protease and analyze its phylogenetic position by comparing with other filarial and non-filarial nematode homologs. Materials and Methods: Partial HtrA gene fragment was amplified from DNA isolated from periodic and sub-periodic Wuchereria bancrofti parasites collected from Pondicherry and Nicobar islands, respectively. The amplicons were sequenced, and sequence homology and phylogenetic relationship with other filarial and non-filarial nematodes were analyzed. Results: Partial orthologue of HtrA-type serine protease from Wolbachia of W. bancrofti was amplified, cloned and sequenced. The deduced amino acid sequence exhibited 87%, 81% and 74% identity with the homologous Wolbachia proteases identified from Brugia malayi, Onchocerca volvulus and Drosophila melanogaster, respectively. The Wb-HtrA has arthologues in several proteobacteria with very high homology and hence is highly conserved not only among Wolbachia of filarial parasites but also across proteobacteria. The phylogenetic tree constructed using Neighbor-Joining method showed two main clusters: cluster-I containing bacteria that dwell in diverse habitats such as soil, fresh and marine waters and plants and cluster-II comprising Anaplasma sp. and Erlichia, and Wolbachia endosymbionts of insects and nematodes, in distinct groups. Conclusions: HtrA-type serine protease from Wolbachia of W. bancrofti is highly conserved among filarial parasites. It will be of interest to know whether filarial Wolbachia HtrA type of serine protease might influence apoptosis and lymphatic epithelium, thereby playing a role in the filarial pathogenesis. Such information will be useful for identifying targets for the development of newer drugs for filariasis treatment, especially for preventing lymphatic pathology. PMID:23508470

  14. Identification and transcriptional analysis of the Escherichia coli htrE operon which is homologous to pap and related pilin operons.

    PubMed Central

    Raina, S; Missiakas, D; Baird, L; Kumar, S; Georgopoulos, C

    1993-01-01

    We have characterized a new Escherichia coli operon consisting of two genes, ecpD and htrE. The ecpD gene encodes a 27-kDa protein which is 40% identical at the amino acid level to the pilin chaperone PapD family of proteins. Immediately downstream of the ecpD gene is the htrE gene. The htrE gene encodes a polypeptide of 95 kDa which is processed to a 92-kDa mature species. The HtrE protein is 38% identical to the type II pilin porin protein PapC. The ecpD htrE operon is located at 3.3 min on the genetic map, corresponding to the region from kbp 153 to 157 of the E. coli physical map. The htrE gene was identified on the basis of a Tn5 insertion mutation which resulted in a temperature-sensitive growth phenotype above 43.5 degrees C. The transcription of this operon is induced with a temperature shift from 22 to 37 or 42 degrees C but not to higher temperatures, e.g., 50 degrees C. Consistent with this result, the temperature-induced transcription was shown to be independent of the rpoH gene product (sigma 32). The transcription of this operon was further shown to require functional integration host factor protein, since himA or himD mutant bacteria possessed lower levels of ecpD htrE transcripts. Among the three transcriptional start sites discovered, one, defined by the P2 promoter, was found to be under the positive regulation of the katF (rpoS) gene, which encodes a putative sigma factor required for the transcription of many growth phase-regulated genes. Images PMID:8102362

  15. High Temperature Reactor (HTR) Deep Burn Core and Fuel Analysis: Design Selection for the Prismatic Block Reactor With Results from FY-2011 Activities

    SciTech Connect

    Michael A. Pope

    2011-10-01

    The Deep Burn (DB) Project is a U.S. Department of Energy sponsored feasibility study of Transuranic Management using high burnup fuel in the high temperature helium cooled reactor (HTR). The DB Project consists of seven tasks: project management, core and fuel analysis, spent fuel management, fuel cycle integration, TRU fuel modeling, TRU fuel qualification, and HTR fuel recycle. In the Phase II of the Project, we conducted nuclear analysis of TRU destruction/utilization in the HTR prismatic block design (Task 2.1), deep burn fuel/TRISO microanalysis (Task 2.3), and synergy with fast reactors (Task 4.2). The Task 2.1 covers the core physics design, thermo-hydraulic CFD analysis, and the thermofluid and safety analysis (low pressure conduction cooling, LPCC) of the HTR prismatic block design. The Task 2.3 covers the analysis of the structural behavior of TRISO fuel containing TRU at very high burnup level, i.e. exceeding 50% of FIMA. The Task 4.2 includes the self-cleaning HTR based on recycle of HTR-generated TRU in the same HTR. Chapter IV contains the design and analysis results of the 600MWth DB-HTR core physics with the cycle length, the average discharged burnup, heavy metal and plutonium consumptions, radial and axial power distributions, temperature reactivity coefficients. Also, it contains the analysis results of the 450MWth DB-HTR core physics and the analysis of the decay heat of a TRU loaded DB-HTR core. The evaluation of the hot spot fuel temperature of the fuel block in the DB-HTR (Deep-Burn High Temperature Reactor) core under full operating power conditions are described in Chapter V. The investigated designs are the 600MWth and 460MWth DB-HTRs. In Chapter VI, the thermo-fluid and safety of the 600MWth DB-HTRs has been analyzed to investigate a thermal-fluid design performance at the steady state and a passive safety performance during an LPCC event. Chapter VII describes the analysis results of the TRISO fuel microanalysis of the 600MWth and 450

  16. Assignment of the 5HT7 receptor gene (HTR7) to chromosome 10q and exclusion of genetic linkage with Tourette syndrome

    SciTech Connect

    Gelernter, J.; Rao, P.A.; Pauls, D.L.

    1995-03-20

    A novel serotonin receptor designated 5HT7 (genetic locus HTR7) was cloned in 1993. This receptor has interesting properties related to ligand affinity and CNS distribution that render HTR7 a very interesting candidate gene for neuropsychiatric disorders. We mapped this gene, first by physical methods and then by genetic linkage. First, we made a tentative assignment to chromosome 10, based on hybridization of an HTR7 probe to a Southern blot of DNA from somatic cell hybrids. We then identified a genetic polymorphism at the HTR7 locus. We identified one extended pedigree where the polymorphism segregated. Using the LEPED computer program for pairwise linkage analysis, we confirmed the assignment of the gene to chromosome 10, specifically 10q21-q24, based on a lod score of 5.37 at 0% recombination between HTR7 and D10S20 (a chromosome 10 reference marker). Finally, we excluded genetic linkage between this locus and Tourette syndrome under a reasonable set of assumptions. 15 refs., 1 fig., 1 tab.

  17. HtrA, a Temperature- and Stationary Phase-Activated Protease Involved in Maturation of a Key Microbial Virulence Determinant, Facilitates Borrelia burgdorferi Infection in Mammalian Hosts.

    PubMed

    Ye, Meiping; Sharma, Kavita; Thakur, Meghna; Smith, Alexis A; Buyuktanir, Ozlem; Xiang, Xuwu; Yang, Xiuli; Promnares, Kamoltip; Lou, Yongliang; Yang, X Frank; Pal, Utpal

    2016-08-01

    High-temperature requirement protease A (HtrA) represents a family of serine proteases that play important roles in microbial biology. Unlike the genomes of most organisms, that of Borrelia burgdorferi notably encodes a single HtrA gene product, termed BbHtrA. Previous studies identified a few substrates of BbHtrA; however, their physiological relevance could not be ascertained, as targeted deletion of the gene has not been successful. Here we show that BbhtrA transcripts are induced during spirochete growth either in the stationary phase or at elevated temperature. Successful generation of a BbhtrA deletion mutant and restoration by genetic complementation suggest a nonessential role for this protease in microbial viability; however, its remarkable growth, morphological, and structural defects during cultivation at 37°C confirm a high-temperature requirement for protease activation and function. The BbhtrA-deficient spirochetes were unable to establish infection of mice, as evidenced by assessment of culture, PCR, and serology. We show that transcript abundance as well as proteolytic processing of a borrelial protein required for cell fission and infectivity, BB0323, is impaired in BbhtrA mutants grown at 37°C, which likely contributed to their inability to survive in a mammalian host. Together, these results demonstrate the physiological relevance of a unique temperature-regulated borrelial protease, BbHtrA, which further enlightens our knowledge of intriguing aspects of spirochete biology and infectivity. PMID:27271745

  18. the active site residue V266 of Chlamydial HtrA is critical for substrate binding during both in vitro and in vivo conditions.

    PubMed

    Gloeckl, Sarina; Tyndall, Joel D A; Stansfield, Scott H; Timms, Peter; Huston, Wilhelmina M

    2012-01-01

    HtrA is a complex, multimeric chaperone and serine protease important for the virulence and survival of many bacteria. Chlamydia trachomatis is an obligate, intracellular bacterial pathogen that is responsible for severe disease pathology. C. trachomatis HtrA (CtHtrA) has been shown to be highly expressed in laboratory models of disease. In this study, molecular modelling of CtHtrA protein active site structure identified putative S1-S3 subsite residues I242, I265, and V266. These residues were altered by site-directed mutagenesis, and these changes were shown to considerably reduce protease activity on known substrates and resulted in a narrower and distinct range of substrates compared to wild type. Bacterial two-hybrid analysis revealed that CtHtrA is able to interact in vivo with a broad range of protein sequences with high affinity. Notably, however, the interaction was significantly altered in 35 out of 69 clones when residue V266 was mutated, indicating that this residue has an important function during substrate binding. PMID:22353774

  19. HtrA2/Omi Terminates Cytomegalovirus Infection and Is Controlled by the Viral Mitochondrial Inhibitor of Apoptosis (vMIA)

    PubMed Central

    McCormick, A. Louise; Roback, Linda; Mocarski, Edward S.

    2008-01-01

    Viruses encode suppressors of cell death to block intrinsic and extrinsic host-initiated death pathways that reduce viral yield as well as control the termination of infection. Cytomegalovirus (CMV) infection terminates by a caspase-independent cell fragmentation process after an extended period of continuous virus production. The viral mitochondria-localized inhibitor of apoptosis (vMIA; a product of the UL37x1 gene) controls this fragmentation process. UL37x1 mutant virus-infected cells fragment three to four days earlier than cells infected with wt virus. Here, we demonstrate that infected cell death is dependent on serine proteases. We identify mitochondrial serine protease HtrA2/Omi as the initiator of this caspase-independent death pathway. Infected fibroblasts develop susceptibility to death as levels of mitochondria-resident HtrA2/Omi protease increase. Cell death is suppressed by the serine protease inhibitor TLCK as well as by the HtrA2-specific inhibitor UCF-101. Experimental overexpression of HtrA2/Omi, but not a catalytic site mutant of the enzyme, sensitizes infected cells to death that can be blocked by vMIA or protease inhibitors. Uninfected cells are completely resistant to HtrA2/Omi induced death. Thus, in addition to suppression of apoptosis and autophagy, vMIA naturally controls a novel serine protease-dependent CMV-infected cell-specific programmed cell death (cmvPCD) pathway that terminates the CMV replication cycle. PMID:18769594

  20. The interaction between PmHtrA2 and PmIAP and its effect on the activity of Pm caspase.

    PubMed

    Saleeart, Anchulee; Mongkorntanyatip, Karntichar; Sangsuriya, Pakkakul; Senapin, Saengchan; Rattanarojpong, Triwit; Khunrae, Pongsak

    2016-08-01

    Apoptosis is an essential mechanism in multicellular organisms which results in the induction of cell death. Important apoptotic proteins, including high temperature requirement A2 (PmHtrA2; also known as serine protease), inhibitor of apoptosis protein (PmIAP) and Pm caspase, have been previously identified in black tiger shrimp, Penaeus monodon. However, the relevance among these proteins in apoptosis regulation has not been established yet in shrimp. Here, we showed that PmHtrA2 was able to interact with PmIAP and the binding of the two proteins was mediated by the BIR2 domain of PmIAP. In addition, the BIR2 of PmIAP was shown to be able to inhibit Pm caspase activity. The inhibitory effect of the BIR2 domain on Pm caspase was impaired under the presence of the IBM peptide of PmHtrA2, implying a role for PmHtrA2 in apoptosis activation. Our combined results suggested that P. monodon possesses a conserved mechanism by which the caspase-3 activity is modulated by HtrA2 and IAP, as previously seen in insects and mammals. PMID:27328308

  1. Polar studies of the sphericity degree of V/HTR nuclear fuel particles

    SciTech Connect

    Robert-Inacio, F. . E-mail: frederique.robert@isen.fr; Boschet, C.; Charollais, F.

    2006-06-15

    Advanced nuclear power reactor designs such as (Very) High Temperature Reactors (V/HTR) employ TRISO fuel particles that typically have a sub-millimetre U-based fuel kernel coated with three isotropic ceramic layers-a layer of silicon carbide sandwiched between pyrocarbon layers of different density. Evaluation of the ceramic layer thickness and of the degree of sphericity of these typical nuclear fuel particles is required at each step of the fabrication, in order to estimate future fuel performance under irradiation conditions. This study is based on the image processing of polished cross-sections, realized near the equatorial plane. From these 2D images, some measurements are carried out, giving an estimation of the diameter values for a sample of particles at each step of the coating process. These values are then statistically extended to the third dimension in order to obtain the thickness of each layer and the degree of sphericity of each particle. A representation of diameter and layer thickness in polar coordinates enables one to identify steps for which the coating process is defective or deviating from nominal objectives.

  2. Temperature modeling for analysis and design of the sintering furnance in HTR fuel type of ball

    SciTech Connect

    Saragi, Elfrida; Setiadji, Moch

    2013-09-09

    One of the factors that determine the safety of the operation of the sintering furnace fuel HTR ball is the temperature distribution in the ceramic tube furnace. The temperature distribution must be determined at design stage. The tube has a temperature of 1600 °C at one end and about 40 °C at the other end. The outside of the tube was cooled by air through natural convection. The tube is a furnace ceramic tube which its geometry are 0.08, 0.09 and 0.5 m correspondingly for the inner tube diameter, outer tube diameter and tube length. The temperature distribution of the tube is determined by the natural convection coefficient (NCF), which is difficult to be calculated manually. The determination of NCF includes the Grasshoff, Prandtl, and Nusselt numbers which is a function of the temperature difference between the surrounding air with the ceramic tube. If the temperature vary along the tube, the complexity of the calculations increases. Thus the proposed modeling was performed to determine the temperature distribution along the tube and heat transfer coefficient using a self-developed software which permit the design process easier.

  3. Influence of HTR core inlet and outlet temperatures on hydrogen generation efficiency using the sulfur-iodine water-splitting cycle

    SciTech Connect

    Buckingham, Robert; Brown, Lloyd; Russ, Ben; Lovera, Patrick; Carles, Philippe; Borgard, Jean-Marc; Yvon, Pascal

    2012-04-15

    The performance of hydrogen production via thermochemical cycles is typically evaluated using thermal efficiency. In this study, the sulfur-iodine cycle with heat supplied by a high-temperature reactor (HTR) is analyzed. Two cases are examined: one flow sheet designed by General Atomics in the United States, the other by Commissariat a l'energie atomique et aux energies alternatives in France. In each case, HTR helium inlet and outlet temperatures are specified. Differences in these temperature specifications lead to process variations between the limy sheets and in how the hydrogen processes interface with the nuclear heat source. Two principal conclusions result from the analysis. First, the thermal efficiency tends to plateau above a certain outlet helium temperature. This is a characteristic effect of the method of Ozturk et al. for sulfuric acid decomposition. Second, it is clear that it is impractical to discuss efficiencies for the hydrogen process that are independent of defined operating parameters of the HTR. (authors)

  4. ADAM19 and HTR4 Variants and Pulmonary Function: The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study

    PubMed Central

    London, Stephanie J.; Gao, Wei; Gharib, Sina A.; Hancock, Dana B.; Wilk, Jemma B.; House, John S.; Gibbs, Richard A.; Muzny, Donna M.; Lumley, Thomas; Franceschini, Nora; North, Kari E.; Psaty, Bruce M.; Kovar, Christie L.; Coresh, Josef; Zhou, Yanhua; Heckbert, Susan R.; Brody, Jennifer A.; Morrison, Alanna C.; Dupuis, Josée

    2014-01-01

    Background The pulmonary function measures of forced expiratory volume in one second (FEV1) and its ratio to forced vital capacity (FVC) are used in the diagnosis and monitoring of lung diseases and predict cardiovascular mortality in the general population. Genome wide association studies (GWAS) have identified numerous loci associated with FEV1 and FEV1/FVC but the causal variants remain uncertain. We hypothesized that novel or rare variants poorly tagged by GWAS may explain the significant associations between FEV1/FVC and two genes: ADAM19 and HTR4. Methods and Results We sequenced ADAM19 and its promoter region along with the approximately 21 kb portion of HTR4 harboring GWAS SNPs for pulmonary function and analyzed associations with FEV1/FVC among 3,983 participants of European ancestry from Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE). Meta-analysis of common variants in each region identified statistically significant associations (316 tests, P < 1.58×10−4) with FEV1/FVC for 14 ADAM19 SNPs and 24 HTR4 SNPs. After conditioning on the sentinel GWAS hit in each gene [ADAM19 rs1422795, minor allele frequency (MAF)=0.33 and HTR4 rs11168048, MAF=0.40] one SNP remained statistically significant (ADAM19 rs13155908, MAF = 0.12, P = 1.56×10−4). Analysis of rare variants (MAF < 1%) using Sequence Kernel Association Test did not identify associations with either region. Conclusions Sequencing identified one common variant associated with FEV1/FVC independently of the sentinel ADAM19 GWAS hit and supports the original HTR4 GWAS findings. Rare variants do not appear to underlie GWAS associations with pulmonary function for common variants in ADAM19 and HTR4. PMID:24951661

  5. HTR3B is associated with alcoholism with antisocial behavior and alpha EEG power—an intermediate phenotype for alcoholism and co-morbid behaviors

    PubMed Central

    Ducci, Francesca; Enoch, Mary-Anne; Yuan, Qiaoping; Shen, Pei-Hong; White, Kenneth V.; Hodgkinson, Colin; Albaugh, Bernard; Virkkunen, Matti; Goldman, David

    2009-01-01

    Alcohol use disorders (AUD) with co-morbid antisocial personality disorder (ASPD) have been associated with serotonin (5-HT) dysfunction. 5-HT3 receptors are potentiated by ethanol and appear to modulate reward. 5-HT3 receptor antagonists may be useful in the treatment of early-onset alcoholics with co-morbid ASPD. Low-voltage alpha electroencephalogram (EEG) power, a highly heritable trait, has been associated with both AUD and ASPD. A recent whole genome linkage scan in one of our samples, Plains American Indians (PI), has shown a suggestive linkage peak for alpha power at the 5-HT3R locus. We tested whether genetic variation within the HTR3A and HTR3B genes influences vulnerability to AUD with comorbid ASPD (AUD + ASPD) and moderates alpha power. Our study included three samples: 284 criminal alcoholic Finnish Caucasians and 234 controls; two independent community-ascertained samples with resting EEG recordings: a predominantly Caucasian sample of 191 individuals (Bethesda) and 306 PI. In the Finns, an intronic HTR3B SNP rs3782025 was associated with AUD + ASPD (P = .004). In the Bethesda sample, the same allele predicted lower alpha power (P = 7.37e-5). Associations between alpha power and two other HTR3B SNPs were also observed among PI (P = .03). One haplotype in the haplotype block at the 3′ region of the gene that included rs3782025 was associated with AUD + ASPD in the Finns (P = .02) and with reduced alpha power in the Bethesda population (P = .00009). Another haplotype in this block was associated with alpha power among PI (P = .03). No associations were found for HTR3A. Genetic variation within HTR3B may influence vulnerability to develop AUD with comorbid ASPD. 5-HT3R might contribute to the imbalance between excitation and inhibition that characterize the brain of alcoholics. PMID:19185213

  6. HTR3B is associated with alcoholism with antisocial behavior and alpha EEG power--an intermediate phenotype for alcoholism and co-morbid behaviors.

    PubMed

    Ducci, Francesca; Enoch, Mary-Anne; Yuan, Qiaoping; Shen, Pei-Hong; White, Kenneth V; Hodgkinson, Colin; Albaugh, Bernard; Virkkunen, Matti; Goldman, David

    2009-02-01

    Alcohol use disorders (AUD) with co-morbid antisocial personality disorder (ASPD) have been associated with serotonin (5-HT) dysfunction. 5-HT3 receptors are potentiated by ethanol and appear to modulate reward. 5-HT3 receptor antagonists may be useful in the treatment of early-onset alcoholics with co-morbid ASPD. Low-voltage alpha electroencephalogram (EEG) power, a highly heritable trait, has been associated with both AUD and ASPD. A recent whole genome linkage scan in one of our samples, Plains American Indians (PI), has shown a suggestive linkage peak for alpha power at the 5-HT3R locus. We tested whether genetic variation within the HTR3A and HTR3B genes influences vulnerability to AUD with comorbid ASPD (AUD+ASPD) and moderates alpha power. Our study included three samples: 284 criminal alcoholic Finnish Caucasians and 234 controls; two independent community-ascertained samples with resting EEG recordings: a predominantly Caucasian sample of 191 individuals (Bethesda) and 306 PI. In the Finns, an intronic HTR3B SNP rs3782025 was associated with AUD+ASPD (P=.004). In the Bethesda sample, the same allele predicted lower alpha power (P=7.37e(-5)). Associations between alpha power and two other HTR3B SNPs were also observed among PI (P=.03). One haplotype in the haplotype block at the 3' region of the gene that included rs3782025 was associated with AUD+ASPD in the Finns (P=.02) and with reduced alpha power in the Bethesda population (P=.00009). Another haplotype in this block was associated with alpha power among PI (P=.03). No associations were found for HTR3A. Genetic variation within HTR3B may influence vulnerability to develop AUD with comorbid ASPD. 5-HT3R might contribute to the imbalance between excitation and inhibition that characterize the brain of alcoholics. PMID:19185213

  7. THAP5 is a human cardiac-specific inhibitor of cell cycle that is cleaved by the proapoptotic Omi/HtrA2 protease during cell death.

    PubMed

    Balakrishnan, Meenakshi P; Cilenti, Lucia; Mashak, Zineb; Popat, Paiyal; Alnemri, Emad S; Zervos, Antonis S

    2009-08-01

    Omi/HtrA2 is a mitochondrial serine protease that has a dual function: while confined in the mitochondria, it promotes cell survival, but when released into the cytoplasm, it participates in caspase-dependent as well as caspase-independent cell death. To investigate the mechanism of Omi/HtrA2's function, we set out to isolate and characterize novel substrates for this protease. We have identified Thanatos-associated protein 5 (THAP5) as a specific interactor and substrate of Omi/HtrA2 in cells undergoing apoptosis. This protein is an uncharacterized member of the THAP family of proteins. THAP5 has a unique pattern of expression and is found predominantly in the human heart, although a very low expression is also seen in the human brain and muscle. THAP5 protein is localized in the nucleus and, when ectopically expressed, induces cell cycle arrest. During apoptosis, THAP5 protein is degraded, and this process can be blocked using a specific Omi/HtrA2 inhibitor, leading to reduced cell death. In patients with coronary artery disease, THAP5 protein levels substantially decrease in the myocardial infarction area, suggesting a potential role of this protein in human heart disease. This work identifies human THAP5 as a cardiac-specific nuclear protein that controls cell cycle progression. Furthermore, during apoptosis, THAP5 is cleaved and removed by the proapoptotic Omi/HtrA2 protease. Taken together, we provide evidence to support that THAP5 and its regulation by Omi/HtrA2 provide a new link between cell cycle control and apoptosis in cardiomyocytes. PMID:19502560

  8. QUANTITATIVE HOMOGENEITY AND IN-CONTACT PARTICLES OF HIGH TEMPERATURE REACTORS (HTR) COMPACTS DETERMINATION VIA X-RAY TOMOGRAPHY

    SciTech Connect

    Lecomte, G.; Letang, J. M.; Tisseur, D.; Banchet, J.; Vitali, M. P.

    2008-02-28

    In AREVA Nuclear Power's High Temperature Reactor (HTR) design called ANTARES, fuel consists of compacts composed of few thousands millimetric quasi-spherical particles dispersed in a graphite matrix. Compact homogeneity, defined as the homogeneous particles spatial distribution in the matrix, as well as the possibility of obtaining particles in contact, need to be assessed since they condition the thermo-mechanical behavior of the nuclear fuel under irradiation. In this paper, image and data processing algorithms are developed to do so, based on X-Ray tomographic images.

  9. Quantitative Homogeneity and In-Contact Particles of High Temperature Reactors (htr) Compacts Determination via X-Ray Tomography

    NASA Astrophysics Data System (ADS)

    Lecomte, G.; Tisseur, D.; Létang, J. M.; Banchet, J.; Vitali, M. P.

    2008-02-01

    In AREVA Nuclear Power's High Temperature Reactor (HTR) design called ANTARES, fuel consists of compacts composed of few thousands millimetric quasi-spherical particles dispersed in a graphite matrix. Compact homogeneity, defined as the homogeneous particles spatial distribution in the matrix, as well as the possibility of obtaining particles in contact, need to be assessed since they condition the thermo-mechanical behavior of the nuclear fuel under irradiation. In this paper, image and data processing algorithms are developed to do so, based on X-Ray tomographic images.

  10. Innovative non-destructive evaluation methods on HTR fuel at AREVA NP: towards a 100% non invasive control strategy

    SciTech Connect

    Banchet, J.; Tisseur, D.; Hermosilla Lara, S.; Piriou, M.; Bargain, R.; Guillermier, P.

    2007-07-01

    High Temperature Reactor (HTR) fuel consists in millimetric multilayered particles called TRISO, embedded, depending on the reactor design, in a pebble or cylinder-shaped graphite matrix called compact. Particles are typically composed of a 500 {mu}m fissile material kernel, a 95 {mu}m porous carbon layer called buffer, a 40 {mu}m dense pyrolytic carbon layer, a 35 {mu}m silicon carbide layer and another 40 {mu}m dense pyrolytic carbon layer. In order to ensure fuel qualification, as well as reactor safety, particles and compacts need to satisfy specifications concerning their physical characteristics and their integrity. In particular, geometrical parameters such as particle diameter and sphericity as well as layers thickness, but also layers density and the absence of structural defects such as cracks or de-cohesions need to be detected and characterized. In the past, a huge R and D work was carried out to build a TRISO particle characterization quality control plan, mainly based on particle sampling as well as destructive characterization methods. However, since then, development of industrial non-destructive evaluation techniques and devices contributed to envisage not only a non invasive control of HTR fuel, but also a 100% production control strategy. Since 2004, AREVA NP is engaged in a R and D program aiming at the development of innovative industrial nondestructive evaluation methods for HTR fuel. After investigating a number of potential techniques, some of them were selected based on their performances and/or their industrial potential. In particular, development has been carried out on high resolution X-Ray imaging allowing accurate layer thickness, layer density and structural defects characterization, X-Ray tomography offering the possibility to characterize fuel element homogeneity and determine the number of in-contact particles contained in a fuel element, infrared thermal imaging (ITI) allowing cracks detection, eddy currents (EC) enabling

  11. AGR-2: The first irradiation of French HTR fuel in Advanced Test Reactor

    SciTech Connect

    T. Lambert; B. Grover; P. Guillermier; D. Moulinier; F. Imbault Huart

    2012-10-01

    AGR-2, the second irradiation of the US program for qualification of the NGNP fuel, is open to international participation within the scope of the Generation IV International Forum. In this frame, it includes in its multi-capsule irradiation rig an irradiation of French HTR fuel manufactured in the CAPRI line (GAIA facility at CEA/Cadarache and AREVA/CERCA compacting line at Romans). The AGR-2 irradiation is designed to place our first fabrications of HTR particles under operating conditions that are representative of ANTARES project while keeping close to the test range of the German fuel as much as possible, which is the reference in terms of irradiation behavior. A few batches of particles and 12 fuel compacts were produced and characterized in 2009 by CEA and CERCA. The fuel main characteristics are in conformity with our specifications and in compliance with INL requirements. The AGR-2 experiment is based on the design and devices used in the first experiment of the AGR program. The design makes it possible to monitor the irradiation conditions and in particular, the temperature, the power and the fission products released from fuel particles. The in pile equipment consists of a multi-capsule device designed to simultaneously irradiate six independent capsules with temperature control. The out-of-core part consists of the equipment for actively controlling temperature and measuring the fission products release on-line. The target conditions for the irradiation experiment were defined with the aim of comparing the results obtained under irradiation with German particles along with the objectives of reaching burn-up and fluence targets to validate the behavior of our fuel in a significant range (15% FIMA – 5 × 1025 n/m2 at 600 EFPD with centerline fuel temperature about 1100 degrees C). These conditions have to be representative of ANTARES project characteristics. These target conditions were compared with final results from neutron and thermal design studies

  12. Emotion moderates the association between HTR2A (rs6313) genotype and antisaccade latency.

    PubMed

    Mills, Mark; Wieda, Olivia; Stoltenberg, Scott F; Dodd, Michael D

    2016-09-01

    The serotonin system is heavily involved in cognitive and emotional control processes. Previous work has typically investigated this system's role in control processes separately for cognitive and emotional domains, yet it has become clear the two are linked. The present study, therefore, examined whether variation in a serotonin receptor gene (HTR2A, rs6313) moderated effects of emotion on inhibitory control. An emotional antisaccade task was used in which participants looked toward (prosaccade) or away (antisaccade) from a target presented to the left or right of a happy, angry, or neutral face. Overall, antisaccade latencies were slower for rs6313 C allele homozygotes than T allele carriers, with no effect of genotype on prosaccade latencies. Thus, C allele homozygotes showed relatively weak inhibitory control but intact reflexive control. Importantly, the emotional stimulus was either present during target presentation (overlap trials) or absent (gap trials). The gap effect (slowed latency in overlap versus gap trials) in antisaccade trials was larger with angry versus neutral faces in C allele homozygotes. This impairing effect of negative valence on inhibitory control was larger in C allele homozygotes than T allele carriers, suggesting that angry faces disrupted/competed with the control processes needed to generate an antisaccade to a greater degree in these individuals. The genotype difference in the negative valence effect on antisaccade latency was attenuated when trial N-1 was an antisaccade, indicating top-down regulation of emotional influence. This effect was reduced in C/C versus T/_ individuals, suggesting a weaker capacity to downregulate emotional processing of task-irrelevant stimuli. PMID:27161551

  13. HTR2 Receptors in a Songbird Premotor Cortical-Like Area Modulate Spectral Characteristics of Zebra Finch Song

    PubMed Central

    Wood, William E.; Roseberry, Thomas K.; Perkel, David J.

    2013-01-01

    Serotonin [5-hydroxytryptamine (5-HT)] is involved in modulating an array of complex behaviors including learning, depression, and circadian rhythms. Additionally, HTR2 receptors on layer V pyramidal neurons are thought to mediate the actions of psychedelic drugs; the native function of these receptors at this site, however, remains unknown. Previously, we found that activation of HTR2 receptors in the zebra finch forebrain song premotor structure the robust nucleus of the arcopallium (RA) led to increased excitation, and that endogenous 5-HT could roughly double spontaneous firing rate. Here, using in vivo single-unit recordings, we found that direct application of 5-HT to these same RA projection neurons, which are analogous to layer V cortical pyramidal neurons, caused a significant increase in the number of action potentials per song-related burst, and a dramatic decrease in signal-to-noise ratio. Injection of the serotonergic neurotoxin 5,7-dihydroxytryptamine into the third ventricle greatly reduced telencephalic 5-HT and resulted in decreased fundamental frequency of harmonic syllables as well as increased goodness of pitch. Both of these results can be explained by the observed actions of 5-HT on RA projection neurons, and both effects recovered to baseline within 2 weeks following the toxin injection. These results show that 5-HT is involved in modulating spectral properties of song, likely via effects on RA projection neurons, but that adult zebra finches can partially compensate for this deficit within 7 d. PMID:23407949

  14. Hyperactivity in Childhood as a Predictor of School Performance in Elementary School: Modifying Effect of a Serotonin Receptor Gene (5-HTR2A)

    ERIC Educational Resources Information Center

    Pulkki-Raback, Laura; Pullmann, Helle; Hintsanen, Mirka; Alatupa, Saija; Ravaja, Niklas; Lehtimaki, Terho; Keltikangas-jarvinen, Liisa

    2010-01-01

    Introduction: Genes have been suggested to interact with predictors of school performance, but evidence is scarce. The purpose was to examine whether a hyperactive temperament leads to different school performance, depending on variability in a serotonin receptor gene (5-HTR2A). Method: The participants were a population-based sample of 909 girls…

  15. Serotonin genes and attention deficit/hyperactivity disorder in a Brazilian sample: preferential transmission of the HTR2A 452His allele to affected boys.

    PubMed

    Guimarães, Ana Paula M; Zeni, Cristian; Polanczyk, Guilherme V; Genro, Julia P; Roman, Tatiana; Rohde, Luis A; Hutz, Mara H

    2007-01-01

    Attention-deficit hyperactivity disorder (ADHD) is one of the most common psychiatric disorders of childhood. The role of genetic factors in its etiology is strongly supported by family, adoption, and twin studies. Low serotonin activity has been associated in both animal and human studies with measures of impulsivity, aggression, and disinhibited behaviors, which make genes from the serotonin system reasonable candidates for ADHD susceptibility. In the present study, we investigated a polymorphism in the promoter region of the serotonin transporter (SLC6A4) and two polymorphisms (-1438 A > G and His452Tyr) in the serotonin 5-HTR2A receptor gene using family based association analyses in a sample of 243 Brazilian ADHD children and adolescents and their parents. No linkage disequilibrium between the two HTR2A polymorphisms was detected in this sample (P = 0.76). Considering several evidences from animal models for sexual dimorphism in serotonin genes expression, analyses were performed separately for the whole sample and for male probands. No evidences for biased transmissions of both HTR2A -1438 A > G and SLC6A4 polymorphisms to ADHD youths were observed. Preferential transmission of the HTR2A His452 allele was observed only in families with affected boys (P = 0.04). Our results suggest that findings from ADHD association studies for serotonin genes might be understood in the context of a gender effect, which may help to explain conflicting results in these association studies. PMID:16958038

  16. Age-Related Macular Degeneration-Associated Silent Polymorphisms in HtrA1 Impair Its Ability To Antagonize Insulin-Like Growth Factor 1

    PubMed Central

    Jacobo, Sarah Melissa P.; DeAngelis, Margaret M.; Kim, Ivana K.

    2013-01-01

    Synonymous single nucleotide polymorphisms (SNPs) within a transcript's coding region produce no change in the amino acid sequence of the protein product and are therefore intuitively assumed to have a neutral effect on protein function. We report that two common variants of high-temperature requirement A1 (HTRA1) that increase the inherited risk of neovascular age-related macular degeneration (NvAMD) harbor synonymous SNPs within exon 1 of HTRA1 that convert common codons for Ala34 and Gly36 to less frequently used codons. The frequent-to-rare codon conversion reduced the mRNA translation rate and appeared to compromise HtrA1's conformation and function. The protein product generated from the SNP-containing cDNA displayed enhanced susceptibility to proteolysis and a reduced affinity for an anti-HtrA1 antibody. The NvAMD-associated synonymous polymorphisms lie within HtrA1's putative insulin-like growth factor 1 (IGF-1) binding domain. They reduced HtrA1's abilities to associate with IGF-1 and to ameliorate IGF-1-stimulated signaling events and cellular responses. These observations highlight the relevance of synonymous codon usage to protein function and implicate homeostatic protein quality control mechanisms that may go awry in NvAMD. PMID:23478260

  17. Detektion von fahrspuren und kreuzungen auf nichtmarkierten straen zum autonomen führen von fahrzeugen

    NASA Astrophysics Data System (ADS)

    Vacek, Stefan; Bürkle, Cornelius; Schröder, Joachim; Dillmann, Rüdiger

    Das Wissen über Position und Verlauf der Straße ist eine der wichtigsten Informationen, die zum Führen autonomer Straßenfahrzeuge benötigt wird. Die meisten Arbeiten gehen davon aus, dass Markierungen auf der Straße vorhanden sind, die die Erkennung enorm erleichtern. Üblicherweise werden die Fahrbahnränder detektiert und die Fahrspur mit Hilfe eines Kaiman-Filters geschätzt [1]. Andere Arbeiten verwenden zusätzlich die Straßenfarbe und kombinieren die verschiedenen Hinweise in einem Partikel-Filter [2]. Ein allgemeiner Überblick über Verfahren zur Fahrspurdetektion findet sich in [3].

  18. HTR-PROTEUS PEBBLE BED EXPERIMENTAL PROGRAM CORES 9 & 10: COLUMNAR HEXAGONAL POINT-ON-POINT PACKING WITH A 1:1 MODERATOR-TO-FUEL PEBBLE RATIO

    SciTech Connect

    John D. Bess

    2013-03-01

    PROTEUS is a zero-power research reactor based on a cylindrical graphite annulus with a central cylindrical cavity. The graphite annulus remains basically the same for all experimental programs, but the contents of the central cavity are changed according to the type of reactor being investigated. Through most of its service history, PROTEUS has represented light-water reactors, but from 1992 to 1996 PROTEUS was configured as a pebble-bed reactor (PBR) critical facility and designated as HTR-PROTEUS. The nomenclature was used to indicate that this series consisted of High Temperature Reactor experiments performed in the PROTEUS assembly. During this period, seventeen critical configurations were assembled and various reactor physics experiments were conducted. These experiments included measurements of criticality, differential and integral control rod and safety rod worths, kinetics, reaction rates, water ingress effects, and small sample reactivity effects (Ref. 3). HTR-PROTEUS was constructed, and the experimental program was conducted, for the purpose of providing experimental benchmark data for assessment of reactor physics computer codes. Considerable effort was devoted to benchmark calculations as a part of the HTR-PROTEUS program. References 1 and 2 provide detailed data for use in constructing models for codes to be assessed. Reference 3 is a comprehensive summary of the HTR-PROTEUS experiments and the associated benchmark program. This document draws freely from these references. Only Cores 9 and 10 are evaluated in this benchmark report due to similarities in their construction. The other core configurations of the HTR-PROTEUS program are evaluated in their respective reports as outlined in Section 1.0. Cores 9 and 10 were evaluated and determined to be acceptable benchmark experiments.

  19. HTR-PROTEUS PEBBLE BED EXPERIMENTAL PROGRAM CORES 9 & 10: COLUMNAR HEXAGONAL POINT-ON-POINT PACKING WITH A 1:1 MODERATOR-TO-FUEL PEBBLE RATIO

    SciTech Connect

    John D. Bess

    2014-03-01

    PROTEUS is a zero-power research reactor based on a cylindrical graphite annulus with a central cylindrical cavity. The graphite annulus remains basically the same for all experimental programs, but the contents of the central cavity are changed according to the type of reactor being investigated. Through most of its service history, PROTEUS has represented light-water reactors, but from 1992 to 1996 PROTEUS was configured as a pebble-bed reactor (PBR) critical facility and designated as HTR-PROTEUS. The nomenclature was used to indicate that this series consisted of High Temperature Reactor experiments performed in the PROTEUS assembly. During this period, seventeen critical configurations were assembled and various reactor physics experiments were conducted. These experiments included measurements of criticality, differential and integral control rod and safety rod worths, kinetics, reaction rates, water ingress effects, and small sample reactivity effects (Ref. 3). HTR-PROTEUS was constructed, and the experimental program was conducted, for the purpose of providing experimental benchmark data for assessment of reactor physics computer codes. Considerable effort was devoted to benchmark calculations as a part of the HTR-PROTEUS program. References 1 and 2 provide detailed data for use in constructing models for codes to be assessed. Reference 3 is a comprehensive summary of the HTR-PROTEUS experiments and the associated benchmark program. This document draws freely from these references. Only Cores 9 and 10 are evaluated in this benchmark report due to similarities in their construction. The other core configurations of the HTR-PROTEUS program are evaluated in their respective reports as outlined in Section 1.0. Cores 9 and 10 were evaluated and determined to be acceptable benchmark experiments.

  20. Acute Necrotizing Pancreatitis Following Olanzapine Treatment and 759C/T Polymorphism of HTR2C Gene: A Case Report.

    PubMed

    Rizos, Emmanouil; Tournikioti, Kalliopi; Alevyzakis, Evangelos; Peppa, Melpomeni; Papazaxos, Konstantinos; Zorbas, Georgios; Michopoulos, Ioannis; Liappas, Ioannis; Papageorgiou, Charalampos; Douzenis, Athanasios

    2015-01-01

    Acute pancreatitis can be attributed to numerous potential causes, such as alcohol abuse, chololithiasis, infection, lesions, tumors, hypercalcemia, hyperlipidemia, and medications. Among psychotropic medications, the use of some atypical antipsychotics, such as clozapine, olanzapine, quetiapine and risperidone, has been implicated in the development of acute pancreatitis, although the underlying mechanism has not been clarified. We describe the case of a young man with no other major medical problems, alcohol abuse or predisposing factors, who developed acute necrotizing pancreatitis following olanzapine administration, possibly through severe elevation of serum triglycerides. A pharmacogenomic analysis revealed the presence of the 5-hydroxytryptamine (serotonin) receptor 2C, G protein-coupled (HTR2C) -759C genotype which is related to increased risk for metabolic syndrome. PMID:26359410

  1. Final Report on Utilization of TRU TRISO Fuel as Applied to HTR Systems Part I: Pebble Bed Reactors

    SciTech Connect

    Brian Boer; Abderrafi M. Ougouag

    2011-03-01

    significant failure is to be expected for the reference fuel particle during normal operation. It was found, however, that the sensitivity of the coating stress to the CO production in the kernel was large. The CO production is expected to be higher in DB fuel than in UO2 fuel, but its exact level has a high uncertainty. Furthermore, in the fuel performance analysis transient conditions were not yet taken into account. The effort of this task in FY 2010 has focused on the optimization of the core to maximize the pebble discharge burnup level, while retaining its inherent safety characteristics. Using generic pebble bed reactor cores, this task will perform physics calculations to evaluate the capabilities of the pebble bed reactor to perform utilization and destruction of LWR used-fuel transuranics. The task will use established benchmarked models, and will introduce modeling advancements appropriate to the nature of the fuel considered (high transuranic [TRU] content and high burn-up). Accomplishments of this work include: •Core analysis of a HTR-MODULE design loaded with Deep-Burn fuel. •Core analysis of a HTR-MODULE design loaded with Deep-Burn fuel and Uranium. •Core analysis of a HTR-MODULE design loaded with Deep-Burn fuel and Modified Open Cycle Components. •Core analysis of a HTR-MODULE design loaded with Deep-Burn fuel and Americium targets.

  2. Comparison of Homogeneous and Heterogeneous CFD Fuel Models for Phase I of the IAEA CRP on HTR Uncertainties Benchmark

    SciTech Connect

    Gerhard Strydom; Su-Jong Yoon

    2014-04-01

    Computational Fluid Dynamics (CFD) evaluation of homogeneous and heterogeneous fuel models was performed as part of the Phase I calculations of the International Atomic Energy Agency (IAEA) Coordinate Research Program (CRP) on High Temperature Reactor (HTR) Uncertainties in Modeling (UAM). This study was focused on the nominal localized stand-alone fuel thermal response, as defined in Ex. I-3 and I-4 of the HTR UAM. The aim of the stand-alone thermal unit-cell simulation is to isolate the effect of material and boundary input uncertainties on a very simplified problem, before propagation of these uncertainties are performed in subsequent coupled neutronics/thermal fluids phases on the benchmark. In many of the previous studies for high temperature gas cooled reactors, the volume-averaged homogeneous mixture model of a single fuel compact has been applied. In the homogeneous model, the Tristructural Isotropic (TRISO) fuel particles in the fuel compact were not modeled directly and an effective thermal conductivity was employed for the thermo-physical properties of the fuel compact. On the contrary, in the heterogeneous model, the uranium carbide (UCO), inner and outer pyrolytic carbon (IPyC/OPyC) and silicon carbide (SiC) layers of the TRISO fuel particles are explicitly modeled. The fuel compact is modeled as a heterogeneous mixture of TRISO fuel kernels embedded in H-451 matrix graphite. In this study, a steady-state and transient CFD simulations were performed with both homogeneous and heterogeneous models to compare the thermal characteristics. The nominal values of the input parameters are used for this CFD analysis. In a future study, the effects of input uncertainties in the material properties and boundary parameters will be investigated and reported.

  3. Genome-Wide Association Studies Identify CHRNA5/3 and HTR4 in the Development of Airflow Obstruction

    PubMed Central

    Shrine, Nick R. G.; Loehr, Laura R.; Zhao, Jing Hua; Manichaikul, Ani; Lopez, Lorna M.; Smith, Albert Vernon; Heckbert, Susan R.; Smolonska, Joanna; Tang, Wenbo; Loth, Daan W.; Curjuric, Ivan; Hui, Jennie; Latourelle, Jeanne C.; Henry, Amanda P.; Aldrich, Melinda; Bakke, Per; Beaty, Terri H.; Bentley, Amy R.; Borecki, Ingrid B.; Brusselle, Guy G.; Burkart, Kristin M.; Chen, Ting-hsu; Couper, David; Crapo, James D.; Davies, Gail; Dupuis, Josée; Franceschini, Nora; Gulsvik, Amund; Hancock, Dana B.; Harris, Tamara B.; Hofman, Albert; Imboden, Medea; James, Alan L.; Khaw, Kay-Tee; Lahousse, Lies; Launer, Lenore J.; Litonjua, Augusto; Liu, Yongmei; Lohman, Kurt K.; Lomas, David A.; Lumley, Thomas; Marciante, Kristin D.; McArdle, Wendy L.; Meibohm, Bernd; Morrison, Alanna C.; Musk, Arthur W.; Myers, Richard H.; North, Kari E.; Postma, Dirkje S.; Psaty, Bruce M.; Rich, Stephen S.; Rivadeneira, Fernando; Rochat, Thierry; Rotter, Jerome I.; Artigas, María Soler; Starr, John M.; Uitterlinden, André G.; Wareham, Nicholas J.; Wijmenga, Cisca; Zanen, Pieter; Province, Michael A.; Silverman, Edwin K.; Deary, Ian J.; Palmer, Lyle J.; Cassano, Patricia A.; Gudnason, Vilmundur; Barr, R. Graham; Loos, Ruth J. F.; Strachan, David P.; London, Stephanie J.; Boezen, H. Marike; Probst-Hensch, Nicole; Gharib, Sina A.; Hall, Ian P.; O’Connor, George T.; Tobin, Martin D.; Stricker, Bruno H.

    2012-01-01

    Rationale: Genome-wide association studies (GWAS) have identified loci influencing lung function, but fewer genes influencing chronic obstructive pulmonary disease (COPD) are known. Objectives: Perform meta-analyses of GWAS for airflow obstruction, a key pathophysiologic characteristic of COPD assessed by spirometry, in population-based cohorts examining all participants, ever smokers, never smokers, asthma-free participants, and more severe cases. Methods: Fifteen cohorts were studied for discovery (3,368 affected; 29,507 unaffected), and a population-based family study and a meta-analysis of case-control studies were used for replication and regional follow-up (3,837 cases; 4,479 control subjects). Airflow obstruction was defined as FEV1 and its ratio to FVC (FEV1/FVC) both less than their respective lower limits of normal as determined by published reference equations. Measurements and Main Results: The discovery meta-analyses identified one region on chromosome 15q25.1 meeting genome-wide significance in ever smokers that includes AGPHD1, IREB2, and CHRNA5/CHRNA3 genes. The region was also modestly associated among never smokers. Gene expression studies confirmed the presence of CHRNA5/3 in lung, airway smooth muscle, and bronchial epithelial cells. A single-nucleotide polymorphism in HTR4, a gene previously related to FEV1/FVC, achieved genome-wide statistical significance in combined meta-analysis. Top single-nucleotide polymorphisms in ADAM19, RARB, PPAP2B, and ADAMTS19 were nominally replicated in the COPD meta-analysis. Conclusions: These results suggest an important role for the CHRNA5/3 region as a genetic risk factor for airflow obstruction that may be independent of smoking and implicate the HTR4 gene in the etiology of airflow obstruction. PMID:22837378

  4. Substance abuse disorder and major depression are associated with the human 5-HT1B receptor gene (HTR1B) G861C polymorphism.

    PubMed

    Huang, Yung-yu; Oquendo, Maria A; Friedman, Jill M Harkavy; Greenhill, Lawrence L; Brodsky, Beth; Malone, Kevin M; Khait, Vadim; Mann, J John

    2003-01-01

    The 5-HT(1B) receptor has been implicated in several psychopathologies, including pathological aggression, alcoholism and suicide. To test these and related potential genetic relationships in a single population, the human 5-HT(1B) receptor (h5-HTR(1B)) genotype for the G861C polymorphism was determined in 394 psychiatric patients and 96 healthy volunteers. Structured clinical interviews generated DSM III-R diagnoses. No significant association of the genotype or allele frequencies of the h5-HTR(1B) G861C locus was observed with diagnoses of alcoholism, bipolar disorder, schizophrenia or a history of a suicide attempt. Exploratory analyses indicated an association of the genotype and allele frequencies of the h5-HTR(1B) G861C locus with a history of substance abuse disorder (chi(2) = 9.51, df = 2, p = 0.009; chi(2) = 7.31, df = 1, p = 0.007, respectively) and with a diagnosis of a major depressive episode (chi(2) = 6.83, df = 2, p = 0.033; chi(2) = 5.81, df = 1, p = 0.016, respectively). Significant gene dose effects on the risk for substance abuse disorder and a major depressive episode were observed with the 861C allele (Armitage linearity tendency test: chi(2) = 7.20, df = 1, p = 0.008; chi(2) = 6.80, df = 1, p = 0.009, respectively). Substance abuse disorder and major depression appear to be associated with the h5-HTR(1B) G861C locus in the patient population, but other psychopathologies such as bipolar disorder, schizophrenia, alcoholism, and suicide attempts were not found to be associated with this polymorphism. This preliminary result will need replication, given the limitations of association studies. PMID:12496953

  5. Interaction between Methylation and CpG Single-Nucleotide Polymorphisms in the HTR2A Gene: Association Analysis with Suicide Attempt in Schizophrenia.

    PubMed

    Bani-Fatemi, Ali; Howe, Aaron S; Matmari, Michelle; Koga, Arthur; Zai, Clement; Strauss, John; De Luca, Vincenzo

    2016-01-01

    Dysfunctional mechanisms in the serotonergic system have been implicated in suicidal behavior among patients with schizophrenia. However, previous association analyses of major serotonin genes have provided inconsistent findings regarding their role in suicidal behavior. The goal of the current study was to identify single-nucleotide polymorphisms (SNP) within HTR2A that directly affect CpG methylation sites in schizophrenic patients with suicidal behavior. Furthermore, direct methylation analysis was performed using genomic DNA from peripheral leukocytes employing bisulfite pyrosequencing to assess the contributions of six CpG sites in HTR2A exon I in 67 schizophrenia patients assessed for lifetime suicide attempt. Potential methylation in 25 CpG SNPs across the entire HTR2A gene was analyzed considering their direct contribution to methylation. When we compared direct methylation between attempters and nonattempters, we found that only the polymorphic T102C (rs6313) was significantly different between the two groups (p = 0.02). Furthermore, in the potential methylation analysis, we found a nominal association with suicide attempt for six of the 25 SNPs analyzed, i.e. rs2770293 (p = 0.045), rs6313 (p = 0.033), rs17068986 (p = 0.029), rs4942578 (p = 0.024), rs1728872 (p = 0.014), and rs9534511 (p = 0.003). The results of this investigation provide preliminary evidence that the combined analysis of CpG SNPs and methylation may be useful for investigating the genetic and epigenetic factors involved in suicidal behavior. PMID:26812280

  6. Structure-Based Design of a Br Halogen Bond at the Complex Interface of the Human Placental HtrA1 PDZ Domain with Its Heptapeptide Ligand.

    PubMed

    Dou, Shuo-Fen; Liu, Hong; Cao, Tong-Mei; Wen, Qing-Li; Li, Jie; Shao, Qing-Chun

    2016-04-01

    The shock-induced serine protease HtrA1 is a potential regulator of human placenta development during pregnancy. The protein contains a functional PDZ domain that has been solved in complex with a phage display-derived heptapeptide: Asp-6 Ser-5 Arg-4 Ile-3 Trp-2 Trp-1 Val0 . In this study, a rationally designed halogen bond was introduced to the domain-peptide complex based on its NMR structure in solution. We computationally compared the stabilization energies and hindrance effects due to the presence of different halogens X (X = F, Cl, Br, or I), using a hybrid quantum mechanics/molecular mechanics (QM/MM) approach, and found that the Br atom could considerably promote the peptide binding free energy (ΔΔG = -5.2 kcal/mol). Fluorescence assays confirmed that the peptide affinity to the HtrA1 PDZ domain was improved by approximately sevenfold upon bromination. Structural analysis identified a geometrically perfect halogen bond between the Br atom of the peptide Trp-1 residue and the carbonyl O atom of the HtrA1 Ile385 residue, with a bond length and an interaction energy of d = 3.20 Å and ΔE = -3.7 kcal/mol, respectively. PMID:26972470

  7. MicroRNA-135b suppresses extravillous trophoblast-derived HTR-8/SVneo cell invasion by directly down regulating CXCL12 under low oxygen conditions.

    PubMed

    Tamaru, Shunsuke; Mizuno, Yosuke; Tochigi, Hideno; Kajihara, Takeshi; Okazaki, Yasushi; Okagaki, Ryugo; Kamei, Yoshimasa; Ishihara, Osamu; Itakura, Atsuo

    2015-05-29

    The expression of numerous microRNAs (miRNAs) in the trophoblasts changes under low oxygen conditions. However, little is known regarding the regulation of the trophoblast invasion by miRNAs under low oxygen conditions. The aim of this study was to identify those miRNAs and their target genes associated with the trophoblast invasion under low oxygen conditions. Culturing the extravillous trophoblast (EVT) cell line, HTR-8/SVneo, at 2% oxygen as compared to 20% oxygen suppressed trophoblast invasion that correlated with increased expression of microRNA-135b (miR-135b) and decreased expression of the its predicted target gene CXCL12. Overexpression of miR-135b suppressed CXCL12 mRNA expression and invasion of HTR-8/SVneo cells. Adding a neutralizing antibody against CXCL12 to the culture medium suppressed HTR-8/SVneo cell invasion. Reporter assays showed that the 3'UTR sequence of CXCL12 was directly targeted by miR-135b. Our results suggest that miR-135b and CXCL12 play important roles in modulating the EVT invasion under low oxygen conditions. PMID:25896762

  8. Hyperexcitable substantia nigra dopamine neurons in PINK1- and HtrA2/Omi-deficient mice.

    PubMed

    Bishop, Matthew W; Chakraborty, Subhojit; Matthews, Gillian A C; Dougalis, Antonios; Wood, Nicholas W; Festenstein, Richard; Ungless, Mark A

    2010-12-01

    The electrophysiological properties of substantia nigra pars compacta (SNC) dopamine neurons can influence their susceptibility to degeneration in toxin-based models of Parkinson's disease (PD), suggesting that excitotoxic and/or hypoactive mechanisms may be engaged during the early stages of the disease. It is unclear, however, whether the electrophysiological properties of SNC dopamine neurons are affected by genetic susceptibility to PD. Here we show that deletion of PD-associated genes, PINK1 or HtrA2/Omi, leads to a functional reduction in the activity of small-conductance Ca(2+)-activated potassium channels. This reduction causes SNC dopamine neurons to fire action potentials in an irregular pattern and enhances burst firing in brain slices and in vivo. In contrast, PINK1 deletion does not affect firing regularity in ventral tegmental area dopamine neurons or substantia nigra pars reticulata GABAergic neurons. These findings suggest that changes in SNC dopamine neuron excitability may play a role in their selective vulnerability in PD. PMID:20926611

  9. A simple and rapid strategy for the molecular cloning and monitoring of mouse HtrA2 serine protease.

    PubMed

    Kim, Goo-Young; Nam, Min-Kyung; Kim, Sang-Soo; Kim, Ho-Young; Lee, Sang-Kyu; Rhim, Hyangshuk

    2008-03-01

    A simple and rapid strategy for molecular cloning using a gel-free and antibiotic selection method is described which allows for the complete elimination of DNA extraction by gel electrophoresis, and thus has several advantages over gel-based cloning methods, including: (i) a cloning efficiency that is approximately 10-times higher due to the prevention of ethidium bromide ultraviolet-induced DNA damage and contamination with ligase inhibitors; (ii) the amount of plasmid DNA required is approximately five times less; and (iii) the cloning time is several hours less. Once the target gene, such as mouse HtrA2 serine protease, was cloned into the pEGFP-N3 plasmid, the integrity of the kanamycin-resistant molecular clone encoding the GFP fusion protein was verified by immunoblot and immunofluorescence assays. In addition, the integrity of the ampicillin-resistant molecular clone was directly evaluated by analyzing the expression and affinity purification of the GST fusion protein and by measuring its enzymatic activity. Therefore, this method is suitable for the routine construction of a plasmid expressing the gene of interest, and the usefulness of this strategy can be demonstrated by monitoring the expression of the target gene in E. coli and mammalian cells. PMID:17939055

  10. Loss-of-Function of HtrA1 Abrogates All-Trans Retinoic Acid-Induced Osteogenic Differentiation of Mouse Adipose-Derived Stromal Cells Through Deficiencies in p70S6K Activation.

    PubMed

    Glanz, Stephan; Mirsaidi, Ali; López-Fagundo, Cristina; Filliat, Gladys; Tiaden, André N; Richards, Peter J

    2016-05-01

    All-trans retinoic acid (ATRA) is a potent inducer of osteogenic differentiation in mouse adipose-derived stromal cells (mASCs), although the underlying mechanisms responsible for its mode of action have yet to be completely elucidated. High temperature requirement protease A1 (HtrA1) is a newly recognized modulator of human multipotent stromal cell (MSC) osteogenesis and as such, may play a role in regulating ATRA-dependent osteogenic differentiation of mASCs. In this study, we assessed the influence of small interfering RNA (siRNA)-induced repression of HtrA1 production on mASC osteogenesis and examined its effects on ATRA-mediated mammalian target of rapamycin (mTOR) signaling. Inhibition of HtrA1 production in osteogenic mASCs resulted in a significant reduction of alkaline phosphatase activity and mineralized matrix formation. Western blot analyses revealed the rapid activation of Akt (Ser473) and p70S6K (Thr389) in ATRA-treated mASCs, and that levels of phosphorylated p70S6K were noticeably reduced in HtrA1-deficient mASCs. Further studies using mTOR inhibitor rapamycin and siRNA specific for the p70S6K gene Rps6kb1 confirmed ATRA-mediated mASC osteogenesis as being dependent on p70S6K activation. Finally, transfection of cells with a constitutively active rapamycin-resistant p70S6K mutant could restore the mineralizing capacity of HtrA1-deficient mASCs. These findings therefore lend further support for HtrA1 as a positive mediator of MSC osteogenesis and provide new insights into the molecular mode of action of ATRA in regulating mASC lineage commitment. PMID:26950191

  11. Experimental Determination of the Ratio of {sup 238}U Capture to {sup 235}U Fission in LEU-HTR Pebble-Bed Configurations

    SciTech Connect

    Koeberl, O.; Chawla, R.

    2004-01-15

    The shift toward low-enrichment uranium (LEU) fuel for gas-cooled high-temperature reactors (HTRs) has revealed a lack of experimental data for validating neutronics codes that are used for the design and licensing of such systems. In the framework of the LEU-HTR experimental program at the PROTEUS critical facility, the safety-related effects of accidental moderation increase (ingress of water or other hydrogeneous compounds) in pebble-bed HTR core configurations employing low-enriched (16.7%) fuel were investigated. An important neutron balance component in this context is the integral reaction rate ratio of {sup 238}U capture (C{sub 8}) relative to {sup 235}U fission (F{sub 5}).It was necessary to develop new experimental techniques for the accurate measurement of C{sub 8}/F{sub 5} in the doubly heterogeneous fuel pebbles. These have involved the utilization of specially prepared particle foils on the one hand and the counting of whole fuel pebbles on the other. Core-center measurements employing both experimental methods have been carried out in two different HTR-PROTEUS configurations (with and without accidental moderation increase simulation, respectively). In each case, satisfactory agreement was obtained between the experimental results based on the two techniques. By carrying out a comparison of particle-foil C{sub 8}/F{sub 5} measurements in the PROTEUS reactor's thermal column with the results of standard foil-activation measurement techniques, the systematic uncertainty (1{sigma}) of the core-center measurements could be reduced by {approx}0.6%, yielding a net experimental error of {+-}1% with either of the new methods. A comparison of the experimental results with calculations based on the MICROX-2/TWODANT codes in conjunction with JEF-1 cross sections has indicated that this calculational route overpredicts the core-center C{sub 8}/F{sub 5} value by {approx}2.5% in both the investigated configurations.

  12. Association of HTR2A T102C and A-1438G polymorphisms with susceptibility to major depressive disorder: a meta-analysis.

    PubMed

    Zhao, Xue; Sun, Liang; Sun, Ye-Huan; Ren, Cizao; Chen, Jian; Wu, Zhen-Qiang; Jiang, Yu-Hong; Lv, Xiao-Ling

    2014-12-01

    Serotonin 2A receptor (HTR2A) gene was implicated to be associated with major depressive disorder (MDD) susceptibility due to its role of key neurotransmitter in many physiologic processes. A great number of related studies reported in different populations have emerged. The results of these studies, however, have been inconsistent and thereby definite conclusions are difficult to establish. With the cumulative data in recent years, it was necessary to carry out a comprehensive analysis of previous findings. Electronic databases were systematically searched for studies published before May 2013. Pooled odds ratios (OR) and 95 % confidence interval (CI) were estimated under three different genetic models. Subgroup and sensitivity analyses were also performed. A total of 21 studies, 3,299 patients and 4,092 controls, met the selection criteria. 15 studies included HTR2A T102C polymorphism (with a total of 2,409 patients and 3,130 controls), and 9 studies included HTR2A A-1438G polymorphism (with a total of 1,510 patients and 2,281 controls). Our results showed that no significant association of MDD susceptibility with T102C polymorphism was found in allelic analysis and genotypic analysis (For T vs. C: OR = 1.06, 95 % CI = 0.95-1.18, P = 0.307; For TT + TC vs. CC: OR = 1.07, 95 % CI = 0.90-1.28, P = 0.451; For TT vs. TC + CC: OR = 1.08, 95 % CI = 0.95-1.22, P = 0.235). With respect to A-1438G polymorphism, however, carriers with A allele tend to suffer from MDD (AA + AG vs. GG: OR = 1.20, 95 % CI = 1.02-1.43, P = 0.030). When stratified by race for T102C polymorphism and A-1438G polymorphism of the HTR2A, we found no significant association. In conclusions, our study suggests that the A allele of A-1438G polymorphism might play a role in susceptibility to MDD. On the contrary, T102C polymorphism does not seem to be capable of modifying MDD risk. PMID:25270656

  13. Polymorphism in the Serotonin Receptor 2a (HTR2A) Gene as Possible Predisposal Factor for Aggressive Traits

    PubMed Central

    Banlaki, Zsofia; Elek, Zsuzsanna; Nanasi, Tibor; Szekely, Anna; Nemoda, Zsofia; Sasvari-Szekely, Maria; Ronai, Zsolt

    2015-01-01

    Aggressive manifestations and their consequences are a major issue of mankind, highlighting the need for understanding the contributory factors. Still, aggression-related genetic analyses have so far mainly been conducted on small population subsets such as individuals suffering from a certain psychiatric disorder or a narrow-range age cohort, but no data on the general population is yet available. In the present study, our aim was to identify polymorphisms in genes affecting neurobiological processes that might explain some of the inter-individual variation between aggression levels in the non-clinical Caucasian adult population. 55 single nucleotide polymorphisms (SNP) were simultaneously determined in 887 subjects who also filled out the self-report Buss-Perry Aggression Questionnaire (BPAQ). Single marker association analyses between genotypes and aggression scores indicated a significant role of rs7322347 located in the HTR2A gene encoding serotonin receptor 2a following Bonferroni correction for multiple testing (p = 0.0007) both for males and females. Taking the four BPAQ subscales individually, scores for Hostility, Anger and Physical Aggression showed significant association with rs7322347 T allele in themselves, while no association was found with Verbal Aggression. Of the subscales, relationship with rs7322347 was strongest in the case of Hostility, where statistical significance virtually equaled that observed with the whole BPAQ. In conclusion, this is the first study to our knowledge analyzing SNPs in a wide variety of genes in terms of aggression in a large sample-size non-clinical adult population, also describing a novel candidate polymorphism as predisposal to aggressive traits. PMID:25658328

  14. Wie Deutschland zum Leitanbieter für Elektromobilität werden kann, acatech BEZIEHT POSITION

    NASA Astrophysics Data System (ADS)

    Rund drei Viertel der anthropogen bedingten CO2-Emissionen werden weltweit in Ballungsräumen verursacht, wovon ein guter Teil auf die kaum abschätzbare Zahl täglicher Personen- und Güterverkehre mit Nahdistanzen zurückzuführen ist. Der Verkehrssektor in Deutschland ist für ein Viertel des Endenergieverbrauchs verantwortlich und trägt mit einem knappen Fünftel der Emissionen in nicht unerheblichem Umfang zum Ausstoß von Treibhausgasen bei. Der Straßenverkehr macht innerhalb des Gesamtverkehrs mehr als zwei Drittel der Emissionen aus, europaweit sind es 80 Prozent. Hier wird langfristig sogar mit einer Verdopplung des Energieverbrauchs im Straßensektor gerechnet.

  15. Verify Super Double-Heterogeneous Spherical Lattice Model for Equilibrium Fuel Cycle Analysis AND HTR Spherical Super Lattice Model for Equilibrium Fuel Cycle Analysis

    SciTech Connect

    Gray S. Chang

    2005-11-01

    The currently being developed advanced High Temperature gas-cooled Reactors (HTR) is able to achieve a simplification of safety through reliance on innovative features and passive systems. One of the innovative features in these HTRs is reliance on ceramic-coated fuel particles to retain the fission products even under extreme accident conditions. Traditionally, the effect of the random fuel kernel distribution in the fuel pebble / block is addressed through the use of the Dancoff correction factor in the resonance treatment. However, the Dancoff correction factor is a function of burnup and fuel kernel packing factor, which requires that the Dancoff correction factor be updated during Equilibrium Fuel Cycle (EqFC) analysis. An advanced KbK-sph model and whole pebble super lattice model (PSLM), which can address and update the burnup dependent Dancoff effect during the EqFC analysis. The pebble homogeneous lattice model (HLM) is verified by the burnup characteristics with the double-heterogeneous KbK-sph lattice model results. This study summarizes and compares the KbK-sph lattice model and HLM burnup analyzed results. Finally, we discuss the Monte-Carlo coupling with a fuel depletion and buildup code - ORIGEN-2 as a fuel burnup analysis tool and its PSLM calculated results for the HTR EqFC burnup analysis.

  16. Family-based clinical associations and functional characterization of the serotonin 2A receptor gene (HTR2A) in autism spectrum disorder.

    PubMed

    Smith, Ryan M; Banks, Wesley; Hansen, Emily; Sadee, Wolfgang; Herman, Gail E

    2014-08-01

    The serotonin 2A receptor gene (HTR2A) harbors two functional single nucleotide polymorphisms (SNPs) that are frequent in populations of African and European descent; rs6311, which affects mRNA expression, and rs6314, which changes the amino acid sequence of the encoded protein and affects the signaling properties of the receptor. Multiple clinical associations support a role for these SNPs in cognitive and neuropsychiatric phenotypes, although studies in autism spectrum disorder (ASD) remain equivocal. Here, we tested transmission disequilibrium of rs6311 and rs6314 in a cohort of 158 ASD trios (simplex and multiplex), observing significant under-transmission of the minor "A" allele of rs6311 to offspring with ASD (permuted P = 0.0004). Consistent with our previous findings in the dorsolateral prefrontal cortex of unaffected individuals, rs6311/A decreases expression of HTR2A mRNA with an extended 5' untranslated region (UTR) in the frontopolar cortex in brain samples from 54 ASD patients and controls. Interpreting the clinical results in the context of our mRNA expression analysis, we speculate that any risk associated with rs6311 is conferred by greater expression of the long 5'UTR mRNA isoform. The current study corroborates earlier associations between rs6311 and ASD in a family study, supporting the hypothesis that rs6311 plays a modulatory role in ASD risk. PMID:24753316

  17. Effect of hepatitis B virus infection on trophoblast cell line (HTR-8/SVneo) and choriocarcinoma cell line (JEG3) is linked to CD133-2 (AC141) expression.

    PubMed

    Cui, Hong; Chen, Jing; Na, Quan

    2016-01-01

    Mother-to-infant transmission of hepatitis B virus (HBV) plays an important role in the chronic carrier state in China. In our studies, the response of trophoblast cell and choriocarcinoma cell to HBV infection regarding the expression of CD133-2 (AC141) was evaluated. Western blot and RT-PCR showed that a high level of CD133-2 protein and mRNA in HTR-8/SVneo cells, but a low level in JEG-3 cells. Lower proliferation and mobility, and higher apoptosis were observed in HTR-8/SVneo cells and JEG-3-CD133-2(+) cells after HBV infection than those in HTR-8-CD133-2(-) cells and JEG-3 cells. Our main finding is that CD133-negative cells (HTR-8-CD133-2(-) and JEG-3) are prone to HBV infection. In the last, our data indicated that the activation of Smad signaling pathway and the induction of epithelial-mesenchymal transition (EMT) in CD133-negative cells after HBV infection. In summary, our study demonstrated that CD133 is a key factor that mediated HBV infection to trophoblast cell and choriocarcinoma cell. PMID:27508045

  18. Effect of hepatitis B virus infection on trophoblast cell line (HTR-8/SVneo) and choriocarcinoma cell line (JEG3) is linked to CD133-2 (AC141) expression

    PubMed Central

    Cui, Hong; Chen, Jing; Na, Quan

    2016-01-01

    Mother-to-infant transmission of hepatitis B virus (HBV) plays an important role in the chronic carrier state in China. In our studies, the response of trophoblast cell and choriocarcinoma cell to HBV infection regarding the expression of CD133-2 (AC141) was evaluated. Western blot and RT-PCR showed that a high level of CD133-2 protein and mRNA in HTR-8/SVneo cells, but a low level in JEG-3 cells. Lower proliferation and mobility, and higher apoptosis were observed in HTR-8/SVneo cells and JEG-3-CD133-2+ cells after HBV infection than those in HTR-8-CD133-2- cells and JEG-3 cells. Our main finding is that CD133-negative cells (HTR-8-CD133-2- and JEG-3) are prone to HBV infection. In the last, our data indicated that the activation of Smad signaling pathway and the induction of epithelial-mesenchymal transition (EMT) in CD133-negative cells after HBV infection. In summary, our study demonstrated that CD133 is a key factor that mediated HBV infection to trophoblast cell and choriocarcinoma cell. PMID:27508045

  19. Results of the Simulation of the HTR-Proteus Core 4.2 Using PEBBED-COMBINE: FY10 Report

    SciTech Connect

    Hans Gougar

    2010-07-01

    ABSTRACT The Idaho National Laboratory’s deterministic neutronics analysis codes and methods were applied to the computation of the core multiplication factor of the HTR-Proteus pebble bed reactor critical facility. This report is a follow-on to INL/EXT-09-16620 in which the same calculation was performed but using earlier versions of the codes and less developed methods. In that report, results indicated that the cross sections generated using COMBINE-7.0 did not yield satisfactory estimates of keff. It was concluded in the report that the modeling of control rods was not satisfactory. In the past year, improvements to the homogenization capability in COMBINE have enabled the explicit modeling of TRIS particles, pebbles, and heterogeneous core zones including control rod regions using a new multi-scale version of COMBINE in which the 1-dimensional discrete ordinate transport code ANISN has been integrated. The new COMBINE is shown to yield benchmark quality results for pebble unit cell models, the first step in preparing few-group diffusion parameters for core simulations. In this report, the full critical core is modeled once again but with cross sections generated using the capabilities and physics of the improved COMBINE code. The new PEBBED-COMBINE model enables the exact modeling of the pebbles and control rod region along with better approximation to structures in the reflector. Initial results for the core multiplication factor indicate significant improvement in the INL’s tools for modeling the neutronic properties of a pebble bed reactor. Errors on the order of 1.6-2.5% in keff are obtained; a significant improvement over the 5-6% error observed in the earlier This is acceptable for a code system and model in the early stages of development but still too high for a production code. Analysis of a simpler core model indicates an over-prediction of the flux in the low end of the thermal spectrum. Causes of this discrepancy are under investigation. New

  20. HTR-PROTEUS PEBBLE BED EXPERIMENTAL PROGRAM CORES 5, 6, 7, & 8: COLUMNAR HEXAGONAL POINT-ON-POINT PACKING WITH A 1:2 MODERATOR-TO-FUEL PEBBLE RATIO

    SciTech Connect

    John D. Bess

    2013-03-01

    PROTEUS is a zero-power research reactor based on a cylindrical graphite annulus with a central cylindrical cavity. The graphite annulus remains basically the same for all experimental programs, but the contents of the central cavity are changed according to the type of reactor being investigated. Through most of its service history, PROTEUS has represented light-water reactors, but from 1992 to 1996 PROTEUS was configured as a pebble-bed reactor (PBR) critical facility and designated as HTR-PROTEUS. The nomenclature was used to indicate that this series consisted of High Temperature Reactor experiments performed in the PROTEUS assembly. During this period, seventeen critical configurations were assembled and various reactor physics experiments were conducted. These experiments included measurements of criticality, differential and integral control rod and safety rod worths, kinetics, reaction rates, water ingress effects, and small sample reactivity effects (Ref. 3). HTR-PROTEUS was constructed, and the experimental program was conducted, for the purpose of providing experimental benchmark data for assessment of reactor physics computer codes. Considerable effort was devoted to benchmark calculations as a part of the HTR-PROTEUS program. References 1 and 2 provide detailed data for use in constructing models for codes to be assessed. Reference 3 is a comprehensive summary of the HTR-PROTEUS experiments and the associated benchmark program. This document draws freely from these references. Only Cores 9 and 10 are evaluated in this benchmark report due to similarities in their construction. The other core configurations of the HTR-PROTEUS program are evaluated in their respective reports as outlined in Section 1.0. Cores 9 and 10 were evaluated and determined to be acceptable benchmark experiments.

  1. HTR-Proteus Pebble Bed Experimental Program Cores 5,6,7,&8: Columnar Hexagonal Point-on-Point Packing with a 1:2 Moderator-to-Fuel Pebble Ratio

    SciTech Connect

    Bess, John D.; Sterbentz, James W.; Snoj, Luka; Lengar, Igor; Koberl, Oliver

    2015-03-01

    PROTEUS is a zero-power research reactor based on a cylindrical graphite annulus with a central cylindrical cavity. The graphite annulus remains basically the same for all experimental programs, but the contents of the central cavity are changed according to the type of reactor being investigated. Through most of its service history, PROTEUS has represented light-water reactors, but from 1992 to 1996 PROTEUS was configured as a pebble-bed reactor (PBR) critical facility and designated as HTR-PROTEUS. The nomenclature was used to indicate that this series consisted of High Temperature Reactor experiments performed in the PROTEUS assembly. During this period, seventeen critical configurations were assembled and various reactor physics experiments were conducted. These experiments included measurements of criticality, differential and integral control rod and safety rod worths, kinetics, reaction rates, water ingress effects, and small sample reactivity effects (Ref. 3). HTR-PROTEUS was constructed, and the experimental program was conducted, for the purpose of providing experimental benchmark data for assessment of reactor physics computer codes. Considerable effort was devoted to benchmark calculations as a part of the HTR-PROTEUS program. References 1 and 2 provide detailed data for use in constructing models for codes to be assessed. Reference 3 is a comprehensive summary of the HTR-PROTEUS experiments and the associated benchmark program. This document draws freely from these references. Only Cores 9 and 10 are evaluated in this benchmark report due to similarities in their construction. The other core configurations of the HTR-PROTEUS program are evaluated in their respective reports as outlined in Section 1.0. Cores 9 and 10 were evaluated and determined to be acceptable benchmark experiments.

  2. A putatively functional polymorphism in the HTR2C gene is associated with depressive symptoms in white females reporting significant life stress.

    PubMed

    Brummett, Beverly H; Babyak, Michael A; Williams, Redford B; Harris, Kathleen Mullan; Jiang, Rong; Kraus, William E; Singh, Abanish; Costa, Paul T; Georgiades, Anastasia; Siegler, Ilene C

    2014-01-01

    Psychosocial stress is well known to be positively associated with subsequent depressive symptoms. Cortisol response to stress may be one of a number of biological mechanisms that links psychological stress to depressive symptoms, although the precise causal pathway remains unclear. Activity of the x-linked serotonin 5-HTR2C receptor has also been shown to be associated with depression and with clinical response to antidepressant medications. We recently demonstrated that variation in a single nucleotide polymorphism on the HTR2C gene, rs6318 (Ser23Cys), is associated with different cortisol release and short-term changes in affect in response to a series of stress tasks in the laboratory. Based on this observation, we decided to examine whether rs6318 might moderate the association between psychosocial stress and subsequent depressive symptoms. In the present study we use cross-sectional data from a large population-based sample of young adult White men (N = 2,366) and White women (N = 2,712) in the United States to test this moderation hypothesis. Specifically, we hypothesized that the association between self-reported stressful life events and depressive symptoms would be stronger among homozygous Ser23 C females and hemizygous Ser23 C males than among Cys23 G carriers. In separate within-sex analyses a genotype-by-life stress interaction was observed for women (p = .022) but not for men (p = .471). Homozygous Ser23 C women who reported high levels of life stress had depressive symptom scores that were about 0.3 standard deviations higher than female Cys23 G carriers with similarly high stress levels. In contrast, no appreciable difference in depressive symptoms was observed between genotypes at lower levels of stress. Our findings support prior work that suggests a functional SNP on the HTR2C gene may confer an increased risk for depressive symptoms in White women with a history of significant life stress. PMID:25514629

  3. HTR-PROTEUS PEBBLE BED EXPERIMENTAL PROGRAM CORE 4: RANDOM PACKING WITH A 1:1 MODERATOR-TO-FUEL PEBBLE RATIO

    SciTech Connect

    John D. Bess; Leland M. Montierth

    2013-03-01

    In its deployment as a pebble bed reactor (PBR) critical facility from 1992 to 1996, the PROTEUS facility was designated as HTR-PROTEUS. This experimental program was performed as part of an International Atomic Energy Agency (IAEA) Coordinated Research Project (CRP) on the Validation of Safety Related Physics Calculations for Low Enriched HTGRs. Within this project, critical experiments were conducted for graphite moderated LEU systems to determine core reactivity, flux and power profiles, reaction-rate ratios, the worth of control rods, both in-core and reflector based, the worth of burnable poisons, kinetic parameters, and the effects of moisture ingress on these parameters. One benchmark experiment was evaluated in this report: Core 4. Core 4 represents the only configuration with random pebble packing in the HTR-PROTEUS series of experiments, and has a moderator-to-fuel pebble ratio of 1:1. Three random configurations were performed. The initial configuration, Core 4.1, was rejected because the method for pebble loading, separate delivery tubes for the moderator and fuel pebbles, may not have been completely random; this core loading was rejected by the experimenters. Cores 4.2 and 4.3 were loaded using a single delivery tube, eliminating the possibility for systematic ordering effects. The second and third cores differed slightly in the quantity of pebbles loaded (40 each of moderator and fuel pebbles), stacked height of the pebbles in the core cavity (0.02 m), withdrawn distance of the stainless steel control rods (20 mm), and withdrawn distance of the autorod (30 mm). The 34 coolant channels in the upper axial reflector and the 33 coolant channels in the lower axial reflector were open. Additionally, the axial graphite fillers used in all other HTR-PROTEUS configurations to create a 12-sided core cavity were not used in the randomly packed cores. Instead, graphite fillers were placed on the cavity floor, creating a funnel-like base, to discourage ordering

  4. HTR-PROTEUS PEBBLE BED EXPERIMENTAL PROGRAM CORE 4: RANDOM PACKING WITH A 1:1 MODERATOR-TO-FUEL PEBBLE RATIO

    SciTech Connect

    John D. Bess; Leland M. Montierth

    2014-03-01

    In its deployment as a pebble bed reactor (PBR) critical facility from 1992 to 1996, the PROTEUS facility was designated as HTR-PROTEUS. This experimental program was performed as part of an International Atomic Energy Agency (IAEA) Coordinated Research Project (CRP) on the Validation of Safety Related Physics Calculations for Low Enriched HTGRs. Within this project, critical experiments were conducted for graphite moderated LEU systems to determine core reactivity, flux and power profiles, reaction-rate ratios, the worth of control rods, both in-core and reflector based, the worth of burnable poisons, kinetic parameters, and the effects of moisture ingress on these parameters. One benchmark experiment was evaluated in this report: Core 4. Core 4 represents the only configuration with random pebble packing in the HTR-PROTEUS series of experiments, and has a moderator-to-fuel pebble ratio of 1:1. Three random configurations were performed. The initial configuration, Core 4.1, was rejected because the method for pebble loading, separate delivery tubes for the moderator and fuel pebbles, may not have been completely random; this core loading was rejected by the experimenters. Cores 4.2 and 4.3 were loaded using a single delivery tube, eliminating the possibility for systematic ordering effects. The second and third cores differed slightly in the quantity of pebbles loaded (40 each of moderator and fuel pebbles), stacked height of the pebbles in the core cavity (0.02 m), withdrawn distance of the stainless steel control rods (20 mm), and withdrawn distance of the autorod (30 mm). The 34 coolant channels in the upper axial reflector and the 33 coolant channels in the lower axial reflector were open. Additionally, the axial graphite fillers used in all other HTR-PROTEUS configurations to create a 12-sided core cavity were not used in the randomly packed cores. Instead, graphite fillers were placed on the cavity floor, creating a funnel-like base, to discourage ordering

  5. Association between the HTR2C rs1414334 C/G gene polymorphism and the development of the metabolic syndrome in patients treated with atypical antipsychotics

    PubMed Central

    Rico-Gomis, José María; Triano-García, Irene; Mahecha-García, Luis Fabián; García-Monsalve, Ana; Navarro-Ruiz, Andrés; Villagordo-Peñalver, Berta; Jiménez-Abril, Jessica; Martínez-Hortelano, Alicia; Gil-Guillén, Vicente Francisco

    2016-01-01

    Few studies have assessed the association between the rs1414334 C/G polymorphism in the HTR2C gene and the development of the metabolic syndrome in patients treated with atypical antipsychotics. To provide further evidence, a cross-sectional study was conducted in Spain between 2012 and 2013 in 166 patients with these characteristics. In these patients, the association between the polymorphism and the presence of the metabolic syndrome was determined by implementing binary logistic regression models adjusted for variables associated with the metabolic syndrome. We did not confirm previous claims that the C allele of the polymorphism was linked to the metabolic syndrome: the association was in the opposite direction and non-significant. This conclusion held after taking gender and lifestyle variables into account. PMID:27441116

  6. HTR-PROTEUS Pebble Bed Experimental Program Cores 1, 1A, 2, and 3: Hexagonal Close Packing with a 1:2 Moderator-to-Fuel Pebble Ratio

    SciTech Connect

    John D. Bess; Barbara H. Dolphin; James W. Sterbentz; Luka Snoj; Igor Lengar; Oliver Köberl

    2012-03-01

    In its deployment as a pebble bed reactor (PBR) critical facility from 1992 to 1996, the PROTEUS facility was designated as HTR-PROTEUS. This experimental program was performed as part of an International Atomic Energy Agency (IAEA) Coordinated Research Project (CRP) on the Validation of Safety Related Physics Calculations for Low Enriched HTGRs. Within this project, critical experiments were conducted for graphite moderated LEU systems to determine core reactivity, flux and power profiles, reaction-rate ratios, the worth of control rods, both in-core and reflector based, the worth of burnable poisons, kinetic parameters, and the effects of moisture ingress on these parameters. Four benchmark experiments were evaluated in this report: Cores 1, 1A, 2, and 3. These core configurations represent the hexagonal close packing (HCP) configurations of the HTR-PROTEUS experiment with a moderator-to-fuel pebble ratio of 1:2. Core 1 represents the only configuration utilizing ZEBRA control rods. Cores 1A, 2, and 3 use withdrawable, hollow, stainless steel control rods. Cores 1 and 1A are similar except for the use of different control rods; Core 1A also has one less layer of pebbles (21 layers instead of 22). Core 2 retains the first 16 layers of pebbles from Cores 1 and 1A and has 16 layers of moderator pebbles stacked above the fueled layers. Core 3 retains the first 17 layers of pebbles but has polyethylene rods inserted between pebbles to simulate water ingress. The additional partial pebble layer (layer 18) for Core 3 was not included as it was used for core operations and not the reported critical configuration. Cores 1, 1A, 2, and 3 were determined to be acceptable benchmark experiments.

  7. HTR-PROTEUS Pebble Bed Experimental Program Cores 1, 1A, 2, and 3: Hexagonal Close Packing with a 1:2 Moderator-to-Fuel Pebble Ratio

    SciTech Connect

    John D. Bess; Barbara H. Dolphin; James W. Sterbentz; Luka Snoj; Igor Lengar; Oliver Köberl

    2013-03-01

    In its deployment as a pebble bed reactor (PBR) critical facility from 1992 to 1996, the PROTEUS facility was designated as HTR-PROTEUS. This experimental program was performed as part of an International Atomic Energy Agency (IAEA) Coordinated Research Project (CRP) on the Validation of Safety Related Physics Calculations for Low Enriched HTGRs. Within this project, critical experiments were conducted for graphite moderated LEU systems to determine core reactivity, flux and power profiles, reaction-rate ratios, the worth of control rods, both in-core and reflector based, the worth of burnable poisons, kinetic parameters, and the effects of moisture ingress on these parameters. Four benchmark experiments were evaluated in this report: Cores 1, 1A, 2, and 3. These core configurations represent the hexagonal close packing (HCP) configurations of the HTR-PROTEUS experiment with a moderator-to-fuel pebble ratio of 1:2. Core 1 represents the only configuration utilizing ZEBRA control rods. Cores 1A, 2, and 3 use withdrawable, hollow, stainless steel control rods. Cores 1 and 1A are similar except for the use of different control rods; Core 1A also has one less layer of pebbles (21 layers instead of 22). Core 2 retains the first 16 layers of pebbles from Cores 1 and 1A and has 16 layers of moderator pebbles stacked above the fueled layers. Core 3 retains the first 17 layers of pebbles but has polyethylene rods inserted between pebbles to simulate water ingress. The additional partial pebble layer (layer 18) for Core 3 was not included as it was used for core operations and not the reported critical configuration. Cores 1, 1A, 2, and 3 were determined to be acceptable benchmark experiments.

  8. Isolation and Characterization of Human Trophoblast Side-Population (SP) Cells in Primary Villous Cytotrophoblasts and HTR-8/SVneo Cell Line

    PubMed Central

    Takao, Tomoka; Asanoma, Kazuo; Kato, Kiyoko; Fukushima, Kotaro; Tsunematsu, Ryosuke; Hirakawa, Toshio; Matsumura, Sueo; Seki, Hiroyuki; Takeda, Satoru; Wake, Norio

    2011-01-01

    Recently, numerous studies have identified that immature cell populations including stem cells and progenitor cells can be found among “side-population” (SP) cells. Although SP cells isolated from some adult tissues have been reported elsewhere, isolation and characterization of human trophoblast SP remained to be reported. In this study, HTR-8/SVneo cells and human primary villous cytotrophoblasts (vCTBs) were stained with Hoechst 33342 and SP and non-SP (NSP) fractions were isolated using a cell sorter. A small population of SP cells was identified in HTR-8/SVneo cells and in vCTBs. SP cells expressed several vCTB-specific markers and failed to express syncytiotrophoblast (STB) or extravillous cytotrophopblast (EVT)-specific differentiation markers. SP cells formed colonies and proliferated on mouse embryonic fibroblast (MEF) feeder cells or in MEF conditioned medium supplemented with heparin/FGF2, and they also showed long-term repopulating property. SP cells could differentiate into both STB and EVT cell lineages and expressed several differentiation markers. Microarray analysis revealed that IL7R and IL1R2 were exclusively expressed in SP cells and not in NSP cells. vCTB cells sorted as positive for both IL7R and IL1R2 failed to express trophoblast differentiation markers and spontaneously differentiated into both STB and EVT in basal medium. These features shown by the SP cells suggested that IL7R and IL1R2 are available as markers to detect the SP cells and that vCTB progenitor cells and trophoblast stem cells were involved in the SP cell population. PMID:21760941

  9. Protective Effect of Nuclear Factor E2-Related Factor 2 on Inflammatory Cytokine Response to Brominated Diphenyl Ether-47 in the HTR-8/SVneo Human First Trimester Extravillous Trophoblast Cell Line

    PubMed Central

    Park, Hae-Ryung; Loch-Caruso, Rita

    2014-01-01

    Polybrominated diphenyl ethers (PBDEs) are widely used flame retardants, and BDE-47 is a prevalent PBDE congener detected in human tissues. Exposure to PBDEs has been linked to adverse pregnancy outcomes in humans. Although the underlying mechanisms of adverse birth outcomes are poorly understood, critical roles for oxidative stress and inflammation are implicated. The present study investigated antioxidant responses in a human extravillous trophoblast cell line, HTR-8/SVneo, and examined the role of nuclear factor E2-related factor 2 (Nrf2), an antioxidative transcription factor, in BDE-47-induced inflammatory responses in the cells. Treatment of HTR-8/SVneo cells with 5, 10, 15, and 20 μM BDE-47 for 24 h increased intracellular glutathione (GSH) levels compared to solvent control. Treatment of HTR-8/SVneo cells with 20 μM BDE-47 for 24 h induced the antioxidant response element (ARE) activity, indicating Nrf2 transactivation by BDE-47 treatment, and resulted in differential expression of redox-sensitive genes compared to solvent control. Pretreatment with tert-butyl hydroquinone (tBHQ) or sulforaphane, known Nrf2 inducers, reduced BDE-47-stimulated IL-6 release with increased ARE reporter activity, reduced nuclear factor kappa B (NF-κB) reporter activity, increased GSH production, and stimulated expression of antioxidant genes compared to non-Nrf2 inducer pretreated groups, suggesting that Nrf2 may play a protective role against BDE-47-mediated inflammatory responses in HTR-8/SVneo cells. These results suggest that Nrf2 activation significantly attenuated BDE-47-induced IL-6 release by augmentation of cellular antioxidative system via upregulation of Nrf2 signaling pathways, and that Nrf2 induction may be a potential therapeutic target to reduce adverse pregnancy outcomes associated with toxicant-induced oxidative stress and inflammation. PMID:25305463

  10. The Cytotoxic and Pro-Apoptotic Activities of the Novel Fluoropyrimidine F10 Towards Prostate Cancer Cells are Enhanced by Zn2+-Chelation and Inhibiting the Serine Protease Omi/HtrA2

    PubMed Central

    Gmeiner, William H.; Boyacioglu, Olcay; Stuart, Christopher H.; Jennings-Gee, Jamie; Balaji, K.C.

    2014-01-01

    BACKGROUND Intracellular Zn2+ levels decrease during prostate cancer progression and agents that modulate intracellular Zn2+ are cytotoxic to prostate cancer cells by an incompletely described mechanism. F10 is a new polymeric fluoropyrimidine drug-candidate that displays strong activity with minimal systemic toxicity in pre-clinical models of prostate cancer and other malignancies. The effects of exogenous Zn2+ or Zn2+ chelation for enhancing F10 cytotoxicity are investigated as is the role of Omi/HtrA2, a serine protease that promotes apoptosis in response to cellular stress. METHODS To test the hypothesis that the pro-apoptotic effects of F10 could be enhanced by modulating intracellular Zn2+ we investigated cell-permeable and cell-impermeable Zn2+ chelators and exogenous Zn2+ and evaluated cell viability and apoptosis in cellular models of castration-resistant prostate cancer (CRPC; PC3, C4-2). The role of Omi/HtrA2 for modulating apoptosis was evaluated by pharmacological inhibition and Western blotting. RESULTS Exogenous Zn2+ initially reduced prostate cancer cell viability but these effects were transitory and were ineffective at enhancing F10 cytotoxicity. The cell-permeable Zn2+-chelator tetrakis-(2-pyridylmethl)ethylenediamine (TPEN) induced apoptosis in prostate cancer cells and enhanced the pro-apoptotic effects of F10. The pro-apoptotic effects of Zn2+-chelation in combination with F10 treatment were enhanced by inhibiting Omi/HtrA2 implicating this serine protease as a novel target for prostate cancer treatment. CONCLUSIONS Zn2+-chelation enhances the pro-apoptotic effects of F10 and may be useful for enhancing the effectiveness of F10 for treatment of advanced prostate cancer. The serine protease Omi/HtrA2 modulates Zn2+-dependent apoptosis in prostate cancer cells and represents a new target for treatment of CRPC. PMID:25408502

  11. Melker Meilensteine auf dem Weg in ein naturwissenschaftliches Zeitalter - Glanzlichter der Ausstellung zum Internationalen Astronomiejahr 2009 in der Melker Stiftsbibliothek.

    NASA Astrophysics Data System (ADS)

    Beck, Paul G.; Zotti, Georg

    2009-06-01

    Das Mittelalter wird weithin als die dunkle Epoche in der Geschichte der Europäischen Wissenschaften betrachtet, und insbesondere das Leben in den Klöstern galt lange Zeit als frei von jeglichem Interesse für Naturwissenschaften abseits der Medizin. Im Mittelalter galt die Astronomie bloß als Mittel zum Zweck, um religiöse und zivile Kalender erstellen zu können. Durch den Bestand der Handschriftenkammer der Melker Stiftsbibliothek eröffnet sich uns eine neue Sichtweise auf das gegen Ende des Mittelalters wachsende Interesse an den Naturwissenschaften. Dies wurde durch die starke Aufwertung der Klosterbibliothek im Rahmen der 'Melker Reform' im 15. Jahrhundert noch weiter verstärkt. Diese Epoche fällt mit der Frühphase der Universität Wien und der 'ersten Wiener Schule der Astronomie' zusammen. Dieser Artikel beleuchtet ausgewählte astronomischen Werke in der Melker Stiftsbibliothek zwischen dem frühen 9 und dem 18. Jahrhundert. Einen Schwerpunkt stellt das Wirken der Wiener Schule der Astronomie dar, wobei wir u.a. die Melker Abschrift von Peuerbachs Gutachten über den Kometen von 1456 sowie die im Stift Melk durchgeführte Beobachtung der Mondfinsternis von 1457 durch Regiomontanus und Peuerbach beleuchten. Dieser Beitrag ist der einführende Übersichtsartikel zum Ausstellungsprojekt in der Melker Stiftsbibliothek im Rahmen des Internationalen Jahres der Astronomie 2009. The medieval period is commonly seen as a dark epoch for science in Europe. Especially monasteries were seen as institutions without interest in natural sciences except for medicine. Astronomy was allegedly only a tool to construct religious and civil calendars. The inventory of the medieval manuscript collection of the library of the Abbey of Melk allows a new view on the growing interest in the exact sciences towards the end of the medieval ages. This interest was intensified through the increased importance of the monastery library due to the monastery reform

  12. Xanthohumol impairs glucose uptake by a human first-trimester extravillous trophoblast cell line (HTR-8/SVneo cells) and impacts the process of placentation.

    PubMed

    Correia-Branco, Ana; Azevedo, Cláudia F; Araújo, João R; Guimarães, João T; Faria, Ana; Keating, Elisa; Martel, Fátima

    2015-10-01

    In this study, we aimed to investigate modulation of glucose uptake by the HTR-8/SVneo human first-trimester extravillous trophoblast cell line by a series of compounds and to study its consequences upon cell proliferation, viability and migration. We observed that uptake of (3)H-deoxy-d-glucose ((3)H-DG; 10 nM) was time-dependent, saturable, inhibited by cytochalasin B (50 and 100 µM), phloretin (0.5 mM) and phloridzin (1 mM), insulin-insensitive and sodium-independent. In the short term (30 min), neither 5-HT (100-1000 µM), melatonin (10 nM) nor the drugs of abuse ethanol (100 mM), nicotine (100 µM), cocaine (25 µM), amphetamine (10-25 µM) and 3,4-methylenedioxy-N-methamphetamine (10 µM) affected (3)H-DG uptake, while dexamethasone (100-1000 µM), fluoxetine (100-300 µM), quercetin, epigallocatechin-3-gallate (30-1000 µM), xanthohumol (XH) and resveratrol (1-500 µM) decreased it. XH was the most potent inhibitor [IC50 = 3.55 (1.37-9.20) µM] of (3)H-DG uptake, behaving as a non-competitive inhibitor of (3)H-DG uptake, both after short- and long-term (24 h) treatment. The effect of XH (5 µM; 24 h) upon (3)H-DG uptake involved mammalian target of rapamycin, tyrosine kinases and c-Jun N-terminal kinases intracellular pathways. Moreover, XH appeared to decrease cellular uptake of lactate due to inhibition of the monocarboxylate transporter 1. Additionally, XH (24 h; 5 µM) decreased cell viability, proliferation, culture growth and migration. The effects of XH upon cell viability and culture growth, but not the antimigratory effect, were mimicked by low extracellular glucose conditions and reversed by high extracellular glucose conditions. We thus suggest that XH, by inhibiting glucose cellular uptake and impairing HTR-8/SVneo cell viability and proliferation, may have a deleterious impact in the process of placentation. PMID:26194608

  13. Decommissioning of the Dragon High Temperature Reactor (HTR) Located at the Former United Kingdom Atomic Energy Authority (UKAEA) Research Site at Winfrith - 13180

    SciTech Connect

    Smith, Anthony A.

    2013-07-01

    The Dragon Reactor was constructed at the United Kingdom Atomic Energy Research Establishment at Winfrith in Dorset through the late 1950's and into the early 1960's. It was a High Temperature Gas Cooled Reactor (HTR) with helium gas coolant and graphite moderation. It operated as a fuel testing and demonstration reactor at up to 20 MW (Thermal) from 1964 until 1975, when international funding for this project was terminated. The fuel was removed from the core in 1976 and the reactor was put into Safestore. To meet the UK's Nuclear Decommissioning Authority (NDA) objective to 'drive hazard reduction' [1] it is necessary to decommission and remediate all the Research Sites Restoration Ltd (RSRL) facilities. This includes the Dragon Reactor where the activated core, pressure vessel and control rods and the contaminated primary circuit (including a {sup 90}Sr source) still remain. It is essential to remove these hazards at the appropriate time and return the area occupied by the reactor to a safe condition. (author)

  14. The HtrA/DegP family protease MamE is a bifunctional protein with roles in magnetosome protein localization and magnetite biomineralization

    PubMed Central

    Quinlan, Anna; Murat, Dorothée; Vali, Hojatollah; Komeili, Arash

    2011-01-01

    Summary Magnetotactic bacteria contain nanometer-sized, membrane-bound organelles, called magnetosomes, which are tasked with the biomineralization of small crystals of the iron oxide magnetite allowing the organism to use geomagnetic field lines for navigation. A key player in this process is the HtrA/DegP family protease MamE. In its absence, Magnetospirillum magneticum str AMB-1 is able to form magnetosome membranes but not magnetite crystals, a defect previously linked to the mislocalization of magnetosome proteins. In this work we use a directed genetic approach to find that MamE, and another predicted magnetosome-associated protease, MamO, likely function as proteases in vivo. However, as opposed to the complete loss of mamE where no biomineralization is observed, the protease-deficient variant of this protein still supports the initiation and formation of small, 20 nm-sized crystals of magnetite, too small to hold a permanent magnetic dipole moment. This analysis also reveals that MamE is a bifunctional protein with a protease-independent role in magnetosome protein localization and a protease-dependent role in maturation of small magnetite crystals. Together these results imply the existence of a previously unrecognized “checkpoint” in biomineralization where MamE moderates the completion of magnetite formation and thus committal to magneto-aerotaxis as the organism’s dominant mode of navigating the environment. PMID:21414040

  15. A Small Physiological Electric Field Mediated Responses of Extravillous Trophoblasts Derived from HTR8/SVneo Cells: Involvement of Activation of Focal Adhesion Kinase Signaling

    PubMed Central

    Zhang, Juan; Ren, Rongmei; Luo, Xuefeng; Fan, Ping; Liu, Xinghui; Liang, Shanshan; Ma, Lei; Yu, Ping; Bai, Huai

    2014-01-01

    Moderate invasion of trophoblast cells into endometrium is essential for the placental development and normal pregnancy. Electric field (EF)-induced effects on cellular behaviors have been observed in many cell types. This study was to investigate the effect of physiological direct current EF (dc EF) on cellular responses such as elongation, orientation and motility of trophoblast cells. Immortalized first trimester extravillous trophoblast cells (HTR-8/SVneo) were exposed to the dc EF at physiological magnitude. Cell images were recorded and analyzed by image analyzer. Cell lysates were used to detect protein expression by Western blot. Cultured in the dc EFs the cells showed elongation, orientation and enhanced migration rate compared with non-EF stimulated cells at field strengths of 100 mV/mm to 200 mV/mm. EF exposure increased focal adhesion kinase (FAK) phosphorylation in a time-dependent manner and increased expression levels of MMP-2. Pharmacological inhibition of FAK impaired the EF-induced responses including motility and abrogated the elevation of MMP-2 expression. However, the expression levels of integrins like integrin α1, α5, αV and β1 were not affected by EF stimulation. Our results demonstrate the importance of FAK activation in migration/motility of trophobalst cells driven by EFs. In addition, it raises the feasibility of using applied EFs to promote placentation through effects on trophoblast cells. PMID:24643246

  16. Results of a Neutronic Simulation of HTR-Proteus Core 4.2 using PEBBED and other INL Reactor Physics Tools: FY-09 Report

    SciTech Connect

    Hans D. Gougar

    2009-08-01

    The Idaho National Laboratory’s deterministic neutronics analysis codes and methods were applied to the computation of the core multiplication factor of the HTR-Proteus pebble bed reactor critical facility. A combination of unit cell calculations (COMBINE-PEBDAN), 1-D discrete ordinates transport (SCAMP), and nodal diffusion calculations (PEBBED) were employed to yield keff and flux profiles. Preliminary results indicate that these tools, as currently configured and used, do not yield satisfactory estimates of keff. If control rods are not modeled, these methods can deliver much better agreement with experimental core eigenvalues which suggests that development efforts should focus on modeling control rod and other absorber regions. Under some assumptions and in 1D subcore analyses, diffusion theory agrees well with transport. This suggests that developments in specific areas can produce a viable core simulation approach. Some corrections have been identified and can be further developed, specifically: treatment of the upper void region, treatment of inter-pebble streaming, and explicit (multiscale) transport modeling of TRISO fuel particles as a first step in cross section generation. Until corrections are made that yield better agreement with experiment, conclusions from core design and burnup analyses should be regarded as qualitative and not benchmark quality.

  17. Magnetite Biomineralization in Magnetospirillum magneticum Is Regulated by a Switch-like Behavior in the HtrA Protease MamE.

    PubMed

    Hershey, David M; Browne, Patrick J; Iavarone, Anthony T; Teyra, Joan; Lee, Eun H; Sidhu, Sachdev S; Komeili, Arash

    2016-08-19

    Magnetotactic bacteria are aquatic organisms that produce subcellular magnetic particles in order to orient in the earth's geomagnetic field. MamE, a predicted HtrA protease required to produce magnetite crystals in the magnetotactic bacterium Magnetospirillum magneticum AMB-1, was recently shown to promote the proteolytic processing of itself and two other biomineralization factors in vivo Here, we have analyzed the in vivo processing patterns of three proteolytic targets and used this information to reconstitute proteolysis with a purified form of MamE. MamE cleaves a custom peptide substrate with positive cooperativity, and its autoproteolysis can be stimulated with exogenous substrates or peptides that bind to either of its PDZ domains. A misregulated form of the protease that circumvents specific genetic requirements for proteolysis causes biomineralization defects, showing that proper regulation of its activity is required during magnetite biosynthesis in vivo Our results represent the first reconstitution of the proteolytic activity of MamE and show that its behavior is consistent with the previously proposed checkpoint model for biomineralization. PMID:27302060

  18. Protective effect of nuclear factor E2-related factor 2 on inflammatory cytokine response to brominated diphenyl ether-47 in the HTR-8/SVneo human first trimester extravillous trophoblast cell line

    SciTech Connect

    Park, Hae-Ryung Loch-Caruso, Rita

    2014-11-15

    Polybrominated diphenyl ethers (PBDEs) are widely used flame retardants, and BDE-47 is a prevalent PBDE congener detected in human tissues. Exposure to PBDEs has been linked to adverse pregnancy outcomes in humans. Although the underlying mechanisms of adverse birth outcomes are poorly understood, critical roles for oxidative stress and inflammation are implicated. The present study investigated antioxidant responses in a human extravillous trophoblast cell line, HTR-8/SVneo, and examined the role of nuclear factor E2-related factor 2 (Nrf2), an antioxidative transcription factor, in BDE-47-induced inflammatory responses in the cells. Treatment of HTR-8/SVneo cells with 5, 10, 15, and 20 μM BDE-47 for 24 h increased intracellular glutathione (GSH) levels compared to solvent control. Treatment of HTR-8/SVneo cells with 20 μM BDE-47 for 24 h induced the antioxidant response element (ARE) activity, indicating Nrf2 transactivation by BDE-47 treatment, and resulted in differential expression of redox-sensitive genes compared to solvent control. Pretreatment with tert-butyl hydroquinone (tBHQ) or sulforaphane, known Nrf2 inducers, reduced BDE-47-stimulated IL-6 release with increased ARE reporter activity, reduced nuclear factor kappa B (NF-κB) reporter activity, increased GSH production, and stimulated expression of antioxidant genes compared to non-Nrf2 inducer pretreated groups, suggesting that Nrf2 may play a protective role against BDE-47-mediated inflammatory responses in HTR-8/SVneo cells. These results suggest that Nrf2 activation significantly attenuated BDE-47-induced IL-6 release by augmentation of cellular antioxidative system via upregulation of Nrf2 signaling pathways, and that Nrf2 induction may be a potential therapeutic target to reduce adverse pregnancy outcomes associated with toxicant-induced oxidative stress and inflammation. - Highlights: • BDE-47 stimulated ARE reporter activity and GSH production. • BDE-47 resulted in differential

  19. Construction of an attenuated Salmonella enterica serovar Paratyphi A vaccine strain harboring defined mutations in htrA and yncD.

    PubMed

    Zhu, Chunyue; Xiong, Kun; Chen, Zhijin; Hu, Xiaomei; Li, Jianhua; Wang, Yiran; Rao, Xiancai; Cong, Yanguang

    2015-08-01

    The global epidemic features of enteric fever have changed greatly in recent years. The incidence of enteric fever caused by Salmonella enterica serovar Paratyphi A has progressively increased. In some areas of Asia, infections with S. Paratyphi A have exceeded those with S. Typhi, resulting in S. Paratyphi A becoming the main causative agent of enteric fever. However, two currently licensed typhoid vaccines do not confer adequate cross-protection against S. Paratyphi A infection. Therefore, development of specific vaccines against enteric fever caused by S. Paratyphi A is urgently needed. In the present study, an attenuated strain was constructed by double deletion of the htrA and yncD genes in a wild-type strain of S. Paratyphi A and its safety and immunogenicity assessed. In a mouse model, the 50% lethal dose of the double deletion mutant and the wild-type strain were 3.0 × 10(8) CFU and 1.9 × 10(3) CFU, respectively, suggesting that the double deletion resulted in remarkably decreased bacterial virulence. Bacterial colonization of the double deletion mutant in the livers and spleens of infected mice was strikingly less than that of the wild-type strain. A single nasal administration of the attenuated vaccine candidate elicited high concentrations of anti-LPS and anti-flagellin IgG in a mouse model and protected immunized mice against lethal challenge with the wild-type strain. Thus, our findings suggest that the attenuated vaccine strain is a promising candidate worthy of further evaluation both as a human enteric fever vaccine and as a vaccine delivery vector for heterologous antigens. PMID:26084199

  20. Assignment of the gene encoding the 5-HT{sub 1E} serotonin receptor (S31) (locus HTR1E) to human chromosome 6q14-q15

    SciTech Connect

    Levy, F.O.; Tasken, K.; Solberg, R.

    1994-08-01

    The human gene for the 5-HT{sub 1E} serotonin receptor was recently cloned, but no chromosomal assignment has yet been given to this gene (locus HTR1E). In this work, we demonstrate by two independent polymerase chain reactions on a panel of human-hamster somatic cell hybrid genomic DNA that the 5-HT{sub 1E} serotonin receptor gene is localized on human chromosome 6. Furthermore, by means of in situ hybridization to human metaphase chromosomes, using the cloned 5-HT{sub 1E} receptor gene (phage clone {lambda}-S31) as a probe, we demonstrate that this gene is localized to the q14-q15 region on chromosome 6. Screening of genomic DNA from 15 unrelated Caucasian individuals, using as a probe the open reading frame of the cloned 5-HT{sub 1E} receptor gene, did not reveal any restriction fragment length polymorphisms with the enzymes BamHI, BanII, BglII, EcoRI, HincII, HindIII, HinfI, MspI, PstI, and PvuII. Since the 5-HT{sub 1E} receptor is found mainly in the cerebral cortex and abnormal function of the serotonergic system has been implicated in a variety of neurologic and psychiatric diseases, the precise chromosomal assignment of the 5-HT{sub 1E} receptor gene is the crucial first step toward the evaluation of this locus as a candidate for mutations in such syndromes. 28 refs., 2 figs., 2 tabs.

  1. Vom Urknall zum Durchknall

    NASA Astrophysics Data System (ADS)

    Unzicker, Alexander

    Lautstarker Applaus erhob sich im Salon III/IV des Marriott-Hotels von Crystal City im amerikanischen Bundesstaat Virginia. In dem überfüllten Konferenzraum starrten alle wie gebannt auf die Leinwand, wo nicht mehr zu sehen war als ein nüchternes Diagramm aus zahlreichen Punkten und einer geschwungenen Kurve. Nureine eigenartige Personengruppe konnte sich davon zu Emotionen hinreißen lassen - Physiker auf der Jahrestagung der Astronomischen Gesellschaft, die ihren Begeisterungssturm noch minutenlang fortsetzten. Was war geschehen? Die im Diagramm aufgetragenen Daten bestätigten mit einer nie da gewesenen Genauigkeit ein fundamentales Naturgesetz zur Wärmeabstrahlung von heißen Körpern. 1900 von Max Planck entdeckt, leuchtete es nun in geradezu mathematischer Reinheit auf. Noch sensationeller war der Ursprung der Daten - Mikrowellensignale verschiedener Frequenzen, die nicht aus einem irdischen Labor stammten, sondern von einem heißen Urzustand des Universums! Ein Feuerball aus Wasserstoff und Helium, noch ohne jegliche Strukturen, die irgendwann Leben ermöglichen sollten, ließ damals seinem Licht freien Lauf. Mehr als zehn Milliarden Jahre war es bis zu den Detektoren des vom Menschen gebauten Satelliten COBE unterwegs, der wenige Tage zuvor die Daten übertragen hatte. Wenn ich das alles wie einen Film in meiner Vorstellung ablaufen lasse, bekomme ich immer eine Gänsehaut, als würde ich die inzwischen extrem abgekühlte Strahlung tatsächlich spüren. Ihre Gleichverteilung im Raum macht uns auch deutlich, dass wir uns nicht einbilden dürfen, an einem besonderen Ort im Universum zu leben - intelligente Aliens könnten sich seitdem überall entwickelt haben! Sollten sie - was nicht wahrscheinlich ist - uns wirklich von Zeit zu Zeit über die Schulter schauen, dann hätten sie an jenem Nachmittag des 13. Januar 1990, als der Vortrag stattfand, bestimmt anerkennend mit ihrem großen Kopf genickt.

  2. Comparison of effect of sex hormone manipulation during neonatal period, on mRNA expression of Slc9a4, Nr3c2, Htr5b and Mas1 in hippocampus and frontal cortex of male and female rats.

    PubMed

    Karimi, B; Hafidzi, M N; Panandam, J M; Fuzina, N H

    2013-01-01

    It has long been known that spatial memory and the ability to navigate through space are sexually dimorphic traits among mammals, and numerous studies have shown that these traits can be altered by means of sex hormone manipulation. Hippocampus, the main organ involved in this kind of memory, has specific signature genes with high expression level compared to other regions of the brain. Based on their expression levels and the role that products of these genes can play in processes like signal transduction, mediation of hormone effects and long term potentiation, these genes can be considered as genes necessary for routine tasks of hippocampus. Male and female rat pups were injected with estradiol and testosterone respectively. at early stage of their lives to examine the effect of sex hormone manipulation on mRNA expression of Slc9a4, Nr3c2, Htr5b and Mas1 using comparative quantitative real-time polymerase chain reaction. The results showed that expressions of these genes are strongly influenced by sex hormones in both the frontal cortex and hippocampus, especially in male hippocampus, in which expression of all genes were up-regulated. Htr5b was the only gene that was affected only in the males. Expression of Mas1 was contrary to expectations, showed stronger changes in its expression in cortex than in hippocampus. Nr3c2 was down regulated in all samples but up regulated in male hippocampus, and Slc9a4 also showed a huge up-regulation in male hippocampus compared to other samples. PMID:24152851

  3. Creation of a Full-Core HTR Benchmark with the Fort St. Vrain Initial Core and Assessment of Uncertainties in the FSV Fuel Composition and Geometry

    SciTech Connect

    Martin, William R.; Lee, John C.; baxter, Alan; Wemple, Chuck

    2012-03-31

    Information and measured data from the intial Fort St. Vrain (FSV) high temperature gas reactor core is used to develop a benchmark configuration to validate computational methods for analysis of a full-core, commercial HTR configuration. Large uncertainties in the geometry and composition data for the FSV fuel and core are identified, including: (1) the relative numbers of fuel particles for the four particle types, (2) the distribution of fuel kernel diameters for the four particle types, (3) the Th:U ratio in the initial FSV core, (4) and the buffer thickness for the fissile and fertile particles. Sensitivity studies were performed to assess each of these uncertainties. A number of methods were developed to assist in these studies, including: (1) the automation of MCNP5 input files for FSV using Python scripts, (2) a simple method to verify isotopic loadings in MCNP5 input files, (3) an automated procedure to conduct a coupled MCNP5-RELAP5 analysis for a full-core FSV configuration with thermal-hydraulic feedback, and (4) a methodology for sampling kernel diameters from arbitrary power law and Gaussian PDFs that preserved fuel loading and packing factor constraints. A reference FSV fuel configuration was developed based on having a single diameter kernel for each of the four particle types, preserving known uranium and thorium loadings and packing factor (58%). Three fuel models were developed, based on representing the fuel as a mixture of kernels with two diameters, four diameters, or a continuous range of diameters. The fuel particles were put into a fuel compact using either a lattice-bsed approach or a stochastic packing methodology from RPI, and simulated with MCNP5. The results of the sensitivity studies indicated that the uncertainties in the relative numbers and sizes of fissile and fertile kernels were not important nor were the distributions of kernel diameters within their diameter ranges. The uncertainty in the Th:U ratio in the intial FSV core was

  4. No association of age-related maculopathy susceptibility protein 2/HtrA serine peptidase 1 or complement factor H polymorphisms with early age-related maculopathy in a Chinese cohort

    PubMed Central

    Chen, Jian-Huan; Yang, Yunli; Zheng, Yuqian; Qiu, Minghui; Xie, Mingliang; Lin, Wenjie; Zhang, Mingzhi; Pang, Chi Pui

    2013-01-01

    Purpose Single nucleotide polymorphisms (SNPs) of age-related maculopathy susceptibility protein 2/HtrA serine peptidase 1 (ARMS2/HTRA1) and complement factor H (CFH) have been reported to be associated with age-related macular degeneration (AMD). The purpose of this study was to investigate the association of ARMS2/HTRA1 and CFH SNPs with early age-related maculopathy (ARM) in a Han Chinese cohort. Methods The cohort consisted of 315 unrelated subjects, including 158 patients with early ARM and 157 recruited controls. Early ARM was diagnosed and graded according to the Age-Related Eye Disease Study criteria. Four SNPs in ARMS2/HTRA1 and six SNPs in CFH previously reported to be associated with AMD were genotyped using TaqMan genotyping assays. Logistic regression implemented with the R statistical language was used for association analysis. Results None of the ARMS2/HTRA1 and CFH SNPs showed any significant association with early ARM (all p>0.453), with the odds ratios ranging from 0.88 to 1.17. None of the SNPs were associated with unilateral or bilateral early ARM or any grade of early ARM (all p>0.249). Conclusions The association of ARMS2/HTRA1 and CFH SNPs in early ARM was not detected in our cohort. The findings in the current study indicated that the effects of ARMS2/HTRA1 and CFH in early ARM could be much lower compared to those in AMD. PMID:23687431

  5. Differentiation of cartilaginous anlage in entire embryonic mouse limbs cultured in a rotating bioreactor.

    NASA Astrophysics Data System (ADS)

    Duke, P.; Oakley, C.; Montufar-Solis, D.

    The embryonic mammalian limb is sensitive both in vivo and in vitro to changes in gravitational force. Hypergravity of centrifugation and microgravity of space decreased size of elements due to precocious or delayed chondrogenesis respectively. In recapitulating spaceflight experiments, premetatarsals were cultured in suspension in a low stress, low sheer rotating bioreactor, and found to be shorter than those cultured in standard culture dishes, and cartilage development was delayed. This study only measured length of the metatarsals, and did not account for possible changes in width and/or in form of the skeletal elements. Shorter cartilage elements in limbbuds cultured in the bioreactor may be due to the ability of the system to reproduce a more in vivo 3D shape than traditional organ cultures. Tissues subjected to traditional organ cultures become flattened by their own weight, attachment to the filter, and restrictions imposed by nutrient diffusion. The purpose of the current experiment was to determine if entire limb buds could be successfully cultured in the bioreactor, and to compare the effects on 3D shape with that of culturing in a culture dish system. Fore and hind limbs from E11-E13 ICR mouse embryos were placed either in the bioreactor, in Trowell culture, or fixed as controls. Limbbuds were cultured for six days, fixed, and processed either as whole mounts or embedded for histology. Qualitative analysis revealed that the Trowell culture specimens were flattened, while bioreactor culture specimens had a more in vivo-like 3D limb shape. Sections of limbbuds from both types of cultures had excellent cartilage differentiation, with apparently more cell maturation, and hypertrophy in the specimens cultured in the bioreactor. Morphometric quantitation of the cartilaginous elements for comparisons of the two culture systems was complicated due to some limb buds fusing together during culture. This problem was especially noticeable in the younger limbs, and may be rectified by embedding the limbs in a matrix (e.g. alginate) to maintain integrity of the tissue while in culture in the bioreactor. The bioreactor supported differentiation of skeletal elements in entire limbs, and maintained better external limb morphology than did the Trowell system. Supported by NIH/NIDCR Training Grant T358DE07252-08.

  6. An Unusual Variant of Anlage Tumor of Pineal Region in an Infant

    PubMed Central

    Kothari, Kanchan; Goel, Naina; Mahore, Amit

    2015-01-01

    A 9-month-old male child was brought with complaints of increasing head size for 2 months, increasing lethargy and vomiting for the last 2 days. Radiology revealed a heterogeneously enhancing, globular lesion in the pineal region with hydrocephalus. Near total excision of the tumor was carried out. The histopathological examination of the lesion showed heterogenous elements in the form of mature neuroepithelial and ectomesenchymal tissue. The pathology and radiology of this unusual lesion is discussed with relevant review of literature. PMID:25977909

  7. Identification, expression, and pharmacology of a Cys{sub 23}-Ser{sub 23} substitution in the human 5-HT{sub 2C} receptor gene (HTR2C)

    SciTech Connect

    Lappalainen, J.; Ozaki, N.; Goldman, D.

    1995-05-20

    The function of brain serotonin-2C (5-HT{sub 2C}) receptors, including behavioral and neurochemical responses to 5-HT{sub 2C} agonist challenge, has been suggested to be abnormal in individuals with neuropsychiatric disorders. Thus, it is important to identify polymorphisms and functional variants within this gene. Using SSCP analysis, the authors identified a Cys{sub 23}-Ser{sub 23} substitution (designated 5-HT{sub 2Ccys} and 5-HT{sub 2Cser}) in the first hydrophobic region of the human 5-HT{sub 2C} receptor. Allele frequencies in unrelated Caucasians were 0.13 and 0.87 for 5-HT{sub 2Cser} and 5-HT{sub 2Ccys}, respectively. DNAs from informative CEPH families were typed for this polymorphism and analyzed with respect to 20 linked markers on the X chromosome. Linkage analysis placed the 5-HT{sub 2C} receptor gene (HTR2C) on Xq24. To evaluate whether this amino acid substitution causes a variant function of this receptor, recombinant human 5-HT{sub 2Ccys} and 5-HT{sub 2Cser} receptors were expressed in Xenopus oocytes and tested for responses to 5-HT using electrophysiological techniques. Concentration-response curves for 5-HT were not significantly different in oocytes expressing either form of the receptor, suggesting that the 5-HT{sub 2Ccys} and 5-HT{sub 2Cser} receptor proteins may not differ in their responses to serotonin under baseline physiological conditions. 43 refs., 3 figs., 1 tab.

  8. Safe Hydrogen Generation by Nuclear HTR

    SciTech Connect

    Sochet, Isabelle; Viossat, Anne-Laure; Rouyer, Jean-Loup

    2004-07-01

    Several concepts of new high temperature nuclear reactors are designed to generate electricity and hydrogen. Hydrogen processes envisaged here are sulfur iodine thermo-chemical process and high temperature electrolysis. Proximity of hydrogen generation is a safety challenge for nuclear reactor. This paper describes prevention and protection against hydrogen hazards as a function of inventories and type of operation of the processes. This study is important for the designers because long distance between reactor and hydrogen facility induces difficult technological equipment. (authors)

  9. Longitude - critical examination of a bestselling book (German Title: Längengrad - Kritische Betrachtung eines Bestsellers)

    NASA Astrophysics Data System (ADS)

    Lühning, Felix

    The history of longitude determination at sea in connection with John Harrison's clock constructions was widely disseminated by Dana Sobel's novel. It is shown that this novel, however, is very inaccurate and even flawed in its basic concept and in many details. This contribution traces the true historical courses and yields distinct insights in the history of the longitude problem.

  10. Molekulare Methoden zum Nachweis, zur Quantifizierung und zum Monitoring der Mykotoxinbildung lebensmittelrelevanter Pilze

    NASA Astrophysics Data System (ADS)

    Geisen, Rolf

    Schimmelpilze kommen ubiquitär vor und spielen besonders bei pflanzlichen Lebensmitteln und Rohprodukten eine besondere Rolle als Verderbsorganismen. Es wird geschätzt, dass 20-25 % der jährlichen Produktion an pflanzlichen Produkten durch Schimmelpilze verdorben werden (Smith et al., 1994). Viele der lebensmittelrelevanten Schimmelpilze sind zudem in der Lage, Mykotoxine, toxische Sekundärmetabolite, zu bilden, was das Ausmaß des Problems deutlich macht. Die wichtigsten mykotoxinbildenden Spezies gehören zu den Fusarien (Trichothecene, Fumonisine, Zearalenon), Aspergillen (Aflatoxin, Ochratoxin, Cyclopiazonsäure) und Penicillien (Patulin, Ochratoxin). Für viele Mykotoxine, wie die Aflatoxine, Ochratoxin, Fumonisine und Trichothecene sind Grenzwerte erlassen worden, die die Verkehrsfähigkeit betroffener Produkte regeln. Die Einhaltung der Grenzwerte kann sehr genau durch offizielle chemisch-analytische Methoden, wie HPLC, GC-MS etc. kontrolliert werden. Diese analytischen Methoden sind aber für die Anwendung eines HACCP-Ansatzes zur Kontrolle der Mykotoxinbildung nur bedingt geeignet, da sie Endpunktkontrollen darstellen und nur das über eine längere Zeit gebildete Mykotoxin bestimmen. Sie sagen daher nichts über die biologischen Bedingungen zur Zeit der Bildung durch den Pilz aus.

  11. Fabrication of Uranium Oxycarbide Kernels for HTR Fuel

    SciTech Connect

    Charles Barnes; CLay Richardson; Scott Nagley; John Hunn; Eric Shaber

    2010-10-01

    Babcock and Wilcox (B&W) has been producing high quality uranium oxycarbide (UCO) kernels for Advanced Gas Reactor (AGR) fuel tests at the Idaho National Laboratory. In 2005, 350-µm, 19.7% 235U-enriched UCO kernels were produced for the AGR-1 test fuel. Following coating of these kernels and forming the coated-particles into compacts, this fuel was irradiated in the Advanced Test Reactor (ATR) from December 2006 until November 2009. B&W produced 425-µm, 14% enriched UCO kernels in 2008, and these kernels were used to produce fuel for the AGR-2 experiment that was inserted in ATR in 2010. B&W also produced 500-µm, 9.6% enriched UO2 kernels for the AGR-2 experiments. Kernels of the same size and enrichment as AGR-1 were also produced for the AGR-3/4 experiment. In addition to fabricating enriched UCO and UO2 kernels, B&W has produced more than 100 kg of natural uranium UCO kernels which are being used in coating development tests. Successive lots of kernels have demonstrated consistent high quality and also allowed for fabrication process improvements. Improvements in kernel forming were made subsequent to AGR-1 kernel production. Following fabrication of AGR-2 kernels, incremental increases in sintering furnace charge size have been demonstrated. Recently small scale sintering tests using a small development furnace equipped with a residual gas analyzer (RGA) has increased understanding of how kernel sintering parameters affect sintered kernel properties. The steps taken to increase throughput and process knowledge have reduced kernel production costs. Studies have been performed of additional modifications toward the goal of increasing capacity of the current fabrication line to use for production of first core fuel for the Next Generation Nuclear Plant (NGNP) and providing a basis for the design of a full scale fuel fabrication facility.

  12. HTR fuel design, qualification and analyses at PBMR

    SciTech Connect

    Van Der Merwe, J. J.; Venter, J. H.

    2006-07-01

    This paper presents an overview of the safety and design requirements of PBMR fuel, design and performance analyses performed, analyses models and software being developed, and the current program to qualify PBMR fuel for use in the demonstration power plant. PBMR fuel design is based on the German reference fuel design, and will be utilised inside the operating envelope of the original German fuel qualification program. Fuel design, safety functions of the fuel, phenomena that influence fuel performance and fission product release and the design criteria derived from these functions and phenomena are described. Fuel qualification and validation of analyses methods are achieved by evaluations of previous experimental irradiation data and a fuel qualification programme for PBMR type fuel. The performed and planned validation and qualification efforts are presented with some results and issues discussed. The fuel performance analyses methods and legacy software products inherited from the German fuel program are being further developed at PBMR. New models and software are being developed as new requirements such as Monte Carlo design analyses become necessary. (authors)

  13. Transport Corrections in Nodal Diffusion Codes for HTR Modeling

    SciTech Connect

    Abderrafi M. Ougouag; Frederick N. Gleicher

    2010-08-01

    The cores and reflectors of High Temperature Reactors (HTRs) of the Next Generation Nuclear Plant (NGNP) type are dominantly diffusive media from the point of view of behavior of the neutrons and their migration between the various structures of the reactor. This means that neutron diffusion theory is sufficient for modeling most features of such reactors and transport theory may not be needed for most applications. Of course, the above statement assumes the availability of homogenized diffusion theory data. The statement is true for most situations but not all. Two features of NGNP-type HTRs require that the diffusion theory-based solution be corrected for local transport effects. These two cases are the treatment of burnable poisons (BP) in the case of the prismatic block reactors and, for both pebble bed reactor (PBR) and prismatic block reactor (PMR) designs, that of control rods (CR) embedded in non-multiplying regions near the interface between fueled zones and said non-multiplying zones. The need for transport correction arises because diffusion theory-based solutions appear not to provide sufficient fidelity in these situations.

  14. Examination and improvement of the SHEM energy group structure for HTR and deep burn HTR design and analysis

    NASA Astrophysics Data System (ADS)

    Ngeleka, Tholakele Prisca

    The purpose of this study was to study and improve the SHEM energy group structures (281 and 361) and General Atomics-193 energy group structure utilizing the more systematic, consistent, and sophisticated energy group selection method referred to as contribution and point-wise cross-section driven (CPXSD) method. The SHEM-281 and -361 energy group structures were developed for LWR and General Atomics energy group structure was developed for the fast reactors. Pebble bed and Prismatic hexagonal block type fuel are used for cell analysis. DRAGON transport code was used for this task taking advantage of its capability to compute adjoint fluxes for reactor analysis. MCNP5 was used for generation of the reference solution selected due to its accuracy of neutron transport calculations. Comparisons with DRAGON calculations are presented. Pebble fuel element and Prismatic hexagonal block models were created for both codes. In the DRAGON code, analysis are conducted for the starting energy group structure by computing both forward and adjoint fluxes as well as the reaction rates and k-effective. Then forward and adjoint fluxes were used in computing the importance function of the groups, and the groups with high importance function are subdivided accordingly. The whole energy group interval of interest was divided into fast, epithermal and thermal regions. Firstly, the improvement was done for fast region and a new library was created and applied in the fuel cell analysis until the selected target criteria’s were met (10 pcm relative deviation of Δk/k and 1 percent deviation of reaction rate of interest). Then similar procedure was repeated for epithermal and thermal regions. The dominant parameters for each energy region were considered as required such as the fission cross section for fast region, absorption and scattering cross sections for epithermal region and absorption cross section for thermal region and k-effective applied for all energy regions. Pebble fuel element and the Prismatic hexagonal block were analyzed for depletion based on the improved energy group structure SHEM_TPN-531.

  15. Gasturbinen-Kraftwerke

    NASA Astrophysics Data System (ADS)

    Zahoransky, Richard; Allelein, Hans-Josef; Bollin, Elmar; Oehler, Helmut; Schelling, Udo

    Stationäre Gasturbinen-Kraftwerke zur Stromerzeugung wurden zuerst von Holzwarth Anfang des 20. Jahrhunderts zur kommerziellen Reife entwickelt und bis zum 2. Weltkrieg hergestellt. Hierbei handelte es sich um Verpuffungs-Gasturbinen mit isochorer Wärmezufuhr [6.1]. 1939 präsentierte die Firma BBC auf der Zürcher Landesausstellung die erste stationäre Gasturbine mit isobarer Wärmezufuhr, nach deren Prinzip die heutigen Gasturbinen aufgebaut sind. Diese 4 MW Maschine ist noch heute in Neuchâtel betriebsbereit. Friedrich Stolze gilt als Erfinder dieser Gasturbinen-Bauweise. Seine erste, schon 1904 bei BBC gebaute Anlage erbrachte wegen zu geringer Maschinenwirkungsgrade und zu geringer Turbineneintrittstemperatur jedoch keine Nutzleistung [6.2].

  16. Hermann Wilhelm Abich im Kaukasus: Zum zweihundertsten Geburtstag

    NASA Astrophysics Data System (ADS)

    Seibold, Ilse; Seibold, Eugen

    2006-11-01

    Hermann Abich was born in 1806 in Berlin and died in 1886 in Graz. He grew up in a wealthy family which had friendly relations with famous scientists like Alexander von Humboldt, Leopold von Buch or Carl Ritter. After his studies in Heidelberg and Berlin he turned to extended fieldwork at the volcanoes of Italy. In 1833 1834 he published excellent petrological/chemical results and got soon a good scientific reputation. Thus he was nominated as Professor for Geology and Mineralogy of the prestigious Russian University in Dorpat (now Tartu, Esthonia) in 1842. In 1844 he was sent to Armenia by the Russian authorities. For the next three decades his fieldwork with about 190 publications was concentrated on the Great and Lesser Caucasus. This was a period of Russian expansion to the South with long-lasting regional fights. But he enjoyed the support of powerful governors. He was an indefatigable and enthusiastic explorer and a precise observer and designer. His interests covered many fields: morphology, glaciology, structural geology, volcanology with Thermal Springs, mineral resources from hydrocarbons, coal, salt to ores, stratigraphy and paleontology as a base for geological maps. But he also gave advice for practical problems, and he was active in meteorology, botany and archaeology. Alltogether he became “the Father of Caucasus Geology”. The following sketch stresses only on three aspects of his activities. He was one of the first pioneers in hydrocarbon exploration, especially around the anticlines with the mud volcanoes near Baku. In many respects, however, his fundamental ideas were erronous. He explained the structure of the Great Caucasus by the traditional theories of Leopold von Buch and Elie de Beaumont. The Caucasus anticline “was elevated by forces acting from beneath”. Following them he tried to discover regularities in the strike of mountain chains. Similarily he treated volcanism like Alexander von Humboldt and Leopold von Buch with their two groups of phenomena: voluminous, mostly basaltic “elevation craters” versus isolated, mostly trachytic and relatively small cones of “true volcanoes”. In spite of the isolation of the Caucasus region he had cultivated continuously contacts with leading geologists in Europe and was honoured by many institutions. He left Russia in 1876 for Vienna planning to write there the final monograph volumes about his investigations but he died before he could complete them.

  17. Werner Heisenberg zum 100. Geburtstag: Pionier der Quantenmechanik

    NASA Astrophysics Data System (ADS)

    Jacobi, Manfred

    2001-11-01

    Werner Heisenberg war eine der prägendsten Gestalten der Physik des 20. Jahrhunderts. Zu seinen wichtigsten Verdiensten gehören die Grundlegung der Quantenmechanik, die Formulierung der Unschärferelationen sowie die Beteiligung an der Ausarbeitung der Kopenhagener Deutung der Quantenmechanik. Darüber hinaus lieferte er Arbeiten von fundamentalem Charakter zur Theorie des Atomkerns, zur kosmischen Strahlung und zur Quantenfeldtheorie. Während des Krieges war er an den Arbeiten des Uranvereins beteiligt, der die Möglichkeit einer Entwicklung von Kernwaffen untersuchte, jedoch über Vorarbeiten zur Reaktorphysik nicht hinauskam. Wegen dieser Tätigkeit wurde er bei Kriegsende für einige Monate in England interniert. Nach seiner Rückkehr widmete er sich vor allem dem Aufbau der Physik in Deutschland, die während der NS-Zeit nahezu ihrer gesamten Substanz beraubt worden war.

  18. Zum Uebersetzen fachlicher Texte (On the Translation of Technical Texts)

    ERIC Educational Resources Information Center

    Friederich, Wolf

    1975-01-01

    Reviews a 1974 East German publication on translation of scientific literature from Russian to German. Considers terminology, different standard levels of translation in East Germany, and other matters related to translation. (Text is in German.) (DH)

  19. GLATT Wirbelschichttechnologie zum Coating von Pulvern, Pellets und Mikropellets

    NASA Astrophysics Data System (ADS)

    Grave, Annette; Pöllinger, Norbert

    Wirbelschichtverfahren wurden ursprünglich in der chemischen Verfahrenstechnik angewandt. Ende der 1950er Jahre fand die Wirbelschichttrocknung Eingang in die pharmazeutische Industrie, da eine verbesserte Trocknungseffizienz im Vergleich zu bestehenden Verfahren erzielt werden konnte. Viele Granulationsprozesse wurden durch Feuchtgranulation in einem Zwangsmischer durchgeführt, worauf ein Trocknungsschritt in einem Hordentrockner folgte. Je nach Produktqualität kann eine Hordentrocknung allerdings mehrere Tage dauern. Derart lange Trocknungszeiten können bei Anwendung der Wirbelschichttrocknung häufig auf weniger als eine Stunde verkürzt werden. Die Wirbelschichttrocknung ist eine besonders effektive und schonende Art der Trocknung, da die gesamte Oberfläche der einzelnen Partikel für den Wärme- und Feuchteübergang zur Verfügung steht.

  20. Untersuchungen zum Harnsäuremetabolismus von Littorina littorea (Gastropoda)

    NASA Astrophysics Data System (ADS)

    Heil, K. P.; Eichelberg, D.

    1983-12-01

    Periwinkles, as typical inhabitants of sea-shores, are subjected to extreme changes of environmental conditions, which affect their excretion. In Littorina littorea uric acid, urea and ammonium were detected particularly in the kidney, but the only metabolite excreted was ammonium. Only the concentration of uric acid was dependent on the availability of water; decreasing periods of submersion during low tide and raised salinities caused a higher concentration of uric acid, while increasing periods of submersion and lowered salinities effected the opposite. Transfer of periwinkles within their intertidal habitat and laboratory experiments to test the effect of salinity showed that the concentration of uric acid in the kidney is adaptable. The dependence of uric acid concentration in the kidney on environmental conditions and the ammoniotelic excretion of L. littorea are discussed with regard to its particular living conditions. It is suggested that uric acid serves as nitrogen depot and has a particular function in osmoregulation.

  1. Vom Urknall zum Zerfall. Die Welt zwischen Anfang und Ende.

    NASA Astrophysics Data System (ADS)

    Fritzsch, H.

    Contents: Der Tanz mit dem Ozean. Galaktische Landkarte. Das Maß der Dinge. Der würfelnde Gott der Quantenphysik. Geheimnisvolle Felder. Materie und Antimaterie. Quarks - Urstoff unserer Welt. Zerfallende Protonen und die Einheit der Physik. Der Zauberofen. Das überschaubare Universum. Das explodierende Universum. Nachhall der Schöpfung. Der achtfache Weg der kosmischen Entwicklung. Das Ende der Welt. Einheit in der Vielfalt. Das geistige Universum. Gott und das absurde Universum.

  2. Zum Problem der Hochschulreform in Spanien: Einige ausgewahlte Daten.

    ERIC Educational Resources Information Center

    Val, Jose Cajide; Philipp, Rita Radl; Castro, Ana Porto

    1998-01-01

    Investigates the teaching, research, and management entailed in four new degree programs--physics, agricultural engineering, agricultural food-processing technology, and pharmacy courses--at Spain's University of Santiago de Compostela. Reports students' opinions of reforms in these courses, revealing dissatisfaction with facilities for practical…

  3. Zum Wissenschaftsverständnis der modernen Evolutionsbiologie

    NASA Astrophysics Data System (ADS)

    Sommer, Ralf J.

    Die moderne Evolutionsbiologie hat ihren Ursprung in den Arbeiten von Charles Darwin und Alfred Wallace (Darwin 1963). Der gemeinsame Ausgangspunkt des Evolutionsgedanken ist dabei die Beobachtung, dass die biologische Welt nicht konstant ist. Biologische Systeme und alle darin lebenden Organismen unterliegen über längere Zeiträume hinweg einer stetigen Veränderung. Diese grundlegende Eigenschaft biologischer Systeme macht die Biologie zu einer historischen Wissenschaft und stellt einen wichtigen Gegensatz zu großen Teilen der Physik dar. Obwohl die Aussage von der Veränderlichkeit der Arten heute trivial klingt, war sie im 19. Jahrhundert eine Revolution, da die Konstanz der Arten und der Welt eine vorherrschende Stellung im damaligen Weltbild hatte (Amundson 2005).

  4. Mecp2 deficiency leads to altered Htr2c pre-mRNA editing and HTR2C isoform distribution in mouse hippocampus and cerebellum

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Rett Syndrome (RTT) is a neurodevelopmental disorder caused by mutations in MECP2, a methyl-CpG binding protein and transcriptional repressor. CpG methylation plays an important role in genomic imprinting since imprinted genes are regulated by regions of differentially methylated CpGs (or ICs). A ...

  5. Evaluation of [11C]metergoline as a PET radiotracer for 5HTR in nonhuman primates

    SciTech Connect

    Hooker, J.M.; Hooker, J.M.; Kim, S.W.; Reibel, A.T.; Alexoff, D.; Xu, Y.; Shea, C.

    2010-04-20

    Metergoline, a serotonin receptor antagonist, was labeled with carbon-11 in order to evaluate its pharmacokinetics and distribution in non-human primates using positron emission tomography. [{sup 11}C]Metergoline had moderate brain uptake and exhibited heterogeneous specific binding, which was blocked by pretreatment with metergoline and altanserin throughout the cortex. Non-specific binding and insensitivity to changes in synaptic serotonin limit its potential as a PET radiotracer. However, the characterization of [{sup 11}C]metergoline pharmacokinetics and binding in the brain and peripheral organs using PET improves our understanding of metergoline drug pharmacology.

  6. Volkszählung und Mikrozensus1

    NASA Astrophysics Data System (ADS)

    Grohmann, Heinz

    Die Volkszählung (Zensus) ist seit langem weltweit eine statistische Erhebung über Bevölkerung und Erwerbstätigkeit. In vielen Ländern wird sie heute in etwa 10jährigem Abstand durchgeführt. In Deutschland wurde sie in den 80er Jahren zum Politikum. Datenschutzängste, verbunden mit politischen Vorgängen (Friedensbewegung), erregten die Menschen, und das Bundesverfassungsgericht steckte neue Grenzen ab. Nach kontroversen Auseinandersetzungen, an denen die Deutsche Statistische Gesellschaft (DStatG) konstruktiv beteiligt war, kam es zur Volkszählung 1987. Den nachfolgenden Paradigmenwechsel hin zu einem registergestützten Zensus 2011 hat die DStatG ebenfalls kreativ mitgestaltet. Im Beitrag wird dieser Weg nachgezeichnet. Das neue Konzept wird vorgestellt und kritisch gewürdigt. Betroffen war auch der Mikrozensus als größte Bevölkerungs- und Arbeitsmarktstichprobe zwischen den Zensen. Nicht zuletzt durch das Wirken eines wissenschaftlichen Beirats, dessen Mitglieder von der DStatG vorgeschlagen wurden, blieb diese Erhebung in ihrem Kern für die Zukunft erhalten.

  7. Anmerkungen zum Studienabbruch (Some Remarks about Students' Dropout). ZIFF Papiere 73.

    ERIC Educational Resources Information Center

    Peters, Otto

    This article presents reflections on the high dropout rate at distance education universities in general and at the FernUniversitat in particular. The introduction outlines four reasons why the dropout rate should not be as high as it is. The first chapter--on general aspects--addresses problems of definition of dropout, the astounding differences…

  8. Zum Einfluss der Filtergeschwindigkeit des Grundwassers auf die effektive Wärmeleitfähigkeit

    NASA Astrophysics Data System (ADS)

    Huber, Heiko; Arslan, Ulvi; Sass, Ingo

    2014-09-01

    By means of experimental investigation with a custom-built laboratory test station for measuring thermal conduction and convection, the increase in effective thermal conductivity due to the Darcy velocity in geothermal systems was investigated. The applicability of the database to in-situ geothermal systems was tested via extensive investigation at geothermal field sites. The increase in effective thermal conductivity due to groundwater flow was determined for sands of low, medium and high permeability. As a result of the study, additional recommendations have been developed for the design of groundwater-influenced geothermal systems which can complement the present directive (VDI-4640-1, 2010).

  9. Zum Franzosischunterricht in der Primarschule (French Instruction in the Primary School).

    ERIC Educational Resources Information Center

    Mader, Rolf

    1968-01-01

    This article discusses innovations in the teaching of French to German-speaking Swiss students at the primary level, based on a structural approach. Phonemics and morphology are explained, as well as the stress placed on the primary of aural comprehension and oral exercises. Word-by-word construction of sentences is eschewed and is replaced by…

  10. Zum Auf und Ab des Meeresspiegels in Skandinavien: Langer Streit um Eustasie oder Isostasie

    NASA Astrophysics Data System (ADS)

    Seibold, Eugen; Seibold, Ilse

    2012-03-01

    The phenomenon of the rise of the Scandinavian shield during the Holocene and the concomitant fall in level of the Baltic Sea has been investigated for centuries. Already in medieval times, there were reports about the coastlines of the Gulf of Bothnia that are full of relevant observations. During the eighteenth century, scientists such as Celsius and Linnaeus collected observations such as these. The result was that the search for the possible explanations of this rise-and-fall phenomenon intensified. The generally favoured explanation was that there was an active sinking of sea level in the Baltic rather than an active rising of the land surface in Fennoscandia. This was because water was seen as mobile, in contrast to a „terra firma". The relevant discussion was often emotional, and here, we try to illustrate it using material from the Geologenarchiv Freiburg (von Hoff, von Buch and Goethe). No more than a few decades later, it became obvious by the theory of Ice Age that both the sea level and the land could be mobile (eustatic sea level changes—glacial isostasy). Additionally, of course, plate tectonics had some influence: Norway is situated at the western end of the Eurasian plate and is part of a passive continental margin. There are still open research problems, many of which can be addressed using modern methods of satellite-based geophysics and geodesy. Some other aspects as the permanent uplift trend of Scandinavia since the Cambrium or the rhythmic to and fro of magma in the upper mantle during the Pleistocene are mentioned.

  11. Jahre Entwicklung der Instandhaltung - von der ausfallorientierten Instandhaltung zum gemeinsamen TPM und RCM

    NASA Astrophysics Data System (ADS)

    Iske, Friedhelm

    Zur Einleitung meines Beitrages möchte ich von einem Gespräch mit einem Mitarbeiter berichten, das ich als junger Vorgesetzter einer Instandhaltungsgruppe 1988 führte. Der engagierte Mitarbeiter feierte damals sein vierzigjähriges Dienstjubiläum und war stolz auf das von ihm Geleistete sowie auf den besonderen Einsatz seiner Altersgruppe, die nach dem Zweiten Weltkrieg das Werk wieder aufgebaut hatte. Auf meine Frage, was denn damals die erste Aufgabe in der Firma war, bekam ich kurz und knapp und mit einer Selbstverständlichkeit die selbstbewusste Antwort: "Unser Pferd füttern und mit dem Pferd die innerbetrieblichen Transporte erledigen“. Als junger, technisch orientierter Vorgesetzter war ich über diese Antwort sehr überrascht. Gedanklich weit entfernt war die Vorstellung, dass in der Vergangenheit Transporte mit einem Pferd erledigt wurden.

  12. Mit Training vom Tragen Wissen zum Kompetenten Handeln? (With Training from Inert Knowledge to Competent Acting?).

    ERIC Educational Resources Information Center

    Wahl, Diethelm

    2002-01-01

    Argues that all forms of education have difficulty moving from knowledge to competent acting. Discusses practical exercise as an alternative to bridge the gap. Recognizes that exercises have to be embedded in trans-situational aims and planning and must include inert emotions. Proposes different training schemes for methodological-didactic and…

  13. Lehrer in der Bundesrepublik Deutschland. Eine Kritische Analyse Statistischer Daten uber das Lehrpersonal an Allgemeinbildenden Schulen. (Education in the Federal Republic of Germany. A Statistical Study of Teachers in Schools of General Education.)

    ERIC Educational Resources Information Center

    Kohler, Helmut

    The purpose of this study was to analyze the available statistics concerning teachers in schools of general education in the Federal Republic of Germany. An analysis of the demographic structure of the pool of full-time teachers showed that in 1971 30 percent of the teachers were under age 30, and 50 percent were under age 35. It was expected that…

  14. Fission product retention in TRISCO coated UO sub 2 particle fuels subjected to HTR simulated core heating tests

    SciTech Connect

    Baldwin, C.A.; Kania, M.J.

    1990-11-01

    Results of the examination and analysis of 25,730 individual microspheres from spherical fuel elements HFR-K3/1 and HFR-K3/3 are reported. The parent spheres were irradiated in excess of end-of-life exposure and subsequently subjected to simulated core heating tests in a special high-temperature furnace at Forschungszentrum, Juelich, GmbH (KFA). Following the heating tests, the spheres were electrolytically deconsolidated to obtain unbonded fuel particles for Irradiated Microsphere Gamma Analyzer (IMGA) analysis. For sphere HFR-K3/1, which was heated for 500 h at 1600{degree}C, only four particles were identified as having released fission products. The remaining particles from the sphere showed no statistical evidence of fission product release. Scanning Electron Microscopy (SEM) examination showed that three of the defect particles had large sections of the TRISO coating missing, while the fourth appeared normal. For sphere HFR-K3/3, which was heated for 100 h at 1800{degree}C, the IMGA data revealed that fission product release (cesium) from individual particles was significant and that there was large particle-to-particle variation in retention capabilities. Individual particle release (cesium) averaged ten times the KFA-measured integral spherical fuel element release value. In addition, the bimodal distribution of the individual particle data indicated that two distinct modes of failure at fuel temperatures of 1800{degree}C and above may exist. 6 refs., 6 figs., 4 tabs.

  15. Effects of thermal treatment on the mechanical integrity of silicon carbide in HTR fuel up to 2200 °C

    NASA Astrophysics Data System (ADS)

    Rohbeck, Nadia; Xiao, Ping

    2014-08-01

    Achieving inherent safety of the High Temperature Reactor relies on the exceptional performance of its fuel. The design foresees complete encapsulation of all fissionable material by layers of carbon and silicon carbide (SiC) forming the tristructural-isotropic fuel particle. Its mechanical integrity and ability to fully retain fission products even in the event of an accident is a vital safety concern. The present study investigates the effect of post-deposition annealing on the SiC coating at design-based accident temperatures and beyond. Therefore, samples of simulated fuel have been fabricated by fluidized bed chemical vapour deposition and thermally treated in inert atmosphere up to 2200 °C. Nanoindentation and crush test measurements showed only minor reductions of elastic modulus and fracture strength up to 2000 °C. Substantial weight loss and crystal growth were observed at annealing temperatures of 2100 °C and above. Raman spectroscopy identified the formation of a multi-layered graphene film covering the SiC grains after annealing and scanning electron microscopy revealed significant porosity formation within the coating from 1800 °C onwards. These observations were attributed towards an evaporation-precipitation mechanism of SiC at very elevated temperatures that only slightly diminishes the hardness, elastic modulus or fracture strength, but might still be problematic in respect to fission product retention of the SiC layer.

  16. HTR 2014 Paper - Comparison of fission product release predictions using PARFUME with results from the AGR-1 safety tests

    SciTech Connect

    Blaise P. Collin

    2001-10-01

    Safety tests were conducted on fourteen fuel compacts from AGR-1, the first irradiation experiment of the Advanced Gas Reactor (AGR) Fuel Development and Qualification program, at temperatures ranging from 1600 to 1800°C to determine fission product release at temperatures that bound reactor accident conditions. The PARFUME (PARticle FUel ModEl) code was used to predict the release of fission products silver, cesium, strontium, and krypton from fuel compacts containing tristructural isotropic (TRISO) coated particles during the safety tests, and the predicted values were compared with experimental results. Preliminary comparisons between PARFUME predictions and post-irradiation examination (PIE) results of the safety tests show an overall over-prediction of the fractional release of these fission products, which is largely attributed to an over-estimation of the diffusivities used in the modeling of fission product transport in TRISO-coated particles. Correction factors to these diffusivities were assessed for silver and cesium in order to enable a better match between the modeling predictions and the safety testing results. In the case of strontium, correction factors could not be assessed because potential release during the safety tests could not be distinguished from matrix content released during irradiation. In the case of krypton, all the coating layers are partly retentive and the available data did not allow to determine their respective retention powers, hence preventing to derive any correction factors.

  17. HTR-2014 Paper Comparison of fission product release predictions using PARFUME with results from the AGR-1 irradiation experiment

    SciTech Connect

    Blaise Collin

    2001-10-01

    The PARFUME (PARticle FUel ModEl) code was used to predict fission product release from tristructural isotropic (TRISO) coated fuel particles and compacts during the first irradiation experiment (AGR-1) of the Advanced Gas Reactor Fuel Development and Qualification program. The PARFUME model for the AGR-1 experiment used the fuel compact volume average temperature for each of the 620 days of irradiation to calculate the release of fission products silver, cesium, and strontium from a representative particle for a select number of AGR-1 compacts. Post-irradiation examination (PIE) measurements provided data on release of fission products from fuel compacts and fuel particles, and retention of fission products in the compacts outside of the SiC layer. PARFUME-predicted fractional release of these fission products was determined and compared to the PIE measurements. Results show an overall over-prediction of the fractional release of cesium by PARFUME. For particles with failed silicon carbide (SiC) layers, the over-prediction is by a factor of about two, corresponding to an over-estimation of the diffusivity in uranium oxycarbide (UCO) by a factor of about 100. For intact particles, whose release is much lower, the over-prediction is by an average of about an order of magnitude, which could additionally be attributed to an over-estimated diffusivity in SiC by about 30%. The release of strontium from intact particles is also over-estimated by PARFUME, which also points towards an over-estimated diffusivity of strontium in either SiC or UCO, or possibly both. The measured strontium fractional release from intact particles varied considerably from compact to compact, making it difficult to assess the effective over-estimation of the diffusivities. Furthermore, the release of strontium from particles with failed SiC is difficult to observe experimentally due to the release from intact particles, preventing any conclusions to be made on the accuracy or validity of the PARFUME predictions and the modeled diffusivity of strontium in UCO. In the case of silver, the comparisons between PARFUME and PIE are better than for cesium and strontium. They show a trend of over-prediction at low burnup and under-prediction at high burnup. PARFUME has limitations in the modeling of the temporal and spatial distributions of the temperature and burnup across the compacts, which affects the accuracy of its predictions. Nevertheless, the comparisons lie in the same order of magnitude.

  18. Final Report on Utilization of TRU TRISO Fuel as Applied to HTR Systems Part II: Prismatic Reactor Cross Section Generation

    SciTech Connect

    Vincent Descotes

    2011-03-01

    The deep-burn prismatic high temperature reactor is made up of an annular core loaded with transuranic isotopes and surrounded in the center and in the periphery by reflector blocks in graphite. This disposition creates challenges for the neutronics compared to usual light water reactor calculation schemes. The longer mean free path of neutrons in graphite affects the neutron spectrum deep inside the blocks located next to the reflector. The neutron thermalisation in the graphite leads to two characteristic fission peaks at the inner and outer interfaces as a result of the increased thermal flux seen in those assemblies. Spectral changes are seen at least on half of the fuel blocks adjacent to the reflector. This spectral effect of the reflector may prevent us from successfully using the two step scheme -lattice then core calculation- typically used for light water reactors. We have been studying the core without control mechanisms to provide input for the development of a complete calculation scheme. To correct the spectrum at the lattice level, we have tried to generate cross-sections from supercell calculations at the lattice level, thus taking into account part of the graphite surrounding the blocks of interest for generating the homogenised cross-sections for the full-core calculation. This one has been done with 2 to 295 groups to assess if increasing the number of groups leads to more accurate results. A comparison with a classical single block model has been done. Both paths were compared to a reference calculation done with MCNP. It is concluded that the agreement with MCNP is better with supercells, but that the single block model remains quite close if enough groups are kept for the core calculation. 26 groups seems to be a good compromise between time and accu- racy. However, some trials with depletion have shown huge variations of the isotopic composition across a block next to the reflector. It may imply that at least an in- core depletion for the number density calculation may be necessary in the complete calculation scheme.

  19. Lernen und Lehren von Mathematik-Analysen zum Unterrichtshandeln II - Band 6, IDM-Reihe, Untersuchungen zum Mathematikunterricht. (Learning and Teaching of Mathematics - Analysis of Instructional Actions II - Volume 6, IDM Series, Inquiries into Mathematics Instruction.)

    ERIC Educational Resources Information Center

    Bauersfeld, Heinrich; And Others

    This set of five papers, written in German with abstracts in English, was collected by the Institut fuer Didaktit der Mathematik (Institute for the Teaching of Mathematics) at the University of Bielefeld in West Germany. In the first paper, Bauersfeld considers domains of subjective experiences as the best issue for an interactive theory of…

  20. Zum Ausgleich von generativer und energetischer Sprachbetrachtung (A Comparison of the "Generative" and "Energetic" Views of Language)

    ERIC Educational Resources Information Center

    Weisgerber, Leo

    1972-01-01

    Discussion of two basic conceptions: Wilhelm von Humboldt's idea of language as energeia'' existing within and without man, and Noam Chomsky's idea of language generated by the speaker according to an innate apparatus. Revised version of lectures presented at the University of Bonn, West Germany in August 1971. (RS)

  1. Sinn und Möglichkeiten der Theoretischen Physik. Zum 300. Jahrestag von Newtons Philosophiae Naturalis Principia Mathematica

    NASA Astrophysics Data System (ADS)

    Rompe, R.; Thiessen, P. A.; Treder, H.-J.

    Die Newtonschen Prinzipien und die aus ihnen gewonnene Erkenntnis der Existenz von Elementarkonstanten nach Planck, Einstein und Bohr erweisen sich zunehmend als tragfähiges Fundament nicht nur der Physik und ihrer Anwendung in der Technik, sondern überhaupt aller exakten Wissenschaften in breitestem Sinne des Wortes.Die physikalisch inhaltliche Klärung der Begriffe erfolgt seit Newton in engem Verbund mit der Entwicklung mathematischer Methoden. Diese Kombination erweist sich weiterhin als produktiv und sichert den Fortschritt der Physik und der exakten Wissenschaften.Wohl alle Probleme, die im Bereich der Technik Bedeutung haben können, lassen sich bei entsprechendem Aufwand bereits mit dem vorhandenen Fundus an Erkenntnissen und Methoden erfolgreich angehen.Der in der Wirklichkeit verankerte Zusammenhang von Gesetz und Zufall erweist sich als eine Manifestation der Dialektik in der Natur. Es gibt keinen absoluten Zufall. Sie kommt in allen Zweigen der Physik, nicht nur in der Thermodynamik und Quantenphysik, zutage, und muß bereits auf dem Niveau der Newtonschen Prinzipien und der Elementarkonstanten behandelt werden.Die theoretische Physik, so wie sie von Newton initiiert worden ist, wurde so angelegt, daß sie alle Seiten der Wirklichkeit, so weit sie in die Kompetenz der Physik fallen, umfaßt. Es besteht darum kein Gegensatz zwischen der klassischen Physik und der Quantenphysik. Es handelt sich lediglich um eine Differenzierung nach den unterschiedlichen physikalischen Inhalten und den angemessenen mathematischen Methoden, die natürlich von der Wahl der Probleme abhängen.Die theoretische Physik stellt eine allgemein zugängliche Zusammenfassung des gesicherten Wissens der Physik dar, das zugleich das Fundament der exakten Wissenschaften ist.Die theoretische Physik ist damit das Mittel der Verständigung innerhalb der Kooperation, die notwendig ist zur Lösung der großen komplexen Aufgaben der Wissenschaft und Technik.Translated AbstractThe Meaning and Abilities of Theoretical PhysicsThe Newtonean principles and - derived from them - the congnition of the exixtence of elementary constants according to Planck, Einstein and Bohr increasingly prove to be a strong base not only of physics and its apllication in technology but also of each kind of exact sciences in the broadest sense of the word.Since Newton the clarification of concepts with regard so their physical takes place in close connection with the development of mathematical methods. This combination proves to be further productive and ensures the progress of physics an of the exact sciences.Most likely all problems which may be of importance in the realm of life can be treated successfully - adequate expenditure taken for granted - with the existing fund of knowledge and methods.The connection between law and accident resting on reality proves to be a relation of complementarity (there is no absolute accident). This becomes evident in all branches in all branches of physics, not only in thermodynamics and quantum physics, and can be treated already on the level of the Newtonean principles and elementary constants.Theoretical physics as initiated by newton was designed to comprise all parts of nature. About that there is no contrast between classical physics and quantum physics. It is only a matter of differentiation with regard to the different physical contents and the appropriate mathematical methods, dependent of course on the choice problems.Theoretical physics represents a generally available concentration of the reliable knowledge of physics, which is at the same time the foundation of the exact sciences.In this way theoretical physics is the means of communication within the cooperation necessary for the solution of the great complex tasks of science and technology.

  2. Taxonomy and phylogeny of two species of the genus Deviata (Protista, Ciliophora) from China, with description of a new soil form, Deviata parabacilliformis sp. nov.

    PubMed

    Li, Fengchao; Lv, Zhao; Yi, Zhenzhen; Al-Farraj, Saleh A; Al-Rasheid, Khaled A S; Shao, Chen

    2014-11-01

    The morphology and morphogenesis of a soil hypotrichous ciliate, Deviata parabacilliformis sp. nov., isolated from northern China, were investigated. D. parabacilliformis measures about 75-210 × 25-60 µm in vivo, with an elongate and flexible body. It possesses one right marginal row, two to four left marginal rows and three dorsal kineties. The main morphogenetic features of D. parabacilliformis are: (i) the oral primordium originates de novo; (ii) anlage IV of the opisthe originates from parental frontoventral row V, anlage V originates de novo, and anlage VI forms from frontoventral row VI; and (iii) anlage I of the proter originates from the anterior portion of the parental paroral, anlage II originates from the buccal cirrus, anlage III originates from the parabuccal cirri, anlage IV originates from parental frontoventral row IV and anlage V forms from the anterior of parental frontoventral row VI. The morphology of an edaphic population of another species of the genus Deviata, Deviata bacilliformis (Gelei 1954) Eigner 1995, was also investigated. This work also provides the first record of SSU rRNA gene sequences for species of the genus Deviata. Molecular phylogenetic analysis suggests that Deviata is not monophyletic, and its position is poorly resolved due to weak phylogenetic signal of the 18S marker in the Stichotrichida. PMID:25139418

  3. Linguistic Challenges in Mendelian Genetics: Teachers' Talk in Action

    ERIC Educational Resources Information Center

    Thörne, Karin; Gericke, Niklas M.; Hagberg, Mariana

    2013-01-01

    This study investigates Swedish teachers' use of language when teaching Mendelian genetics in compulsory school. The primary objective of the study is to explore how teachers use the related concepts "gene," "allele," and "anlag" (a Swedish variant of the German word "anlage") and how these are related…

  4. Identification of a cys-ser substitution in the 5-HT{sub 2C} (HTR2C) receptor gene and allelic association to violent behavior and alcoholism

    SciTech Connect

    Lappalainen, J.; Ozaki, N.; Goldman, D.

    1994-09-01

    Several lines of evidence suggest that brain serotonergic functions, including behavioral and neurochemical responses to 5-HT{sub 2C} agonist, are abnormal in some individuals with alcoholism and aggressive behaviors. The aim of the present study was to identify coding sequence variants in the human 5-HT{sub 2C} receptor gene which may cause abnormal or variant function of this receptor. Using SSCP analysis, a non-conservative cys-ser substitution was found in the 5-HT{sub 2C} receptor (designated 5-HT{sub 2Ccys} and 5-HT{sub 2Cser}). The polymorphism was typed in CEPH families to genetically map the gene. To test for association of the variant to alcoholism, violent behavior and serotonin function, the 5-HT{sub 2C} genotypes of 151 non-related Finnish male alcoholic violent offenders and impulsive fire setters and 127 Finnish psychiatrically interviewed healthy male volunteers were determined. CSF 5-HIAA concentrations were available for 74 alcoholic violent offenders and 25 healthy volunteers. Linkage analysis placed the 5-HT{sub 2C} gene on Xq21, a region that has been previously shown to contain genes for several mental retardation syndromes. The 5-HT{sub 2Ccys}/5-HT{sub 2Cser} genotype frequencies in alcoholic violent offenders and controls differed significantly (0.90/0.10 and 0.82/0.18, respectively, P=0.048). The association was found to be strongest in the violent offenders who did not fulfill the criteria for antisocial personality disorder (5-HT{sub 2Ccys}/5-HT{sub 2Cser} 0.93/0.07, p=0.021). No association was found between CSF 5-HIAA concentrations and 5-HT{sub 2C} genotype. These results implicate a 5-HT{sub 2C} receptor amino acid substitution in predisposition to alcohol abuse and violent behavior in a subgroup of alcoholics.

  5. Mapping of the serotonin 5-HT{sub 1D{alpha}} autoreceptor gene (HTR1D) on chromosome 1 using a silent polymorphism in the coding region

    SciTech Connect

    Ozaki, N.; Lappalainen, J.; Linnoila, M.

    1995-04-24

    Serotonin (5-HT){sub ID} receptors are 5-HT release-regulating autoreceptors in the human brain. Abnormalities in brain 5-HT function have been hypothesized in the pathophysiology of various psychiatric disorders, including obsessive-compulsive disorder, autism, mood disorders, eating disorders, impulsive violent behavior, and alcoholism. Thus, mutations occurring in 5-HT autoreceptors may cause or increase the vulnerability to any of these conditions. 5-HT{sub 1D{alpha}} and 5-HT{sub 1D{Beta}} subtypes have been previously localized to chromosomes 1p36.3-p34.3 and 6q13, respectively, using rodent-human hybrids and in situ localization. In this communication, we report the detection of a 5-HT{sub 1D{alpha}} receptor gene polymorphism by single strand conformation polymorphism (SSCP) analysis of the coding sequence. The polymorphism was used for fine scale linkage mapping of 5-HT{sub 1D{alpha}} on chromosome 1. This polymorphism should also be useful for linkage studies in populations and in families. Our analysis also demonstrates that functionally significant coding sequence variants of the 5-HT{sub 1D{alpha}} are probably not abundant either among alcoholics or in the general population. 14 refs., 1 fig., 1 tab.

  6. Color-specific conditioning effects due to both orange and blue stimuli are observed in a Halobacterium salinarum strain devoid of putative methylatable sites on HtrI.

    PubMed

    Lucia, S; Cercignani, G; Frediani, A; Petracchi, D

    2003-01-01

    Behavioral responses of Halobacterium salinarum appear as changes in the frequency of motion reversals. Turning on orange light decreases the reversal frequency, whereas blue light induces reversals. Light pulses normally induce the same response as step-up stimuli. However, anomalous behavioral reactions, including inverse responses, are seen when stimuli are applied in sequence. The occurrence of a prior stimulus is conditioning for successive stimulation on a time scale of the same order of adaptational processes. These prolonged conditioning effects are color-specific. The only adaptation process identified so far is methylation of the transducers, and this could be somehow color-specific. Therefore we tested for the behavioral anomalies in a mutant in which all methylation sites on the transducer have been eliminated. The results show that behavioral anomalies are unaffected by the absence of methylation processes on the transducer. PMID:12856891

  7. Serotonin 1B Receptor Gene (HTR1B) Methylation as a Risk Factor for Callous-Unemotional Traits in Antisocial Boys.

    PubMed

    Moul, Caroline; Dobson-Stone, Carol; Brennan, John; Hawes, David J; Dadds, Mark R

    2015-01-01

    The serotonin system is thought to play a role in the aetiology of callous-unemotional (CU) traits in children. Previous research identified a functional single nucleotide polymorphism (SNP) from the promoter region of the serotonin 1B receptor gene as being associated with CU traits in boys with antisocial behaviour problems. This research tested the hypothesis that CU traits are associated with reduced methylation of the promoter region of the serotonin 1B receptor gene due to the influence of methylation on gene expression. Participants (N = 117) were boys with antisocial behaviour problems aged 3-16 years referred to University of New South Wales Child Behaviour Research Clinics. Participants volunteered a saliva sample from which the genotype of a SNP from the promoter region of the serotonin 1B receptor gene and the methylation levels of 30 CpG sites from 3 CpG regions surrounding the location of this polymorphism were assayed. Lower levels of serotonin 1B receptor gene methylation were associated with higher levels of CU traits. This relationship, however, was found to be moderated by genotype and carried exclusively by two CpG sites for which levels of methylation were negatively associated with overall methylation levels in this region of the gene. Results provide support to the emerging literature that argues for a genetically-driven system-wide alteration in serotonin function in the aetiology of CU traits. Furthermore, the results suggest that there may be two pathways to CU traits that involve methylation of the serotonin 1B receptor gene; one that is driven by a genotypic risk and another that is associated with risk for generally increased levels of methylation. Future research that aims to replicate and further investigate these results is required. PMID:25993020

  8. High-temperature gas-cooled reactor technology development program. Annual progress report for period ending December 31, 1980

    SciTech Connect

    Not Available

    1981-08-01

    Research activities are described concerning HTGR chemistry; fueled graphite development; prestressed concrete pressure vessel development; structural materials; HTGR graphite studies; HTR core evaluation; reactor physics; shielding; application and project assessments; and HTR Core Flow Test Loop studies.

  9. The time resolution domain of stellar radio astronomy

    NASA Technical Reports Server (NTRS)

    Bookbinder, J.

    1985-01-01

    The high time resolution (HTR) radio observation of late-type stars and RS CVn systems is discussed. Some examples of these sources are addressed, identifying what information HTR observations can provide. HTR can provide important information on flares in late-type stars, and can be used to study coronal structure and the particle acceleration mechanism in these stars. The possible use of HTR to establish the nature of quiescent emission form RS CVn systems is discussed.

  10. AXIAL SKELETAL AND HOX EXPRESSION DOMAIN ALTERATIONS INDUCED BY RETINOIC ACID, VALPROIC ACID AND BROMOXYNIL DURING MURINE DEVELOPMENT

    EPA Science Inventory

    ABSTRACT

    Retinoic acid (RA) alters the developmental fate of the axial skeletal anlage. "Anteriorizations" or "posteriorizations", the assumption of characteristics of embryonic areas normally anterior or posterior to the affected tissues, are correlated with altered emb...

  11. Friedrich Möglich - sein Beitrag zum Aufbau der Physik in der DDR. Friedrich Möglich - langjähriger Mitherausgeber und Chefredakteur der Annalen der Physik

    NASA Astrophysics Data System (ADS)

    Rompe, Robert

    Friedrich Möglich, ein Schüler von Max von Laue und Erwin Schrödinger, übernahm 1947 die Chefredaktion der Annalen der Physik.Translated AbstractFriedrich Möglich - His Contributions to the Formation of Physics in GDRFriedrich Möglich a student of Max von Laue and Erwin Schrödinger took over as editor in chief of Annalen der Physik in 1947.

  12. Die Indirekte Rede als Diskursstrategie: Innovative Lehrmethoden zum Konjunktiv I (Indirect Speech as a Discourse Strategy: Innovative Teaching Methods for the Subjunctive).

    ERIC Educational Resources Information Center

    Gramberg, Anne-Kathrin; Heinze, Karin U.

    1993-01-01

    This article talks about the subjunctive of indirect speech, in which its important functions and meanings are depicted. An analysis of the instructional materials used in the first and second years of language study, followed by practical curriculum recommendations, demonstrates how this grammatical phenomenon can be established in an advanced…

  13. On the 300th anniversary of the death of Gottfried Kirch, astronomer and calendar-maker (German Title: Zum 300. Todestag des Astronomen und Kalendermachers Gottfried Kirch)

    NASA Astrophysics Data System (ADS)

    Herbst, Klaus-Dieter

    2010-12-01

    Almost ten years ago, an article on Gottfried Kirch written by the present author appeared in Vol. 8 of this series, in which new biographical material drawn mainly from unpublished sources (church and burgher registers, letters) was presented. In the meantime, Kirch's correspondence appeared in print. The life of this scientist of early modern times can be traced in more detail from the correspondence and from newly found sources - numerous large writing calendars written by Kirch, previously thought to be lost. Kirch's 300th year of death offers an apt opportunity to prepare a sketch from this rich fund to recall his personality not only as an astronomer and calendar maker, but also as someone who was inclined to the spirit of the early Enlightenment and grounded in the Christianity movement of the Pietists.

  14. Philippus Feselius - Biographical notes on the unknown medicus of Kepler's Tertius Interveniens. (German Title: Philippus Feselius - Biographische Notizen zum unbekannten Medicus aus Keplers Tertius Interveniens)

    NASA Astrophysics Data System (ADS)

    Lenke, Nils; Roudet, Nicolas

    Until now, Philipp Feselius has been perceived only indirectly as Kepler's antagonist. Not much is known about his life besides his work as Baden private physician and his book against astrology which was cited intensely in Kepler's «Tertius Interveniens». This paper traces the stations of his career as a physician, about his presumable provenance and education in Strasbourg, his academic career in Tübingen, Strasbourg, Rostock and Padua, the doctorate in Basel in 1592, up to his employment, in 1599, as a court physician in Sulzburg and later in Durlach. Further hand-written and printed traces of Feselius are presented, and his social environment is investigated so that his personality becomes clearer, and relations can be established between his education and his writing against astrology.

  15. Zum Problem der Korrektur und Bewertung des commentaire de texte als Arbeits - und Pruefungsform (On the Problem of Correcting and Grading Text Commentary in Graduation Exams in French)

    ERIC Educational Resources Information Center

    Hornung, Walter

    1976-01-01

    Discusses two conflicting concepts of correcting and grading high school graduation examinations in French: "mathematical" grading of complex exercises versus objective grading of reduced segments. Recommends higher valuation on goal-orientation as against extreme objectivity. Students' performance must be evaluated individually. Various concrete…

  16. Konfektionierung und Individualisierung im Fernstudium (Ready-Made and Individualized Systems in Distance Study). Bericht zum ZIFF-Projekt 2.23. ZIFF Papiere-58.

    ERIC Educational Resources Information Center

    Lehner, H.; Weingartz, M.

    The typical traits of a ready-made system as well as those of an individualized system are constituent characteristics of distance education. Within the framework set by these qualities and the extent to which they differ from one another, one seeks to achieve the fundamental educational aim of distance students' autonomy. The way institutions see…

  17. Angleichung statt Vereinheitlichung. Ein Diskussionsbeitrag zum Thema "Normenbuch Englisch" (Assimilation Instead of Standardization. A Contribution to the Discussion of the Theme "Normenbuch Englisch")

    ERIC Educational Resources Information Center

    Schuhmacher, Karl Erhard

    1976-01-01

    Among the comments on the "Normbook for English" are: it is admirably flexible; its limiting of learning goals to "basic skills" is too undifferentiated; for the graduate exam, it rightly prefers a text assignment to a theme assignment; goal-oriented auditory understanding exercises should be added. (Text is in German.) (IFS/WGA)

  18. Neue Lautzeichen im Advanced Learners Dictionary (ALD). Stellungnahmen zum Pro und Kontra (New Sound Symbols in the Advanced Learners Dictionary [ALD]. Considerations Pro and Con)

    ERIC Educational Resources Information Center

    Zielsprache Englisch, 1976

    1976-01-01

    The phonetic symbols in the "Advanced Learners Dictionary" (Oxford University Press, London) are discussed critically in articles by L. Alfes, H. Arndt, E. Bauch, G. Dahlmann-Resing, W. Friedrich, E. Germer, B. Haycraft, H. P. Kelz. Reference is made to an earlier article "Neue Zeichen", by H. G. Hoffmann. (Text is in German.) (IFS/WGA)

  19. Zum Problem des Tests, insbesondere des Einstufungstests, im Deutschunterricht fuer Auslaender (On the Problem of Tests, Particularly Placement Tests, in Teaching German to Foreigners)

    ERIC Educational Resources Information Center

    Breitung, H. A.; And Others

    1974-01-01

    New placement procedure at Humboldt University includes interviews and placement tests. Interviews reveal response ability, tempo, pronunciation, comprehension, etc. The 60-minute test that follows is described and results discussed, as well as difficulty level and grading. Results: better grouping of students, less shifting, better work. (Text is…

  20. Probable involvement of p11 with interferon alpha induced depression

    PubMed Central

    Guo, Jiqiang; Zhang, Wen; Zhang, Lili; Ding, Huaxia; Zhang, Jingjing; Song, Chen; Zhang, Yanfei; Xia, Namei; Li, Mingfang; Liang, Yinming; Hu, Xianzhang; Luan, Haojiang; Wang, Hui

    2016-01-01

    Depression is one of the major side effects of interferon alpha (IFN-α) treatment, but the molecular mechanism underlying IFN-α-induced depression remains unclear. Several studies have shown that the serotonin receptors 5-HTR1b and 5-HTR4 play key roles in the anti-depression effects associated with p11 (S100A10). We investigated the effects of IFN-α on the regulation of p11, 5-HTR1b and 5-HTR4 in mice and human neuroblastoma cells (SH-sy5y). We found that intraperitoneal injection with IFN-α in Balb/c mice resulted in an increased immobility in FST and TST, and potently lowered the protein levels of p11, 5-HTR1b and 5-HTR4 in the hippocampus or cingulate gyrus. IFN-α significantly down-regulated the protein levels of p11, 5-HTR1b and 5-HTR4 in SH-sy5y cells, in a time- and dose-dependent manner. Our study revealed that over-expression of p11 could prevent the IFN-α-induced down-regulation of 5-HTR1b and 5-HTR4. The results indicated that IFN-α treatment resulted in p11 down-regulation, which subsequently decreased 5-HTR1b and 5-HTR4 in vitro or in vivo. Our findings suggested that p11 might be a potential regulator on 5-HTR1b and 5-HTR4 as well as a predictor of or a therapeutic target for IFN-α-induced depression. PMID:26821757

  1. Structure and Function of the Virulence-Associated High-Temperature Requirement A of Mycobacterium tuberculosis

    SciTech Connect

    MohamedMohaideen, Nilofar N.; Palaninathan, Satheesh K.; Morin, Paul M.; Williams, Brad J.; Braunstein, Miriam; Tichy, Shane E.; Locker, Joseph; Russell, David H.; Jacobs, Jr., William R.; Sacchettini, James C.

    2008-06-13

    The high-temperature requirement A (HtrA) family of serine proteases has been shown to play an important role in the environmental and cellular stress damage control system in Escherichia coli. Mycobacterium tuberculosis (Mtb) has three putative HtrA-like proteases, HtrA1, HtrA2, and HtrA3. The deletion of htrA2 gives attenuated virulence in a mouse model of TB. Biochemical analysis reveals that HtrA2 can function both as a protease and as a chaperone. The three-dimensional structure of HtrA2 determined at 2.0 {angstrom} resolution shows that the protease domains form the central core of the trimer and the PDZ domains extend to the periphery. Unlike E. coli DegS and DegP, the protease is naturally active due to the formation of the serine protease-like catalytic triad and its uniquely designed oxyanion hole. Both protease and PDZ binding pockets of each HtrA2 molecule are occupied by autoproteolytic peptide products and reveal clues for a novel autoregulatory mechanism that might have significant importance in HtrA-associated virulence of Mtb.

  2. HTR1B, ADIPOR1, PPARGC1A, and CYP19A1 and Obesity in a Cohort of Caucasians and African Americans: An Evaluation of Gene-Environment Interactions and Candidate Genes

    PubMed Central

    Edwards, Todd L.; Velez Edwards, Digna R.; Villegas, Raquel; Cohen, Sarah S.; Buchowski, Maciej S.; Fowke, Jay H.; Schlundt, David; Long, Ji Rong; Cai, Qiuyin; Zheng, Wei; Shu, Xiao-Ou; Hargreaves, Margaret K.; Jeffrey, Smith; Williams, Scott M.; Signorello, Lisa B.; Blot, William J.; Matthews, Charles E.

    2012-01-01

    The World Health Organization estimates that the number of obese and overweight adults has increased to 1.6 billion, with concomitant increases in comorbidity. While genetic factors for obesity have been extensively studied in Caucasians, fewer studies have investigated genetic determinants of body mass index (BMI; weight (kg)/height (m)2) in African Americans. A total of 38 genes and 1,086 single nucleotide polymorphisms (SNPs) in African Americans (n = 1,173) and 897 SNPs in Caucasians (n = 1,165) were examined in the Southern Community Cohort Study (2002–2009) for associations with BMI and gene × environment interactions. A statistically significant association with BMI survived correction for multiple testing at rs4140535 (β = −0.04, 95% confidence interval: −0.06, −0.02; P = 5.76 × 10−5) in African Americans but not in Caucasians. Gene-environment interactions were observed with cigarette smoking and a SNP in ADIPOR1 in African Americans, as well as between a different SNP in ADIPOR1 and physical activity in Caucasians. A SNP in PPARGC1A interacted with alcohol consumption in African Americans, and a different SNP in PPARGC1A was nominally associated in Caucasians. A SNP in CYP19A1 interacted with dietary energy intake in African Americans, and another SNP in CYP191A had an independent association with BMI in Caucasians. PMID:22106445

  3. Deep Burn: Development of Transuranic Fuel for High-Temperature Helium-Cooled Reactors- Monthly Highlights October 2010

    SciTech Connect

    Snead, Lance Lewis; Besmann, Theodore M; Collins, Emory D; Bell, Gary L

    2010-11-01

    The DB Program monthly highlights report for September 2010, ORNL/TM-2010/252, was distributed to program participants by email on October 26. This report discusses: (1) Core and Fuel Analysis; (2) Spent Fuel Management; (3) Fuel Cycle Integration of the HTR (high temperature helium-cooled reactor); (4) TRU (transuranic elements) HTR Fuel Qualification; (5) HTR Spent Fuel Recycle - (a) TRU Kernel Development (ORNL), (b) Coating Development (ORNL), (c) Characterization Development and Support, (d) ZrC Properties and Handbook; and (6) HTR Fuel Recycle.

  4. Partielle Geschlechtertrennung--Enttauschte Hoffnungen? Monoedukative Lernumgebungen zum Chancenausgleich im Unterricht auf dem Prufstand (Partial Separation of the Sexes--Disappointed Hopes? An Assessment of Non-Educative Learning Environments for Equalizing Educational Opportunities).

    ERIC Educational Resources Information Center

    Ludwig, Peter H.

    2003-01-01

    Argues that the thesis of discrimination against girls in coeducation schools has been replaced by a belief that, during certain phases or in specific subjects, abandonment of coeducation would promote equal opportunities. Questions whether classic or recent surveys provide empirical evidence for this moderate skeptical attitude towards…

  5. Auf dem Weg zu einem neuen Weltcurriculum? Zum Grundbildungskonzept von PISA und der Aufgabenzuweisung an die Schule (Towards a World Curriculum? -- The Concept of Basic Education (Literacy) underlying PISA and the tasks allocated to Schooling).

    ERIC Educational Resources Information Center

    Fuchs, Hans-Werner

    2003-01-01

    Recognizes that the debate on the Program for International Student Assessment 2000 (PISA) has been dominated by comparisons of the ranks achieved and by the question of the consequences to be drawn from the results. Discusses the educational concept forming the basis for the investigation and aims of PISA. (CAJ)

  6. Astronomical dilettante or misunderstood genius? On Johann Hieronymus Schroeter's image in the history of science. (German Title: Astronomischer Dilettant oder verkanntes Genie? Zum Bild Johann Hieronymus Schroeters in der Wissenschaftsgeschichte)

    NASA Astrophysics Data System (ADS)

    Oestmann, Günther

    The paper deals with contemporary assessments of Johann Hieronymus Schroeter's (1745-1816) astronomical works - especially by Wilhelm Olbers and Carl Friedrich Gauß - and also later judgements of the scientific importance and significance of his observations voiced by astronomers and historians.

  7. Ergebnisse einer Lehrerbefragung zum Hintergrund des Englischunterrichts in der Hauptschuloberstufe (Results of a Teacher Questionnaire on the Background of Instruction in English in the Upper Grades of the Hauptschule [9-grade "terminal" school]).

    ERIC Educational Resources Information Center

    Hellwig, Karlheinz

    1980-01-01

    The questionnaire dealt with: earmarks of weaker students, parents' attitude, the teachers' training and working conditions, problems of individual instruction, time-frame, existence of professional associations, evaluation of professional conferences, and the use of media. Some evaluations are appended. (IFS/WGA)

  8. Unwilling to see with others' eyes - Mästlin's position to the scientific progress of his time. (German Title: Nicht mit fremden Augen sehen wollen - Mästlins Stellung zum wissenschaftlichen Fortschritt seiner Zeit)

    NASA Astrophysics Data System (ADS)

    Bialas, Volker

    Michael Mästlin, particularly well known as Kepler's teacher at Tübingen University, often commented on the scientific problems of his time. But before recognizing an innovation or discovery as a contribution to scientific progress, he felt bound to verify it thoroughly, as for example Galileo's celestial discoveries with the telescope. Mästlin's Lutheran beliefs abd subjective honesty let him always to search for convincing arguments to support his hesitantly expressed and critical views. We ourselves may ask whether his scientific postulate ``Unwilling to see with others' eyes'' may still be important for our own times.

  9. Michael Mästlin as a Tübingen professor - academic everyday life at the beginning of the 17th century. (German Title: Michael Mästlin als Tübinger Professor - akademischer Alltag an der Schwelle zum 17. Jahrhundert)

    NASA Astrophysics Data System (ADS)

    Wischnath, Johannes Michael

    This contribution elucidates everyday academic at Tübingen University at the beginning of the 17th century, which formed a framework for Michael Mästlin's life as a teacher ad researcher. These activities included administrative tasks, meetings and negotiations, disputations and examinations, church services, academic festivities, group ceremonies and meals. This reconstruction is not only based on unpublished files and minutes of the university and the faculty of arts, but also on the diary of the Greek scholar Martin Crusius, which contains numerous surprising and colourful details from the life of the astronomer.

  10. Zwischen Marginalitat und Allmachtsfantasien - Neuere Publikationen zum Padagogikunterricht in der Gymnasialen Oberstufe (Between Marginalization and Phantasies of Omnipotence- Recent Publications on the Teaching of Pedagogics on the Upper Secondary Level).

    ERIC Educational Resources Information Center

    Baumgart, Franzjorg; Bubenzer, Kirsten

    2001-01-01

    Sketches the institutionalization of the school subject pedagogics, the situation of the didactics of pedagogical instruction, a short survey on the recent differentiation of the field of discourse. Reports on studies that are characteristic of recent discussion on pedagogical didactics. (CMK)

  11. New variants of the human and rat nuclear hormone receptor, TR4: Expression and chromosomal localization of the human gene

    SciTech Connect

    Yoshikawa, Takeo; Detera-Wadleigh, S.D.; DuPont, B.R.

    1996-07-15

    TR4 is a new member of the nuclear hormone receptor family. This receptor is highly conserved in rat and human, but an in-frame insertion of 19 amino acid residues in the amino-terminal (A/B) region was found in the human, but an in-frame insertion of 19 amino acid residues in the amino-terminal (A/B) region was found in the human homolog, which we refer to as hTR4{alpha}1. which is homologous to hTR4{alpha}1 since it contains the extra 19 amino acids in the A/B region. The two rat transcripts showed a differential tissue distribution. Analysis of the exon-intron organization of the hTR4 A/B region showed that the 19-amino-acid peptide insert in hTR4{alpha}1 was encoded by a separate exon, indicating that hTR4{alpha}1 and hTR4{alpha}2 transcripts were produced by the differential usage of the exon. RT-PCR analysis revealed that both hTR4{alpha}1 and hTR4{alpha}2 were detectable in brain, placenta, and ovary. In contrast, the human ovarian cancer cell line, PA1, failed to express hTR4{alpha}1. By fluorescence in situ hybridization, we have mapped the hTR4 gene to 3p25, a region deleted in some forms of cancer. 24 refs., 6 figs., 1 tab.

  12. Modulation of anxiety by cortical serotonin 1A receptors

    PubMed Central

    Piszczek, Lukasz; Piszczek, Agnieszka; Kuczmanska, Joanna; Audero, Enrica; Gross, Cornelius T.

    2015-01-01

    Serotonin (5-HT) plays an important role in the modulation of behavior across animal species. The serotonin 1A receptor (Htr1a) is an inhibitory G-protein coupled receptor that is expressed both on serotonin and non-serotonin neurons in mammals. Mice lacking Htr1a show increased anxiety behavior suggesting that its activation by serotonin has an anxiolytic effect. This outcome can be mediated by either Htr1a population present on serotonin (auto-receptor) or non-serotonin neurons (hetero-receptor), or both. In addition, both transgenic and pharmacological studies have shown that serotonin acts on Htr1a during development to modulate anxiety in adulthood, demonstrating a function for this receptor in the maturation of anxiety circuits in the brain. However, previous studies have been equivocal about which Htr1a population modulates anxiety behavior, with some studies showing a role of Htr1a hetero-receptor and others implicating the auto-receptor. In particular, cell-type specific rescue and suppression of Htr1a expression in either forebrain principal neurons or brainstem serotonin neurons reached opposite conclusions about the role of the two populations in the anxiety phenotype of the knockout. One interpretation of these apparently contradictory findings is that the modulating role of these two populations depends on each other. Here we use a novel Cre-dependent inducible allele of Htr1a in mice to show that expression of Htr1a in cortical principal neurons is sufficient to modulate anxiety. Together with previous findings, these results support a hetero/auto-receptor interaction model for Htr1a function in anxiety. PMID:25759645

  13. The Empty Fortress; Infantile Autism and the Birth of the Self.

    ERIC Educational Resources Information Center

    Bettelheim, Bruno

    The nature, origin, and treatment of infantile autism are explored with a consideration of the child's world of encounter and case histories. The beginning of life, called the region of shadows, is mentioned; and the world of the newborn, body language, mutuality, autonomy, the autistic anlage, and the right side of time are examined for the…

  14. Ontogeny of the Saccus Vasculosus, a Seasonal Sensor in Fish.

    PubMed

    Maeda, Ryosuke; Shimo, Takayuki; Nakane, Yusuke; Nakao, Nobuhiro; Yoshimura, Takashi

    2015-11-01

    TSH secreted from the pars distalis (PD) of the pituitary gland stimulates the thyroid gland. In contrast, TSH secreted from the pars tuberalis (PT) of the pituitary gland regulates seasonal reproduction. The ontogeny of thyrotrophs and the regulatory mechanisms of TSH are apparently different between the PD and the PT. Interestingly, fish do not have an anatomically distinct PT, and the saccus vasculosus (SV) of fish is suggested to act as a seasonal sensor. Thus, it is possible that the SV is analogous to the PT. Here we examined the ontogeny of the pituitary gland and SV using rainbow trout. A histological analysis demonstrated the development of the pituitary anlage followed by that of the SV. Lhx3 and Pit-1, which are required for the development of PD thyrotrophs, clearly labeled the pituitary anlage. The common glycoprotein α-subunit (CGA) and TSH β-subunit (TSHB) genes were also detected in the pituitary anlage. In contrast, none of these genes were detected in the SV anlage. We then performed a microarray analysis and identified parvalbumin (Pvalb) as a marker for SV development. Because Pvalb expression was not detected in the pituitary anlage, no relationship was observed between the development of the SV and the pituitary gland. In contrast to embryos, Lhx3, Pit-1, CGA, and TSHB were all expressed in the adult SV. These results suggest that the morphological differentiation of SV occurs during the embryonic stage but that the functional differentiation into a seasonal sensor occurs in a later developmental stage. PMID:26270731

  15. Telomerase Contributes to Fludarabine Resistance in Primary Human Leukemic Lymphocytes

    PubMed Central

    Shawi, May; Chu, Tsz Wai; Martinez-Marignac, Veronica; Yu, Y.; Gryaznov, Sergei M.; Johnston, James B.; Lees-Miller, Susan P.; Assouline, Sarit E.; Autexier, Chantal; Aloyz, Raquel

    2013-01-01

    We report that Imetelstat, a telomerase inhibitor that binds to the RNA component of telomerase (hTR), can sensitize primary CLL lymphocytes to fludarabine in vitro. This effect was observed in lymphocytes from clinically resistant cases and with cytogenetic abnormalities associated with bad prognosis. Imetelstat mediated-sensitization to fludarabine was not associated with telomerase activity, but with the basal expression of Ku80. Since both Imetelstat and Ku80 bind hTR, we assessed 1) if Ku80 and Imetelstat alter each other's binding to hTR in vitro and 2) the effect of an oligonucleotide complementary to the Ku binding site in hTR (Ku oligo) on the survival of primary CLL lymphocytes exposed to fludarabine. We show that Imetelstat interferes with the binding of Ku70/80 (Ku) to hTR and that the Ku oligo can sensitize CLL lymphocytes to FLU. Our results suggest that Ku binding to hTR may contribute to fludarabine resistance in CLL lmphocytes. This is the first report highlighting the potentially broad effectiveness of Imetelstat in CLL, and the potential biological and clinical implications of a functional interaction between Ku and hTR in primary human cancer cells. PMID:23922990

  16. Deep Burn: Development of Transuranic Fuel for High-Temperature Helium-Cooled Reactors- Monthly Highlights September 2010

    SciTech Connect

    Snead, Lance Lewis; Besmann, Theodore M; Collins, Emory D; Bell, Gary L

    2010-10-01

    The DB Program monthly highlights report for August 2010, ORNL/TM-2010/184, was distributed to program participants by email on September 17. This report discusses: (1) Core and Fuel Analysis - (a) Core Design Optimization in the HTR (high temperature helium-cooled reactor) Prismatic Design (Logos), (b) Core Design Optimization in the HTR Pebble Bed Design (INL), (c) Microfuel analysis for the DB HTR (INL, GA, Logos); (2) Spent Fuel Management - (a) TRISO (tri-structural isotropic) repository behavior (UNLV), (b) Repository performance of TRISO fuel (UCB); (3) Fuel Cycle Integration of the HTR (high temperature helium-cooled reactor) - Synergy with other reactor fuel cycles (GA, Logos); (4) TRU (transuranic elements) HTR Fuel Qualification - (a) Thermochemical Modeling, (b) Actinide and Fission Product Transport, (c) Radiation Damage and Properties; (5) HTR Spent Fuel Recycle - (a) TRU Kernel Development (ORNL), (b) Coating Development (ORNL), (c) Characterization Development and Support, (d) ZrC Properties and Handbook; and (6) HTR Fuel Recycle - (a) Graphite Recycle (ORNL), (b) Aqueous Reprocessing, (c) Pyrochemical Reprocessing METROX (metal recovery from oxide fuel) Process Development (ANL).

  17. Inferring Infection Patterns Based on a Connectivity Map of Host Transcriptional Responses.

    PubMed

    Han, Lu; He, Haochen; Li, Fei; Cui, Xiuliang; Xie, Dafei; Liu, Yang; Zheng, Xiaofei; Bai, Hui; Wang, Shengqi; Bo, Xiaochen

    2015-01-01

    Host responses to infections represent an important pathogenicity determiner, and delineation of host responses can elucidate pathogenesis processes and inform the development of anti-infection therapies. Low cost, high throughput, easy quantitation, and rich descriptions have made gene expression profiling generated by DNA microarrays an optimal approach for describing host transcriptional responses (HTRs). However, efforts to characterize the landscape of HTRs to diverse pathogens are far from offering a comprehensive view. Here, we developed an HTR Connectivity Map based on systematic assessment of pairwise similarities of HTRs to 50 clinically important human pathogens using 1353 gene-expression profiles generated from >60 human cells/tissues. These 50 pathogens were further partitioned into eight robust "HTR communities" (i.e., groups with more consensus internal HTR similarities). These communities showed enrichment in specific infection attributes and differential gene expression patterns. Using query signatures of HTRs to external pathogens, we demonstrated four distinct modes of HTR associations among different pathogens types/class, and validated the reliability of the HTR community divisions for differentiating and categorizing pathogens from a host-oriented perspective. These findings provide a first-generation HTR Connectivity Map of 50 diverse pathogens, and demonstrate the potential for using annotated HTR community to detect functional associations among infectious pathogens. PMID:26508266

  18. Inferring Infection Patterns Based on a Connectivity Map of Host Transcriptional Responses

    PubMed Central

    Han, Lu; He, Haochen; Li, Fei; Cui, Xiuliang; Xie, Dafei; Liu, Yang; Zheng, Xiaofei; Bai, Hui; Wang, Shengqi; Bo, Xiaochen

    2015-01-01

    Host responses to infections represent an important pathogenicity determiner, and delineation of host responses can elucidate pathogenesis processes and inform the development of anti-infection therapies. Low cost, high throughput, easy quantitation, and rich descriptions have made gene expression profiling generated by DNA microarrays an optimal approach for describing host transcriptional responses (HTRs). However, efforts to characterize the landscape of HTRs to diverse pathogens are far from offering a comprehensive view. Here, we developed an HTR Connectivity Map based on systematic assessment of pairwise similarities of HTRs to 50 clinically important human pathogens using 1353 gene-expression profiles generated from >60 human cells/tissues. These 50 pathogens were further partitioned into eight robust “HTR communities” (i.e., groups with more consensus internal HTR similarities). These communities showed enrichment in specific infection attributes and differential gene expression patterns. Using query signatures of HTRs to external pathogens, we demonstrated four distinct modes of HTR associations among different pathogens types/class, and validated the reliability of the HTR community divisions for differentiating and categorizing pathogens from a host-oriented perspective. These findings provide a first-generation HTR Connectivity Map of 50 diverse pathogens, and demonstrate the potential for using annotated HTR community to detect functional associations among infectious pathogens. PMID:26508266

  19. High Temporal Resolution Dynamic MRI and Arterial Input Function for Assessment of GFR in Pediatric Subjects

    PubMed Central

    Yoruk, Umit; Saranathan, Manojkumar; Loening, Andreas M; Hargreaves, Brian A; Vasanawala, Shreyas S

    2015-01-01

    Purpose To introduce a respiratory-gated high-spatiotemporal-resolution dynamic-contrast-enhanced MRI technique and a high-temporal-resolution aortic input function (HTR-AIF) estimation method for glomerular filtration rate (GFR) assessment in children. Methods A high-spatiotemporal-resolution DCE-MRI method with view-shared reconstruction was modified to incorporate respiratory-gating, and an AIF estimation method that uses a fraction of the k-space data from each respiratory period was developed (HTR-AIF). The method was validated using realistic digital phantom simulations and demonstrated on clinical subjects. The GFR estimates using HTR-AIF were compared to estimates obtained by using an AIF derived directly from the view-shared images. Results Digital phantom simulations showed that using the HTR-AIF technique gives more accurate AIF estimates (RMSE = 0.0932) compared to the existing estimation method (RMSE = 0.2059) that used view-sharing (VS). For simulated GFR > 27 ml/min, GFR estimation error was between 32% and 17% using view-shared AIF, whereas estimation error was less than 10% using HTR-AIF. In all clinical subjects, the HTR-AIF method resulted in higher GFR estimations than the view-shared method. Conclusion The HTR-AIF method improves the accuracy of both the AIF and GFR estimates derived from the respiratory-gated acquisitions, and makes GFR estimation feasible in free-breathing pediatric subjects. PMID:25946307

  20. Telomerase contributes to fludarabine resistance in primary human leukemic lymphocytes.

    PubMed

    Shawi, May; Chu, Tsz Wai; Martinez-Marignac, Veronica; Yu, Y; Gryaznov, Sergei M; Johnston, James B; Lees-Miller, Susan P; Assouline, Sarit E; Autexier, Chantal; Aloyz, Raquel

    2013-01-01

    We report that Imetelstat, a telomerase inhibitor that binds to the RNA component of telomerase (hTR), can sensitize primary CLL lymphocytes to fludarabine in vitro. This effect was observed in lymphocytes from clinically resistant cases and with cytogenetic abnormalities associated with bad prognosis. Imetelstat mediated-sensitization to fludarabine was not associated with telomerase activity, but with the basal expression of Ku80. Since both Imetelstat and Ku80 bind hTR, we assessed 1) if Ku80 and Imetelstat alter each other's binding to hTR in vitro and 2) the effect of an oligonucleotide complementary to the Ku binding site in hTR (Ku oligo) on the survival of primary CLL lymphocytes exposed to fludarabine. We show that Imetelstat interferes with the binding of Ku70/80 (Ku) to hTR and that the Ku oligo can sensitize CLL lymphocytes to FLU. Our results suggest that Ku binding to hTR may contribute to fludarabine resistance in CLL lmphocytes. This is the first report highlighting the potentially broad effectiveness of Imetelstat in CLL, and the potential biological and clinical implications of a functional interaction between Ku and hTR in primary human cancer cells. PMID:23922990

  1. Aortic Valve Cyclic Stretch Causes Increased Remodeling Activity and Enhanced Serotonin Receptor Responsiveness

    PubMed Central

    Balachandran, Kartik; Bakay, Marina A.; Connolly, Jeanne M.; Zhang, Xuemei; Yoganathan, Ajit P.; Levy, Robert J.

    2011-01-01

    Background Increased serotonin(5HT) receptor(5HTR) signaling has been associated with cardiac valvulopathy. Prior cell culture studies of 5HTR signaling in heart valve interstitial cells have provided mechanistic insights concerning only static conditions. We investigated the hypothesis that aortic valve biomechanics participate in the regulation of both 5HTR expression and inter-related extracellular matrix remodeling events. Methods The effects of cyclic-stretch on aortic valve 5HTR, expression, signaling and extracellular matrix remodeling were investigated using a tensile stretch bioreactor in studies which also compared the effects of adding 5HT and/or the 5HT-transporter inhibitor, Fluoxetine. Results Cyclic-stretch alone increased both proliferation and collagen in porcine aortic valve cusp samples. However, with cyclic-stretch, unlike static conditions, 5HT plus Fluoxetine caused the greatest increase in proliferation (p<0.0001), and also caused significant increases in collagen(p<0.0001) and glycosaminoglycans (p<0.0001). DNA microarray data demonstrated upregulation of 5HTR2A and 5HTR2B (>4.5 fold) for cyclic-stretch versus static (p<0.001), while expression of the 5HT transporter was not changed significantly. Extracellular matrix genes (eg. Collagen Types I,II,III, and proteoglycans) were also upregulated by cyclic-stretch. Conclusions Porcine aortic valve cusp samples subjected to cyclic stretch upregulate 5HTR2A and 2B, and also initiate remodeling activity characterized by increased proliferation and collagen production. Importantly, enhanced 5HTR responsiveness, due to increased 5HTR2A and 2B expression, results in a significantly greater response in remodeling endpoints (proliferation, collagen and GAG production) to 5HT in the presence of 5HT transporter blockade. PMID:21718840

  2. The potential role of myocardial serotonin receptor 2B expression in canine dilated cardiomyopathy.

    PubMed

    Fonfara, Sonja; Hetzel, Udo; Oyama, Mark A; Kipar, Anja

    2014-03-01

    Serotonin signalling in the heart is mediated by receptor subtype 2B (5-HTR2B). A contribution of serotonin to valvular disease has been reported, but myocardial expression of 5-HTR2B and its role in canine dilated cardiomyopathy (DCM) is not known. The aim of the present study was to investigate myocardial 5-HTR2B mRNA expression in dogs with DCM and to correlate results with expression of markers for inflammation and remodelling. Myocardial samples from eight healthy dogs, four dogs with DCM, five with cardiac diseases other than DCM and six with systemic non-cardiac diseases were investigated for 5-HTR2B mRNA expression using quantitative PCR (qPCR). The results were compared to mRNA expression of selected cytokines, matrix metalloproteinases (MMP) and tissue inhibitors of matrix metalloproteinase (TIMP). Laser microdissection with subsequent qPCR and immunohistochemistry were employed to identify the cells expressing 5-HTR2B. The myocardium of control dogs showed constitutive 5-HTR2B mRNA expression. In dogs with DCM, 5-HTR2B mRNA values were significantly greater than in all other groups, with highest levels of expression in the left ventricle and right atrium. Myocytes were identified as the source of 5-HTR2B mRNA and protein. A significant positive correlation of 5-HTR2B mRNA with expression of several cytokines, MMPs and TIMPs was observed. The findings suggest that serotonin might play a role in normal cardiac structure and function and could contribute to myocardial remodelling and functional impairment in dogs with DCM. PMID:24440442

  3. Deep Burn Develpment of Transuranic Fuel for High-Temperature Helium-Cooled Reactors - July 2010

    SciTech Connect

    Snead, Lance Lewis; Besmann, Theodore M; Collins, Emory D; Bell, Gary L

    2010-08-01

    The DB Program Quarterly Progress Report for April - June 2010, ORNL/TM/2010/140, was distributed to program participants on August 4. This report discusses the following: (1) TRU (transuranic elements) HTR (high temperature helium-cooled reactor) Fuel Modeling - (a) Thermochemical Modeling, (b) 5.3 Radiation Damage and Properties; (2) TRU HTR Fuel Qualification - (a) TRU Kernel Development, (b) Coating Development, (c) ZrC Properties and Handbook; and (3) HTR Fuel Recycle - (a) Recycle Processes, (b) Graphite Recycle, (c) Pyrochemical Reprocessing - METROX (metal recovery from oxide fuel) Process Development.

  4. Der Physik-Nobelpreis vor 100 Jahren Eine neue Eigenschaft der Materie

    NASA Astrophysics Data System (ADS)

    Jacobi, Manfred

    2003-11-01

    Im Jahre 1903 erhielten Henri Becquerel sowie Marie und Pierre Curie den Physik-Nobelpreis für die Entdeckung der Radioaktivität. Schon damals stellte Pierre Curie die Frage nach Nutzen und Gefahr dieser neuen Eigenschaft von Materie. Er war der Überzeugung, dass der Fortschritt letztlich mehr zum Nutzen als zum Schaden der Menschen beitrage.

  5. Mixture regression analysis on age at onset in bipolar disorder patients: investigation of the role of serotonergic genes.

    PubMed

    Manchia, Mirko; Zai, Clement C; Squassina, Alessio; Vincent, John B; De Luca, Vincenzo; Kennedy, James L

    2010-09-01

    Bipolar Disorder (BPD) is a complex psychiatric disease with a relevant underlying genetic basis. HTR2A T102C, HTR2C Cys23Ser, SLC6A4 5-HTTLPR and rs25531 polymorphisms were genotyped in 230 BPD patients and inserted as covariates in a mixture regression model of age at onset (AAO). 5-HTTLPR polymorphism associated with early onset component under recessive and additive model. HTR2A T102C, HTR2C Cys23Ser and 5-HTTLPR interaction terms associated with early onset component under dominant, recessive and additive model. These findings suggest a role of genes codifying for elements of the serotonergic system in influencing the AAO in BPD. PMID:20452754

  6. Gas-cooled reactor programs: High-Temperature Gas-Cooled Reactor Base-Technology Program. Annual progress report for period ending December 31, 1979

    SciTech Connect

    Not Available

    1980-07-01

    Progress in HTGR studies is reported in the following areas: HTGR chemistry; fueled graphite development; prestressed concrete pressure vessel development; structural materials; HTGR graphite studies; and evaluation of the pebble-bed HTR.

  7. A vapor-dominated reservoir exceeding 600{degrees}F at the Geysers, Sonoma County, California

    SciTech Connect

    Walters, M.A.; Sternfeld, J.N.; Haizlip, J.R.; Drenick, A.F.; Combs, Jim

    1988-01-01

    A high-temperature vapor-dominated reservoir underlies a portion of the Northwest Geysers area, Sonoma County, California. The high-temperature reservoir (HTR) is defined by flowing fluid temperatures exceeding 500º F, rock temperatures apparently exceeding 600º F and steam enthalpies of about 1320 BTU/lb. Steam from existing wells drilled in the Northwest Geysers is produced from both a “typical” Geysers reservoir and the HTR. In all cases, the HTR is in the lower portion of the wells and is overlain by a “typical” Geysers reservoir. Depth to the high-temperature reservoir is relatively uniform at about -5900 ft subsea. There are no identified lithologic or mineralogic conditions that separate the HTR from the “typical” reservoir, although the two reservoirs are vertically distinct and can be located in most wells to within about 200 ft by the use of downhole temperature-depth measurements. Gas concentrations in steam from the HTR are higher (6 to 9 wt %) than from the “typical” Geysers reservoir (0.85 to 2.6 wt %). Steam from the HTR is enriched in chloride and the heavy isotopes of water relative to the “typical” reservoir. Available static and dynamic measurements show pressures are subhydrostatic in both reservoirs with no anomalous differences between the two: the HTR pressure being near 520 psia at sea level datum. The small observed differences in pressure between the reservoirs appear to vary along a steam density gradient. It is postulated that the Northwest Geysers area evolved more slowly toward vapor-dominated conditions than other parts of The Geysers field because of its poor connection with the surface. In this paper, a model is presented in which the boundary between the HTR and “typical” reservoir is a thermodynamic feature only, resulting from recent deep venting of a liquid-dominated system in which conduction is still an important component of heat transfer.

  8. High Temperature Requirement A1, Transforming Growth Factor Beta 1, phosphoSmad2 and Ki67 in Eutopic and Ectopic Endometrium of Women With Endometriosis

    PubMed Central

    Goteri, G.; Altobelli, E.; Tossetta, G.; Zizzi, A.; Avellini, C.; Licini, C.; Lorenzi, T.; Castellucci, M.; Ciavattini, A.

    2015-01-01

    Increasing evidence supports the hypothesis that TGFβ1 signalling may be mediated by high temperature requirement A1 (HtrA1) serine protease, acting on important regulatory mechanisms such as cell proliferation and mobility. Evidence is now accumulating to suggest that HtrA1 is involved in the development and progression of several pathologies. The aim of this study was to evaluate: i) if HtrA1 and TGFβ1 expressions differ in eutopic and ectopic endometrium in women with endometriosis; ii) if HtrA1 correlates to TGFβ1, pSmad and Ki67. This study was carried out including 10 women with ovarian endometriosis (cases) and 10 women with non endometriotic diseases (controls). Endometrial tissue underwent immunohistochemical H-score analysis for HtrA1, TGFβ1, pSmad and Ki67 molecules. Data evaluation was performed by a nonparametric Kruskal-Wallis test and Spearman correlation was applied to evaluate the relationship among the molecules investigated in the epithelial and in the stromal compartment. The HtrA1 was significantly decreased in ectopic and eutopic endometrium of women with endometriosis when compared with control endometrium in epithelial compartment. TGFβ1was significantly increased in eutopic endometrium and decreased in ectopic endometrium in epithelial and stromal compartment. In addition, Ki67 was significantly increased and an increase, but not significant, was detected for pSMAd2 in eutopic and ectopic endometrium compared to control one. In summary, the significant direct correlation between TGFβ1 and pSmad2 as well as between HtrA1 and TGFβ1 and the very significant increase of Ki67 in stromal compartment of eutopic endometrium suggest a possible involvement of HtrA1 in the pathogenesis of endometriosis. PMID:26708185

  9. DNA Hypermethylation of the Serotonin Receptor Type-2A Gene Is Associated with a Worse Response to a Weight Loss Intervention in Subjects with Metabolic Syndrome

    PubMed Central

    Perez-Cornago, Aurora; Mansego, Maria L.; Zulet, María Angeles; Martinez, José Alfredo

    2014-01-01

    Understanding the regulation of gene activities depending on DNA methylation has been the subject of much recent study. However, although polymorphisms of the HTR2A gene have been associated with both obesity and psychiatric disorders, the role of HTR2A gene methylation in these illnesses remains uncertain. The aim of this study was to evaluate the association of HTR2A gene promoter methylation levels in white blood cells (WBC) with obesity traits and depressive symptoms in individuals with metabolic syndrome (MetS) enrolled in a behavioural weight loss programme. Analyses were based on 41 volunteers (mean age 49 ± 1 year) recruited within the RESMENA study. Depressive symptoms (as determined using the Beck Depression Inventory), anthropometric and biochemical measurements were analysed at the beginning and after six months of weight loss treatment. At baseline, DNA from WBC was isolated and cytosine methylation in the HTR2A gene promoter was quantified by a microarray approach. In the whole-study sample, a positive association of HTR2A gene methylation with waist circumference and insulin levels was detected at baseline. Obesity measures significantly improved after six months of dietary treatment, where a lower mean HTR2A gene methylation at baseline was associated with major reductions in body weight, BMI and fat mass after the treatment. Moreover, mean HTR2A gene methylation at baseline significantly predicted the decrease in depressive symptoms after the weight loss treatment. In conclusion, this study provides newer evidence that hypermethylation of the HTR2A gene in WBC at baseline is significantly associated with a worse response to a weight-loss intervention and with a lower decrease in depressive symptoms after the dietary treatment in subjects with MetS. PMID:24959950

  10. DETERMINATION OF GENOTYPE COMBINATIONS THAT CAN PREDICT THE OUTCOME OF THE TREATMENT OF ALCOHOL DEPENDENCE USING THE 5-HT3 ANTAGONIST ONDANSETRON

    PubMed Central

    Johnson, Bankole A.; Seneviratne, Chamindi; Wang, Xin-Qun; Ait-Daoud, Nassima; Li, Ming D.

    2013-01-01

    Objective Previously, we reported that the 5′-HTTLPR-LL and rs1042173-TT (SLC6A4-LL/TT) genotypes in the serotonin transporter gene predicted a significant reduction in the severity of alcohol consumption among alcoholics receiving the 5-HT3 antagonist ondansetron. In this study, we explored additional markers of ondansetron treatment response in alcoholics by examining polymorphisms in the HTR3A and HTR3B genes, which regulate directly the function and binding of 5-HT3 receptors to ondansetron. Method We genotyped 1 rare and 18 common single-nucleotide polymorphisms in HTR3A and HTR3B in the same sample that we had genotyped for SLC6A4-LL/TT in the previous randomized, double-blind, 11-week clinical trial. Participants were 283 European Americans who received oral ondansetron (4 μg/kg twice daily) or placebo along with weekly cognitive behavioral therapy. Associations of individual and combined genotypes with treatment response on drinking outcomes were analyzed. Results Individuals carrying one or more of genotypes rs1150226-AG and rs1176713-GG in HTR3A and rs17614942-AC in HTR3B showed a significant overall mean difference between ondansetron and placebo in drinks per drinking day (−2.50; effect size (ES)=0.867), percentage of heavy drinking days (−20.58%; ES=0.780), and percentage of days abstinent (18.18%; ES=0.683). Combining these HTR3A/HTR3B and SLC6A4-LL/TT genotypes increased the target cohort from approaching 20% (identified in our previous study) to 34%. Conclusions We present initial evidence suggesting that a combined 5-marker genotype panel can be used to predict the outcome of treatment of alcohol dependence with ondansetron. Additional, larger pharmacogenetic studies would help to validate our results. PMID:23897038

  11. On the flexibility of high temperature reactor cores for high-and low-enriched fuel

    SciTech Connect

    Bzandes, S.; Lonhert, G.

    1982-07-01

    The operational flexibility of a high temperature reactor (HTR) is not restricted to either a low- or a high-enriched fuel cycle. Both fuel cycles are possible for the same core design. The fuel cycle cost is, however, penalized for low-enriched fuel; in addition, higher uranium consumption is required. Hence, an HTR is most economical to operate in the high-enriched thorium-uranium fuel cycle.

  12. Recuperative supercritical carbon dioxide cycle

    SciTech Connect

    Sonwane, Chandrashekhar; Sprouse, Kenneth M; Subbaraman, Ganesan; O'Connor, George M; Johnson, Gregory A

    2014-11-18

    A power plant includes a closed loop, supercritical carbon dioxide system (CLS-CO.sub.2 system). The CLS-CO.sub.2 system includes a turbine-generator and a high temperature recuperator (HTR) that is arranged to receive expanded carbon dioxide from the turbine-generator. The HTR includes a plurality of heat exchangers that define respective heat exchange areas. At least two of the heat exchangers have different heat exchange areas.

  13. Investigation of the ionisation density dependence of the glow curve characteristics of LIF:MG,TI (TLD-100)

    PubMed Central

    Horowitz, Y. S.; Horowitz, A.; Oster, L.; Marino, S.; Datz, H.; Margaliot, M.

    2008-01-01

    The dependence of the shape of the glow curve of LiF:Mg,Ti (TLD-100) on ionisation density was investigated using irradiation with 90Sr/90Y beta rays, 60 and 250 kVp X rays, various heavy-charged particles and 0.2 and 14 MeV neutrons. Special attention is focused on the properties of high-temperature thermoluminescence; specifically, the behaviour of the high-temperature ratio (HTR) of Peaks 7 and 8 as a function of batch and annealing protocol. The correlation of Peaks 7 and 8 with average linear-energy-transfer (LET) is also investigated. The HTR of Peak 7 is found to be independent of LET for values of LET approximately >30 keV µm−1. The behaviour of the HTR of Peak 8 with LET is observed to be erratic, which suggests that applications using the HTR should separate the contributions of Peaks 7 and 8 using computerised glow curve deconvolution. The behaviour of the HTR following neutron irradiation is complex and not fully understood. The shape of composite Peak 5 is observed to be broader following high ionisation alpha particle irradiation, suggesting that the combined use of the HTR and the shape of Peak 5 could lead to improved ionisation density discrimination for particles of high LET. PMID:18667402

  14. Telomerase RNA Accumulates in Cajal Bodies in Human Cancer Cells

    PubMed Central

    Zhu, Yusheng; Tomlinson, Rebecca L.; Lukowiak, Andrew A.; Terns, Rebecca M.; Terns, Michael P.

    2004-01-01

    Telomerase synthesizes telomeric DNA repeats at the ends of eukaryotic chromosomes. The RNA component of the enzyme (hTR) provides the template for telomere synthesis, which is catalyzed by telomerase reverse transcriptase (hTERT). Little is known regarding the subcellular localization of hTR and hTERT and the pathway by which telomerase is assembled. Here we report the first glimpse of the detailed subcellular localization of endogenous hTR in human cells, which we obtained by fluorescence in situ hybridization (FISH). Our studies have revealed a distinctive hTR localization pattern in cancer cells. We have found that hTR accumulates within intranuclear foci called Cajal bodies in all typical tumor-derived cell lines examined (in which telomerase is active), but not in primary or ALT cells (where little or no hTERT is present). Accumulation of hTR in the Cajal bodies of primary cells is induced when hTERT is ectopically expressed. Moreover, we report that hTERT is also found in Cajal bodies. Our data suggest that Cajal bodies are involved in the assembly and/or function of human telomerase. PMID:14528011

  15. A new idea for simple and rapid monitoring of gene expression: requirement of nucleotide sequences encoding an N-terminal HA tag in the T7 promoter-driven expression in E. coli.

    PubMed

    Moon, Jeong-Mi; Kim, Goo-Young; Rhim, Hyangshuk

    2012-10-01

    Mammalian expression vectors are used to overexpress genes of interest in mammalian cells. High temperature requirement protein A1 (HtrA1), used as a specific target, was expressed from the pHA-M-HtrA1 plasmid in HEK293T cells, inducing cell death. Expression of HtrA1 was driven by the pHA-M-HtrA1 mammalian expression vector in E. coli resulting in growth suppression of E. coli in an HtrA1 serine protease-dependent manner. By using various combinations of promoters, target genes and N-terminal tags, the T7 promoter and N-terminal HA tag in the mammalian expression vector were shown to be responsible for expression of target genes in E. coli. Thus the pHA-M-HtrA1 plasmid can be used as a novel, rapid pre-test system for expression and cytotoxicity of the specific target gene in E. coli before assessing its functions in mammalian cells. PMID:22714269

  16. Gas-cooled reactor programs. High-temperature gas-cooled reactor technology development program. Annual progress report, December 31, 1983

    SciTech Connect

    Kasten, P.R.; Rittenhouse, P.L.; Bartine, D.E.; Sanders, J.P.

    1984-06-01

    ORNL continues to make significant contributions to the national program. In the HTR fuels area, we are providing detailed statistical information on the fission product retention performance of irradiated fuel. Our studies are also providing basic data on the mechanical, physical, and chemical behavior of HTR materials, including metals, ceramics, graphite, and concrete. The ORNL has an important role in the development of improved HTR graphites and in the specification of criteria that need to be met by commercial products. We are also developing improved reactor physics design methods. Our work in component development and testing centers in the Component Flow Test Loop (CFTL), which is being used to evaluate the performance of the HTR core support structure. Other work includes experimental evaluation of the shielding effectiveness of the lower portions of an HTR core. This evaluation is being performed at the ORNL Tower Shielding Facility. Researchers at ORNL are developing welding techniques for attaching steam generator tubing to the tubesheets and are testing ceramic pads on which the core posts rest. They are also performing extensive testing of aggregate materials obtained from potential HTR site areas for possible use in prestressed concrete reactor vessels. During the past year we continued to serve as a peer reviewer of small modular reactor designs being developed by GA and GE with balance-of-plant layouts being developed by Bechtel Group, Inc. We have also evaluated the national need for developing HTRs with emphasis on the longer term applications of the HTRs to fossil conversion processes.

  17. Shape and oligomerization state of the cytoplasmic domain of the phototaxis transducer II from Natronobacterium pharaonis

    PubMed Central

    Budyak, Ivan L.; Pipich, Vitaliy; Mironova, Olga S.; Schlesinger, Ramona; Zaccai, Giuseppe; Klein-Seetharaman, Judith

    2006-01-01

    Phototaxis allows archaea to adjust flagellar motion in response to light. In the photophobic response of Natronobacterium pharaonis, light-activated sensory rhodopsin II causes conformational changes in the transducer II protein (pHtrII), initiating the two-component signaling system analogous to bacterial chemotaxis. pHtrII’s cytoplasmic domain (pHtrII-cyt) is homologous to the cytoplasmic domains of eubacterial chemotaxis receptors. Chemotaxis receptors require dimerization for activity and are in vivo-organized in large clusters. In this study we investigated the oligomerization and aggregation states of pHtrII-cyt by using chemical cross-linking, analytical gel-filtration chromatography, and small-angle neutron scattering. We show that pHtrII-cyt is monomeric in dilute buffers, but forms dimers in 4 M KCl, the physiological salt concentration for halophilic archaea. At high ammonium sulfate concentration, the protein forms higher-order aggregates. The monomeric protein has a rod-like shape, 202 Å in length and 14.4 Å in diameter; upon dimerization the length increases to 248 Å and the diameter to 18.2 Å. These results suggest that under high salt concentration the shape and oligomerization state of pHtrII-cyt are comparable to those of chemotaxis receptors. PMID:17032755

  18. Impulsive alcohol-related risk-behavior and emotional dysregulation among individuals with a serotonin 2B receptor stop codon.

    PubMed

    Tikkanen, R; Tiihonen, J; Rautiainen, M R; Paunio, T; Bevilacqua, L; Panarsky, R; Goldman, D; Virkkunen, M

    2015-01-01

    A relatively common stop codon (Q20*) was identified in the serotonin 2B receptor gene (HTR2B) in a Finnish founder population in 2010 and it was associated with impulsivity. Here we examine the phenotype of HTR2B Q20* carriers in a setting comprising 14 heterozygous HTR2B Q20* carriers and 156 healthy controls without the HTR2B Q20*. The tridimensional personality questionnaire, Brown-Goodwin lifetime aggression scale, the Michigan alcoholism screening test and lifetime drinking history were used to measure personality traits, impulsive and aggressive behavior, both while sober and under the influence of alcohol, and alcohol consumption. Regression analyses showed that among the HTR2B Q20* carriers, temperamental traits resembled a passive-dependent personality profile, and the presence of the HTR2B Q20* predicted impulsive and aggressive behaviors particularly under the influence of alcohol. Results present examples of how one gene may contribute to personality structure and behaviors in a founder population and how personality may translate into behavior. PMID:26575222

  19. Analysis of the structure of human telomerase RNA in vivo

    PubMed Central

    Antal, Mária; Boros, Éva; Solymosy, Ferenc; Kiss, Tamás

    2002-01-01

    Telomerase is a ribonucleoprotein reverse transcriptase that synthesises telomeric DNA. The RNA component of telomerase acts as a template for telomere synthesis and binds the reverse transcriptase. In this study, we have performed in vivo and in vitro structural analyses of human telomerase RNA (hTR). In vivo mapping experiments showed that the 5′-terminal template domain of hTR folds into a long hairpin structure, in which the template sequence occupies a readily accessible position. Intriguingly, neither in vivo nor in vitro mapping of hTR confirmed formation of a stable ‘pseudoknot’ helix, suggesting that this functionally essential long range interaction is formed only temporarily. In vitro control mappings demonstrated that the 5′-terminal template domain of hTR cannot fold correctly in the absence of cellular protein factors. The 3′-terminal domain of hTR, both in vivo and in vitro, folds into the previously predicted box H/ACA snoRNA-like ‘hairpin–hinge–hairpin–tail’ structure. Finally, comparison of the in vivo and in vitro modification patterns of hTR revealed several regions that might be directly involved in binding of telomerase reverse transcriptase or other telomerase proteins. PMID:11842102

  20. One Odontogenic Cell-Population Contributes to the Development of the Mouse Incisors and of the Oral Vestibule.

    PubMed

    Hovorakova, Maria; Lochovska, Katerina; Zahradnicek, Oldrich; Domonkosova Tibenska, Kristina; Dornhoferova, Michaela; Horakova-Smrckova, Lucie; Bodorikova, Silvia

    2016-01-01

    The area of the oral vestibule is often a place where pathologies appear (e.g., peripheral odontomas). The origin of these pathologies is not fully understood. In the present study, we traced a cell population expressing Sonic hedgehog (Shh) from the beginning of tooth development using Cre-LoxP system in the lower jaw of wild-type (WT) mice. We focused on Shh expression in the area of the early appearing rudimentary incisor germs located anteriorly to the prospective incisors. The localization of the labelled cells in the incisor germs and also in the inner epithelial layer of the vestibular anlage showed that the first very early developmental events in the lower incisor area are common to the vestibulum oris and the prospective incisor primordia in mice. Scanning electron microscopic analysis of human historical tooth-like structures found in the vestibular area of jaws confirmed their relation to teeth and thus the capability of the vestibular tissue to form teeth. The location of labelled cells descendant of the early appearing Shh expression domain related to the rudimentary incisor anlage not only in the rudimentary and functional incisor germs but also in the externally located anlage of the oral vestibule documented the odontogenic potential of the vestibular epithelium. This potential can be awakened under pathological conditions and become a source of pathologies in the vestibular area. PMID:27611193

  1. Tibial hemimelia and femoral bifurcation.

    PubMed

    Ugras, Ali Akin; Sungur, Ibrahim; Akyildiz, Mustafa Fehmi; Ercin, Ersin

    2010-02-01

    Femoral bifurcation and tibial agenesis are rare anomalies and have been described in both the Gollop-Wolfgang complex and tibial agenesis-ectrodactyly syndrome. This article presents a case of Gollop-Wolfgang complex without hand ectrodactyly. Tibial agenesis-ectrodactyly syndrome and Gollop-Wolfgang complex are variants of tibial field defect, which includes distal femoral duplication, tibial aplasia, oligo-ectrodactylous toe defects, and preaxial polydactyly, occasionally associated with hand ectrodactyly.This article describes the case of a patient with bilateral tibial hemimelia and left femoral bifurcation. The proximal tibial anlage had not been identified in the patient's left leg. After failed fibular transfer procedure, the knee was disarticulated. The other leg was treated with tibiofibular synostosis and centralization of fibula to os calcis. At 7-year follow-up, the patient ambulates with an above-knee prosthesis and uses an orthopedic boot for ankle stability.In patients with a congenital absence of the tibia, accurate diagnosis is of the utmost importance in planning future treatment. In the absence of proximal tibial anlage, especially in patients with femoral bifurcation, the knee should be disarticulated. Tibiofibular synostosis is a good choice in the presence of a proximal tibial anlage and good quadriceps function. PMID:20192156

  2. Differential expression of 5-HT-related genes in symptomatic pulmonary embolism patients

    PubMed Central

    Jin, Yun; Wang, Lemin; Duan, Qianglin; Gong, Zhu; Yang, Fan; Song, Yanli

    2015-01-01

    Objective: Whole human genome oligo microarrays were employed to systematically investigate the mRNA expression profile of 5-HT synthetase, transporter, receptor, and factors in 5-HT signaling pathway in peripheral blood karyocytes from pulmonary embolism (PE) patients. Methods: A total of 20 PE patients and 20 healthy subjects matched in gender and age were recruited. The human genome microarrays were performed to detect the mRNA expression profile of 5-HT synthetase, transporter, receptor, and factors in 5-HT signal pathway of two groups. The random variance model corrected t-test was used for analysis. Results: Our results showed (1) tryptophan hydroxylase (TPH1)-related gene expression was markedly down-regulated in PE patients (P < 0.01); (2) monoamine oxidases (MAO)-related gene (MAOB) expression was significantly up-regulated in PE patients (P < 0.01); (3) the expression of 17 genes of 7 5-HT receptors showed a down-regulated tendency in PE patients, and significant difference was observed in the expression of HTR1E, HTR3B, HTR4 and HTR5A between them (P < 0.05); (4) the expression of DalDAG-GEF I, Tubby, PKA and EPAC in 5-HT signal pathways was dramatically up-regulated in PE patients (P < 0.05); the expression of SPA1, RIAM, RAPL, Talin, PKC, PLC and Pyk2 was remarkably up-regulated in PE patients (P < 0.05); (5) the expression of integrin genes ITGA2B, ITGB1 and ITGB3 was significantly up-regulated in PE patients (P < 0.05). Conclusion: In PE patients, the expression of TPH1 and HTR4 was down-regulated as a negative feedback; the MAOB expression was up-regulated. Consistent with the expression of 5-HTR1E and 5-HTR4 and the abnormally activated Tubby, the expression of integrins in platelets was activated. PMID:25785024

  3. A Miniaturized Screen of a Schistosoma mansoni Serotonergic G Protein-Coupled Receptor Identifies Novel Classes of Parasite-Selective Inhibitors

    PubMed Central

    Chan, John D.; McCorvy, John D.; Acharya, Sreemoyee; Day, Timothy A.; Roth, Bryan L.; Marchant, Jonathan S.

    2016-01-01

    Schistosomiasis is a tropical parasitic disease afflicting ~200 million people worldwide and current therapy depends on a single drug (praziquantel) which exhibits several non-optimal features. These shortcomings underpin the need for next generation anthelmintics, but the process of validating physiologically relevant targets (‘target selection’) and pharmacologically profiling them is challenging. Remarkably, even though over a quarter of current human therapeutics target rhodopsin-like G protein coupled receptors (GPCRs), no library screen of a flatworm GPCR has yet been reported. Here, we have pharmacologically profiled a schistosome serotonergic GPCR (Sm.5HTR) implicated as a downstream modulator of PZQ efficacy, in a miniaturized screening assay compatible with high content screening. This approach employs a split luciferase based biosensor sensitive to cellular cAMP levels that resolves the proximal kinetics of GPCR modulation in intact cells. Data evidence a divergent pharmacological signature between the parasitic serotonergic receptor and the closest human GPCR homolog (Hs.5HTR7), supporting the feasibility of optimizing parasitic selective pharmacophores. New ligands, and chemical series, with potency and selectivity for Sm.5HTR over Hs.5HTR7 are identified in vitro and validated for in vivo efficacy against schistosomules and adult worms. Sm.5HTR also displayed a property resembling irreversible inactivation, a phenomenon discovered at Hs.5HTR7, which enhances the appeal of this abundantly expressed parasite GPCR as a target for anthelmintic ligand design. Overall, these data underscore the feasibility of profiling flatworm GPCRs in a high throughput screening format competent to resolve different classes of GPCR modulators. Further, these data underscore the promise of Sm.5HTR as a chemotherapeutically vulnerable node for development of next generation anthelmintics. PMID:27187180

  4. A Miniaturized Screen of a Schistosoma mansoni Serotonergic G Protein-Coupled Receptor Identifies Novel Classes of Parasite-Selective Inhibitors.

    PubMed

    Chan, John D; McCorvy, John D; Acharya, Sreemoyee; Johns, Malcolm E; Day, Timothy A; Roth, Bryan L; Marchant, Jonathan S

    2016-05-01

    Schistosomiasis is a tropical parasitic disease afflicting ~200 million people worldwide and current therapy depends on a single drug (praziquantel) which exhibits several non-optimal features. These shortcomings underpin the need for next generation anthelmintics, but the process of validating physiologically relevant targets ('target selection') and pharmacologically profiling them is challenging. Remarkably, even though over a quarter of current human therapeutics target rhodopsin-like G protein coupled receptors (GPCRs), no library screen of a flatworm GPCR has yet been reported. Here, we have pharmacologically profiled a schistosome serotonergic GPCR (Sm.5HTR) implicated as a downstream modulator of PZQ efficacy, in a miniaturized screening assay compatible with high content screening. This approach employs a split luciferase based biosensor sensitive to cellular cAMP levels that resolves the proximal kinetics of GPCR modulation in intact cells. Data evidence a divergent pharmacological signature between the parasitic serotonergic receptor and the closest human GPCR homolog (Hs.5HTR7), supporting the feasibility of optimizing parasitic selective pharmacophores. New ligands, and chemical series, with potency and selectivity for Sm.5HTR over Hs.5HTR7 are identified in vitro and validated for in vivo efficacy against schistosomules and adult worms. Sm.5HTR also displayed a property resembling irreversible inactivation, a phenomenon discovered at Hs.5HTR7, which enhances the appeal of this abundantly expressed parasite GPCR as a target for anthelmintic ligand design. Overall, these data underscore the feasibility of profiling flatworm GPCRs in a high throughput screening format competent to resolve different classes of GPCR modulators. Further, these data underscore the promise of Sm.5HTR as a chemotherapeutically vulnerable node for development of next generation anthelmintics. PMID:27187180

  5. Serotonin 2B Receptor Antagonism Prevents Heritable Pulmonary Arterial Hypertension

    PubMed Central

    Schroer, Alison K.; Chen, Peter; Ryzhova, Larisa M.; Gladson, Santhi; Shay, Sheila; Hutcheson, Joshua D.; Merryman, W. David

    2016-01-01

    Serotonergic anorexigens are the primary pharmacologic risk factor associated with pulmonary arterial hypertension (PAH), and the resulting PAH is clinically indistinguishable from the heritable form of disease, associated with BMPR2 mutations. Both BMPR2 mutation and agonists to the serotonin receptor HTR2B have been shown to cause activation of SRC tyrosine kinase; conversely, antagonists to HTR2B inhibit SRC trafficking and downstream function. To test the hypothesis that a HTR2B antagonist can prevent BMRP2 mutation induced PAH by restricting aberrant SRC trafficking and downstream activity, we exposed BMPR2 mutant mice, which spontaneously develop PAH, to a HTR2B antagonist, SB204741, to block the SRC activation caused by BMPR2 mutation. SB204741 prevented the development of PAH in BMPR2 mutant mice, reduced recruitment of inflammatory cells to their lungs, and reduced muscularization of their blood vessels. By atomic force microscopy, we determined that BMPR2 mutant mice normally had a doubling of vessel stiffness, which was substantially normalized by HTR2B inhibition. SB204741 reduced SRC phosphorylation and downstream activity in BMPR2 mutant mice. Gene expression arrays indicate that the primary changes were in cytoskeletal and muscle contractility genes. These results were confirmed by gel contraction assays showing that HTR2B inhibition nearly normalizes the 400% increase in gel contraction normally seen in BMPR2 mutant smooth muscle cells. Heritable PAH results from increased SRC activation, cellular contraction, and vascular resistance, but antagonism of HTR2B prevents SRC phosphorylation, downstream activity, and PAH in BMPR2 mutant mice. PMID:26863209

  6. Organoids as an ex vivo model for studying the serotonin system in the murine small intestine and colon epithelium.

    PubMed

    Tsuruta, Takeshi; Saito, Shinichi; Osaki, Yosuke; Hamada, Akihiro; Aoki-Yoshida, Ayako; Sonoyama, Kei

    2016-05-20

    Intestinal organoids were recently established as an ex vivo model of the intestinal epithelium. The present study investigated the serotonin (5-hydroxytryptamine, 5-HT) system using organoids. Organoids from murine small intestinal and colonic crypts were successfully cultured. Reverse transcription-polymerase chain reaction (RT-PCR) analysis showed that small intestinal and colonic organoids express mRNAs encoding tryptophan hydroxylase-1 (TPH1) (the rate-limiting enzyme of 5-HT synthesis), serotonin reuptake transporter (SERT), 5-HT receptor (HTR)2A, HTR2B, and HTR4. SERT mRNA levels were significantly higher in the small intestine than in the colon in both the mucosal tissues and organoids, as estimated by quantitative real-time RT-PCR. Although the 5-HT concentration and levels of chromogranin A (CgA) (an enteroendocrine cell marker), TPH1, and HTR4 mRNAs were significantly higher in the colonic mucosa than the small intestinal mucosa, they were the same in small intestinal and colonic organoids. There were no significant differences in HTR2A and HTR2B mRNA levels between the small intestine and colon in either the mucosal tissues or organoids. Immunofluorescence staining showed that the number of CgA-positive cells in the colonic organoids appeared to increase upon culturing with acetate. Acetate supplementation significantly increased CgA, TPH1, and HTR4 mRNA levels in the colonic organoids. We propose that organoids are useful for investigating the 5-HT system in the intestinal epithelium, even though colonic organoids may require gut microbiota-derived factors such as short-chain fatty acids. PMID:27105910

  7. Association Between 5HT1b Receptor Gene and Methamphetamine Dependence

    PubMed Central

    Ujike, H; Kishimoto, M; Okahisa, Y; Kodama, M; Takaki, M; Inada, T; Uchimura, N; Yamada, M; Iwata, N; Iyo, M; Sora, I; Ozaki, N

    2011-01-01

    Several lines of evidence implicate serotonergic dysfunction in diverse psychiatric disorders including anxiety, depression, and drug abuse. Mice with a knock-out of the 5HT1b receptor gene (HTR1B) displayed increased locomotor response to cocaine and elevated motivation to self-administer cocaine and alcohol. Previous genetic studies showed significant associations of HTR1B with alcohol dependence and substance abuse, but were followed by inconsistent results. We examined a case-control genetic association study of HTR1B with methamphetamine-dependence patients in a Japanese population. The subjects were 231 patients with methamphetamine dependence, 214 of whom had a co-morbidity of methamphetamine psychosis, and 248 age- and sex-matched healthy controls. The three single nucleotide polymorphisms (SNPs), rs130058 (A-165T), rs1228814 (A-700C) and rs1228814 (A+1180G) of HTR1B were genotyped. There was no significant difference in allelic and genotypic distributions of the SNPs between methamphetamine dependence and the control. Genetic associations of HTR1B were tested with several clinical phenotypes of methamphetamine dependence and/or psychosis, such as age at first abuse, duration of latency from the first abuse to onset of psychosis, prognosis of psychosis after therapy, and complication of spontaneous relapse of psychotic state. There was, however, no asscocation between any SNP and the clinical phenotypes. Haplotype analyses showed the three SNPs examined were within linkage disequilibrium, which implied that the three SNPs covered the whole HTR1B, and distribution of estimated haplotype frequency was not different between the groups. The present findings may indicate that HTR1B does not play a major role in individual susceptibility to methamphetamine dependence or development of methamphetamine-induced psychosis. PMID:21886584

  8. The effect of the sigma-1 receptor selective compound LS-1-137 on the DOI-induced head twitch response in mice.

    PubMed

    Malik, Maninder; Rangel-Barajas, Claudia; Mach, Robert H; Luedtke, Robert R

    2016-09-01

    Several receptor mediated pathways have been shown to modulate the murine head twitch response (HTR). However, the role of sigma receptors in the murine (±)-2,5-dimethoxy-4-iodoamphetamine (DOI)-induced HTR has not been previously investigated. We examined the ability of LS-1-137, a novel sigma-1 vs. sigma-2 receptor selective phenylacetamide, to modulate the DOI-induced HTR in DBA/2J mice. We also assessed the in vivo efficacy of reference sigma-1 receptor antagonists and agonists PRE-084 and PPCC. The effect of the sigma-2 receptor selective antagonist RHM-1-86 was also examined. Rotarod analysis was performed to monitor motor coordination after LS-1-137 administration. Radioligand binding techniques were used to determine the affinity of LS-1-137 at 5-HT2A and 5-HT2C receptors. LS-1-137 and the sigma-1 receptor antagonists haloperidol and BD 1047 were able to attenuate a DOI-induced HTR, indicating that LS-1-137 was acting in vivo as a sigma-1 receptor antagonist. LS-1-137 did not compromise rotarod performance within a dose range capable of attenuating the effects of DOI. Radioligand binding studies indicate that LS-1-137 exhibits low affinity binding at both 5-HT2A and 5-HT2C receptors. Based upon the results from these and our previous studies, LS-1-137 is a neuroprotective agent that attenuates the murine DOI-induced HTR independent of activity at 5-HT2 receptor subtypes, D2-like dopamine receptors, sigma-2 receptors and NMDA receptors. LS-1-137 appears to act as a sigma-1 receptor antagonist to inhibit the DOI-induced HTR. Therefore, the DOI-induced HTR can be used to assess the in vivo efficacy of sigma-1 receptor selective compounds. PMID:27397487

  9. Mars Express & Co

    NASA Astrophysics Data System (ADS)

    Borgeest, Ulf; Staude, Jakob; Kratzenber-Annies, Volker; Coradini, Marcello; Flury, Walter; Jaumann, Ralf; Neukum, Gerhard; Ongaro, Franco; Lemke, Dietrich; Althaus, Tilmann; Fuhrmeister, Birgit

    Contents: Europa und der übrige Kosmos. Der Weltraum und das öffentliche Interesse an ihm. Europa besucht Mars. INTEGRAL - Blick ins Herz der Galaxis. ISO - Von der Idee zum Instrument. Dienstreisen ins All. ENVISAT.

  10. Zum Problem des kommunikativen Handelns, der "Grammatik" und der Vermittlung der kommunikativen Kompetenz im Bereich "Deutsch als Fremdsprache" (On the Problem of Communicative Activity of Grammar and of the Developing of Communicative Competence in the Area of German as a Foreign Language). Acts of the Colloquium of the Swiss Interuniversity Commission for Applied Linguistics. CILA Bulletin, No. 24.

    ERIC Educational Resources Information Center

    Kummer, Irmela; Willeke, Ottomar

    "Communicative Competence" is today the avowed primary aim of foreign language teaching. This paper points out that communicative competence in this context differs from communicative competence between two native speakers of the same language. In the two cases the difficulties that appear are not the same. Various possible dialogue elements are…

  11. Intergenerationale Transmission von kulturellem Kapital unter Migrationsbedingungen: Zum Bildungserfolg von Kindern und Jugendlichen aus Migrantenfamilien in Deutschland (Intergenerational Transmission of Cultural Capital under the Conditions of Migration--On the Educational Achievement of Children and Adolescents from Migrant Families in Germany).

    ERIC Educational Resources Information Center

    Nauck, Bernhard; Diefenbach, Heike; Petri, Kornelia

    1998-01-01

    Examines the factors that lead to the existing ethnic inequalities within the German educational system. Analyzes, in relation to migration, the significance of the intergenerational transmission of education as cultural capital in combination with economic and social capital. Discusses the findings. (CMK)

  12. PCR und ELISA - Alternativen zum Maustest für die Analyse des Botulismus-Neurotoxin-C1 Giftbildungspotentiales in Umweltproben? [PCR and ELISA - in vitro alternatives to the mouse-bioassay for assessing the botulinum-neurotoxin-C1 production potential in environmental samples?

    USGS Publications Warehouse

    Zechmeister, T.C.; Farnleitner, A.H.; Rocke, T.E.; Pittner, F.; Rosengarten, R.; Mach, R.L.; Herzig, A.; Kirschner, A.K.T.

    2002-01-01

    Botulism is one of the most important bird diseases world-wide and is caused by the intoxication with Botulinum-Neurotoxin-C1 (BoNt-C1), which is produced by toxigenic clostridia under appropriate conditions. Avian botulism leads regularly to large losses among the migrating bird populations breeding and resting at the saltwater pools of the Austrian national park Neusiedler See-Seewinkel. Despite of its ethical dubiousness and its high technical expense the mouse-bioassay is still used as the routine standard method for the detection of BoNt-C1. According to the 3R-concept, in vitro alternative methods for the qualitative detection of BoNt-C1 (immunostick-ELISA) and a corresponding BoNt-C1 gene fragment (nested-PCR) were established. In order to estimate the BoNt-C1 production potential the methods were tested with sediment samples from different saltwater pools subjected to cultivation conditions appropriate for in vitro BoNt-C1-production. With the mouse-bioassay, 52 out of 77 samples were found to have a positive toxin production potential. The immunostick-ELISA showed a similar sensitivity as the mouse-bioassay and exhibited a highly significant positive correlation (r=0.94; p<0.001) with the mouse-bioassay in detecting BoNt-C1. The nested-PCR approach revealed higher numbers of positive BoNt-C1 gene fragment detections as compared to the direct toxin analysis approaches. A weak correlation (r=0.21; p=0.07) with the mouse-bioassay was discernible, no correlation was found with the immunostick-ELISA (r=0.09; p=0.46). Obviously, the PCR approach detected the BoNt-C1 gene fragment in some of the samples where no toxin expression has occurred. Thus it is suggested that the qualitative immunostick-ELISA represents a potential in vitro alternative to the mouse-bioassay for assessing the BoNt-C1 production potential in environmental samples. In contrast, qualitative BoNt-C1 gene fragment detection via PCR led to an overestimation of the actual toxin production potential.

  13. A Phenotyping Regimen for Genetically Modified Mice Used to Study Genes Implicated in Human Diseases of Aging.

    PubMed

    Patterson, Victoria L; Thompson, Brian S; Cherry, Catherine; Wang, Shao-Bin; Chen, Bo; Hoh, Josephine

    2016-01-01

    Age-related diseases are becoming increasingly prevalent and the burden continues to grow as our population ages. Effective treatments are necessary to lessen the impact of debilitating conditions but remain elusive in many cases. Only by understanding the causes and pathology of diseases associated with aging, can scientists begin to identify potential therapeutic targets and develop strategies for intervention. The most common age-related conditions are neurodegenerative disorders such as Parkinson's disease and blindness. Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly. Genome wide association studies have previously identified loci that are associated with increased susceptibility to this disease and identified two regions of interest: complement factor H (CFH) and the 10q26 locus, where the age-related maculopathy susceptibility 2 (ARMS2) and high-temperature requirement factor A1 (HtrA1) genes are located. CFH acts as a negative regulator of the alternative pathway (AP) of the complement system while HtrA1 is an extracellular serine protease. ARMS2 is located upstream of HtrA1 in the primate genome, although the gene is absent in mice. To study the effects of these genes, humanized knock-in mouse lines of Cfh and ARMS2, knockouts of Cfh, HtrA1, HtrA2, HtrA3 and HtrA4 as well as a conditional neural deletion of HtrA2 were generated. Of all the genetically engineered mice produced only mice lacking HtrA2, either systemically or in neural tissues, displayed clear phenotypes. In order to examine these mice thoroughly and systematically, an initial phenotyping schedule was established, consisting of a series of tests related to two main diseases of interest: AMD and Parkinson's. Genetically modified mice can be subjected to appropriate experiments to identify phenotypes that may be related to the associated diseases in humans. A phenotyping regimen with a mitochondrial focus is presented here alongside representative results

  14. Differences and similarities in the serotonergic diathesis for suicide attempts and mood disorders: a 22-year longitudinal gene-environment study.

    PubMed

    Brezo, J; Bureau, A; Mérette, C; Jomphe, V; Barker, E D; Vitaro, F; Hébert, M; Carbonneau, R; Tremblay, R E; Turecki, G

    2010-08-01

    To investigate similarities and differences in the serotonergic diathesis for mood disorders and suicide attempts, we conducted a study in a cohort followed longitudinally for 22 years. A total of 1255 members of this cohort, which is representative of the French-speaking population of Quebec, were investigated. Main outcome measures included (1) mood disorders (bipolar disorder and major depression) and suicide attempts by early adulthood; (2) odds ratios and probabilities associated with 143 single nucleotide polymorphisms in 11 serotonergic genes, acting directly or as moderators in gene-environment interactions with childhood sexual or childhood physical abuse (CPA), and in gene-gene interactions; (3) regression coefficients for putative endophenotypes for mood disorders (childhood anxiousness) and suicide attempts (childhood disruptiveness). Five genes showed significant adjusted effects (HTR2A, TPH1, HTR5A, SLC6A4 and HTR1A). Of these, HTR2A variation influenced both suicide attempts and mood disorders, although through different mechanisms. In suicide attempts, HTR2A variants (rs6561333, rs7997012 and rs1885884) were involved through interactions with histories of sexual and physical abuse whereas in mood disorders through one main effect (rs9316235). In terms of phenotype-specific contributions, TPH1 variation (rs10488683) was relevant only in the diathesis for suicide attempts. Three genes contributed exclusively to mood disorders, one through a main effect (HTR5A (rs1657268)) and two through gene-environment interactions with CPA (HTR1A (rs878567) and SLC6A4 (rs3794808)). Childhood anxiousness did not mediate the effects of HTR2A and HTR5A on mood disorders, nor did childhood disruptiveness mediate the effects of TPH1 on suicide attempts. Of the serotonergic genes implicated in mood disorders and suicidal behaviors, four exhibited phenotype-specific effects, suggesting that despite their high concordance and common genetic determinants, suicide attempts

  15. Social status differences regulate the serotonergic system of a cichlid fish, Astatotilapia burtoni

    PubMed Central

    Loveland, Jasmine L.; Uy, Natalie; Maruska, Karen P.; Carpenter, Russ E.; Fernald, Russell D.

    2014-01-01

    Serotonin (5-HT) inhibits aggression and modulates aspects of sexual behaviour in many species, but the mechanisms responsible are not well understood. Here, we exploited the social dominance hierarchy of Astatotilapia burtoni to understand the role of the serotonergic system in long-term maintenance of social status. We identified three populations of 5-HT cells in dorsal and ventral periventricular pretectal nuclei (PPd, PPv), the nucleus of the paraventricular organ (PVO) and raphe. Dominant males had more 5-HT cells than subordinates in the raphe, but the size of these cells did not differ between social groups. Subordinates had higher serotonergic turnover in the raphe and preoptic area (POA), a nucleus essential for hypothalamic-pituitary–gonadal (HPG) axis function. The relative abundance of mRNAs for 5-HT receptor (5-HTR) subtypes 1A and 2A (htr1a, htr2a) was higher in subordinates, a difference restricted to the telencephalon. Because social status is tightly linked to reproductive capacity, we asked whether serotonin turnover and the expression of its receptors correlated with testes size and circulating levels of 11-ketotestosterone (11-KT). We found negative correlations between both raphe and POA serotonin turnover and testes size, as well as between htr1a mRNA levels and circulating 11-KT. Thus, increased serotonin turnover in non-aggressive males is restricted to specific brain nuclei and is associated with increased expression of 5-HTR subtypes 1A and 2A exclusively in the telencephalon. PMID:24855673

  16. Efficiency-corrected dose verification with thermoluminescence dosemeters in heavy-ion beams.

    PubMed

    Berger, Thomas; Hajek, Michael; Fugger, Mamfred; Vana, Norbert

    2006-01-01

    One of the most essential difficulties in heavy-ion dosimetry by means of thermoluminescence dosemeters (TLDs)--often seen as a serious disadvantage of TLD utilisation--regards the changing TL-efficiency with increasing linear energy transfer (LET) of the particle. This behaviour leads to a falsification of absorbed dose that can be significant for many applications, e.g. in space or radiotherapeutic dosimetry. The high-temperature TL emission of LiF:Mg,Ti TL detectors can be exploited to obtain information about the LET of the heavy-ion radiation field under study. The high-temperature ratio (HTR) is used as a parameter to determine average LET. To correct the absorbed dose according to the TL-efficiency, the detailed dependence of HTR- and TL-efficiency on LET was recorded. These investigations were accomplished at the Heavy Ion Medical Accelerator (HIMAC) in Chiba, Japan, with a variety of high-energy ion beams (helium, carbon, neon, silicon and iron) ranging in LET from 2.2 to 393 keV microm(-1). The obtained relationships HTR vs. LET and TL-efficiency vs. LET were combined into a TL efficieny vs. HTR relationship. This enables correction of the absorbed dose (HTR-B method). The methodology is demonstrated by means of TLD 700 ((7)LiF:Mg,Ti) measurements in carbon beams of 290 and 400 MeV n(-1) available from HIMAC. PMID:16709709

  17. Minimized human telomerase maintains telomeres and resolves endogenous roles of H/ACA proteins, TCAB1, and Cajal bodies

    PubMed Central

    Vogan, Jacob M; Zhang, Xiaozhu; Youmans, Daniel T; Regalado, Samuel G; Johnson, Joshua Z; Hockemeyer, Dirk; Collins, Kathleen

    2016-01-01

    We dissected the importance of human telomerase biogenesis and trafficking pathways for telomere maintenance. Biological stability of human telomerase RNA (hTR) relies on H/ACA proteins, but other eukaryotes use other RNP assembly pathways. To investigate additional rationale for human telomerase assembly as H/ACA RNP, we developed a minimized cellular hTR. Remarkably, with only binding sites for telomerase reverse transcriptase (TERT), minimized hTR assembled biologically active enzyme. TERT overexpression was required for cellular interaction with minimized hTR, indicating that H/ACA RNP assembly enhances endogenous hTR-TERT interaction. Telomere maintenance by minimized telomerase was unaffected by the elimination of the telomerase holoenzyme Cajal body chaperone TCAB1 or the Cajal body scaffold protein Coilin. Surprisingly, wild-type hTR also maintained and elongated telomeres in TCAB1 or Coilin knockout cells, with distinct changes in telomerase action. Overall, we elucidate trafficking requirements for telomerase biogenesis and function and expand mechanisms by which altered telomere maintenance engenders human disease. DOI: http://dx.doi.org/10.7554/eLife.18221.001 PMID:27525486

  18. Minimized human telomerase maintains telomeres and resolves endogenous roles of H/ACA proteins, TCAB1, and Cajal bodies.

    PubMed

    Vogan, Jacob M; Zhang, Xiaozhu; Youmans, Daniel T; Regalado, Samuel G; Johnson, Joshua Z; Hockemeyer, Dirk; Collins, Kathleen

    2016-01-01

    We dissected the importance of human telomerase biogenesis and trafficking pathways for telomere maintenance. Biological stability of human telomerase RNA (hTR) relies on H/ACA proteins, but other eukaryotes use other RNP assembly pathways. To investigate additional rationale for human telomerase assembly as H/ACA RNP, we developed a minimized cellular hTR. Remarkably, with only binding sites for telomerase reverse transcriptase (TERT), minimized hTR assembled biologically active enzyme. TERT overexpression was required for cellular interaction with minimized hTR, indicating that H/ACA RNP assembly enhances endogenous hTR-TERT interaction. Telomere maintenance by minimized telomerase was unaffected by the elimination of the telomerase holoenzyme Cajal body chaperone TCAB1 or the Cajal body scaffold protein Coilin. Surprisingly, wild-type hTR also maintained and elongated telomeres in TCAB1 or Coilin knockout cells, with distinct changes in telomerase action. Overall, we elucidate trafficking requirements for telomerase biogenesis and function and expand mechanisms by which altered telomere maintenance engenders human disease. PMID:27525486

  19. Serotonin receptor 2C gene polymorphism associated with post-stroke depression in Chinese patients.

    PubMed

    Tang, W K; Tang, N; Liao, C D; Liang, H J; Mok, V C T; Ungvari, G S; Wong, K S

    2013-01-01

    The serotonin receptor 2C (HTR2C) gene has been shown to play a pivotal role in major depression. We examined the association between post-stroke depression (PSD) and polymorphism in HTR2C. A cohort of 223 patients with acute lacunar stroke admitted to the stroke unit of a university-affiliated regional hospital in Hong Kong was recruited. Three months after the onset of the index stroke, a research assistant administered the locally validated 15-item Geriatric Depression Scale. PSD was defined as a geriatric depression scale score of 7 or above. Possible confounding factors, including previous history of stroke, severity of stroke, level of social support, and recent life events, were investigated. All patients were genotyped for polymorphisms of HTR2C. Separate analyses were performed for males and females. Sixty-one patients were found to have PSD. There were significant associations between the HTR2C gene and PSD status in the male patients, but not in the female ones. After adjusting for possible confounders, the rs12837651 T allele (odds ratio = 4.020) and the rs2192371 G allele (odds ratio = 2.866) were found to be significantly associated with PSD in males. Genetic variation in HTR2C receptors appears to be involved in the pathogenesis of PSD in Chinese males. PMID:23765961

  20. [Role of peripheral serotonin in the insulin secretion and glucose homeostasis].

    PubMed

    Cataldo, Luis Rodrigo; Cortés, Víctor Antonio; Galgani, José Eduardo; Olmos, Pablo Roberto; Santos, José Luis

    2014-01-01

    The most studied roles of serotonin (5-hydroxytryptamine, 5HT) have been related to its action in the Central Nervous System (CNS). However, most of 5HT is produced outside the CNS, mainly in the enterochromaffin cells of the gut. Additionally, other tissues such as the endocrine pancreas, particularly β-cells, have its own serotonin system able to synthesize, secrete and respond to extracellular 5HT through cell surface receptors subtypes that have been grouped in 7 families (HTR1-7). Interestingly, 5HT is stored in granules and released together with insulin from β-cells and its biological significance is likely a combination of intra and extracellular actions. The expression of enzymes involved in 5HT synthesis and their receptors varied markedly in β-pancreatic cells during pregnancy, in parallel with an increase in their insulin secretion potential (probably through the action of Htr3a) and an increase in β-cell mass (through the action of Htr2b and Htr1d). In addition, it has been suggested that gut-derived 5HT may promote hepatic gluconeogenesis during prolonged fasting through Htr2b receptor. Taken together, these findings suggest that peripheral 5HT plays an important role in the regulation of glucose homeostasis through the differential expression and activation of 5-HT membrane receptors on the surface of hepatocytes, adipocytes and pancreatic β-cells. PMID:25238823

  1. Human telomerase RNA and box H/ACA scaRNAs share a common Cajal body-specific localization signal.

    PubMed

    Jády, Beáta E; Bertrand, Edouard; Kiss, Tamás

    2004-03-01

    Telomerase is a ribonucleoprotein reverse transcriptase that uses its RNA component as a template for synthesis of telomeric DNA repeats at the ends of linear eukaryotic chromosomes. Here, fluorescence in situ hybridization demonstrates that in HeLa cancer cells, human telomerase RNA (hTR) accumulates in the nucleoplasmic Cajal bodies (CBs). Localization of transiently expressed hTR to CBs is supported by a short sequence motif (411-UGAG-414) that is located in the 3'-terminal box H/ACA RNA-like domain of hTR and that is structurally and functionally indistinguishable from the CB-specific localization signal of box H/ACA small CB-specific RNAs. In synchronized HeLa cells, hTR shows the most efficient accumulation in CBs during S phase, when telomeres are most likely synthesized. CBs may function in post-transcriptional maturation (e.g., cap hypermethylation of hTR), but they may also play a role in the assembly and/or function of telomerase holoenzyme. PMID:14981093

  2. Susceptibility loci for heroin and cocaine addiction in the serotonergic and adrenergic pathways in populations of different ancestry

    PubMed Central

    Levran, Orna; Peles, Einat; Randesi, Matthew; Correa da Rosa, Joel; Ott, Jurg; Rotrosen, John; Adelson, Miriam; Kreek, Mary Jeanne

    2016-01-01

    Background Drug addiction is influenced by genetic factors. Aim To determine if genetic variants in the serotonergic and adrenergic pathways are associated with heroin and/or cocaine addiction. Subjects & methods The study examined 140 polymorphisms in 19 genes in 1855 subjects with predominantly European or African ancestries. Results A total of 38 polymorphisms (13 genes) showed nominal associations, including novel associations in S100A10 (p11) and SLC18A2 (VMAT2). The association of HTR3B SNP rs11606194 with heroin addiction in the European ancestry subgroup remained significant after correction for multiple testing (pcorrected = 0.04). Conclusion The study strengthens our previous findings of association of polymorphisms in HTR3A, HTR3B and ADRA1A. The study suggests partial overlap in genetic susceptibility between populations of different ancestry and between heroin and cocaine addiction. PMID:26227246

  3. The rpoE gene of Escherichia coli, which encodes sigma E, is essential for bacterial growth at high temperature.

    PubMed Central

    Hiratsu, K; Amemura, M; Nashimoto, H; Shinagawa, H; Makino, K

    1995-01-01

    In vitro transcription analysis has shown that only RNA polymerase containing an alternative sigma subunit, sigma E, activates transcription from one of the rpoH promoters and the htrA promoter. The location of the rpoE gene encoding sigma E on the Escherichia coli chromosome has recently been established, but no rpoE mutant has yet become available for phenotypic testing. We cloned the rpoE gene from the lambda-ordered clones of the E. coli genome and confirmed that the reconstituted RNA polymerase containing the gene product (E sigma E) can transcribe htrA in vitro. We constructed an rpoE-defective strain by gene disruption using the cloned rpoE gene. We demonstrate that expression of htrA is completely dependent on the rpoE gene in vivo and that the rpoE gene is essential for bacterial growth at high temperature. PMID:7751307

  4. 5-HT2A Gene Variants Moderate the Association between PTSD and Reduced Default Mode Network Connectivity

    PubMed Central

    Miller, Mark W.; Sperbeck, Emily; Robinson, Meghan E.; Sadeh, Naomi; Wolf, Erika J.; Hayes, Jasmeet P.; Logue, Mark; Schichman, Steven A.; Stone, Angie; Milberg, William; McGlinchey, Regina

    2016-01-01

    The default mode network (DMN) has been used to study disruptions of functional connectivity in a wide variety of psychiatric and neurological conditions, including posttraumatic stress disorder (PTSD). Studies indicate that the serotonin system exerts a modulatory influence on DMN connectivity; however, no prior study has examined associations between serotonin receptor gene variants and DMN connectivity in either clinical or healthy samples. We examined serotonin receptor single nucleotide polymorphisms (SNPs), PTSD, and their interactions for association with DMN connectivity in 134 White non-Hispanic veterans. We began by analyzing candidate SNPs identified in prior meta-analyses of relevant psychiatric traits and found that rs7997012 (an HTR2A SNP), implicated previously in anti-depressant medication response in the Sequenced Treatment Alternatives for Depression study (STAR*D; McMahon et al., 2006), interacted with PTSD to predict reduced connectivity between the posterior cingulate cortex (PCC) and the right medial prefrontal cortex and right middle temporal gyrus (MTG). rs130058 (HTR1B) was associated with connectivity between the PCC and right angular gyrus. We then expanded our analysis to 99 HTR1B and HTR2A SNPs and found two HTR2A SNPs (rs977003 and rs7322347) that significantly moderated the association between PTSD severity and the PCC-right MTG component of the DMN after correcting for multiple testing. Finally, to obtain a more precise localization of the most significant SNP × PTSD interaction, we performed a whole cortex vertex-wise analysis of the rs977003 effect. This analysis revealed the locus of the pre-frontal effect to be in portions of the superior frontal gyrus, while the temporal lobe effect was centered in the middle and inferior temporal gyri. These findings point to the influence of HTR2A variants on DMN connectivity and advance knowledge of the role of 5-HT2A receptors in the neurobiology of PTSD. PMID:27445670

  5. Monocular inhibition reveals temporal and spatial changes in gene expression in the primary visual cortex of marmoset

    PubMed Central

    Nakagami, Yuki; Watakabe, Akiya; Yamamori, Tetsuo

    2013-01-01

    We investigated the time course of the expression of several activity-dependent genes evoked by visual inputs in the primary visual cortex (V1) in adult marmosets. In order to examine the rapid time course of activity-dependent gene expression, marmosets were first monocularly inactivated by tetrodotoxin (TTX), kept in darkness for two days, and then exposed to various length of light stimulation. Activity-dependent genes including HTR1B, HTR2A, whose activity-dependency were previously reported by us, and well-known immediate early genes (IEGs), c-FOS, ZIF268, and ARC, were examined by in situ hybridization. Using this system, first, we demonstrated the ocular dominance type of gene expression pattern in V1 under this condition. IEGs were expressed in columnar patterns throughout layers II–VI of all the tested monocular marmosets. Second, we showed the regulation of HTR1B and HTR2A expressions by retinal spontaneous activity, because HTR1B and HTR2A mRNA expressions sustained a certain level regardless of visual stimulation and were inhibited by a blockade of the retinal activity with TTX. Third, IEGs dynamically changed its laminar distribution from half an hour to several hours upon a stimulus onset with the unique time course for each gene. The expression patterns of these genes were different in neurons of each layer as well. These results suggest that the regulation of each neuron in the primary visual cortex of marmosets is subjected to different regulation upon the change of activities from retina. It should be related to a highly differentiated laminar structure of marmoset visual systems, reflecting the functions of the activity-dependent gene expression in marmoset V1. PMID:23576954

  6. Identification, functional characterization, and pharmacological profile of a serotonin type-2b receptor in the medically important insect, Rhodnius prolixus

    PubMed Central

    Paluzzi, Jean-Paul V.; Bhatt, Garima; Wang, Chang-Hui J.; Zandawala, Meet; Lange, Angela B.; Orchard, Ian

    2015-01-01

    In the Chagas disease vector, Rhodnius prolixus, two diuretic hormones act synergistically to dramatically increase fluid secretion by the Malpighian tubules (MTs) during the rapid diuresis that is initiated upon engorgement of vertebrate blood. One of these diuretic hormones is the biogenic amine, serotonin (5-hydroxytryptamine, 5-HT), which controls a variety of additional activities including cuticle plasticization, salivary gland secretion, anterior midgut absorption, cardioacceleratory activity, and myotropic activities on a number of visceral tissues. To better understand the regulatory mechanisms linked to these various physiological actions of serotonin, we have isolated and characterized a serotonin type 2b receptor in R. prolixus, Rhopr5HTR2b, which shares sequence similarity to the vertebrate serotonin type 2 receptors. Rhopr5HTR2b transcript is enriched in well-recognized physiological targets of serotonin, including the MTs, salivary glands and dorsal vessel (i.e., insect heart). Notably, Rhopr5HTR2b was not enriched in the anterior midgut where serotonin stimulates absorption and elicits myotropic control. Using a heterologous functional receptor assay, we examined Rhopr5HTR2b activation characteristics and its sensitivity to potential agonists, antagonists, and other biogenic amines. Rhopr5HTR2b is dose-dependently activated by serotonin with an EC50 in the nanomolar range. Rhopr5HTR2b is sensitive to alpha-methyl serotonin and is inhibited by a variety of serotonin receptor antagonists, including propranolol, spiperone, ketanserin, mianserin, and cyproheptadine. In contrast, the cardioacceleratory activity of serotonin revealed a unique pharmacological profile, with no significant response induced by alpha-methyl serotonin and insensitivity to ketanserin and mianserin. This distinct agonist/antagonist profile indicates that a separate serotonin receptor type may mediate cardiomodulatory effects controlled by serotonin in R. prolixus. PMID:26041983

  7. Editing of the serotonin 2C receptor pre-mRNA: Effects of the Morris Water Maze.

    PubMed

    Du, Yunzhi; Stasko, Melissa; Costa, Alberto C; Davisson, Muriel T; Gardiner, Katheleen J

    2007-04-15

    The pre-mRNA encoding the serotonin 2C receptor, HTR2C (official mouse gene symbol, Htr2c), is subject to adenosine deamination that produces inosine at five sites within the coding region. Combinations of this site-specific A-to-I editing can produce 32 different mRNA sequences encoding 24 different protein isoforms with differing biochemical and pharmacological properties. Studies in humans have reported abnormalities in patterns of HTR2C editing in psychiatric disorders, and studies in rodents show altered patterns of editing in response to drug treatments and stressful situations. To further explore the biological significance of editing of the Htr2c mRNA and its regulation, we have examined patterns of Htr2c editing in C57BL/6J mice after exposure to the hidden platform version of the Morris Water Maze, a test of spatial learning that, in mice, is also associated with stress. In brains of both swimming controls and mice trained to find the platform, subtle time dependent changes in editing patterns are seen as soon as 1 h after a probe trial and typically last less than 24 h. Changes in whole brain with cerebellum removed differ from those seen in isolated hippocampus and cortex. Unexpectedly, in hippocampi from subsets of mice, abnormally low levels of editing were seen that were not correlated with behavior or with editing levels in cortex. These data implicate responses to spatial learning and stress, in addition to stochastic processes, in the generation of subtle changes in editing patterns of Htr2c. PMID:17307311

  8. Editing of the Serotonin 2C Receptor Pre-mRNA: Effects of the Morris Water Maze

    PubMed Central

    Du, Yunzhi; Stasko, Melissa; Costa, Alberto C.; Davisson, Muriel T.; Gardiner, Katheleen J.

    2007-01-01

    The pre-mRNA encoding the serotonin 2C receptor, HTR2C (official mouse gene symbol, Htr2c), is subject to adenosine deamination that produces inosine at five sites within the coding region. Combinations of this site-specific A-to-I editing can produce 32 different mRNA sequences encoding 24 different protein isoforms with differing biochemical and pharmacological properties. Studies in humans have reported abnormalities in patterns of HTR2C editing in psychiatric disorders, and studies in rodents show altered patterns of editing in response to drug treatments and stressful situations. To further explore the biological significance of editing of the Htr2c mRNA and its regulation, we have examined patterns of Htr2c editing in C57BL/6J mice after exposure to the hidden platform version of the Morris Water Maze, a test of spatial learning that, in mice, is also associated with stress. In brains of both swimming controls and mice trained to find the platform, subtle time dependent changes in editing patterns are seen as soon as one hour after a probe trial and typically last less than 24 hours. Changes in whole brain with cerebellum removed differ from those seen in isolated hippocampus and cortex. Unexpectedly, in hippocampi from subsets of mice, abnormally low levels of editing were seen that were not correlated with behavior or with editing levels in cortex. These data implicate responses to spatial learning and stress, in addition to stochastic processes, in the generation of subtle changes in editing patterns of Htr2c. PMID:17307311

  9. Identification, functional characterization, and pharmacological profile of a serotonin type-2b receptor in the medically important insect, Rhodnius prolixus.

    PubMed

    Paluzzi, Jean-Paul V; Bhatt, Garima; Wang, Chang-Hui J; Zandawala, Meet; Lange, Angela B; Orchard, Ian

    2015-01-01

    In the Chagas disease vector, Rhodnius prolixus, two diuretic hormones act synergistically to dramatically increase fluid secretion by the Malpighian tubules (MTs) during the rapid diuresis that is initiated upon engorgement of vertebrate blood. One of these diuretic hormones is the biogenic amine, serotonin (5-hydroxytryptamine, 5-HT), which controls a variety of additional activities including cuticle plasticization, salivary gland secretion, anterior midgut absorption, cardioacceleratory activity, and myotropic activities on a number of visceral tissues. To better understand the regulatory mechanisms linked to these various physiological actions of serotonin, we have isolated and characterized a serotonin type 2b receptor in R. prolixus, Rhopr5HTR2b, which shares sequence similarity to the vertebrate serotonin type 2 receptors. Rhopr5HTR2b transcript is enriched in well-recognized physiological targets of serotonin, including the MTs, salivary glands and dorsal vessel (i.e., insect heart). Notably, Rhopr5HTR2b was not enriched in the anterior midgut where serotonin stimulates absorption and elicits myotropic control. Using a heterologous functional receptor assay, we examined Rhopr5HTR2b activation characteristics and its sensitivity to potential agonists, antagonists, and other biogenic amines. Rhopr5HTR2b is dose-dependently activated by serotonin with an EC50 in the nanomolar range. Rhopr5HTR2b is sensitive to alpha-methyl serotonin and is inhibited by a variety of serotonin receptor antagonists, including propranolol, spiperone, ketanserin, mianserin, and cyproheptadine. In contrast, the cardioacceleratory activity of serotonin revealed a unique pharmacological profile, with no significant response induced by alpha-methyl serotonin and insensitivity to ketanserin and mianserin. This distinct agonist/antagonist profile indicates that a separate serotonin receptor type may mediate cardiomodulatory effects controlled by serotonin in R. prolixus. PMID:26041983

  10. Histone H3 Dynamics Reveal Domains with Distinct Proliferation Potential in the Arabidopsis Root.

    PubMed

    Otero, Sofía; Desvoyes, Bénédicte; Peiró, Ramón; Gutierrez, Crisanto

    2016-06-01

    A coordinated transition from cell proliferation to differentiation is crucial for organogenesis. We found that extensive chromatin reorganization, shown here for histone H3 proteins, characterizes cell population dynamics in the root developmental compartments. The canonical H3.1 protein, incorporated during S-phase, is maintained at high levels in cells dividing at a high rate but is massively evicted in cells undergoing their last cell cycle before exit to differentiation. A similar pattern was observed in the quadruple mutant for the H3.1-encoding genes HTR1, HTR2, HTR3, and HTR9 (htr1,2,3,9), in which H3.1 is expressed only from the HTR13 gene. H3 eviction is a fast process occurring within the G2 phase of the last cell cycle, which is longer than G2 in earlier cell cycles. This longer G2 likely contributes to lower the H3.1/H3.3 ratio in cells leaving the root meristem. The high H3.1/H3.3 ratio and H3.1 eviction process also occurs in endocycling cells before differentiation, revealing a common principle of H3 eviction in the proliferating and endocycling domains of the root apex. Mutants in the H3.1 chaperone CAF-1 (fas1-4) maintain a pattern similar to that of wild-type roots. Our studies reveal that H3 incorporation and eviction dynamics identify cells with different cell division potential during organ patterning. PMID:27207857

  11. Positive association between a DNA sequence variant in the serotonin 2A receptor gene and schizophrenia

    SciTech Connect

    Inayama, Y.; Yoneda, H.; Sakai, T.

    1996-02-16

    Sixty-two patients with schizophrenia and 96 normal controls were investigated for genetic association with restriction fragment length polymorphisms (RFLPs) in the serotonin receptor genes. A positive association between the serotonin 2A receptor gene (HTR2A) and schizophrenia was found, but not between schizophrenia and the serotonin 1A receptor gene. The positive association we report here would suggest that the DNA region with susceptibility to schizophrenia lies in the HTR2A on the long arm of chromosome 13. 15 refs., 2 tabs.

  12. Evaluation of proposed German safety criteria for high-temperature gas-cooled reactors

    SciTech Connect

    Barsell, A.W.

    1980-05-01

    This work reviews proposed safety criteria prepared by the German Bundesministerium des Innern (BMI) for future licensing of gas-cooled high-temperature reactor (HTR) concepts in the Federal Republic of Germany. Comparison is made with US General Design Criteria (GDCs) in 10CFR50 Appendix A and with German light water reactor (LWR) criteria. Implications for the HTR design relative to the US design and safety approach are indicated. Both inherent characteristics and design features of the steam cycle, gas turbine, and process heat concepts are taken into account as well as generic design options such as a pebble bed or prismatic core.

  13. Hypothesis: Hemolytic Transfusion Reactions Represent an Alternative Type of Anaphylaxis

    PubMed Central

    Hod, Eldad A.; Sokol, Set A.; Zimring, James C.; Spitalnik, Steven L.

    2009-01-01

    Classical anaphylaxis is the most severe, and potentially fatal, type of allergic reaction, manifested by hypotension, bronchoconstriction, and vascular permeability. Similarly, a hemolytic transfusion reaction (HTR) is the most feared consequence of blood transfusion. Evidence for the existence of an alternative, IgG-mediated pathway of anaphylaxis may be relevant for explaining the pathophysiology of IgG-mediated-HTRs. The purpose of this review is to summarize the evidence for this alternative pathway of anaphylaxis and to present the hypothesis that an IgG-mediated HTR is one example of this type of anaphylaxis. PMID:18830382

  14. Development of the excretory system in a polyplacophoran mollusc: stages in metanephridial system development

    PubMed Central

    2012-01-01

    Background Two types of excretory systems, protonephridia and metanephridial systems are common among bilaterians. The homology of protonephridia of lophotrochozoan taxa has been widely accepted. In contrast, the homology of metanephridial systems – including coelomic cavities as functional units – among taxa as well as the homology between the two excretory systems is a matter of ongoing discussion. This particularly concerns the molluscan kidneys, which are mostly regarded as being derived convergently to the metanephridia of e.g. annelids because of different ontogenetic origin. A reinvestigation of nephrogenesis in polyplacophorans, which carry many primitive traits within molluscs, could shed light on these questions. Results The metanephridial system of Lepidochitona corrugata develops rapidly in the early juvenile phase. It is formed from a coelomic anlage that soon achieves endothelial organization. The pericardium and heart are formed from the central portion of the anlage. The nephridial components are formed by outgrowth from lateral differentiations of the anlage. Simultaneously with formation of the heart, podocytes appear in the atrial wall of the pericardium. In addition, renopericardial ducts, kidneys and efferent nephroducts, all showing downstream ciliation towards the internal lumen, become differentiated (specimen length: 0.62 mm). Further development consists of elongation of the kidney and reinforcement of filtration and reabsorptive structures. Conclusions During development and in fully formed condition the metanephridial system of Lepidochitona corrugata shares many detailed traits (cellular and overall organization) with the protonephridia of the same species. Accordingly, we suggest a serial homology of various cell types and between the two excretory systems and the organs as a whole. The formation of the metanephridial system varies significantly within Mollusca, thus the mode of formation cannot be used as a homology criterion

  15. Relationship between the chondrocyte maturation cycle and the endochondral ossification in the diaphyseal and epiphyseal ossification centers.

    PubMed

    Pazzaglia, Ugo E; Congiu, Terenzio; Sibilia, Valeria; Pagani, Francesca; Benetti, Anna; Zarattini, Guido

    2016-09-01

    The chondrocyte maturation cycle and endochondral ossification were studied in human, fetal cartilage Anlagen and in postnatal meta-epiphyses. The relationship between the lacunar area, the inter-territorial fibril network variations, and calcium phosphorus nucleation in primary and secondary ossification centers were assessed using light microscopy and scanning electron microscopy (SEM) morphometry. The Anlage topographic, zonal classification was derived from the anatomical nomenclature of the completely developed long bone (diaphysis, metaphyses and epiphyses). A significant increase in the chondrocyte lacunar area was documented in the Anlage of epiphyseal zones 4 and 3 to zone 2 (metaphysis) and zone 1 (diaphysis), with the highest variation from zone 2 to zone 1. An inverse reduction in the intercellular matrix area and matrix interfibrillar empty space was also documented. These findings are consistent with the osmotic passage of free cartilage water from the interfibrillar space into the swelling chondrocytes, which increased the ion concentrations to a critical threshold for mineral precipitation in the matrix. The mineralized cartilage served as a scaffold for osteoblast apposition both in primary and secondary ossification centers and in the metaphyseal growth plate cartilage, though at different periods of bone Anlage development and with distinct patterns for each zone. All developmental processes shared a common initial pathway but progressed at different rates, modes and organization in diaphysis, metaphysis and epiphysis. In the ossification phase the developing vascular supply appeared to play a key role in determining the cortical or trabecular structure of the long bones. J. Morphol. 277:1187-1198, 2016. © 2016 Wiley Periodicals, Inc. PMID:27312928

  16. Complex life forms may arise from electrical processes

    PubMed Central

    2010-01-01

    There is still not an appealing and testable model to explain how single-celled organisms, usually following fusion of male and female gametes, proceed to grow and evolve into multi-cellular, complexly differentiated systems, a particular species following virtually an invariant and unique growth pattern. An intrinsic electrical oscillator, resembling the cardiac pacemaker, may explain the process. Highly auto-correlated, it could live independently of ordinary thermodynamic processes which mandate increasing disorder, and could coordinate growth and differentiation of organ anlage. PMID:20576122

  17. Biology of sexuality inborn determinants of human sexual response.

    PubMed

    Goodman, R E

    1983-09-01

    Opinions vary on the relative importance of biological and learning processes in the aetiology of sexual expression and deviance. The structure of personality, consistency of fantasy patterns, and the familial nature of homosexuality hint at a biological anlage. Research with the HY-antigen complex and X chromosome, and the elucidation of the interactions of intrauterine testosterone and its products with the foetal brain and neurotransmitters, have given us new models to understand the programming of sexuality. However, gonadotrophin feedback is not relevant as an indicator of brain feminization in primates and man. Finally, the interaction of masculinization and defeminization provides us with a model for understanding homosexual behaviour. PMID:6138111

  18. Hadron multiplicity in pp and AA collisions at LHC from the color glass condensate

    SciTech Connect

    Levin, Eugene; Rezaeian, Amir H.

    2010-09-01

    We provide quantitative predictions for the rapidity, centrality and energy dependencies of inclusive charged-hadron productions for the forthcoming LHC measurements in nucleus-nucleus collisions based on the idea of gluon saturation in the color-glass condensate framework. Our formulation gives very good descriptions of the first data from the LHC for the inclusive charged-hadron production in proton-proton collisions, the deep inelastic scattering at the Hadron-Elektron-Ring-Anlage at small Bjorken x, and the hadron multiplicities in nucleus-nucleus collisions at the Relativistic Heavy Ion Collider.

  19. Stabile Expression von Sulfotransferasen - allein oder in Kombination mit Cytochrom P450 - in Zelllinien für Mutagenitätsuntersuchungen

    NASA Astrophysics Data System (ADS)

    Pabel, Ulrike

    2003-10-01

    Aromatische Amine und Amide (aAA) sind aufgrund ihrer starken Verbreitung in der menschlichen Umwelt und ihres kanzerogenen Potenzials von groer toxikologischer Bedeutung. Die Kanzerogenität der aAA wird durch die Mutagenität hochreaktiver Stoffwechselprodukte vermittelt, die in zwei sequenziellen katalytischen Reaktionen entstehen. Die erste ist meistens eine N-Hydroxylierung, die oft durch Cytochrom P450 1A2 (CYP1A2) katalysiert wird. Daran schliet sich eine O-Konjugation durch Sulfotransferasen (SULT) oder N-Acetyltransferasen (NAT) an. Die Bioaktivierung ist ein kritischer Parameter für die Übertragbarkeit von Ergebnissen aus Tiermodellen auf den Menschen. Rekombinante in vitro Systeme, die fremdstoffmetabolisierende Enzyme verschiedener Spezies exprimieren, ermöglichen die vergleichende Untersuchung der Bioaktivierung im Menschen und in Versuchstieren. Ziel des Projektes war die Aufklärung der Bioaktivierung der aAA durch humane Enzyme. Im Vordergrund stand die Untersuchung der Rolle humaner SULT in diesem Prozess. Es wurden rekombinante in vitro Systeme, konstruiert, die CYP1A2 und SULT des Menschen koexprimieren. SULT-cDNAs wurden in den Säugerzell Expressionsvektor pMPSV kloniert und in Standardindikatorzellen für Mutagenitätsuntersuchungen (V79 Zellen aus dem Chinesischen Hamster) transfiziert. Das Expressionsniveau von CYP1A2 und SULT wurde mittels Immunblotanalyse und radiometrischen Aktivitätsmessungen charakterisiert. In den rekombinanten Zellen wurden vier aAA als Modellsubstanzen (2-Acetylaminofluoren, 2-Aminoanthracen, 3′-Methyl-4-dimethylaminoazobenzol, 2,4-Diaminotoluol) auf ihre Mutagenität am hprt-Locus hin untersucht.Die aAA waren in Zellen, die keine rekombinanten Enzyme oder lediglich CYP1A2 exprimierten, nicht mutagen. In Zellen, die CYP1A2 und SULT der Subfamilie 1A koexprimierten, erzeugten sie bereits in geringen Konzentrationen klare mutagene Effekte (0,3 µM für 2-Acetylaminofluoren und 3′-Methyl-4

  20. Triazole fungicide tebuconazole disrupts human placental trophoblast cell functions.

    PubMed

    Zhou, Jinghua; Zhang, Jianyun; Li, Feixue; Liu, Jing

    2016-05-01

    Triazole fungicides are one of the top ten classes of current-use pesticides. Although exposure to triazole fungicides is associated with reproductive toxicity in mammals, limited information is available regarding the effects of triazole fungicides on human placental trophoblast function. Tebuconazole (TEB) is a common triazole fungicide that has been extensively used for fungi control. In this work, we showed that TEB could reduce cell viability, disturb normal cell cycle distribution and induce apoptosis of human placental trophoblast cell line HTR-8/SVneo (HTR-8). Bcl-2 protein expression decreased and the level of Bax protein increased after TEB treatment in HTR-8 cells. The results demonstrated that this fungicide induced apoptosis of trophoblast cells via mitochondrial pathway. Importantly, we found that the invasive and migratory capacities of HTR-8 cells decreased significantly after TEB administration. TEB altered the expression of key regulatory genes involved in the modulation of trophoblast functions. Taken together, TEB suppressed human trophoblast invasion and migration through affecting the expression of protease, hormones, angiogenic factors, growth factors and cytokines. As the invasive and migratory abilities of trophoblast are essential for successful placentation and fetus development, our findings suggest a potential risk of triazole fungicides to human pregnancy. PMID:26852204

  1. Human cells lacking coilin and Cajal bodies are proficient in telomerase assembly, trafficking and telomere maintenance

    PubMed Central

    Chen, Yanlian; Deng, Zhiqiang; Jiang, Shuai; Hu, Qian; Liu, Haiying; Songyang, Zhou; Ma, Wenbin; Chen, Shi; Zhao, Yong

    2015-01-01

    The RNA component of human telomerase (hTR) localizes to Cajal bodies, and it has been proposed that Cajal bodies play a role in the assembly of telomerase holoenzyme and telomerase trafficking. Here, the role of Cajal bodies was examined in Human cells deficient of coilin (i.e. coilin-knockout (KO) cells), in which no Cajal bodies are detected. In coilin-KO cells, a normal level of telomerase activity is detected and interactions between core factors of holoenzyme are preserved, indicating that telomerase assembly occurs in the absence of Cajal bodies. Moreover, dispersed hTR aggregates and forms foci specifically during S and G2 phase in coilin-KO cells. Colocalization of these hTR foci with telomeres implies proper telomerase trafficking, independent of Cajal bodies. Therefore, telomerase adds similar numbers of TTAGGG repeats to telomeres in coilin-KO and controls cells. Overexpression of TPP1-OB-fold blocks cell cycle-dependent formation of hTR foci and inhibits telomere extension. These findings suggest that telomerase assembly, trafficking and extension occur with normal efficiency in Cajal bodies deficient human cells. Thus, Cajal bodies, as such, are not essential in these processes, although it remains possible that non-coilin components of Cajal bodies and/or telomere binding proteins (e.g. TPP1) do play roles in telomerase biogenesis and telomere homeostasis. PMID:25477378

  2. 75 FR 43049 - Airworthiness Directives; Empresa Brasileira de Aeronautica S.A. (EMBRAER) Model EMB-500 Airplanes

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-07-23

    ...: --DC BUS 1 OFF displayed on Crew Alerting System--CAS in conjunction with STBY HTR FAIL (which means loss of power on DC BUS 1); or --EMER BUS OFF displayed on CAS (which means loss of power on EMERGENCY... 2, 2009, we issued AD 2009-23-11, Amendment 39-16085 (74 FR 58195; November 12, 2009). That...

  3. Simulation study of gust alleviation in a tilt rotor aircraft, volume 1

    NASA Technical Reports Server (NTRS)

    Amos, A. K.; Alexander, H. R.

    1977-01-01

    The response to vertical turbulence in cruise of the HTR XV-15 design is studied using simulation techniques. This design is a modified version of the XV-15 with a hingeless fiberglass soft-in-plane rotor system. The parameters of a gust alleviation system are determined and the performance of the system is evaluated over a range of cruise velocities and altitudes.

  4. A new principle of oligomerization of plant DEG7 protease based on interactions of degenerated protease domains

    PubMed Central

    Schuhmann, Holger; Mogg, Ulrike; Adamska, Iwona

    2011-01-01

    Deg/HtrA proteases are a large group of ATP-independent serine endoproteases found in almost every organism. Their usual domain arrangement comprises a trypsin-type protease domain and one or more PDZ domains. All Deg/HtrA proteases form homo-oligomers with trimers as the basic unit, where the active protease domain mediates the interaction between individual monomers. Among the members of the Deg/HtrA protease family, the plant protease DEG7 is unique since it contains two protease domains (one active and one degenerated) and four PDZ domains. In the present study, we investigated the oligomerization behaviour of this unusual protease using yeast two-hybrid analysis in vivo and with recombinant protein in vitro. We show that DEG7 forms trimeric complexes, but in contrast with other known Deg/HtrA proteases, it shows a new principle of oligomerization, where trimerization is based on the interactions between degenerated protease domains. We propose that, during evolution, a duplicated active protease domain degenerated and specialized in protein–protein interaction and complex formation. PMID:21247409

  5. Inflammatory markers associated with osteoarthritis after destabilization surgery in young mice with and without Receptor for Advanced Glycation End-products (RAGE)

    PubMed Central

    Larkin, D. Justin; Kartchner, Jeffrey Z.; Doxey, Alexander S.; Hollis, Weston R.; Rees, Jeffrey L.; Wilhelm, Spencer K.; Draper, Christian S.; Peterson, Danielle M.; Jackson, Gregory G.; Ingersoll, Chelsey; Haynie, S. Scott; Chavez, Elizabeth; Reynolds, Paul R.; Kooyman, David L.

    2013-01-01

    HtrA1, Ddr-2, and Mmp-13 are reliable biomarkers for osteoarthritis (OA), yet the exact mechanism for the upregulation of HtrA-1 is unknown. Some have shown that chondrocyte hypertrophy is associated with early indicators of inflammation including TGF-β and the Receptor for Advanced Glycation End-products (RAGE). To examine the correlation of inflammation with the expression of biomarkers in OA, we performed right knee destabilization surgery on 4-week-old-wild type and RAGE knock-out (KO) mice. We assayed for HtrA-1, TGF-β1, Mmp-13, and Ddr-2 in articular cartilage at 3, 7, 14, and 28 days post-surgery by immunohistochemistry on left and right knee joints. RAGE KO and wild type mice both showed staining for key OA biomarkers. However, RAGE KO mice were significantly protected against OA compared to controls. We observed a difference in the total number of chondrocytes and percentage of chondrocytes staining positive for OA biomarkers between RAGE KO and control mice. The percentage of cells staining for OA biomarkers correlated with severity of cartilage degradation. Our results indicate that the absence of RAGE did protect against the development of advanced OA. We conclude that HtrA-1 plays a role in lowering TGF-β1 expression in the process of making articular cartilage vulnerable to damage associated with OA progression. PMID:23755017

  6. Associations between Serotonergic Genes and Escitalopram Treatment Responses in Patients with Depressive Disorder and Acute Coronary Syndrome: The EsDEPACS Study

    PubMed Central

    Kang, Hee-Ju; Bae, Kyung-Yeol; Kim, Sung-Wan; Shin, Il-Seon; Hong, Young Joon; Ahn, Youngkeun; Jeong, Myung Ho; Park, Sung-Woo; Kim, Young-Hoon; Yoon, Jin-Sang

    2016-01-01

    Genes related to serotonin are associated with responses to treatment for depression. We examined associations between the serotonin transporter (5-HTT) and serotonin 2a receptor (5-HTR2a) genes and responses to treatment for depressive disorders in acute coronary syndrome (ACS). A total of 255 patients who met the DSM-IV major or minor depressive disorder and recently developed ACS were randomly assigned to the escitalopram (n=127) or placebo (n=128) group in this 24-week double-blind trial (ClinicalTrial.gov identifier: NCT00419471). Remission was defined as a Hamilton Rating Scale for Depression (HAMD) score ≤7. Assays were performed for the 5-HTTLPR, STin2 VNTR, 5-HTR2a 102T/C, and 5-HTR2a 1438A/G genotypes. Escitalopram was superior to placebo for treating depressive disorder with ACS but there were no significant associations between serotonergic genes and treatment responses even when considering ACS severity. The effect of escitalopram was independent of 5-HTT and 5-HTR2a polymorphisms. PMID:26766959

  7. Associations between Serotonergic Genes and Escitalopram Treatment Responses in Patients with Depressive Disorder and Acute Coronary Syndrome: The EsDEPACS Study.

    PubMed

    Kang, Hee-Ju; Bae, Kyung-Yeol; Kim, Sung-Wan; Shin, Il-Seon; Hong, Young Joon; Ahn, Youngkeun; Jeong, Myung Ho; Park, Sung-Woo; Kim, Young-Hoon; Yoon, Jin-Sang; Kim, Jae-Min

    2016-01-01

    Genes related to serotonin are associated with responses to treatment for depression. We examined associations between the serotonin transporter (5-HTT) and serotonin 2a receptor (5-HTR2a) genes and responses to treatment for depressive disorders in acute coronary syndrome (ACS). A total of 255 patients who met the DSM-IV major or minor depressive disorder and recently developed ACS were randomly assigned to the escitalopram (n=127) or placebo (n=128) group in this 24-week double-blind trial (ClinicalTrial.gov identifier: NCT00419471). Remission was defined as a Hamilton Rating Scale for Depression (HAMD) score ≤7. Assays were performed for the 5-HTTLPR, STin2 VNTR, 5-HTR2a 102T/C, and 5-HTR2a 1438A/G genotypes. Escitalopram was superior to placebo for treating depressive disorder with ACS but there were no significant associations between serotonergic genes and treatment responses even when considering ACS severity. The effect of escitalopram was independent of 5-HTT and 5-HTR2a polymorphisms. PMID:26766959

  8. Feasibility of Burning First- and Second-Generation Plutonium in Pebble Bed High-Temperature Reactors

    SciTech Connect

    Haas, J.B.M. de; Kuijper, J.C

    2005-08-15

    The core physics investigations at the Nuclear Research Consultancy Group in the Netherlands, as part of the activities within the HTR-N project of the European Fifth Framework Program, are focused on the incineration of pure (first- and second-generation) Pu fuels in the reference pebble bed high-temperature gas-cooled reactor (HTR) HTR-MODUL with a continuous reload [MEDUL, (MEhrfach DUrchLauf, multipass)] fueling strategy in which the spherical fuel elements, or pebbles, pass through the core a number of times before being permanently discharged. For pebbles fueled with different loadings of plutonium, the feasibility of a sustained fuel cycle under nominal reactor conditions was investigated by means of the reactivity and temperature coefficients of the reactor. The HTR-MODUL was found to be a very effective reactor to reduce the stockpile of first-generation plutonium. It reduces the amount of plutonium to about one-sixth of the original and reduces the risk of proliferation by denaturing the plutonium vector. For second-generation plutonium the incineration is less favorable, as the amount of plutonium is only halved.

  9. Examining the Role of Trait Reactance and Sensation Seeking on Perceived Threat, State Reactance, and Reactance Restoration

    ERIC Educational Resources Information Center

    Quick, Brian L.; Stephenson, Michael T.

    2008-01-01

    The present investigation sought to advance Psychological Reactance Theory (PRT) by examining whether trait reactance and sensation seeking influence the magnitude of a perceived threat, state reactance, and reactance restoration. Results revealed that high trait reactant (HTR) and low trait reactant (LTR) individuals and high sensation seekers…

  10. Head-twitch response in rodents induced by the hallucinogen 2,5-dimethoxy-4-iodoamphetamine: a comprehensive history, a re-evaluation of mechanisms, and its utility as a model

    PubMed Central

    Canal, Clint E.; Morgan, Drake

    2013-01-01

    Two primary animal models persist for assessing hallucinogenic potential of novel compounds and for examining the pharmacological and neurobiological substrates underlying the actions of classical hallucinogens, the two-lever drug discrimination procedure and the drug-induced head-twitch response (HTR) in rodents. The substituted amphetamine hallucinogen, serotonin 2 (5-HT2) receptor agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI) has emerged as the most popular pharmacological tool used in HTR studies of hallucinogens. Synthesizing classic, recent, and relatively overlooked findings, addressing ostensibly conflicting observations, and considering contemporary theories in receptor and behavioural pharmacology, this review provides an up-to-date and comprehensive synopsis of DOI and the HTR model, from neural mechanisms to utility for understanding psychiatric diseases. Also presented is support for the argument that, although both the two-lever drug discrimination and the HTR models in rodents are useful for uncovering receptors, interacting proteins, intracellular signalling pathways, and neurochemical processes affected by DOI and related classical hallucinogens, results from both models suggest they are not reporting hallucinogenic experiences in animals. PMID:22517680

  11. The silent and selective 5-HT1A antagonist, WAY 100635, produces via an indirect mechanism, a 5-HT2A receptor-mediated behaviour in mice during the day but not at night. Short communication.

    PubMed

    Darmani, N A

    1998-01-01

    The head-twitch response (HTR) in rodents is considered to be a functional index for the activation of 5-HT2A receptors. Intraperitoneal administration of the silent and selective 5-HT1A receptor antagonist, WAY 100635, produced the HTR in mice in a dose-dependent bell-shaped manner. The induced behaviour followed a diurnal pattern in that WAY 100635 only produced a robust HTR frequency during the light period of the 24h daily cycle. Pretreatment with the selective 5-HT2A/C receptor antagonist, SR 46349B, potently, and in a dose-dependent manner attenuated the induced behaviour. It appears that WAY 100635 produces the HTR indirectly via disinhibition of endogenous serotonergic inhibitory tone operating on the somatodenritic pulse-modulating 5-HT1A autoreceptors. The latter antagonism seems to potentiate endogenous 5-HT release in serotonergic terminal field synapses which subsequently stimulates postsynaptic 5-HT2A receptors to produce the head-twitch behaviour. PMID:9826108

  12. LINKAGE AND RH MAPPING OF 10 GENES TO A QTL REGION FOR FATNESS AND MUSCLING TRAITS ON PIG CHROMOSOME X

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In this study 10 genes located on human chromosome region Xq13.1 - Xq24 homologous to a QTL region for fatness and body conformation traits were linkage and RH mapped in the pig. PCR primers for amplification of porcine genomic DNAs were designed from orthologous human or porcine (HTR2C) sequences. ...

  13. New evidence for a magmatic origin of some gases in the Geysers geothermal reservoir

    SciTech Connect

    Truesdell, A.H.; Kennedy, B.M.; Walters, M.A.; D'Amore, F.

    1994-01-20

    The Geysers vapor-dominated geothermal reservoir is known to have a wide range of gas concentrations in steam (<100 to >75,000 ppmw), but the variations in gas compositions and the origin of the gases have been little studied. Low gas concentrations and steam isotopes similar to meteoric waters are found in the SE Geysers, but steam high in gas and HCI from a high temperature reservoir (HTR) in the NW Geysers has been thought to be related to metamorphic or magmatic brine. New analyses of noble gas isotopes show that the highest gas steam from the HTR has high {sup 3}He/{sup 4}He (8.3 Ra), and very low {sup 36}Ar and radiogenic {sup 40}Ar/{sup 4}He, indicating a strong magmatic component and essentially no atmospheric or crustal noble gases. Other samples from the HTR show various amounts of atmospheric dilution of the magmatic gas and lower HCI and total gas contents. The occurrence of steam in the NW Geysers highly enriched in heavy isotopes of oxygen and hydrogen supports the indications of remnant magmatic fluid: The existence of this fluid strongly suggests that the HTR was formed by rapid heating and catastrophic boiling resulting from injection of magma.

  14. Physical Connectivity Mapping by Circular Permutation of Human Telomerase RNA Reveals New Regions Critical for Activity and Processivity.

    PubMed

    Mefford, Melissa A; Zappulla, David C

    2015-01-01

    Telomerase is a specialized ribonucleoprotein complex that extends the 3' ends of chromosomes to counteract telomere shortening. However, increased telomerase activity is associated with ∼90% of human cancers. The telomerase enzyme minimally requires an RNA (hTR) and a specialized reverse transcriptase protein (TERT) for activity in vitro. Understanding the structure-function relationships within hTR has important implications for human disease. For the first time, we have tested the physical-connectivity requirements in the 451-nucleotide hTR RNA using circular permutations, which reposition the 5' and 3' ends. Our extensive in vitro analysis identified three classes of hTR circular permutants with altered function. First, circularly permuting 3' of the template causes specific defects in repeat-addition processivity, revealing that the template recognition element found in ciliates is conserved in human telomerase RNA. Second, seven circular permutations residing within the catalytically important core and CR4/5 domains completely abolish telomerase activity, unveiling mechanistically critical portions of these domains. Third, several circular permutations between the core and CR4/5 significantly increase telomerase activity. Our extensive circular permutation results provide insights into the architecture and coordination of human telomerase RNA and highlight where the RNA could be targeted for the development of antiaging and anticancer therapeutics. PMID:26503788

  15. Are serotonin 3A and 3B receptor genes associated with suicidal behavior in schizophrenia subjects?

    PubMed

    Souza, Renan P; De Luca, Vincenzo; Manchia, Mirko; Kennedy, James L

    2011-02-11

    Suicide is a major contributor to the morbidity and mortality of schizophrenia, accounting for approximately 10% of deaths in these patients. Genetic factors have been reported to modulate the risk for suicide, although the precise mechanism and magnitude of the genetic contribution are unknown. Further, suicide attempters present abnormalities in the serotonergic system. We evaluated whether genetic variants in the serotonin receptors HTR3A (rs897692, rs1150226, rs1176724, rs2276302, rs3737457, rs897687 and rs1176713) and HTR3B (rs3758987, rs10502180, rs11606194, rs17116121, rs1176744, rs17116138, rs2276307, rs3782025 and rs1176761) were susceptibility components for suicidal behavior in 154 Caucasians schizophrenia subjects (20.1% of suicide attempters). In a second step, we compared haplotype and gene-gene interaction approaches because both genes are located in the chromosome 11q23 approximately 28Kbp apart. We did not observe allelic or genotypic associations. Six haplotypes were nominally significant associated with suicide. Gene-gene interaction using Helix Tree software showed two nominally significant interactions reproduced by haplotype association. Likewise, haplotypes composed by the markers included in the best multidimensional reduction three-locus model were nominally significant. Our results suggest that HTR3A and HTR3B polymorphisms may not play a major role in the susceptibility for suicidal behavior in schizophrenia subjects. Moreover, gene-gene interaction and haplotype association may have consistent results for genes located in the same chromosome. PMID:21184810

  16. Association of the Serotonin Receptor 3E Gene as a Functional Variant in the MicroRNA-510 Target Site with Diarrhea Predominant Irritable Bowel Syndrome in Chinese Women

    PubMed Central

    Zhang, Yu; Li, Yaoyao; Hao, Zhenfeng; Li, Xiangming; Bo, Ping; Gong, Weijuan

    2016-01-01

    Background/Aims The functional variant (rs56109847) in the 3′-untranslated regions (3′-UTR) of the serotonin receptor 3E (HTR3E) gene is associated with female diarrhea predominant irritable bowel syndrome (IBS-D) in British populations. However, the relationship of the polymorphism both to HTR3E expression in the intestine and to the occurrence of Chinese functional gastrointestinal disorders has yet to be examined. Methods Polymerase chain reaction amplification and restriction fragment length polymorphism analyses were employed to detect polymorphisms among Chinese Han women, particularly 107 patients with IBS-D, 99 patients with functional dyspepsia (FD), 115 patients with mixed IBS and 69 patients with IBS-D + FD. We also assessed microRNA-510 (miR-510) and HTR3E expression in human colonic mucosal tissues with immunohistochemistry and other methods. Dual-luciferase reporter assays were conducted to examine the binding ability of miR-510 and HTR3E 3′-UTR. Results Genotyping data showed the variant rs56109847 was significantly associated with IBS-D, but not with FD, mixed-IBS, or FD + IBS-D. HTR3E was abundantly expressed around the colonic mucosal glands but less expressed in the stroma. miR-510 expression decreased, whereas HTR3E expression increased in the colonic mucosal tissue of patients with IBS-D compared with those in controls. HTR3E expression was significantly higher in patients with the GA genotype than that in patients with the GG genotype. The single-nucleotide polymorphisms disrupted the binding site of miR-510 and significantly upregulated luciferase expression in HEK293 and HT-29 cells. Conclusions The single-nucleotide polymorphisms rs56109847 led to reduced microRNA binding and overexpression of the target gene in intestinal cells, thereby increasing IBS-D risk in the Chinese Han population. The decreased expression of miR-510 might contribute to IBS-D. PMID:26787495

  17. The Depth of 60-80 km as the Boundary of External Factor Influence on the Earth's Lithosphere

    NASA Astrophysics Data System (ADS)

    Sasorova, E. V.; Levin, B. W.

    2007-05-01

    The results of statistical analysis of worldwide seismic catalogs (ISC and NEIC), which was carried out in frame of two projects are presented. In both cases we extracted the evens occurred in the Pacific region from 1964 to 2004 with Mb>=4.0. The aftershocks were canceled from the list. All events were divided into following magnitude levels: 4<=Mb<4.5; 4.5<=Mb<5; 5<=Mb<5.5; 5.5<=Mb<6.0; 6<=Mb. The events in each magnitude level were subdivided into two groups: shallow events (H<=Htr) and deep events (H>Htr), where Htr is threshold value of the EQ source depth. In frame of the first project statistical verification of hypothesis about within-year variability existence for the events of various energy levels was carried out for the Pacific region (PO). The whole PO was subdivided into 31 subregions (Japan, Kuril Islands, Kamchatka, Aleutian Islands, Alaska, California, and so on along the perimeter of the Pacific). Then we were checking if the distributions of the events during the year period are uniform or these distributions are non- uniform. We were testing it separately for each region, for every magnitude level and for every depth level (total number of the samples under study was 310). It was disproved the null hypothesis about uniform EQ distributions in the course of year for shallow events (with less than 2% significance level), and it was confirmed the null hypothesis for deep earthquakes. It was shown that the main maximum of the seismic activity take place in November-March (minimum of the Earth-Sun distance) for both Hemispheres and the minimum - in April. It was found by using special software procedure that the Htr boundary between the shallow and the deep events was arranged in deep 60-80 km. Thus the EQ with sources located above this boundary are affected by external (astronomical) factors, which may trigger the process of EQ generation. While the external factors don't influence on the EQ sources located below this boundary. In frame of the

  18. Intelligente Objekte - Klein, Vernetzt, Sensitiv, acatech BEZIEHT POSITION

    NASA Astrophysics Data System (ADS)

    Schon im Juni 2005 stand das Thema auf der Tagesordnung - beim acatech Symposium in Berlin zum Thema Computer in der Alltagswelt - Chancen für Deutschland?" unter der Leitung von Prof. Dr. Dieter Spath. Zum einen ging es darum, in wieweit Intelligente Objekte bereits Alltag und Wirtschaftsleben durchdringen. Zum andern um die Chancen für Deutschland, die der große Wachstumsmarkt der so genannten Ambient Intelligence" bietet. Die Beiträge dieses Symposiums analysierten insbesondere die Marktmöglichkeiten aus Sicht der Wirtschaft und die Rahmenbedingungen aus Sicht von Politik und Gesellschaft. Darüber hinaus wurden die Themen Sicherheit, die Etablierung von Anwendungen und die Integration des neuen Wissensgebietes in die Ausbildung diskutiert.

  19. Grundlagen und Vollzug der amtlichen Lebensmittelkontrolle in Deutschland

    NASA Astrophysics Data System (ADS)

    Neuhaus, Annette

    Für Menschen besteht ein täglicher Bedarf an Lebensmitteln, die gesundheitlich unbedenklich, allgemein zum Verzehr geeignet und unverfälscht sein sollen. Lebensmittel sind vergängliche Naturprodukte und bergen in sich Gefahren, die mit dem natürlichen Verderbnisvorgang verbunden sind. Zusätzlich bestehen Risiken durch eine unsachgemäße Herstellung, Behandlung oder Verarbeitung, zum Beispiel durch ungeeignete Zutaten oder technologische Verfahren, falsche Lagertemperaturen oder Verwendung ungeeigneter Behältnisse. So lange wie Lebensmittel zum Zweck der Gewinnerzielung an andere abgegeben werden, besteht darüber hinaus die Versuchung, Kunden durch Verfälschung oder andere Manipulation zu übervorteilen.

  20. [Naturheilkunde und Komplementärmedizin in medizinischen Leitlinien - können europäische Normen Leitlinien für Naturheilkunde und Komplementärmedizin verdrängen?].

    PubMed

    Jütte, Robert

    2016-01-01

    Leitlinien machen in der Komplementärmedizin, wie das Beispiel der Naturheilkunde zeigt, durchaus Sinn. Sie ergänzen zum Wohle des Patienten und zur besseren Orientierung des Therapeuten die bislang, auch auf europäischer Ebene, bereits bestehenden Leitlinien, die ständig weiterentwickelt werden. Diese Ergänzung ist dringend notwendig, weil die meisten der vorliegenden Leitlinien einzelner Fachgesellschaften die Forschungsergebnisse der Komplementärmedizin, die zum Teil beachtlich und auch evidenzbasiert sind, zum Nachteil des Patienten ignorieren. Es ist bedauerlich, dass einige Richtungen der Komplementärmedizin jedoch meinen, dass eine europäische Norm, wie sie beispielsweise Osteopathen und Homöopathen mithilfe des europäischen Normungsinstituts (CEN) durchzusetzen hoffen, sie in ihrem Kampf um Anerkennung weiterbringen wird. Der Patient, der auf eine individuelle und bestmögliche Behandlung wert legt, wird jedenfalls davon nicht profitieren. PMID:27404104

  1. Transmutation Analysis of Enriched Uranium and Deep Burn High Temperature Reactors

    SciTech Connect

    Michael A. Pope

    2012-07-01

    High temperature reactors (HTRs) have been under consideration for production of electricity, process heat, and for destruction of transuranics for decades. As part of the transmutation analysis efforts within the Fuel Cycle Research and Development (FCR&D) campaign, a need was identified for detailed discharge isotopics from HTRs for use in the VISION code. A conventional HTR using enriched uranium in UCO fuel was modeled having discharge burnup of 120 GWd/MTiHM. Also, a deep burn HTR (DB-HTR) was modeled burning transuranic (TRU)-only TRU-O2 fuel to a discharge burnup of 648 GWd/MTiHM. For each of these cases, unit cell depletion calculations were performed with SCALE/TRITON. Unit cells were used to perform this analysis using SCALE 6.1. Because of the long mean free paths (and migration lengths) of neutrons in HTRs, using a unit cell to represent a whole core can be non-trivial. The sizes of these cells were first set by using Serpent calculations to match a spectral index between unit cell and whole core domains. In the case of the DB-HTR, the unit cell which was arrived at in this way conserved the ratio of fuel to moderator found in a single block of fuel. In the conventional HTR case, a larger moderator-to-fuel ratio than that of a single block was needed to simulate the whole core spectrum. Discharge isotopics (for 500 nuclides) and one-group cross-sections (for 1022 nuclides) were delivered to the transmutation analysis team. This report provides documentation for these calculations. In addition to the discharge isotopics, one-group cross-sections were provided for the full list of 1022 nuclides tracked in the transmutation library.

  2. Effect of Peripheral 5-HT on Glucose and Lipid Metabolism in Wether Sheep

    PubMed Central

    Watanabe, Hitoshi; Saito, Ryo; Nakano, Tatsuya; Takahashi, Hideyuki; Takahashi, Yu; Sumiyoshi, Keisuke; Sato, Katsuyoshi; Chen, Xiangning; Okada, Natsumi; Iwasaki, Shunsuke; Harjanti, Dian W.; Sekiguchi, Natsumi; Sano, Hiroaki; Kitazawa, Haruki; Rose, Michael T.; Ohwada, Shyuichi; Watanabe, Kouichi; Aso, Hisashi

    2014-01-01

    In mice, peripheral 5-HT induces an increase in the plasma concentrations of glucose, insulin and bile acids, and a decrease in plasma triglyceride, NEFA and cholesterol concentrations. However, given the unique characteristics of the metabolism of ruminants relative to monogastric animals, the physiological role of peripheral 5-HT on glucose and lipid metabolism in sheep remains to be established. Therefore, in this study, we investigated the effect of 5-HT on the circulating concentrations of metabolites and insulin using five 5-HT receptor (5HTR) antagonists in sheep. After fasting for 24 h, sheep were intravenously injected with 5-HT, following which-, plasma glucose, insulin, triglyceride and NEFA concentrations were significantly elevated. In contrast, 5-HT did not affect the plasma cholesterol concentration, and it induced a decrease in bile acid concentrations. Increases in plasma glucose and insulin concentrations induced by 5-HT were attenuated by pre-treatment with Methysergide, a 5HTR 1, 2 and 7 antagonist. Additionally, decreased plasma bile acid concentrations induced by 5-HT were blocked by pre-treatment with Ketanserin, a 5HTR 2A antagonist. However, none of the 5HTR antagonists inhibited the increase in plasma triglyceride and NEFA levels induced by 5-HT. On the other hand, mRNA expressions of 5HTR1D and 1E were observed in the liver, pancreas and skeletal muscle. These results suggest that there are a number of differences in the physiological functions of peripheral 5-HT with respect to lipid metabolism between mice and sheep, though its effect on glucose metabolism appears to be similar between these species. PMID:24505376

  3. Assessments of Water Ingress Accidents in a Modular High-Temperature Gas-Cooled Reactor

    SciTech Connect

    Zhang Zuoyi; Dong Yujie; Scherer, Winfried

    2005-03-15

    Severe water ingress accidents in the 200-MW HTR-module were assessed to determine the safety margins of modular pebble-bed high-temperature gas-cooled reactors (HTR-module). The 200-MW HTR-module was designed by Siemens under the criteria that no active safety protection systems were necessary because of its inherent safe nature. For simulating the behavior of the HTR-module during severe water ingress accidents, a water, steam, and helium multiphase cavity model was developed and implemented in the dynamic simulator for nuclear power plants (DSNP) simulation system. Comparisons of the DSNP simulations incorporating these models with experiments and with calculations using the time-dependent neutronics and temperature dynamics code were made to validate the simulation. The analysis of the primary circuit showed that the maximum water concentration increase in the reactor core was <0.3 kg/(m{sup 3}s). The water vaporization in the steam generator and characteristics of water transport from the steam generator to the reactor core would reduce the rate of water ingress into the reactor core. The analysis of a full cavitation of the feedwater pump showed that if the secondary circuit could be depressurized, the feedwater pump would be stopped by the full cavitation. This limits the water transported from the deaerator to the steam generator. A comprehensive simulation of the HTR-module power plant showed that the water inventory in the primary circuit was limited to {approx}3000 kg. The nuclear reactivity increase caused by the water ingress would lead to a fast power excursion, which would be inherently counterbalanced by negative feedback effects. The integrity of the fuel elements, because the safety-relevant temperature limit of 1600 deg. C is not reached in any case, is not challenged.

  4. Development of the Platysma Muscle and the Superficial Musculoaponeurotic System (Human Specimens at 8–17 Weeks of Development)

    PubMed Central

    De la Cuadra-Blanco, C.; Peces-Peña, M. D.; Carvallo-de Moraes, L. O.; Herrera-Lara, M. E.; Mérida-Velasco, J. R.

    2013-01-01

    There is controversy regarding the description of the different regions of the face of the superficial musculoaponeurotic system (SMAS) and its relationship with the superficial mimetic muscles. The purpose of this study is to analyze the development of the platysma muscle and the SMAS in human specimens at 8–17 weeks of development using an optical microscope. Furthermore, we propose to study the relationship of the anlage of the SMAS and the neighbouring superficial mimetic muscles. The facial musculature derives from the mesenchyme of the second arch and migrates towards the different regions of the face while forming premuscular laminae. During the 8th week of development, the cervical, infraorbital, mandibular, and temporal laminae are observed to be on the same plane. The platysma muscle derives from the cervical lamina and its mandibular extension enclosing the lower part of the parotid region and the cheek, while the SMAS derives from the upper region. During the period of development analyzed in this study, we have observed no continuity between the anlage of the SMAS and that of the superficial layer of the temporal fascia and the zygomaticus major muscle. Nor have we observed any structure similar to the SMAS in the labial region. PMID:24396304

  5. CXCR4 and Gab1 cooperate to control the development of migrating muscle progenitor cells

    PubMed Central

    Vasyutina, Elena; Stebler, Jürg; Brand-Saberi, Beate; Schulz, Stefan; Raz, Erez; Birchmeier, Carmen

    2005-01-01

    Long-range migrating progenitor cells generate hypaxial muscle, for instance the muscle of the limbs, hypoglossal cord, and diaphragm. We show here that migrating muscle progenitors express the chemokine receptor CXCR4. The corresponding ligand, SDF1, is expressed in limb and branchial arch mesenchyme; i.e., along the routes and at the targets of the migratory cells. Ectopic application of SDF1 in the chick limb attracts muscle progenitor cells. In CXCR4 mutant mice, the number of muscle progenitors that colonize the anlage of the tongue and the dorsal limb was reduced. Changes in the distribution of the muscle progenitor cells were accompanied by increased apoptosis, indicating that CXCR4 signals provide not only attractive cues but also control survival. Gab1 encodes an adaptor protein that transduces signals elicited by tyrosine kinase receptors, for instance the c-Met receptor, and plays a role in the migration of muscle progenitor cells. We found that CXCR4 and Gab1 interact genetically. For instance, muscle progenitors do not reach the anlage of the tongue in CXCR4;Gab1 double mutants; this target is colonized in either of the single mutants. Our analysis reveals a role of SDF1/CXCR4 signaling in the development of migrating muscle progenitors and shows that a threshold number of progenitor cells is required to generate muscle of appropriate size. PMID:16166380

  6. CXCR4 and Gab1 cooperate to control the development of migrating muscle progenitor cells.

    PubMed

    Vasyutina, Elena; Stebler, Jürg; Brand-Saberi, Beate; Schulz, Stefan; Raz, Erez; Birchmeier, Carmen

    2005-09-15

    Long-range migrating progenitor cells generate hypaxial muscle, for instance the muscle of the limbs, hypoglossal cord, and diaphragm. We show here that migrating muscle progenitors express the chemokine receptor CXCR4. The corresponding ligand, SDF1, is expressed in limb and branchial arch mesenchyme; i.e., along the routes and at the targets of the migratory cells. Ectopic application of SDF1 in the chick limb attracts muscle progenitor cells. In CXCR4 mutant mice, the number of muscle progenitors that colonize the anlage of the tongue and the dorsal limb was reduced. Changes in the distribution of the muscle progenitor cells were accompanied by increased apoptosis, indicating that CXCR4 signals provide not only attractive cues but also control survival. Gab1 encodes an adaptor protein that transduces signals elicited by tyrosine kinase receptors, for instance the c-Met receptor, and plays a role in the migration of muscle progenitor cells. We found that CXCR4 and Gab1 interact genetically. For instance, muscle progenitors do not reach the anlage of the tongue in CXCR4;Gab1 double mutants; this target is colonized in either of the single mutants. Our analysis reveals a role of SDF1/CXCR4 signaling in the development of migrating muscle progenitors and shows that a threshold number of progenitor cells is required to generate muscle of appropriate size. PMID:16166380

  7. Proximal tibiofibular bifurcation synostosis for the management of longitudinal deficiency of the tibia.

    PubMed

    Davids, J R; Meyer, L C

    1998-01-01

    Three adults with severe longitudinal deficiency of the tibia (LDT), in which an unossified proximal tibial anlage was present, who had been treated with proximal tibiofibular bifurcation synostosis (PTFBS) in early childhood, were evaluated between 20 and 31 years after the index procedure. All three were found to be functioning well as below-the-knee (BK) amputees. Mediolateral stability and anteroposterior instability of the knee were present in all cases. Instrumented motion analysis revealed diminished loading characteristics of the prosthetic limb, similar to that described for BK amputees in general. The most significant gait deviations at the knee unique to this study group were a quadriceps-avoidance gait pattern and an increased dynamic varus alignment. Instrumented muscle testing suggested that these deviations were a consequence of ligamentous instability. This study supports the concept that the presence of a proximal tibial anlage in severe LDT is indication for a surgical strategy that preserves the biological knee joint. The PTFBS maintains the integrity of the knee-extensor mechanism, the fibular collateral ligament, the tibiofemoral joint capsule, and the medial collateral ligament, enhancing the long-term stability and function of the knee joint. PMID:9449111

  8. Conjugation in Hyalophysa chattoni Bradbury (Apostomatida): An adaptation to a symbiotic life cycle.

    PubMed

    Bradbury, Phyllis Clarke; Hash, Stephen M; Rogers, Faye Kucera; Neptun, Steven H; Zhang, Limin

    2013-11-01

    Hyalophysa chattoni, borne as an encysted phoront on a crustacean's exoskeleton, metamorphoses to the trophont during the host's premolt. After the molt within 15min to 2h conjugants with food vacuoles appear in the exuvium, swimming along with the trophonts. Starvation in other ciliates usually precedes conjugation, but food vacuoles in conjugants do not preclude starvation. Only after ingestion and dehydration of vacuoles ceases, does digestion of exuvial fluid begin. Conjugants resorb their feeding apparatus as they fuse. A single imperforate membrane from each partner forms the junction membrane. In a reproductive cyst conjugants divide synchronously, but now the junction membrane is interrupted by pores and channels. After the last division the daughters undergo meiosis--two meiotic divisions and one mitotic division yielding two prokarya as they simultaneously differentiate into tomites. After fertilization, pairs separate and the synkaryon divides once into a macronuclear anlage and a micronucleus. Exconjugants leave the cyst and seek a host. The parental macronucleus remains active until the phoront stage when the anlage develops. Owing to random association of micronuclei during meiosis, Hyalophysa's exconjugants are more genetically diverse than exconjugants from conventional patterns of conjugation. PMID:23706651

  9. Breast cancer after radiotherapy for skin hemangioma in infancy

    SciTech Connect

    Lundell, M.; Mattsson, A.; Hakulinen, T.; Holm, L.E.

    1996-02-01

    Between 1920 and 1959, 9675 women were irradiated in infancy for skin hemangioma at Radiumhemmet, Stockholm. They were exposed to low to moderate doses of ionizing radiation. The mean age at first exposure was 6 months and the mean absorbed dose to the breast anlage was 0.39 Gy (range < 0.01-35.8 Gy). The breast cancer incidence was analyzed by record linkage with the Swedish Cancer Register for the period 1958-1986. Seventy-five breast cancers were found after a mean absorbed dose of 1.5 Gy in the breasts with cancer. The analyses showed a significant dose-response relationship with a linear model estimate for the excess relative risk (ERR) of 0.38 at 1 Gy (95% CI 0.09-0.85). This relationship was not modified significantly by age at exposure or by dose to the ovaries. The ERR increased significantly with time after exposure and for > 50 years after exposure the ERR at 1 Gy was 2.25 (95% CI 0.59-5.62). The fitted excess absolute risk (EAR) was 22.9 per 10{sup 4} breast-year gray. The breast absorbed dose and time after exposure were important risk determinants for breast cancer excess risk. Forty to 50 years of follow-up was necessary for the excess risk to be expressed. The study confirms previous findings that the breast anlage of female infants is sensitive to ionizing radiation. 17 refs., 6 figs.

  10. Tbx2b is required for the development of the parapineal organ

    PubMed Central

    Snelson, Corey D.; Santhakumar, Kirankumar; Halpern, Marnie E.; Gamse, Joshua T.

    2010-01-01

    Structural differences between the left and right sides of the brain exist throughout the vertebrate lineage. By studying the zebrafish pineal complex, which exhibits notable asymmetries, both the genes and the cell movements that result in left-right differences can be characterized. The pineal complex consists of the midline pineal organ and the left-sided parapineal organ. The parapineal is responsible for instructing the asymmetric architecture of the bilateral habenulae, the brain nuclei that flank the pineal complex. Using in vivo time-lapse confocal microscopy, we find that the cells that form the parapineal organ migrate as a cluster of cells from the pineal complex anlage to the left side of the brain. In a screen for mutations that disrupted brain laterality, we identified a nonsense mutation in the T-box2b (tbx2b) gene, which encodes a transcription factor expressed in the pineal complex anlage. The tbx2b mutant makes fewer parapineal cells, and they remain as individuals near the midline rather than migrating leftward as a group. The reduced number and incorrect placement of parapineal cells result in symmetric development of the adjacent habenular nuclei. We conclude that tbx2b functions to specify the correct number of parapineal cells and to regulate their asymmetric migration. PMID:18385257

  11. Fgf signaling governs cell fate in the zebrafish pineal complex

    PubMed Central

    Clanton, Joshua A.; Hope, Kyle D.; Gamse, Joshua T.

    2013-01-01

    Left-right (L-R) asymmetries in neuroanatomy exist throughout the animal kingdom, with implications for function and behavior. The molecular mechanisms that control formation of such asymmetries are beginning to be understood. Significant progress has been made by studying the zebrafish parapineal organ, a group of neurons on the left side of the epithalamus. Parapineal cells arise from the medially located pineal complex anlage and migrate to the left side of the brain. We have found that Fgf8a regulates a fate decision among anterior pineal complex progenitors that occurs just prior to the initiation of leftward migration. Cell fate analysis shows that in the absence of Fgf8a a subset of cells in the anterior pineal complex anlage differentiate as cone photoreceptors rather than parapineal neurons. Fgf8a acts permissively to promote parapineal fate in conjunction with the transcription factor Tbx2b, but might also block cone photoreceptor fate. We conclude that this subset of anterior pineal complex precursors, which normally become parapineal cells, are bipotential and require Fgf8a to maintain parapineal identity and/or prevent cone identity. PMID:23250206

  12. [The Cytoskelrtal Protein Zvxin Interacts with the Hedgehog Receptor Patched].

    PubMed

    Martynova, N U; Ermolina, L V; Eroshkin, F M; Zarayskiy, A G

    2015-01-01

    Earlier, we demonstrated Zyxin influence upon Hedgehog (Hh)-signaling pathway during early patterning of the central neural system (CNS) anlage of the Xenopus laevis embryo. Now we show that Zyxin can physically interact with the transmembrane receptor of Hh, Patched2 (Ptc2). Binding of Hh by this receptor activates signaling pathway, which regulates many events, including numerous types of cell differentiation during the embryonic development. In particular, patterning of the CNS anlage. The ability of Zyxin to interact with Ptc2 have been confirmed by immunoprecipitation experiments, in which we tested mutual binding affinity of Zyxin and Ptc2, as well as mutual affinity of their deletion mutants. As a result, we have established that in Xenopus levis, Zyxin binding to Ptc2 is due to the interaction of Zyxin 2nd LIM-domain (530-590 aa) with the under-membrane region of the cytoplasmic C-terminus of Ptc2 (1159-1412 aa). We have also demonstrated that similar interaction is valid for the homologous regions of the human Zyxin and human Hh receptor, Ptc1. The data obtained allow to hypothesize existence of evolutionary conserved mechanism that modulates Hh-signaling and based on the interaction of Zyxin with Ptc. PMID:27125030

  13. Offspring's hydromineral adaptive responses to maternal undernutrition during lactation.

    PubMed

    Nuñez, P; Arguelles, J; Perillan, C

    2015-12-01

    Early development, throughout gestation and lactation, represents a period of extreme vulnerability during which susceptibility to later metabolic and cardiovascular injuries increases. Maternal diet is a major determinant of the foetal and newborn developmental environment; maternal undernutrition may result in adaptive responses leading to structural and molecular alterations in various organs and tissues, such as the brain and kidney. New nephron anlages appear in the renal cortex up to postnatal day 4 and the last anlages to be formed develop into functional nephrons by postnatal day 10 in rodents. We used a model of undernutrition in rat dams that were food-restricted during the first half of the lactation period in order to study the long-term effects of maternal diet on renal development, behaviour and neural hydromineral control mechanisms. The study showed that after 40% food restriction in maternal dietary intake, the dipsogenic responses for both water and salt intake were not altered; Fos expression in brain areas investigated involved in hydromineral homeostasis control was always higher in the offspring in response to isoproterenol. This was accompanied by normal plasma osmolality changes and typical renal histology. These results suggest that the mechanisms for the control of hydromineral balance were unaffected in the offspring of these 40% food-restricted mothers. Undernutrition of the pups may not be as drastic as suggested by dams' restriction. PMID:26234469

  14. Von Donuts und Zucker: Mit Neutronen biologische Makromoleküle erforschen

    NASA Astrophysics Data System (ADS)

    May, Roland P.

    2003-05-01

    Für die Erforschung von Biomolekülen bieten Neutronen einzigartige Eigenschaften. Vor allem ihre unterschiedliche Wechselwirkung mit dem natürlichen Wasserstoff und seinem schweren Isotop Deuterium ermöglicht tiefe Einblicke in Struktur, Funktion und Dynamik von Proteinen, Nukleinsäuren und Biomembranen. Bei vielen Fragestellungen zur Strukturaufklärung gibt es kaum oder keine Alternative zum Neutron. Das Institut Laue-Langevin trägt Bahnbrechendes zum Erfolg der Neutronen-Methoden in der Biologie bei.

  15. Study of genes associated with the ‘anger-in’ and ‘anger-out’ emotions of humans using a rat model

    PubMed Central

    GUO, YINGHUI; ZHANG, HUIYUN; GAO, JIE; WEI, SHENG; SONG, CHUNHONG; SUN, PENG; QIAO, MINGQI

    2015-01-01

    The aim of the present study was to investigate the genes associated with ‘anger-in’ (tendency to suppress anger) and ‘anger-out’ (tendency to express anger through verbal or physical means) emotions in humans. Wistar rats were divided into five groups (n=10/group), based on the type of model and the Chinese medicinal formulation administered, and the rat models were established. The five groups were as follows: Normal control (control), anger-in model (AIM), anger-in Jingqianshu-administered (AIA), anger-out model (AOM) and anger-out Jingqianping-administered (AOA). Open-field, resident-intruder and aggressive behavior tests were carried out, as well as gene expression analysis, reverse transcription-quantitative polymerase chain reaction and western blot analyses. The body weights of the rats in the AIM and AOM groups were significantly lower than those of the control group rats. The open-field test indicated that the scores in the AOM group were significantly higher (P<0.05) than those in the AIM group. The aggression scores of the rats in the AOM group were significantly higher than those of the AIM group rats. Jingqianshu and Jingqianping granules attenuated the behavioral changes of the rats. 5-Htr2C, GABABR2 and 5-Htr3B were associated with anger-in and anger-out emotions. Jingqianping and Jingqianshu granules attenuated the changes in the mRNA expression of 5-Htr2C, GABABR2 and 5-Htr3B, as indicated by RT-qPCR, and showed similar effects on protein expression, as demonstrated by western blot analysis. The present study demonstrated that the anger-in and anger-out emotions of rats are closely associated with 5-Htr2C, GABABR2 and 5-Htr3B genes, and that Jingqianshu and Jingqianping granules attenuate the abnormal behaviors of model rats. These findings may be useful for the treatment of emotional disorders associated with anger. PMID:25780450

  16. Nicolaus Copernicus (1473 - 1543) - Revolutionär wider Willen.

    NASA Astrophysics Data System (ADS)

    Wolfschmidt, G.

    Begleitbuch zur Copernicus-Ausstellung vom 22. Juli bis 19. Oktober 1994 im Zeiss-Großplanetarium in Berlin. Contents: 1. Der Weg zum modernen Weltbild. 2. Antikes und mittelalterliches Weltbild. 3. Nicolaus Copernicus (1473 - 1543). 4. Wirkungsgeschichte des Copernicus. 5. Katalog zur Copernicus-Ausstellung. Introduction: Copernicus, Mythos und Moderne (J. Teichmann).

  17. IFLA General Conference, 1987. International Association of Law Libraries. Papers.

    ERIC Educational Resources Information Center

    International Federation of Library Associations, The Hague (Netherlands).

    The five papers in this collection focus on computerized legal databases and their content: (1) "Disk and Dat: Recent Developments in Legal Databases and Emerging Information Technologies in the United States" (Howard Hood, United States); (2) "Online Databanken zum EG-Recht und ihr Angebot (Online Databases for European Community Law and Their…

  18. Analyticity of strictly static and strictly stationary, inheriting and non-inheriting Einstein-Maxwell solutions

    NASA Astrophysics Data System (ADS)

    Tod, Paul

    2007-07-01

    Following the technique of Müller zum Hagen (Proc. Camb. Phil. Soc. 67: 415-421, 1970) we show that strictly static and strictly stationary solutions of the Einstein-Maxwell equations are analytic in harmonic coordinates. This holds whether or not the Maxwell field inherits the symmetry.

  19. Elektronische Citizen Cards in Deutschland und Europa

    NASA Astrophysics Data System (ADS)

    Kowalski, Bernd

    Meine sehr geehrten Damen und Herren, der Bedarf an elektronischen Identitäten entsteht durch die wachsende Mobilität der Gesellschaft bei einem gleichzeitig steigenden Bedarf an Onlinepräsenz. Diese elektronischen Identitäten machen natürlich auch vor den staatlichen Ausweisen nicht halt, wie zum Beispiel dem Reisepass, aber auch dem Personalausweis und weiteren Ausweisdokumenten. Wobei es bei den staatlich herausgegebenen oder kontrollierten Ausweisen immer um zwei verschiedene Dinge geht: Einmal um die hoheitliche Funktion, wie zum Beispiel beim Reisepass. Hier geht es zum Beispiel darum, in einem Europa mit gefallenen Grenzen und bei freiem Reiseverkehr für alle Personen, die in diesem Raum wohnen, insbesondere auch im Schengener Raum, die Möglichkeit zu schaffen, auch künftig noch Personenkontrollen durchzuführen. Auch der Reiseverkehr über die europäischen Grenzen hinaus ist insofern ein Problem, da die Identitätenprüfung an den Grenzkontrollen immer schwieriger wird. Deswegen braucht man an dieser Stelle Möglichkeiten, um eine Personenüberprüfung durchzuführen, um feststellen zu können, dass diese Person auch zum Dokument gehört.

  20. Physik gestern und heute Das Eiskalorimeter

    NASA Astrophysics Data System (ADS)

    Heering, P.

    2003-07-01

    Kalorimetrische Messungen gehören heute zum experimentellen Standardrepertoire im Bereich der Thermodynamik und der physikalischen Chemie. Das erste Gerät für derartige Messungen entwickelten Ende des 18. Jahrhunderts die französischen Wissenschaftler Antoine Laurent Lavoisier und Pierre Simon de Laplace.

  1. Dienstleistung Instandhaltung

    NASA Astrophysics Data System (ADS)

    Horn, Wolfgang

    Die gravierenden Veränderungen des Marktes und des Wettbewerbes infolge der Globalisierung Ende des 20. Jahrhunderts hatten auch einschneidende Auswirkungen auf die industrielle Instandhaltung. Dies galt sowohl für die unternehmensinterne Instandhaltung als auch für die externen Instandhaltungsdienstleister. Die Instandhaltung, die sich in der Vergangenheit schon ständig den sich verändernden wirtschaftlichen Rahmenbedingungen in der Regel auch erfolgreich angepasst hatte, stand vor einer neuen Herausforderung. Sie wurde erneut hinsichtlich ihrer Schnittstellen, Arbeitsteilung und Organisation sowie der Flexibilität, Qualität, Nachhaltigkeit und Gesamteffizienz in vielen Unternehmen sowohl intern als auch extern zunehmend sehr kritisch betrachtet. Es wurde in vielen Unternehmen prinzipiell alles auf den Prüfstand gestellt und bisherige Strukturen, Abläufe, Strategien und Prozesse hinsichtlich des vorhandenen Verbesserungspotenzials hinterfragt. Dabei wurde auch sehr oft über den "eigenen Tellerrand“ geschaut und externer Sachverstand genutzt.

  2. Sichtbeton Atlas

    NASA Astrophysics Data System (ADS)

    Schulz, Joachim

    Bereits 1960, d. h. vor 48 Jahren, hat der Architekt R. Probst einen Artikel verfasst mit dem Thema "Sichtbeton - eine Modetorheit". Er wollte mit diesem Beitrag bewusst provozieren und die Diskussion anregen, damit Architekten sich mehr mit dem Baustoff Sichtbeton auseinandersetzen, ihn kritischer bewerten, ihn bewusster und überlegter einsetzen. Trotz dieser schon damals vorhandenen Kritik an diesem Baustoff und dessen Verwendung, kam es in den 1960er und 1970er Jahren vermehrt zu "Bausünden" mit Sichtbeton. Die Welle der "Sichtbetonitis" kam über das Land und riss viele Planer mit sich. Das Lehrgeld wurde bezahlt. Seit den 1990er Jahren wird Sichtbeton wieder vermehrt von vielen Architekten und Bauherren als gestalterisches Mittel eingesetzt.

  3. Geobasisdaten für die Planung?

    NASA Astrophysics Data System (ADS)

    Zölitz-Möller, Reinhard

    2002-09-01

    Die Nutzer von Geobasisdaten der Vermessungs- und Katasterverwaltungen finden heute vor allem in ATKIS (Amtliches Topographisch-Kartographisches Informationssystem) und in der ALK (automatisiert geführte Liegenschaftskarte; hier noch eingeschränkt) flächendeckende und für eine Fachdatenintegration geeignete Geodatenbestände vor. Gleichwohl wird von Nutzerseite häufig ein differenziertes und in Teilen kritisches Bild gezeichnet. Die Kritik richtet sich v.a. auf die Probleme, die ATKIS-Anwender mit dem Nutzerkomfort, dem komplexen Datenmodell, unrichtigen Flächennutzungsangaben, inkompatiblen Objektdefinitionen, den Preisen sowie mangelnder Aktualität und Vollständigkeit haben. Dennoch gibt es für viele Zwecke auch in der Planung langfristig keine echte Alternative zu den Geobasisdaten.

  4. Suspected acute hemolytic transfusion reaction mediated by anti-Di(a).

    PubMed

    Bennett, Ashwini; Boyapati, Ray K; Hong, Frank S

    2015-01-01

    Anti-Di(a) can mediate hemolytic disease of the fetus and newborn, but it is unclear if it can cause hemolytic transfusion reactions (HTRs). To date, there has only been one report of a possible immediate HTR attributed to anti-Di(a). Our case report details an immediate HTR due to anti-Di(a) in a patient with pre-existing liver failure. This reaction triggered multi-organ failure, and the patient subsequently died. This case also highlights the importance of considering HTRs even when routine antibody screening has been unremarkable, particularly when electronic crossmatch is used, because of the potential for an alloantibody against a low-prevalence antigen. PMID:27187197

  5. A Personal Computer-Based Simulation-and-Control-Integrated Platform for 10-MW High-Temperature Gas-Cooled Reactor

    SciTech Connect

    Shi Lei; Liu Haibin; Yang Xiaojing; Gao Zuying; Dong Yujie; Zhang Zuoyi

    2004-02-15

    A personal computer-based simulation-and-control-integrated platform for the 10-MW high-temperature gas-cooled reactor (HTR-10), HTRSIMU, has been developed by the Institute of Nuclear Energy Technology (INET) of Tsinghua University in China to meet the requirements of safety analysis, operator training, and control system design. The HTRSIMU runs on a personal computer Windows2000 operating system and consists of three parts: simulation computing system (SCS), man/machine interface (MMI) system, and control system design platform (CDP). Simulation models and equations of the SCS are given, including models of the reactor core, the fuel ball, the primary loop, and the steam generator. Furthermore, functions and characteristics of the MMI and CDP are also described in detail. Moreover, steady state, several typical accidents, and a power control process of HTR-10 are simulated by using the HTRSIMU to demonstrate its simulation and control system design capability.

  6. A thermodynamic approach for advanced fuels of gas-cooled reactors

    NASA Astrophysics Data System (ADS)

    Guéneau, C.; Chatain, S.; Gossé, S.; Rado, C.; Rapaud, O.; Lechelle, J.; Dumas, J. C.; Chatillon, C.

    2005-09-01

    For both high temperature reactor (HTR) and gas cooled fast reactor (GFR) systems, the high operating temperature in normal and accidental conditions necessitates the assessment of the thermodynamic data and associated phase diagrams for the complex system constituted of the fuel kernel, the inert materials and the fission products. A classical CALPHAD approach, coupling experiments and thermodynamic calculations, is proposed. Some examples of studies are presented leading with the CO and CO 2 gas formation during the chemical interaction of [UO 2± x/C] in the HTR particle, and the chemical compatibility of the couples [UN/SiC], [(U, Pu)N/SiC], [(U, Pu)N/TiN] for the GFR system. A project of constitution of a thermodynamic database for advanced fuels of gas-cooled reactors is proposed.

  7. Coordinated DNA dynamics during the human telomerase catalytic cycle

    NASA Astrophysics Data System (ADS)

    Parks, Joseph W.; Stone, Michael D.

    2014-06-01

    The human telomerase reverse transcriptase (hTERT) utilizes a template within the integral RNA subunit (hTR) to direct extension of telomeres. Telomerase exhibits repeat addition processivity (RAP) and must therefore translocate the nascent DNA product into a new RNA:DNA hybrid register to prime each round of telomere repeat synthesis. Here, we use single-molecule FRET and nuclease protection assays to monitor telomere DNA structure and dynamics during the telomerase catalytic cycle. DNA translocation during RAP proceeds through a previously uncharacterized kinetic substep during which the 3‧-end of the DNA substrate base pairs downstream within the hTR template. The rate constant for DNA primer realignment reveals this step is not rate limiting for RAP, suggesting a second slow conformational change repositions the RNA:DNA hybrid into the telomerase active site and drives the extrusion of the 5‧-end of the DNA primer out of the enzyme complex.

  8. Regulation of systemic energy homeostasis by serotonin in adipose tissues.

    PubMed

    Oh, Chang-Myung; Namkung, Jun; Go, Younghoon; Shong, Ko Eun; Kim, Kyuho; Kim, Hyeongseok; Park, Bo-Yoon; Lee, Ho Won; Jeon, Yong Hyun; Song, Junghan; Shong, Minho; Yadav, Vijay K; Karsenty, Gerard; Kajimura, Shingo; Lee, In-Kyu; Park, Sangkyu; Kim, Hail

    2015-01-01

    Central serotonin (5-HT) is an anorexigenic neurotransmitter in the brain. However, accumulating evidence suggests peripheral 5-HT may affect organismal energy homeostasis. Here we show 5-HT regulates white and brown adipose tissue function. Pharmacological inhibition of 5-HT synthesis leads to inhibition of lipogenesis in epididymal white adipose tissue (WAT), induction of browning in inguinal WAT and activation of adaptive thermogenesis in brown adipose tissue (BAT). Mice with inducible Tph1 KO in adipose tissues exhibit a similar phenotype as mice in which 5-HT synthesis is inhibited pharmacologically, suggesting 5-HT has localized effects on adipose tissues. In addition, Htr3a KO mice exhibit increased energy expenditure and reduced weight gain when fed a high-fat diet. Treatment with an Htr2a antagonist reduces lipid accumulation in 3T3-L1 adipocytes. These data suggest important roles for adipocyte-derived 5-HT in controlling energy homeostasis. PMID:25864946

  9. Analysis of an OECD/NEA high-temperature reactor benchmark

    SciTech Connect

    Hosking, J. G.; Newton, T. D.; Koeberl, O.; Morris, P.; Goluoglu, S.; Tombakoglu, T.; Colak, U.; Sartori, E.

    2006-07-01

    This paper describes analyses of the OECD/NEA HTR benchmark organized by the 'Working Party on the Scientific Issues of Reactor Systems (WPRS)', formerly the 'Working Party on the Physics of Plutonium Fuels and Innovative Fuel Cycles'. The benchmark was specifically designed to provide inter-comparisons for plutonium and thorium fuels when used in HTR systems. Calculations considering uranium fuel have also been included in the benchmark, in order to identify any increased uncertainties when using plutonium or thorium fuels. The benchmark consists of five phases, which include cell and whole-core calculations. Analysis of the benchmark has been performed by a number of international participants, who have used a range of deterministic and Monte Carlo code schemes. For each of the benchmark phases, neutronics parameters have been evaluated. Comparisons are made between the results of the benchmark participants, as well as comparisons between the predictions of the deterministic calculations and those from detailed Monte Carlo calculations. (authors)

  10. Numerical Analysis of Autoignition and Combustion of n-Butane and Air Mixture in Homogeneous-Charge Compression-Ignition Engine Using Elementary Reactions

    NASA Astrophysics Data System (ADS)

    Yamasaki, Yudai; Iida, Norimasa

    The present study focuses on clarifying the combustion mechanism of the homogeneous-charge compression-ignition (HCCI) engine in order to control ignition and combustion as well as to reduce HC and CO emissions and to maintain high combustion efficiency by calculating the chemical kinetics of elementary reactions. For the calculations, n-butane was selected as fuel since it is a fuel with the smallest carbon number in the alkane family that shows two-stage autoignition (heat release with low-temperature reaction (LTR) and with high-temperature reaction (HTR)) similarly to higher hydrocarbons such as gasoline. The CHEMKIN code was used for the calculations assuming zero dimensions in the combustion chamber and adiabatic change. The results reveal the heat release mechanism of the LTR and HTR, the control factor of ignition timing and combustion speed, and the condition need to reduce HC and CO emissions and to maintain high combustion efficiency.

  11. Preliminary assessment of existing experimental data for validation ofreactor physics codes and data for NGNP design and analysis.

    SciTech Connect

    Terry, W. K.; Jewell, J. K.; Briggs, J. B.; Taiwo, T. A.; Park, W.S.; Khalil, H. S.

    2005-10-25

    The Next Generation Nuclear Plant (NGNP), a demonstration reactor and hydrogen production facility proposed for construction at the INEEL, is expected to be a high-temperature gas-cooled reactor (HTGR). Computer codes used in design and safety analysis for the NGNP must be benchmarked against experimental data. The INEEL and ANL have examined information about several past and present experimental and prototypical facilities based on HTGR concepts to assess the potential of these facilities for use in this benchmarking effort. Both reactors and critical facilities applicable to pebble-bed and prismatic block-type cores have been considered. Four facilities--HTR-PROTEUS, HTR-10, ASTRA, and AVR--appear to have the greatest potential for use in benchmarking codes for pebble-bed reactors. Similarly, for the prismatic block-type reactor design, two experiments have been ranked as having the highest priority--HTTR and VHTRC.

  12. Flexibility of the Cytoplasmic Domain of the Phototaxis Transducer II from Natronomonas pharaonis

    PubMed Central

    Budyak, Ivan L.; Mironova, Olga S.; Yanamala, Naveena; Manoharan, Vijayalaxmi; Büldt, Georg; Schlesinger, Ramona; Klein-Seetharaman, Judith

    2008-01-01

    Chemo- and phototaxis systems in bacteria and archaea serve as models for more complex signal transduction mechanisms in higher eukaryotes. Previous studies of the cytoplasmic fragment of the phototaxis transducer (pHtrII-cyt) from the halophilic archaeon Natronomonas pharaonis showed that it takes the shape of a monomeric or dimeric rod under low or high salt conditions, respectively. CD spectra revealed only approximately 24% helical structure, even in 4 M KCl, leaving it an open question how the rod-like shape is achieved. Here, we conducted CD, FTIR, and NMR spectroscopic studies under different conditions to address this question. We provide evidence that pHtrII-cyt is highly dynamic with strong helical propensity, which allows it to change from monomeric to dimeric helical coiled-coil states without undergoing dramatic shape changes. A statistical analysis of predicted disorder for homologous sequences suggests that structural flexibility is evolutionarily conserved within the methyl-accepting chemotaxis protein family. PMID:20107574

  13. Expression of uPAR in human trophoblast and its role in trophoblast invasion

    PubMed Central

    Liu, Shuai; Zheng, Qin; Cui, Xin-Yuan; Dai, Kui-Xing; Yang, Xue-Song; Li, Fa-Sheng; Yan, Qiu

    2015-01-01

    Placental trophoblast cells differentiate into invasive trophoblasts or syncytiotrophoblasts. Abnormal trophoblast invasion results in pregnancy-associated disease and abortion. uPAR is a cell membrane-bound glycosylated protein, involved in physiological and pathological processes. However, uPAR expression in villi during threatened abortion and its role in trophoblast differentiation are unclear. We determined that, uPAR expression in the villi was reduced in threatened abortion patients than that in normal pregnancy. uPARsiRNA inhibited the potential for trophoblast migration and invasion in explants culture and HTR8/SVneo cells. It also enhanced forskolin-induced fusion of HTR8/SVneo cells. Overall, this study provides a possible reason for abortion. PMID:26823748

  14. Overexpression of heparanase is associated with preeclampsia by inhibiting invasion of trophocytes

    PubMed Central

    Wang, Yan-Yun; Zhou, Rong; Zhou, Bin; Wang, Tao; Zhang, Lin; Luo, Dong

    2015-01-01

    Background: Preeclampsia is associated with inadequate invasion of trophocytes and spiral artery remodeling. As a β-D-glucuronidase enzyme, Heparanase is related to tumor angiogenesis, development and invasion. Trophocytes have similar characteristics to tumor cells, and heparanase could therefore play an important role in the pathogenesis of preeclampsia. Methods: The expression of heparanase in severe preeclampsia and normal placentas was detected via real-time PCR, immunohistochemistry and western blotting. The effects of heparanase on trophocytes migration and invasion were investigated by culturing the HTR-8/Svneo cell line with recombinant human heparanase protein in vitro. Results: The levels of inactive 65-kDa heterologous heparanase dimers were obviously increased, and the content of the 50-kDa active polypeptide was decreased in severe preeclampsia. Furthermore, exogenous heparanase protein could reduce the migration and invasion of HTR-8/Svneo cells. Conclusion: Our results suggested that heparanase might be an important factor in the pathogenesis of severe preeclampsia. PMID:26770407

  15. Hypoxia stimulates urokinase receptor expression through a heme protein-dependent pathway.

    PubMed

    Graham, C H; Fitzpatrick, T E; McCrae, K R

    1998-05-01

    Hypoxia underlies a number of biologic processes in which cellular migration and invasion occur. Because earlier studies have shown that the receptor for urokinase-type plasminogen activator (uPAR) may facilitate such events, we studied the effect of hypoxia on the expression of uPAR by first trimester human trophoblasts (HTR-8/SVneo) and human umbilical vein endothelial cells (HUVEC). Compared with control cells cultured under standard conditions (20% O2), HTR-8/SVneo cells and HUVEC cultured in 1% O2 expressed more uPAR, as determined by flow cytometric and [125I]-prourokinase ligand binding analyses. Increased uPAR expression paralleled increases in uPAR mRNA. The involvement of a heme protein in the hypoxia-induced expression of uPAR was suggested by the observations that culture of cells with cobalt chloride, or sodium 4, 5-dihydroxybenzene-1,3-disulfonate (Tiron), an iron-chelating agent, also stimulated uPAR expression, and that the hypoxia-induced uPAR expression was inhibited by adding carbon monoxide to the hypoxic atmosphere. Culture of HTR-8/SVneo cells with vascular endothelial growth factor (VEGF) did not increase uPAR mRNA levels, suggesting that the hypoxia-mediated effect on uPAR expression by these cells did not occur through a VEGF-dependent mechanism. The functional importance of these findings is suggested by the fact that HTR-8/SVneo cells cultured under hypoxia displayed higher levels of cell surface plasminogen activator activity and greater invasion through a reconstituted basement membrane. These results suggest that hypoxia may promote cellular invasion by stimulating the expression of uPAR through a heme protein-dependent pathway. PMID:9558386

  16. SU-E-T-354: Peak Temperature Ratio of TLD Glow Curves to Investigate the Spatial Dependence of LET in a Clinical Proton Beam

    SciTech Connect

    Reft, C; Pankuch, M; Ramirez, H

    2014-06-01

    Purpose: Use the ratio of the two high temperature peaks (HTR) in TLD 700 glow curves to investigate spatial dependence of the linear energy transfer (LET) in proton beams. Studies show that the relative biological effectiveness (RBE) depends upon the physical dose as well as its spatial distribution. Although proton therapy uses a spatially invariant RBE of 1.1, studies suggest that the RBE increases in the distal edge of a spread out Bragg peak (SOBP) due to the increased LET. Methods: Glow curve studies in TLD 700 show that the 280 C temperature peak is more sensitive to LET radiation than the 210 C temperature peak. Therefore, the areas under the individual temperature peaks for TLDs irradiated in a proton beam normalized to the peak ratio for 6 MV photons are used to determine the HTR to obtain information on its LET. TLD 700 chips with dimensions 0.31×0.31×0.038 cc are irradiated with 90 MeV protons at varying depths in a specially designed blue wax phantom to investigate LET spatial dependence. Results: Five TLDs were placed at five different depths of the percent depth dose curve (PDD) of range 16.2 cm: center of the SOPB and approximately at the 99% distal edge, 90%, 75% and 25% of the PDD, respectively. HTR was 1.3 at the center of the SOBP and varied from 2.2 to 3.9 which can be related to an LET variation from 0.5 to 18 KeV/μ via calibration with radiation beams of varying LET. Conclusion: HTR data show a spatially invariant LET slightly greater than the 6 MV radiations in the SOBP, but a rapidly increasing LET at the end of the proton range. These results indicate a spatial variation in RBE with potential treatment consequences when selecting treatment margins to minimize the uncertainties in proton RBE.

  17. Pharmacogenetics of Risperidone and Cardiovascular Risk in Children and Adolescents

    PubMed Central

    Dos Santos-Júnior, Amilton; Henriques, Taciane Barbosa; de Mello, Maricilda Palandi; Della Torre, Osmar Henrique; Paes, Lúcia Arisaka; Ferreira-Neto, Adriana Perez; Sewaybricker, Letícia Esposito; Fontana, Thiago Salum; Celeri, Eloisa Helena Rubello Valler; Guerra-Júnior, Gil; Dalgalarrondo, Paulo

    2016-01-01

    Objective. To identify the frequency of obesity and metabolic complications in child and adolescent users of risperidone. Potential associations with clinical parameters and SNPs of the HTR2C, DRD2, LEP, LEPR, MC4R, and CYP2D6 genes were analyzed. Methods. Samples from 120 risperidone users (8–20 years old) were collected and SNPs were analyzed, alongside assessment of chronological and bone ages, prescribed and weight-adjusted doses, use of other psychotropic drugs, waist circumference, BMI z-scores, blood pressure, HOMA-IR index, fasting levels of serum glucose, insulin, cholesterol, triglycerides, transaminases, and leptin. Results. Thirty-two (26.7%) patients were overweight and 5 (4.2%) obese. Hypertension was recorded in 8 patients (6.7%), metabolic syndrome in 6 (5%), and increased waist circumference in 20 (16.7%). The HOMA-IR was high for 22 patients (18.3%), while total cholesterol and triglycerides were high in 20 (16.7%) and 41 (34.2%) patients, respectively. SNP associations were found for LEP, HTR2C, and CYP2D6 with BMI; CYP2D6 with blood pressure, ALT, and HOMA-IR; HTR2C and LEPR with leptin levels; MC4R and DRD2 with HOMA-IR; HTR2C with WC; and LEP with ALT. Conclusions. Although not higher than in the general pediatric population, a high frequency of patients was overweight/obese, with abnormalities in metabolic parameters and some pharmacogenetic associations. PMID:26880915

  18. Genetic Association Analysis of 30 Genes Related to Obesity in a European American Population

    PubMed Central

    Li, Peng; Tiwari, Hemant K.; Lin, Wan-Yu; Allison, David B.; Chung, Wendy K.; Leibel, Rudolph L.; Yi, Nengjun; Liu, Nianjun

    2013-01-01

    Objective Obesity, which is frequently associated with diabetes, hypertension, and cardiovascular diseases, is primarily the result of a net excess of caloric intake over energy expenditure. Human obesity is highly heritable, but the specific genes mediating susceptibility in non-syndromic obesity remain unclear. We tested candidate genes in pathways related to food intake and energy expenditure for association with body mass index (BMI). Methods We re-analyzed 355 common genetic variants of 30 candidate genes in 7 molecular pathways related to obesity in 1,982 unrelated European Americans from the New York Health Project. Data were analyzed by using a Bayesian hierarchical generalized linear model. The BMIs were log-transformed and then adjusted for covariates including age, age2, gender, and diabetes status. The single nucleotide polymorphisms (SNPs) were modeled as additive effects. Results With the stipulated adjustments, nine SNPs in eight genes were significantly associated with BMI: GHRL (rs35683), AGRP (rs5030980), CPE (rs1946816 and rs4481204), GLP1R (rs2268641), HTR2A (rs912127), NPY5R (Y5R1c52), SOCS3 (rs4969170), and STAT3 (rs4796793). We also found a gender-by-SNP interaction (rs1745837 in HTR2A), which indicated that variants in the gene HTR2A had a stronger association with BMI in males. In addition, NPY1R was detected as having a significant gene effect even though none of the SNPs in this gene was significant. Conclusion Variations in genes AGRP, CPE, GHRL, GLP1R, HTR2A, NPY1R, NPY5R, SOCS3, and STAT3 showed modest associations with BMI in European Americans. The pathways in which these genes participate regulate energy intake and thus these associations are mechanistically plausible in this context. PMID:23900445

  19. Expression, Extracellular Secretion, and Immunogenicity of the Plasmodium falciparum Sporozoite Surface Protein 2 in Salmonella Vaccine Strains

    PubMed Central

    Gómez-Duarte, Oscar G.; Pasetti, Marcela F.; Santiago, Araceli; Sztein, Marcelo B.; Hoffman, Stephen L.; Levine, Myron M.

    2001-01-01

    Deleting transmembrane α-helix motifs from Plasmodium falciparum sporozoite surface protein (SSP-2) allowed its secretion from Salmonella enterica serovar Typhimurium SL3261 and S. enterica serovar Typhi CVD 908-htrA by the Hly type I secretion system. In mice immunized intranasally, serovar Typhimurium constructs secreting SSP-2 stimulated greater gamma interferon splenocyte responses than did nonsecreting constructs (P = 0.04). PMID:11160021

  20. STAT3 and ERK Signaling Pathways Are Implicated in the Invasion Activity by Oncostatin M through Induction of Matrix Metalloproteinases 2 and 9

    PubMed Central

    Ko, Hyun Sun; Park, Byung Joon; Choi, Sae Kyung; Kang, Hee Kyung; Kim, Ahyoung; Kim, Ho Shik; Park, In Yang

    2016-01-01

    Purpose Our previous studies have shown that oncostatin M (OSM) promotes trophoblast invasion activity through increased enzyme activity of matrix metalloproteinase (MMP)-2 and -9. We further investigated OSM-induced intracellular signaling mechanisms associated with these events in the immortalized human trophoblast cell line HTR8/SVneo. Materials and Methods We investigated the effects of OSM on RNA and protein expression of MMP-2 and -9 in the first-trimester extravillous trophoblast cell line (HTR8/SVneo) via Western blot. The selective signal transducer and activator of transcription (STAT)3 inhibitor, stattic, STAT3 siRNA, and extracellular signal-regulated kinase (ERK) siRNA were used to investigate STAT3 and ERK activation by OSM. The effects of STAT3 and ERK inhibitors on OSM-induced enzymatic activities of MMP-2 and -9 and invasion activity were further determined via Western blot and gelatin zymography. Results OSM-induced MMP-2 and -9 protein expression was significantly suppressed by STAT3 inhibition with stattic and STAT3 siRNA silencing, whereas the ERK1/2 inhibitor (U0126) and ERK silencing significantly suppressed OSM-induced MMP-2 protein expression. OSM-induced MMP-2 and MMP-9 enzymatic activities were significantly decreased by stattic pretreatment. The increased invasion activity induced by OSM was significantly suppressed by STAT3 and ERK1/2 inhibition, though to a greater extent by STAT3 inhibition. Conclusion Both STAT3 and ERK signaling pathways are involved in OSM-induced invasion activity of HTR8/SVneo cells. Activation of STAT3 appears to be critical for the OSM-mediated increase in invasiveness of HTR8/SVneo cells. PMID:26996579

  1. Serotonin Modulates Developmental Microglia via 5-HT2B Receptors: Potential Implication during Synaptic Refinement of Retinogeniculate Projections.

    PubMed

    Kolodziejczak, Marta; Béchade, Catherine; Gervasi, Nicolas; Irinopoulou, Theano; Banas, Sophie M; Cordier, Corinne; Rebsam, Alexandra; Roumier, Anne; Maroteaux, Luc

    2015-07-15

    Maturation of functional neuronal circuits during central nervous system development relies on sophisticated mechanisms. First, axonal and dendritic growth should reach appropriate targets for correct synapse elaboration. Second, pruning and neuronal death are required to eliminate redundant or inappropriate neuronal connections. Serotonin, in addition to its role as a neurotransmitter, actively participates in postnatal establishment and refinement of brain wiring in mammals. Brain resident macrophages, that is, microglia, also play an important role in developmentally regulated neuronal death as well as in synaptic maturation and elimination. Here, we tested the hypothesis of cross-regulation between microglia and serotonin during postnatal brain development in a mouse model of synaptic refinement. We found expression of the serotonin 5-HT2B receptor on postnatal microglia, suggesting that serotonin could participate in temporal and spatial synchronization of microglial functions. Using two-photon microscopy, acute brain slices, and local delivery of serotonin, we observed that microglial processes moved rapidly toward the source of serotonin in Htr2B(+/+) mice, but not in Htr2B(-/-) mice lacking the 5-HT2B receptor. We then investigated whether some developmental steps known to be controlled by serotonin could potentially result from microglia sensitivity to serotonin. Using an in vivo model of synaptic refinement during early brain development, we investigated the maturation of the retinal projections to the thalamus and observed that Htr2B(-/-) mice present anatomical alterations of the ipsilateral projecting area of retinal axons into the thalamus. In addition, activation markers were upregulated in microglia from Htr2B(-/-) compared to control neonates, in the absence of apparent morphological modifications. These results support the hypothesis that serotonin interacts with microglial cells and these interactions participate in brain maturation. PMID

  2. Quantification of human telomerase reverse transcriptase mRNA in testicular germ cell tumors by quantitative fluorescence real-time RT-PCR.

    PubMed

    Schrader, Mark; Burger, Angelika M; Müller, Markus; Krause, Hans; Straub, Bernd; Smith, Gilian L; Newlands, Eward S; Miller, Kurt

    2002-01-01

    Telomerase is a ribonucleoprotein enzyme which is endogenously expressed in germ, stem and tumor cells, but absent in benign somatic cells. The two major telomerase components are human telomerase RNA (hTR) and human telomerase reverse transcriptase (hTERT). It has been shown that hTERT is rate-limiting for telomerase activity and that it plays a central role in human carcinogenesis. Here, we investigated the potential of hTERT and hTR gene expression as diagnostic markers in testicular germ cell tumors (TGCT). hTERT mRNA and hTR expression were quantified in 55 testicular germ cell tumors comprising 36 primary and 19 germ cell tumors from retroperitonal sides by fluorescence real-time RT-PCR using the LightCycler technology. Porphobilinogen deaminase (PBGD) was used as housekeeping gene and to enable relative quantification. For comparison to TGCTs, 38 benign testicular biopsies from patients with fertility disorders were assayed. hTERT expression was detected in all examined undifferentiated TGCTs and in the benign testicular tissue specimens with germ cell content (N(hTERT) 38-127). In contrast, mature teratomas from primary and post-chemotherapy masses, which are characterized by well-differentiated tissue components showed a nearly complete downregulation of hTERT expression (N(hTERT) 2-4, p<0.001). hTR levels however, were high in all tumors and independently of the presence of germ cells also in the benign tissue control group. hTERT mRNA is expressed in all undifferentiated TGCTs but repressed in mature teratomas. This suggests an inverse correlation between the differentiation status of germ cell tumors and hTERT expression. Thus, detection of hTERT expression in tumors histopathologically classified as mature teratomas enables a molecular-diagnostic confirmation and might aid decision making for treatment of patients presenting with this tumor subtype. PMID:12168080

  3. Chromatin immunoprecipitation reveals that the 180-bp satellite repeat is the key functional DNA element of Arabidopsis thaliana centromeres.

    PubMed Central

    Nagaki, Kiyotaka; Talbert, Paul B; Zhong, Cathy Xiaoyan; Dawe, R Kelly; Henikoff, Steven; Jiang, Jiming

    2003-01-01

    The centromeres of Arabidopsis thaliana chromosomes contain megabases of complex DNA consisting of numerous types of repetitive DNA elements. We developed a chromatin immunoprecipitation (ChIP) technique using an antibody against the centromeric H3 histone, HTR12, in Arabidopsis. ChIP assays showed that the 180-bp centromeric satellite repeat was precipitated with the antibody, suggesting that this repeat is the key component of the centromere/kinetochore complex in Arabidopsis. PMID:12663558

  4. Pharmacogenetics in major depression: a comprehensive meta-analysis.

    PubMed

    Niitsu, Tomihisa; Fabbri, Chiara; Bentini, Francesco; Serretti, Alessandro

    2013-08-01

    A number of candidate gene studies focused on major depression (MD) and antidepressant (AD) efficacy have been carried out, but results mainly remain inconclusive. We performed a comprehensive meta-analysis of published candidate gene studies focused on AD efficacy in MD to evaluate the cumulative evidence. A random-effect model was applied to study the polymorphisms with genotypic counts available from at least three independent studies. On the base of previous evidence, the analysis was stratified by ethnicity (Caucasian, Asian, and other/mixed), and AD class (SSRIs and mixed/other ADs). Genotypic data were available for 16 polymorphisms in 11 genes. After the exclusion of 5-HTTLPR in SLC6A4 included in another recent meta-analysis, 15 polymorphisms in 11 genes were included in the present meta-analysis (BDNF rs6265, SLC6A4 STin2, HTR1A rs6295, HTR2A rs6311, rs6313 and rs7997012, HTR6 rs1805054, TPH1 rs1800532, SLC6A2 rs5569, COMT rs4680, GNB3 rs5443, FKBP5 rs1360780 and rs3800373, and ABCB1 rs1045642 and rs2032582). Our results suggested that BDNF rs6265 (Val66Met) heterozygous genotype was associated with better SSRIs response compared to the homozygous genotypes, particularly in Asians (OR=1.53, 95%CI 1.12-2.07, p=0.007). SLC6A4 STin2, HTR2A rs6311 and rs7997012, GNB3 rs5443, FKBP5 rs1360780 and rs3800373, and ABCB1 rs2032582 showed associations with AD efficacy, but these results were highly dependent on one or two single studies. In conclusion, our findings suggested the BDNF Val66Met as the best single candidate involved in AD response, with a selective effect on SSRI treatment. Our overall results supported no major effect of any single gene variant on AD efficacy. PMID:23733030

  5. Construction, genotypic and phenotypic characterization, and immunogenicity of attenuated DeltaguaBA Salmonella enterica serovar Typhi strain CVD 915.

    PubMed

    Wang, J Y; Pasetti, M F; Noriega, F R; Anderson, R J; Wasserman, S S; Galen, J E; Sztein, M B; Levine, M M

    2001-08-01

    A promising live attenuated typhoid vaccine candidate strain for mucosal immunization was developed by introducing a deletion in the guaBA locus of pathogenic Salmonella enterica serovar Typhi strain Ty2. The resultant DeltaguaBA mutant, serovar Typhi CVD 915, has a gene encoding resistance to arsenite replacing the deleted sequence within guaBA, thereby providing a marker to readily identify the vaccine strain. CVD 915 was compared in in vitro and in vivo assays with wild-type strain Ty2, licensed live oral typhoid vaccine strain Ty21a, or attenuated serovar Typhi vaccine strain CVD 908-htrA (harboring mutations in aroC, aroD, and htrA). CVD 915 was less invasive than CVD 908-htrA in tissue culture and was more crippled in its ability to proliferate after invasion. In mice inoculated intraperitoneally with serovar Typhi and hog gastric mucin (to estimate the relative degree of attenuation), the 50% lethal dose of CVD 915 (7.7 x 10(7) CFU) was significantly higher than that of wild-type Ty2 (1.4 x 10(2) CFU) and was only slightly lower than that of Ty21a (1.9 x 10(8) CFU). Strong serum O and H antibody responses were recorded in mice inoculated intranasally with CVD 915, which were higher than those elicited by Ty21a and similar to those stimulated by CVD 908-htrA. CVD 915 also elicited potent proliferative responses in splenocytes from immunized mice stimulated with serovar Typhi antigens. Used as a live vector, CVD 915(pTETlpp) elicited high titers of serum immunoglobulin G anti-fragment C. These encouraging preclinical data pave the way for phase 1 clinical trials with CVD 915. PMID:11447145

  6. Constitutive expression of the Vi polysaccharide capsular antigen in attenuated Salmonella enterica serovar typhi oral vaccine strain CVD 909.

    PubMed

    Wang, J Y; Noriega, F R; Galen, J E; Barry, E; Levine, M M

    2000-08-01

    Live oral Ty21a and parenteral Vi polysaccharide vaccines provide significant protection against typhoid fever, albeit by distinct immune mechanisms. Vi stimulates serum immunoglobulin G Vi antibodies, whereas Ty21a, which does not express Vi, elicits humoral and cell-mediated immune responses other than Vi antibodies. Protection may be enhanced if serum Vi antibody as well as cell-mediated and humoral responses can be stimulated. Disappointingly, several new attenuated Salmonella enterica serovar Typhi oral vaccines (e.g., CVD 908-htrA and Ty800) that elicit serum O and H antibody and cell-mediated responses following a single dose do not stimulate serum Vi antibody. Vi expression is regulated in response to environmental signals such as osmolarity by controlling the transcription of tviA in the viaB locus. To investigate if Vi antibodies can be stimulated if Vi expression is rendered constitutive, we replaced P(tviA) in serovar Typhi vaccine CVD 908-htrA with the constitutive promoter P(tac), resulting in CVD 909. CVD 909 expresses Vi even under high-osmolarity conditions and is less invasive for Henle 407 cells. In mice immunized with a single intranasal dose, CVD 909 was more immunogenic than CVD 908-htrA in eliciting serum Vi antibodies (geometric mean titer of 160 versus 49, P = 0.0007), whereas O antibody responses were virtually identical (geometric mean titer of 87 versus 80). In mice challenged intraperitoneally with wild-type serovar Typhi 4 weeks after a single intranasal immunization, the mortality of those immunized with CVD 909 (3 of 8) was significantly lower than that of control mice (10 of 10, P = 0.043) or mice given CVD 908-htrA (9 of 10, P = 0.0065). PMID:10899868

  7. Mechanism of aqueous fructus aurantii immaturus extracts in neuroplexus of cathartic colons

    PubMed Central

    Wang, Shi-Yi; Liu, Yan-Ping; Fan, Yi-Hong; Zhang, Lu; Cai, Li-Jun; Lv, Bin

    2015-01-01

    AIM: To examine the effect of aqueous fructus aurantii immaturus (FAI) extracts on the intestinal plexus of cathartic colons. METHODS: Cathartic colons were induced in rats with dahuang, a laxative used in traditional Chinese medicine. Once the model was established (after approximately 12 wk), rats were administered mosapride (1.54 mg/kg) or various doses of aqueous FAI extracts (1-4 g/kg) for 14 d. Transit function was assessed using an ink propulsion test. Rats were then sacrificed, and the ultramicrostructure of colonic tissue was examined using transmission electron microscopy. The expression of the 5-hydroxytryptamine receptor 4 (5-HTR4) and neurofilament-H was assessed in colon tissues using real-time PCR, Western blot, and immunohistochemistry. RESULTS: Mosapride and high dose (4 g/kg) of aqueous FAI extracts significantly improved the bowel movement in cathartic colons compared to untreated model colons as measured by the intestinal transit rate (70.06 ± 7.25 and 72.02 ± 8.74, respectively, vs 64.12 ± 5.19; P < 0.05 for both). Compared to controls, the ultramicrostructure of cathartic colons showed signs of neural degeneration. Treatment with mosapride and aqueous FAI extracts resulted in recovery of ultrastructural pathology. Treatment with mosapride alone upregulated the gene and protein expression of 5-HTR4 compared to untreated controls (P < 0.05 for both). Treatment with aqueous FAI extracts (≥ 2 g/kg) increased 5-HTR4 mRNA levels (P < 0.05), but no change in protein level was observed by Western blot or immunohistochemistry. The mRNA and protein levels of neurofilament-H were significantly increased with mosapride and ≥ 2 g/kg aqueous FAI extracts compared to controls (P < 0.05 for all). CONCLUSION: Aqueous FAI extracts and mosapride strengthen bowel movement in cathartic colons via increasing the expression of 5-HTR4 and neurofilament-H. PMID:26309361

  8. Effect of Five Genetic Variants Associated with Lung Function on the Risk of Chronic Obstructive Lung Disease, and Their Joint Effects on Lung Function

    PubMed Central

    Soler Artigas, María; Wain, Louise V.; Repapi, Emmanouela; Obeidat, Ma'en; Sayers, Ian; Burton, Paul R.; Johnson, Toby; Zhao, Jing Hua; Albrecht, Eva; Dominiczak, Anna F.; Kerr, Shona M.; Smith, Blair H.; Cadby, Gemma; Hui, Jennie; Palmer, Lyle J.; Hingorani, Aroon D.; Wannamethee, S. Goya; Whincup, Peter H.; Ebrahim, Shah; Smith, George Davey; Barroso, Inês; Loos, Ruth J. F.; Wareham, Nicholas J.; Cooper, Cyrus; Dennison, Elaine; Shaheen, Seif O.; Liu, Jason Z.; Marchini, Jonathan; Dahgam, Santosh; Naluai, Åsa Torinsson; Olin, Anna-Carin; Karrasch, Stefan; Heinrich, Joachim; Schulz, Holger; McKeever, Tricia M.; Pavord, Ian D.; Heliövaara, Markku; Ripatti, Samuli; Surakka, Ida; Blakey, John D.; Kähönen, Mika; Britton, John R.; Nyberg, Fredrik; Holloway, John W.; Lawlor, Debbie A.; Morris, Richard W.; James, Alan L.; Jackson, Cathy M.; Hall, Ian P.

    2011-01-01

    Rationale: Genomic loci are associated with FEV1 or the ratio of FEV1 to FVC in population samples, but their association with chronic obstructive pulmonary disease (COPD) has not yet been proven, nor have their combined effects on lung function and COPD been studied. Objectives: To test association with COPD of variants at five loci (TNS1, GSTCD, HTR4, AGER, and THSD4) and to evaluate joint effects on lung function and COPD of these single-nucleotide polymorphisms (SNPs), and variants at the previously reported locus near HHIP. Methods: By sampling from 12 population-based studies (n = 31,422), we obtained genotype data on 3,284 COPD case subjects and 17,538 control subjects for sentinel SNPs in TNS1, GSTCD, HTR4, AGER, and THSD4. In 24,648 individuals (including 2,890 COPD case subjects and 13,862 control subjects), we additionally obtained genotypes for rs12504628 near HHIP. Each allele associated with lung function decline at these six SNPs contributed to a risk score. We studied the association of the risk score to lung function and COPD. Measurements and Main Results: Association with COPD was significant for three loci (TNS1, GSTCD, and HTR4) and the previously reported HHIP locus, and suggestive and directionally consistent for AGER and TSHD4. Compared with the baseline group (7 risk alleles), carrying 10–12 risk alleles was associated with a reduction in FEV1 (β = –72.21 ml, P = 3.90 × 10−4) and FEV1/FVC (β = –1.53%, P = 6.35 × 10−6), and with COPD (odds ratio = 1.63, P = 1.46 × 10−5). Conclusions: Variants in TNS1, GSTCD, and HTR4 are associated with COPD. Our highest risk score category was associated with a 1.6-fold higher COPD risk than the population average score. PMID:21965014

  9. Modulation of Endotoxicity of Shigella Generalized Modules for Membrane Antigens (GMMA) by Genetic Lipid A Modifications

    PubMed Central

    Rossi, Omar; Pesce, Isabella; Giannelli, Carlo; Aprea, Susanna; Caboni, Mariaelena; Citiulo, Francesco; Valentini, Sara; Ferlenghi, Ilaria; MacLennan, Calman Alexander; D'Oro, Ugo; Saul, Allan; Gerke, Christiane

    2014-01-01

    Outer membrane particles from Gram-negative bacteria are attractive vaccine candidates as they present surface antigens in their natural context. We previously developed a high yield production process for genetically derived particles, called generalized modules for membrane antigens (GMMA), from Shigella. As GMMA are derived from the outer membrane, they contain immunostimulatory components, especially lipopolysaccharide (LPS). We examined ways of reducing their reactogenicity by modifying lipid A, the endotoxic part of LPS, through deletion of late acyltransferase genes, msbB or htrB, in GMMA-producing Shigella sonnei and Shigella flexneri strains. GMMA with resulting penta-acylated lipid A from the msbB mutants showed a 600-fold reduced ability, and GMMA from the S. sonnei ΔhtrB mutant showed a 60,000-fold reduced ability compared with GMMA with wild-type lipid A to stimulate human Toll-like receptor 4 (TLR4) in a reporter cell line. In human peripheral blood mononuclear cells, GMMA with penta-acylated lipid A showed a marked reduction in induction of inflammatory cytokines (S. sonnei ΔhtrB, 800-fold; ΔmsbB mutants, 300-fold). We found that the residual activity of these GMMA is largely due to non-lipid A-related TLR2 activation. In contrast, in the S. flexneri ΔhtrB mutant, a compensatory lipid A palmitoleoylation resulted in GMMA with hexa-acylated lipid A with ∼10-fold higher activity to stimulate peripheral blood mononuclear cells than GMMA with penta-acylated lipid A, mostly due to retained TLR4 activity. Thus, for use as vaccines, GMMA will likely require lipid A penta-acylation. The results identify the relative contributions of TLR4 and TLR2 activation by GMMA, which need to be taken into consideration for GMMA vaccine development. PMID:25023285

  10. Increased DNA methylation of neuropsychiatric genes occurs in borderline personality disorder.

    PubMed

    Dammann, Gerhard; Teschler, Stefanie; Haag, Tanja; Altmüller, Franziska; Tuczek, Frederik; Dammann, Reinhard H

    2011-12-01

    Borderline personality disorder (BPD) is a complex psychiatric disease of increasing importance. Epigenetic alterations are hallmarks for altered gene expression and could be involved in the etiology of BPD. In our study we analyzed DNA methylation patterns of 14 neuropsychiatric genes (COMT, DAT1, GABRA1, GNB3, GRIN2B, HTR1B, HTR2A, 5-HTT, MAOA, MAOB, NOS1, NR3C1, TPH1 and TH). DNA methylation was analyzed by bisulfite restriction analysis and pyrosequencing in whole blood samples of patients diagnosed with DSM-IV BPD and in controls. Aberrant methylation was not detectable using bisulfite restriction analysis, but a significantly increased methylation of HTR2A, NR3C1, MAOA, MAOB and soluble COMT (S-COMT) was revealed for BPD patients using pyrosequencing. For HTR2A the average methylation of four CpG sites was 0.8% higher in BPD patients compared to controls (p = 0.002). The average methylation of NR3C1 was 1.8% increased in BPD patients compared to controls (p = 0.0003) and was higher at 2 out of 8 CpGs (p ≤ 0.04). In females, an increased average methylation (1.5%) of MAOA was observed in BPD patients compared to controls (p = 0.046). A similar trend (1.4% higher methylation) was observed for MAOB in female BPD patients and increased methylation was significant for 1 out of 6 CpG sites. For S-COMT, a higher methylation of 2 out of 4 CpG sites was revealed in BPD patients (p ≤ 0.02). In summary, methylation signatures of several promoter regions were established and a significant increased average methylation (1.7%) occurred in blood samples of BPD patients (p < 0.0001). Our data suggest that aberrant epigenetic regulation of neuropsychiatric genes may contribute to the pathogenesis of BPD. PMID:22139575

  11. Enhanced head-twitch response to 5-HT-related agonists in thiamine-deficient mice.

    PubMed

    Nakagawasai, O; Murata, A; Arai, Y; Ohba, A; Wakui, K; Mitazaki, S; Niijima, F; Tan-No, K; Tadano, T

    2007-01-01

    While many studies suggest an involvement of brain serotonergic systems in neuro-psychiatric disorders such as schizophrenia and depression, their role in Wernicke-Korsakoff syndrome (WKS) remains unclear. Since dietary thiamine deficiency (TD) in mice is considered as a putative model of WKS, it was used in the present study to investigate the function of serotonergic neurons in this disorder. After 20 days of TD feeding, the intensity of tryptophan hydroxylase immunofluorescence was found to be significantly decreased in the dorsal and medial raphe nuclei. In addition, the head-twitch response (HTR) elicited by the intracerebroventricular administration of the 5-HT(2A) agonist 2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) was significantly increased in TD versus control mice, whereas the injection of ketanserin, a 5-HT(2A) receptor antagonist, prevented this enhancement. A single injection of thiamine HCl on the 19th day of TD feeding did not reduce the enhanced DOI-induced HTR. On the other hand, the administration of d-fenfluramine, a 5-HT releaser, did not enhance the HTR in TD mice. Together, our results indicate that TD causes a super-sensitivity of 5-HT(2A) receptors by reducing presynaptic 5-HT synthesis derived from degenerating neurons projecting from the raphe nucleus. PMID:17372673

  12. Coil-bridge transition in a single polymer chain as an unconventional phase transition: Theory and simulation

    NASA Astrophysics Data System (ADS)

    Klushin, Leonid I.; Skvortsov, Alexander M.; Polotsky, Alexey A.; Hsu, Hsiao-Ping; Binder, Kurt

    2014-05-01

    The coil-bridge transition in a self-avoiding lattice chain with one end fixed at height H above the attractive planar surface is investigated by theory and Monte Carlo simulation. We focus on the details of the first-order phase transition between the coil state at large height H ⩾ Htr and a bridge state at H ⩽ Htr, where Htr corresponds to the coil-bridge transition point. The equilibrium properties of the chain were calculated using the Monte Carlo pruned-enriched Rosenbluth method in the moderate adsorption regime at (H/Na)tr ⩽ 0.27 where N is the number of monomer units of linear size a. An analytical theory of the coil-bridge transition for lattice chains with excluded volume interactions is presented in this regime. The theory provides an excellent quantitative description of numerical results at all heights, 10 ⩽ H/a ⩽ 320 and all chain lengths 40 < N < 2560 without free fitting parameters. A simple theory taking into account the effect of finite extensibility of the lattice chain in the strong adsorption regime at (H/Na)tr ⩾ 0.5 is presented. We discuss some unconventional properties of the coil-bridge transition: the absence of phase coexistence, two micro-phases involved in the bridge state, and abnormal behavior in the microcanonical ensemble.

  13. Coil-bridge transition in a single polymer chain as an unconventional phase transition: theory and simulation.

    PubMed

    Klushin, Leonid I; Skvortsov, Alexander M; Polotsky, Alexey A; Hsu, Hsiao-Ping; Binder, Kurt

    2014-05-28

    The coil-bridge transition in a self-avoiding lattice chain with one end fixed at height H above the attractive planar surface is investigated by theory and Monte Carlo simulation. We focus on the details of the first-order phase transition between the coil state at large height H ⩾ Htr and a bridge state at H ⩽ Htr, where Htr corresponds to the coil-bridge transition point. The equilibrium properties of the chain were calculated using the Monte Carlo pruned-enriched Rosenbluth method in the moderate adsorption regime at (H/Na)tr ⩽ 0.27 where N is the number of monomer units of linear size a. An analytical theory of the coil-bridge transition for lattice chains with excluded volume interactions is presented in this regime. The theory provides an excellent quantitative description of numerical results at all heights, 10 ⩽ H/a ⩽ 320 and all chain lengths 40 < N < 2560 without free fitting parameters. A simple theory taking into account the effect of finite extensibility of the lattice chain in the strong adsorption regime at (H/Na)tr ⩾ 0.5 is presented. We discuss some unconventional properties of the coil-bridge transition: the absence of phase coexistence, two micro-phases involved in the bridge state, and abnormal behavior in the microcanonical ensemble. PMID:24880326

  14. Plutonium and minor actinide utilisation in a pebble-bed high temperature reactor

    SciTech Connect

    Petrov, B. Y.; Kuijper, J. C.; Oppe, J.; De Haas, J. B. M.

    2012-07-01

    This paper contains results of the analysis of the pebble-bed high temperature gas-cooled PUMA reactor loaded with plutonium and minor actinide (Pu/MA) fuel. Starting from knowledge and experience gained in the Euratom FP5 projects HTR-N and HTR-N1, this study aims at demonstrating the potential of high temperature reactors to utilize or transmute Pu/MA fuel. The work has been performed within the Euratom FP6 project PUMA. A number of different fuel types and fuel configurations have been analyzed and compared with respect to incineration performance and safety-related reactor parameters. The results show the excellent plutonium and minor actinide burning capabilities of the high temperature reactor. The largest degree of incineration is attained in the case of an HTR fuelled by pure plutonium fuel as it remains critical at very deep burnup of the discharged pebbles. Addition of minor actinides to the fuel leads to decrease of the achievable discharge burnup and therefore smaller fraction of actinides incinerated during reactor operation. The inert-matrix fuel design improves the transmutation performance of the reactor, while the 'wallpaper' fuel does not have advantage over the standard fuel design in this respect. After 100 years of decay following the fuel discharge, the total amount of actinides remains almost unchanged for all of the fuel types considered. Among the plutonium isotopes, only the amount of Pu-241 is reduced significantly due to its relatively short half-life. (authors)

  15. Different modes of proton translocation by sensory rhodopsin I.

    PubMed Central

    Haupts, U; Bamberg, E; Oesterhelt, D

    1996-01-01

    The membrane-bound complex between sensory rhodopsin I (SRI) and its transducer HtrI forms the functional photoreceptor unit that allows transmission of light signals to the flagellar motor. Although being a photosensor, SRI, the mutant SRI-D76N and the HtrI-SRI complex can transport protons, as we demonstrate by using the sensitive and ion-specific black lipid membrane technique. SRI sustains an orange light-driven (one-photon-driven) outward proton transport which is enhanced by additional blue light (two-photon-driven). The vectoriality of the two-photon-driven transport could be reversed at neutral pH from the outward to the inward direction by switching the cut-off wavelength of the long wavelength light from 550 to 630 nm. The cut-off wavelength determining the reversal point decreases with decreasing pH. The currents could be enhanced by azide. A two-photon-driven inward proton transport by SRI-D76N (catalyzed by azide) and by the complex HtrI-SRI is demonstrated. The influence of pH and azide concentration on the rise and decay kinetics of the SRI380 intermediate is analyzed. The different modes of proton translocation of the SRI species are discussed on the basis of a general model of proton translocation of retinal proteins and in the context of signal transduction. Images PMID:8617229

  16. The CMS central hadron calorimeter DAQ system upgrade

    NASA Astrophysics Data System (ADS)

    Whitbeck, A.; Hirschauer, J.

    2015-05-01

    The CMS central hadron calorimeters will undergo a complete replacement of their data acquisition system electronics. The replacement is phased, with portions of the replacement starting in 2014 and continuing through LHC Long Shutdown 2 in 2018. The existing VME electronics will be replaced with a μTCA-based system. New on-detector QIE electronics cards will transmit data at 4.8 GHz to the new μHTR cards residing in μTCA crates in the CMS electronics cavern. The μTCA crates are controlled by the AMC13, which accepts system clock and trigger throttling control from the CMS global DAQ system. The AMC13 distributes the clock to the μHTR and reads out data buffers from the μHTR into the CMS data acquisition system. The AMC 13 also provides the clock for in-crate GLIBs which in turn distribute the clock to the on-detector front end electronics. We report on the design, development status, and schedule of the DAQ system upgrades.

  17. RAPHAEL: The European Union's (Very) High Temperature Reactor Technology Project

    SciTech Connect

    Fuetterer, Michael A.; Besson, D.; Bogusch, E.; Carluec, B.; Hittner, D.; Verrier, D.; Billot, Ph.; Phelip, M.; Buckthorpe, D.; Casalta, S.; Chauvet, V.; Van Heek, A.; Von Lensa, W.; Pirson, J.; Scheuermann, W.

    2006-07-01

    Since the late 1990, the European Union (EU) was conducting work on High Temperature Reactors (HTR) confirming their high potential in terms of safety (inherent safety features), environmental impact (robust fuel with no significant radioactive release), sustainability (high efficiency, potential suitability for various fuel cycles), and economics (simplifications arising from safety features). In April 2005, the EU Commission has started a new 4-year Integrated Project on Very High Temperature Reactors (RAPHAEL: Reactor for Process Heat And Electricity) as part of its 6{sup th} Framework Programme. The European Commission and the 33 partners from industry, R and D organizations and academia finance the project together. After the successful performance of earlier HTR-related EU projects which included the recovery of some earlier German experience and the re-establishment of strategically important R and D capabilities in Europe, RAPHAEL focuses now on key technologies required for an industrial VHTR deployment, both specific to very high temperature and generic to all types of modular HTR with emphasis on combined process heat and electricity generation. Advanced technologies are explored in order to meet the performance challenges required for a VHTR (900-1000 deg C, up to 200 GWd/tHM). To facilitate the planned sharing of significant parts of RAPHAEL results with the signatories of the Generation IV International Forum (GIF) VHTR projects, RAPHAEL is structured in a similar way as the corresponding GIF VHTR projects. (authors)

  18. Campylobacter jejuni outer membrane vesicle-associated proteolytic activity promotes bacterial invasion by mediating cleavage of intestinal epithelial cell E-cadherin and occludin.

    PubMed

    Elmi, Abdi; Nasher, Fauzy; Jagatia, Heena; Gundogdu, Ozan; Bajaj-Elliott, Mona; Wren, Brendan; Dorrell, Nick

    2016-04-01

    Outer membrane vesicles (OMVs) play an important role in the pathogenicity of Gram-negative bacteria. Campylobacter jejuni produces OMVs that trigger IL-8, IL-6, hBD-3 and TNF-α responses from T84 intestinal epithelial cells and are cytotoxic to Caco-2 IECs and Galleria mellonella larvae. Proteomic analysis of 11168H OMVs identified the presence of three proteases, HtrA, Cj0511 and Cj1365c. In this study, 11168H OMVs were shown to possess proteolytic activity that was reduced by pretreatment with specific serine protease inhibitors. OMVs isolated from 11168H htrA, Cj0511 or Cj1365c mutants possess significantly reduced proteolytic activity. 11168H OMVs are able to cleave both E-cadherin and occludin, but this cleavage is reduced with OMVs pretreated with serine protease inhibitors and also with OMVs isolated from htrA or Cj1365c mutants. Co-incubation of T84 monolayers with 11168H OMVs results in a visible reduction in both E-cadherin and occludin. The addition of 11168H OMVs to the co-culture of live 11168H bacteria with T84 cells results in enhanced levels of bacterial adhesion and invasion in a time-dependent and dose-dependent manner. Further investigation of the cleavage of host cell structural proteins by C. jejuni OMVs should enhance our understanding of the interactions of this important pathogen with intestinal epithelial cells. PMID:26451973

  19. Disruptions of sensorimotor gating, cytokines, glycemia, monoamines, and genes in both sexes of rats reared in social isolation can be ameliorated by oral chronic quetiapine administration.

    PubMed

    Ko, Chih-Yuan; Liu, Yia-Ping

    2016-01-01

    The pathogenesis of schizophrenia in patients with metabolic abnormalities remains unclear. Our previous study demonstrated that isolation rearing (IR) induced longitudinal concomitant changes of pro-inflammatory cytokine (pro-CK) levels and metabolic abnormalities with a developmental origin. However, the general consensus, believes that these abnormalities are caused by antipsychotic treatment in schizophrenic patients. The IR paradigm presents with face, construct, and predictive validity for schizophrenia. Therefore, we employed IR rats of both sexes to examine whether chronic quetiapine (QTP, a second-generation antipsychotic medication) treatment induces disruptions of metabolism (body weight, blood pressure, and the glycemic and lipid profiles) or cytokines [interleukin (IL)-1 beta, IL-6, IL-10, interferon-gamma, and tumor necrosis factor (TNF)-alpha], and further, whether it reverses deficits of behaviors [locomotor activity and prepulse inhibition (PPI)] and the expression of monoamines (dopamine and serotonin) and related genes (Htr1a, Htr2a, Htr3a, Drd1a, and Gabbr2). IR induced higher levels of pro-CK, dysglycemia, blood pressure, locomotor activity, and impaired PPI, simultaneously destabilizing cortico-striatal monoamines and relevant genes in both sexes, while QTP demonstrated dose-dependent reversal of these changes, suggesting that QTP might reduce the pro-CKs to regulate these abnormalities. Our data implied that antipsychotics may not be the solitary factor causing metabolic problems in schizophrenia and suggested that inflammatory changes may play a vital role in the developmental pathophysiology of schizophrenia and related metabolic abnormalities. PMID:26254231

  20. Properties of a Telomerase-Specific Cre/Lox Switch for Transcriptionally Targeted Cancer Gene Therapy1

    PubMed Central

    Bilsland, Alan E.; Fletcher-Monaghan, Aileen; Keith, W. Nicol

    2005-01-01

    Abstract Telomerase expression represents a good target for cancer gene therapy. The promoters of the core telomerase catalytic [human telomerase reverse transcriptase (hTERT)] and RNA [human telomerase RNA (hTR)] subunits show selective activity in cancer cells but not in normal cells. This property can be harnessed to express therapeutic transgenes in a wide range of cancer cells. Unfortunately, weak hTR and hTERT promoter activities in some cancer cells could limit the target cell range. Therefore, strategies to enhance telomerase-specific gene therapy are of interest. We constructed a Cre/Lox reporter switch coupling telomerase promoter specificity with Cytomegalovirus (CMV) promoter activity, which is generally considered to be constitutively high. In this approach, a telomerase-specific vector expressing Cre recombinase directs excisive recombination on a second vector, removing a transcriptional blockade to CMV-dependent luciferase expression. We tested switch activation in cell lines over a wide range of telomerase promoter activities. However, Cre/Lox–dependent luciferase expression was not enhanced relative to expression using hTR or hTERT promoters directly. Cell-specific differences between telomerase and CMV promoter activities and incomplete sigmoid switch activation were limiting factors. Notably, CMV activity was not always significantly stronger than telomerase promoter activity. Our conclusions provide a general basis for a more rational design of novel recombinase switches in gene therapy. PMID:16331888

  1. Alcohol misuse in emerging adulthood: Association of dopamine and serotonin receptor genes with impulsivity-related cognition.

    PubMed

    Leamy, Talia E; Connor, Jason P; Voisey, Joanne; Young, Ross McD; Gullo, Matthew J

    2016-12-01

    Impulsivity predicts alcohol misuse and risk for alcohol use disorder. Cognition mediates much of this association. Genes also account for a large amount of variance in alcohol misuse, with dopamine and serotonin receptor genes of particular interest, because of their role in motivated behavior. The precise psychological mechanisms through which such genes confer risk is unclear. Trait impulsivity conveys risk for alcohol misuse by influencing two distinct domains of cognition: beliefs about the reinforcing effects of alcohol consumption (positive alcohol expectancy) and the perceived ability to resist it (drinking refusal self-efficacy). This study investigated the effect of the dopamine-related polymorphism in the DRD2/ANKK1 gene (rs1800497) and a serotonin-related polymorphism in the HTR2A gene (rs6313) on associations between impulsivity, cognition, and alcohol misuse in 120 emerging adults (18-21years). HTR2A predicted lower positive alcohol expectancy, higher refusal self-efficacy, and lower alcohol misuse. However, neither polymorphism moderated the linkages between impulsivity, cognition, and alcohol misuse. This is the first report of an association between HTR2A and alcohol-related cognition. Theoretically-driven biopsychosocial models have potential to elucidate the specific cognitive mechanisms through which distal risk factors like genes and temperament affect alcohol misuse in emerging adulthood. PMID:27399274

  2. 5-hydroxytryptamine medications for the treatment of obesity.

    PubMed

    Burke, L K; Heisler, L K

    2015-06-01

    The central 5-hydroxytryptamine (5-HT; serotonin) system represents a fundamental component of the brain's control of energy homeostasis. Medications targeting the 5-HT pathway have been at the forefront of obesity treatment for the past 15 years. Pharmacological agents targeting 5-HT receptors (5-HTR), in combination with genetic models of 5-HTR manipulation, have uncovered a role for specific 5-HTRs in energy balance and reveal the 5-HT2 C R as the principal 5-HTR mediating this homeostatic process. Capitalising on this neurophysiological machinery, 5-HT2 C R agonists improve obesity and glycaemic control in patient populations. The underlying therapeutic mechanism has been probed using model systems and appears to be achieved primarily through 5-HT2 C R modulation of the brain melanocortin circuit via activation of pro-opiomelanocortin neurones signalling at melanocortin4 receptors. Thus, 5-HT2 C R agonists offer a means to improve obesity and type 2 diabetes, which are conditions that now represent global challenges to human health. PMID:25925636

  3. Purified IgG from Patients with Obstetric but not IgG from Non-obstetric Antiphospholipid Syndrome Inhibit Trophoblast Invasion

    PubMed Central

    Poulton, Katie; Ripoll, Vera M; Pericleous, Charis; Meroni, Pier Luigi; Gerosa, Maria; Ioannou, Yiannis; Rahman, Anisur; Giles, Ian P

    2015-01-01

    Problem Some patients with antiphospholipid syndrome (APS) suffer pregnancy morbidity (PM) but not vascular thrombosis (VT), whilst others suffer VT only. Therefore, we compared the effects of IgG from VT+/PM− and VT−/PM+ subjects on human first-trimester trophoblast (HTR8) cells. Method of study HTR-8 cells were incubated with APS VT+/PM−, APS VT−/PM+ or healthy control (HC) IgG. We measured trophoblast invasion by cell invasion assay; mRNA expression of TLR4 and adaptor proteins; phosphorylation of p38 MAPK, NFκB and ERK; and expression of interleukin (IL)-8 and IL-6. Results VT−/PM+ IgG, but not VT+/PM− IgG significantly reduced HTR-8 invasion. The effects on invasion were blocked by TLR-4 inhibition. Neither VT+/PM− nor VT−/PM+ IgG altered MyD88 mRNA expression, phosphorylation of signalling molecules or cytokine expression. Conclusions VT−/PM+ IgG exert functionally relevant effects on human trophoblast cells but VT+/PM− IgG do not. PMID:25469631

  4. Human monocytes undergo functional re-programming during differentiation to dendritic cell mediated by human extravillous trophoblasts.

    PubMed

    Zhao, Lei; Shao, Qianqian; Zhang, Yun; Zhang, Lin; He, Ying; Wang, Lijie; Kong, Beihua; Qu, Xun

    2016-01-01

    Maternal immune adaptation is required for a successful pregnancy to avoid rejection of the fetal-placental unit. Dendritic cells within the decidual microenvironment lock in a tolerogenic profile. However, how these tolerogenic DCs are induced and the underlying mechanisms are largely unknown. In this study, we show that human extravillous trophoblasts redirect the monocyte-to-DC transition and induce regulatory dendritic cells. DCs differentiated from blood monocytes in the presence of human extravillous trophoblast cell line HTR-8/SVneo displayed a DC-SIGN(+)CD14(+)CD1a(-) phenotype, similar with decidual DCs. HTR8-conditioned DCs were unable to develop a fully mature phenotype in response to LPS, and altered the cytokine secretory profile significantly. Functionally, conditioned DCs poorly induced the proliferation and activation of allogeneic T cells, whereas promoted CD4(+)CD25(+)Foxp3(+) Treg cells generation. Furthermore, the supernatant from DC and HTR-8/SVneo coculture system contained significant high amount of M-CSF and MCP-1. Using neutralizing antibodies, we discussed the role of M-CSF and MCP-1 during monocyte-to-DCs differentiation mediated by extravillous trophoblasts. Our data indicate that human extravillous trophoblasts play an important role in modulating the monocyte-to-DC differentiation through M-CSF and MCP-1, which facilitate the establishment of a tolerogenic microenvironment at the maternal-fetal interface. PMID:26857012

  5. Hypoxia-inducible miR-210 contributes to preeclampsia via targeting thrombospondin type I domain containing 7A

    PubMed Central

    Luo, Rongcan; Wang, Yongqing; Xu, Peng; Cao, Guangming; Zhao, Yangyu; Shao, Xuan; Li, Yu-xia; Chang, Cheng; Peng, Chun; Wang, Yan-ling

    2016-01-01

    Preeclampsia, a relatively common pregnancy disorder, is a major contributor to maternal mortality and morbidity worldwide. An elevation in microRNA-210 (miR-210) expression in the placenta has been reported to be associated with preeclampsia. Our bioinformatic analysis showed that thrombospondin type I domain containing 7A (THSD7A) is a predicted target for miR-210. The aim of this study was to determine whether miR-210 is involved in preeclampsia through its targeting of THSD7A in human placental trophoblasts. In preeclamptic placental tissues, THSD7A levels were significantly downregulated, and were inversely correlated with the levels of miR-210. THSD7A was validated as a direct target of miR-210 using quantitative real time PCR (qRT-PCR), Western blotting, and dual luciferase assays in HTR8/SVneo cells. Transwell insert invasion assays showed that THSD7A mediated the invasion-inhibitory effect of miR-210 in HTR8/SVneo cells. Interestingly, hypoxia markedly increased miR-210 expression while suppressing THSD7A expression in a time-dependent manner in HTR8/SVneo cells. This study provides novel data on the function of THSD7A in human placental cells, and extends our knowledge of how miR-210 is involved in the development of the preeclampsia. PMID:26796133

  6. GATA3 inhibits GCM1 activity and trophoblast cell invasion.

    PubMed

    Chiu, Yueh Ho; Chen, Hungwen

    2016-01-01

    Development of human placenta involves the invasion of trophoblast cells from anchoring villi into the maternal decidua. Placental transcription factor GCM1 regulates trophoblast cell invasion via transcriptional activation of HtrA4 gene, which encodes a serine protease enzyme. The GATA3 transcription factor regulates trophoblast cell differentiation and is highly expressed in invasive murine trophoblast giant cells. The regulation of trophoblastic invasion by GCM1 may involve novel cellular factors. Here we show that GATA3 interacts with GCM1 and inhibits its activity to suppress trophoblastic invasion. Immunohistochemistry demonstrates that GATA3 and GCM1 are coexpressed in villous cytotrophoblast cells, syncytiotrophoblast layer, and extravillous trophoblast cells of human placenta. Interestingly, GATA3 interacts with GCM1, but not the GCM2 homologue, through the DNA-binding domain and first transcriptional activation domain in GCM1 and the transcriptional activation domains and zinc finger 1 domain in GATA3. While GATA3 did not affect DNA-binding activity of GCM1, it suppressed transcriptional activity of GCM1 and therefore HtrA4 promoter activity. Correspondingly, GATA3 knockdown elevated HtrA4 expression in BeWo and JEG-3 trophoblast cell lines and enhanced the invasion activities of both lines. This study uncovered a new GATA3 function in placenta as a negative regulator of GCM1 activity and trophoblastic invasion. PMID:26899996

  7. Telomerase Activity is Downregulated Early During Human Brain Development.

    PubMed

    Ishaq, Abbas; Hanson, Peter S; Morris, Christopher M; Saretzki, Gabriele

    2016-01-01

    Changes in hTERT splice variant expression have been proposed to facilitate the decrease of telomerase activity during fetal development in various human tissues. Here, we analyzed the expression of telomerase RNA (hTR), wild type and α-spliced hTERT in developing human fetal brain (post conception weeks, pcw, 6-19) and in young and old cortices using qPCR and correlated it to telomerase activity measured by TRAP assay. Decrease of telomerase activity occurred early during brain development and correlated strongest to decreased hTR expression. The expression of α-spliced hTERT increased between pcw 10 and 19, while that of wild type hTERT remained unchanged. Lack of expression differences between young and old cortices suggests that most changes seem to occur early during human brain development. Using in vitro differentiation of neural precursor stem cells (NPSCs) derived at pcw 6 we found a decrease in telomerase activity but no major expression changes in telomerase associated genes. Thus, they do not seem to model the mechanisms for the decrease in telomerase activity in fetal brains. Our results suggest that decreased hTR levels, as well as transient increase in α-spliced hTERT, might both contribute to downregulation of telomerase activity during early human brain development between 6 and 17 pcw. PMID:27322326

  8. Telomerase repeat amplification protocol (TRAP) activity upon recombinant expression and purification of human telomerase in a bacterial system.

    PubMed

    Hansen, Debra T; Thiyagarajan, Thirumagal; Larson, Amy C; Hansen, Jeffrey L

    2016-07-01

    Telomerase biogenesis is a highly regulated process that solves the DNA end-replication problem. Recombinant expression has so far been accomplished only within a eukaryotic background. Towards structural and functional analyses, we developed bacterial expression of human telomerase. Positive activity by the telomerase repeat amplification protocol (TRAP) was identified in cell extracts of Escherichia coli expressing a sequence-optimized hTERT gene, the full-length hTR RNA with a self-splicing hepatitis delta virus ribozyme, and the human heat shock complex of Hsp90, Hsp70, p60/Hop, Hsp40, and p23. The Hsp90 inhibitor geldanamycin did not affect post-assembly TRAP activity. By various purification methods, TRAP activity was also obtained upon expression of only hTERT and hTR. hTERT was confirmed by tandem mass spectrometry in a ∼120 kDa SDS-PAGE fragment from a TRAP-positive purification fraction. TRAP activity was also supported by hTR constructs lacking the box H/ACA small nucleolar RNA domain. End-point TRAP indicated expression levels within 3-fold of that from HeLa carcinoma cells, which is several orders of magnitude below detection by the direct assay. These results represent the first report of TRAP activity from a bacterium and provide a facile system for the investigation of assembly factors and anti-cancer therapeutics independently of a eukaryotic setting. PMID:26965413

  9. Pharmacogenetic Study of Serotonin Transporter and 5HT2A Genotypes in Autism

    PubMed Central

    Najjar, Fedra; Owley, Thomas; Mosconi, Matthew W.; Jacob, Suma; Hur, Kwan; Guter, Stephen J.; Sweeney, John A.; Gibbons, Robert D; Bishop, Jeffrey R.

    2015-01-01

    Abstract Objective: The purpose of this study was to determine whether polymorphisms in the serotonin transporter (SLC6A4) and serotonin-2A receptor (HTR2A) genes are associated with response to escitalopram in patients with autism spectrum disorder (ASD). Methods: Forty-four participants with ASD were enrolled in a 6 week, forced titration, open label examination of the selective serotonin reuptake inhibitor (SSRI) escitalopram. Doses increased at weekly intervals starting at 2.5mg daily with a maximum possible dose of 20 mg daily achieved by the end of the study. If adverse events were experienced, participants subsequently received the previously tolerated dose for the duration of study. SLC6A4 (5-HTTLPR) and HTR2A (rs7997012) genotype groups were assessed in relation to treatment outcomes and drug doses. Results: Insistence on sameness and irritability symptoms significantly improved over the course of the 6 week treatment period (p<0.0001) in this open-label trial. There were no significant differences observed in the rate of symptom improvement over time across genotype groups. Similarly, dosing trajectory was not significantly associated with genotype groups. Conclusions: Previous studies have identified SLC6A4 and HTR2A associations with SSRI response in patients with depression and 5-HTTLPR (SLC6A4) associations with escitalopram response in ASD. We did not observe evidence for similar relationships in this ASD study. PMID:26262902

  10. The effect of serotonin 1A receptor polymorphism on the cognitive function of premenstrual dysphoric disorder.

    PubMed

    Yen, Ju-Yu; Tu, Hung-Pin; Chen, Cheng-Sheng; Yen, Cheng-Fang; Long, Cheng-Yu; Ko, Chih-Hung

    2014-12-01

    Estrogen and serotonin play vital roles in the mechanism of premenstrual dysphoric disorder (PMDD). Cognitive deficit in the premenstrual phase contributes to impaired life function among women with PMDD. The aim of this study was to evaluate the difficulties in cognitive control and working memory (WM) in PMDD and to explore the effects of gonadotropic hormone and polymorphism of serotonin 1A receptor (HTR1A; rs6295) on cognitive deficit in PMDD. Women with PMDD completed diagnostic interviewing, questionnaire assessment, the Go/Nogo task, 2-back and 3-back tasks, and gonadotropic hormone analysis in the premenstrual and follicular phases. Further, they were followed up for two menstrual cycles to confirm two consecutive symptomatic cycles. A total of 59 subjects with PMDD and 74 controls completed all evaluation, fulfilled the criteria, and entered into the final analysis. The results demonstrated cognitive control and WM decline in the premenstrual among women with PMDD. The G/G genotype of HTR1A (rs6295) was found to be associated with impaired WM in the premenstrual phase and premenstrual decline of cognitive function. It also contributed to the vulnerability of cognitive function to the menstrual cycle effect and PMDD effect. As the G/G genotype of HTR1A (rs6295) involves in reducing serotonin neurotransmission, our results provide insight into the serotonin mechanism of cognitive function among women with PMDD. PMID:24158751

  11. Culture, serotonin receptor polymorphism and locus of attention

    PubMed Central

    Sherman, David K.; Taylor, Shelley E.; Sasaki, Joni Y.; Chu, Thai Q.; Ryu, Chorong; Suh, Eunkook M.; Xu, Jun

    2010-01-01

    The present research examined the interaction between genes and culture as potential determinants of individuals’ locus of attention. As the serotonin (5-HT) system has been associated with attentional focus and the ability to adapt to changes in reinforcement, we examined the serotonin 1A receptor polymorphism (5-HTR1A). Koreans and European Americans were genotyped and reported their chronic locus of attention. There was a significant interaction between 5-HTR1A genotype and culture in the locus of attention. Koreans reported attending to the field more than European Americans, and this cultural difference was moderated by 5-HTR1A. There was a linear pattern such that those homozygous for the G allele, which is associated with reduced ability to adapt to changes in reinforcement, more strongly endorsed the culturally reinforced mode of thinking than those homozygous for the C allele, with those heterozygous in the middle. Our findings suggest that the same genetic predisposition can result in divergent psychological outcomes, depending on an individual’s cultural context. PMID:19736291

  12. Genome-wide identification, evolutionary, and expression analyses of histone H3 variants in plants.

    PubMed

    Cui, Jinteng; Zhang, Zhanlu; Shao, Yang; Zhang, Kezhong; Leng, Pingsheng; Liang, Zhe

    2015-01-01

    Histone variants alter the nucleosome structure and play important roles in chromosome segregation, transcription, DNA repair, and sperm compaction. Histone H3 is encoded by many genes in most eukaryotic species and is the histone that contains the largest variety of posttranslational modifications. Compared with the metazoan H3 variants, little is known about the complex evolutionary history of H3 variants proteins in plants. Here, we study the identification, evolutionary, and expression analyses of histone H3 variants from genomes in major branches in the plant tree of life. Firstly we identified all the histone three related (HTR) genes from the examined genomes, then we classified the four groups variants: centromeric H3, H3.1, H3.3 and H3-like, by phylogenetic analysis, intron information, and alignment. We further demonstrated that the H3 variants have evolved under strong purifying selection, indicating the conservation of HTR proteins. Expression analysis revealed that the HTR has a wide expression profile in maize and rice development and plays important roles in development. PMID:25815311

  13. Genome-Wide Identification, Evolutionary, and Expression Analyses of Histone H3 Variants in Plants

    PubMed Central

    Cui, Jinteng; Zhang, Zhanlu; Shao, Yang; Zhang, Kezhong; Leng, Pingsheng; Liang, Zhe

    2015-01-01

    Histone variants alter the nucleosome structure and play important roles in chromosome segregation, transcription, DNA repair, and sperm compaction. Histone H3 is encoded by many genes in most eukaryotic species and is the histone that contains the largest variety of posttranslational modifications. Compared with the metazoan H3 variants, little is known about the complex evolutionary history of H3 variants proteins in plants. Here, we study the identification, evolutionary, and expression analyses of histone H3 variants from genomes in major branches in the plant tree of life. Firstly we identified all the histone three related (HTR) genes from the examined genomes, then we classified the four groups variants: centromeric H3, H3.1, H3.3 and H3-like, by phylogenetic analysis, intron information, and alignment. We further demonstrated that the H3 variants have evolved under strong purifying selection, indicating the conservation of HTR proteins. Expression analysis revealed that the HTR has a wide expression profile in maize and rice development and plays important roles in development. PMID:25815311

  14. Tetrabromobisphenol A Activates Inflammatory Pathways in Human First Trimester Extravillous Trophoblasts in vitro

    PubMed Central

    Park, Hae-Ryung; Kamau, Patricia W.; Korte, Cassandra; Loch-Caruso, Rita

    2014-01-01

    Tetrabromobisphenol A (TBBPA) is a widely used flame retardant. Despite the presence of TBBPA in gestational tissues and the importance of proper regulation of inflammatory networks for successful pregnancy, there is no prior study on the effects of TBBPA on inflammatory responses in gestational tissues. The present study aimed to investigate TBBPA activation of inflammatory pathways, specifically cytokine and prostaglandin production, in the human first trimester placental cell line HTR-8/SVneo. TBBPA enhanced release of interleukin (IL)-6, IL-8, and prostaglandin E2 (PGE2), and suppressed TGF-β release in HTR-8/SVneo cells. The lowest effective concentration was 10 μM TBBPA. A commercial immune response PCR array revealed increased expression of genes involved in inflammatory pathways stimulated by TBBPA in HTR-8/SVneo cells. Because proper regulation of inflammatory mediators in the gestational compartment is necessary for normal placental development and successful pregnancy, further investigation on the impact of TBBPA-stimulated responses on trophoblast function is warranted. PMID:25461914

  15. GATA3 inhibits GCM1 activity and trophoblast cell invasion

    PubMed Central

    Chiu, Yueh Ho; Chen, Hungwen

    2016-01-01

    Development of human placenta involves the invasion of trophoblast cells from anchoring villi into the maternal decidua. Placental transcription factor GCM1 regulates trophoblast cell invasion via transcriptional activation of HtrA4 gene, which encodes a serine protease enzyme. The GATA3 transcription factor regulates trophoblast cell differentiation and is highly expressed in invasive murine trophoblast giant cells. The regulation of trophoblastic invasion by GCM1 may involve novel cellular factors. Here we show that GATA3 interacts with GCM1 and inhibits its activity to suppress trophoblastic invasion. Immunohistochemistry demonstrates that GATA3 and GCM1 are coexpressed in villous cytotrophoblast cells, syncytiotrophoblast layer, and extravillous trophoblast cells of human placenta. Interestingly, GATA3 interacts with GCM1, but not the GCM2 homologue, through the DNA-binding domain and first transcriptional activation domain in GCM1 and the transcriptional activation domains and zinc finger 1 domain in GATA3. While GATA3 did not affect DNA-binding activity of GCM1, it suppressed transcriptional activity of GCM1 and therefore HtrA4 promoter activity. Correspondingly, GATA3 knockdown elevated HtrA4 expression in BeWo and JEG-3 trophoblast cell lines and enhanced the invasion activities of both lines. This study uncovered a new GATA3 function in placenta as a negative regulator of GCM1 activity and trophoblastic invasion. PMID:26899996

  16. Human monocytes undergo functional re-programming during differentiation to dendritic cell mediated by human extravillous trophoblasts

    PubMed Central

    Zhao, Lei; Shao, Qianqian; Zhang, Yun; Zhang, Lin; He, Ying; Wang, Lijie; Kong, Beihua; Qu, Xun

    2016-01-01

    Maternal immune adaptation is required for a successful pregnancy to avoid rejection of the fetal–placental unit. Dendritic cells within the decidual microenvironment lock in a tolerogenic profile. However, how these tolerogenic DCs are induced and the underlying mechanisms are largely unknown. In this study, we show that human extravillous trophoblasts redirect the monocyte-to-DC transition and induce regulatory dendritic cells. DCs differentiated from blood monocytes in the presence of human extravillous trophoblast cell line HTR-8/SVneo displayed a DC-SIGN+CD14+CD1a− phenotype, similar with decidual DCs. HTR8-conditioned DCs were unable to develop a fully mature phenotype in response to LPS, and altered the cytokine secretory profile significantly. Functionally, conditioned DCs poorly induced the proliferation and activation of allogeneic T cells, whereas promoted CD4+CD25+Foxp3+ Treg cells generation. Furthermore, the supernatant from DC and HTR-8/SVneo coculture system contained significant high amount of M-CSF and MCP-1. Using neutralizing antibodies, we discussed the role of M-CSF and MCP-1 during monocyte-to-DCs differentiation mediated by extravillous trophoblasts. Our data indicate that human extravillous trophoblasts play an important role in modulating the monocyte-to-DC differentiation through M-CSF and MCP-1, which facilitate the establishment of a tolerogenic microenvironment at the maternal–fetal interface. PMID:26857012

  17. Telomerase Activity is Downregulated Early During Human Brain Development

    PubMed Central

    Ishaq, Abbas; Hanson, Peter S.; Morris, Christopher M.; Saretzki, Gabriele

    2016-01-01

    Changes in hTERT splice variant expression have been proposed to facilitate the decrease of telomerase activity during fetal development in various human tissues. Here, we analyzed the expression of telomerase RNA (hTR), wild type and α-spliced hTERT in developing human fetal brain (post conception weeks, pcw, 6–19) and in young and old cortices using qPCR and correlated it to telomerase activity measured by TRAP assay. Decrease of telomerase activity occurred early during brain development and correlated strongest to decreased hTR expression. The expression of α-spliced hTERT increased between pcw 10 and 19, while that of wild type hTERT remained unchanged. Lack of expression differences between young and old cortices suggests that most changes seem to occur early during human brain development. Using in vitro differentiation of neural precursor stem cells (NPSCs) derived at pcw 6 we found a decrease in telomerase activity but no major expression changes in telomerase associated genes. Thus, they do not seem to model the mechanisms for the decrease in telomerase activity in fetal brains. Our results suggest that decreased hTR levels, as well as transient increase in α-spliced hTERT, might both contribute to downregulation of telomerase activity during early human brain development between 6 and 17 pcw. PMID:27322326

  18. Nicotine attenuates DOI-induced head-twitch response in mice: implications for Tourette syndrome.

    PubMed

    Tizabi, Y; Russell, L T; Johnson, M; Darmani, N A

    2001-10-01

    Tourette syndrome (TS), a chronic neuropsychiatric disorder, is characterized by motor and vocal tics. Preliminary clinical studies indicate possible therapeutic benefits of nicotine in the treatment of Tourette's syndrome (TS). It has been proposed that twitches of the head in mice or twitches of head and shoulders in rats following administration of the selective 5HT(2A/C) agonist DOI (1-)2,5-dimethoxy-4-iodophenyl-2-aminopropane, can serve as an animal model of tics in TS. In this study, the effects of acute and chronic administration of nicotine on DOI-induced head twitch response (HTR) in male albino ICR mice were evaluated. Both acute and chronic nicotine (daily injections for 10 days) reduced the DOI-induced HTR. Moreover, chronic administration of DOI (1 mg/kg/day for 10 days) resulted in 65% increase in [125I]alpha-bungarotoxin binding in cerebellum and 41% increase in striatal [3H]cytisine binding. However, the acute inhibitory effects of nicotine were not blocked by pretreatment with the nicotinic antagonist, mecamylamine. Indeed, at higher doses, mecamylamine also reduced the DOI-induced HTR. The data suggest that both nicotine and mecamylamine may be of therapeutic potential in the treatment of some symptoms of TS. PMID:11513358

  19. Automatische Montagemaschinen

    NASA Astrophysics Data System (ADS)

    Hesse, Stefan

    Seit den 1950er Jahren werden Produkte in größerem Ausmaß automatisch montiert. Besonders bei ausgesprochenen Massenprodukten wurde inzwischen ein hoher technischer Stand erreicht. Die dazu benutzten Montageautomaten sind Sondermaschinen, die fur ein Produkt individuell angepasst sind. Typisch sind mittlerweile ein modularer Aufbau and die Kombination von erprobten Baukastenkomponenten zu einer Anlage. Es gibt verschiedene Bauformen, von denen sich jede in Verbindung mit bestimmten Erzeugnissen and Bedingungen bewährt hat. In manchen Anwendungen mit kleinen Stückzahlen, zahlreichen Varianten oder bei einzelnen diffizilen Arbeitsschritten können Handarbeitsplätze erforderlich sein, was zu sog. hybriden Montagesystemen als Kombination von Hand- und Maschinenarbeitsplätzen führt.

  20. Embryonic development during chronic acceleration

    NASA Technical Reports Server (NTRS)

    Smith, A. H.; Abbott, U. K.

    1982-01-01

    Experiments carried out on chicken eggs indicate that the embryo is affected during very early development, especially over the first four days, and during hatching. In the first four days, the brain develops as well as the anlage for all other organs. In addition, the heart commences to function and the extraembryonic membranes that compartmentalize the egg contents form. The latter require an appreciable extension and folding of tissue which may be disrupted by the mechanical load. Observations of embryonic abnormalities that occur during chronic acceleration suggest an inhibition of development of the axial skeleton, which is rarely seen otherwise, a general retardation of embryonic growth, and circulatory problems. The final stages of development (after 18 days) involve the uptake of fluids, the transition to aerial respiration, and the reorientation of the embryo into a normal hatching position. At 4 G mortality is very high during this period, with a majority of embryos failing to reorient into the normal hatching position.

  1. The significance of diagnostic laparotomy in girls with disorders of sexual development.

    PubMed

    Welte, W A; Tietze, H U; Schwanitz, G

    1983-01-01

    Chromosomal analyses were performed in 5 patients from 13 days to 16 years of age to clarify intersexual genitalia, disorders of secondary sexual development and growth retardation. Laparotomies were felt to be indicated because of discrepancies in the results of chromosoma analyses, clinical picture and endocrinologic findings. Among others, pure gonadal dysgenesis was found in a patient with karyotype 46 XX, functional ovaries in a chromosomal Turner's syndrome and a Müllerian anlage with two dysgenetic testes in a 45 X/46 XY mosaic. Since gonads with one cell line containing Y-chromosomes carry a high danger of malignant change, they should be removed as early as possible. It is known that disorders of sexual development can be caused by many and various anomalies of the sex chromosomes. Cooperation among endocrinologists, human geneticists and pediatric surgeons is essential for clarification of the diagnosis. PMID:6878725

  2. Wireless Josephson Junction Arrays

    NASA Astrophysics Data System (ADS)

    Adams, Laura

    2015-03-01

    We report low temperature, microwave transmission measurements on a wireless two- dimensional network of Josephson junction arrays composed of superconductor-insulator -superconductor tunnel junctions. Unlike their biased counterparts, by removing all electrical contacts to the arrays and superfluous microwave components and interconnects in the transmission line, we observe new collective behavior in the transmission spectra. In particular we will show emergent behavior that systematically responds to changes in microwave power at fixed temperature. Likewise we will show the dynamic and collective response of the arrays while tuning the temperature at fixed microwave power. We discuss these spectra in terms of the Berezinskii-Kosterlitz-Thouless phase transition and Shapiro steps. We gratefully acknowledge the support Prof. Steven Anlage at the University of Maryland and Prof. Allen Goldman at the University of Minnesota. Physics and School of Engineering and Applied Sciences.

  3. Sultan: an 8 Tesla, 1 meter bore test facility for the outer solenoid

    SciTech Connect

    Pasotti, G.; Ricci, M.V.; Sacchetti, N.; Spadoni, M.

    1981-09-01

    In the framework of the international collaboration among SIN-Villigen (CH), ECN-Patten (NL) and CNEN-Frascati (I) aiming at the realization of the SULTAN (SUpraLeitender TestANlage) test facility the CNEN contribution is concerned with the realization of the outer part of the solenoid, i.e., the section which will provide the 6T field in the useful region, the remaining 2T being supplied by the coaxial ECN insert. A description of the 6T superconducting solenoid is presented. The main features are: (1) pancake structure wound by a Nb-Ti multifilamentary hollow cable; and (2) cooling by forced flow of slightly subcooled liquid helium. Details of the design, winding technique and structure, the hydraulic circuitry as well as the status report of the construction are discussed. 10 refs.

  4. Ultrastructure and development of the rhabdomeric eyes in Lineus viridis (Heteronemertea, Nemertea).

    PubMed

    von Döhren, Jörn; Bartolomaeus, Thomas

    2007-01-01

    Nemerteans are undoubtedly members of the Spiralia, although their phylogenetic relationships are still a matter of debate. The apparently acoelomate organization suggests a relationship with the platyhelminths, whereas the blood-vascular system has been interpreted as an equivalent to coelomic cavities of annelids, indicating a close relation between annelids and nemerteans. Like other spiralians, most nemertean species are known to have one or several pairs of rhabdomeric and subepidermally situated eyes when adult. The development of these eyes as well as the mode in which the eyes are multiplied is as yet unknown. This is the first attempt to investigate eye formation in a nemertean. In the heteronemertean Lineus viridis (Müller, 1774) the everse rhabdomeric eyes are located deeply underneath the epidermis and consist of a few pigment cells that form a cup-like structure with interdigitating processes that contain numerous pigment granules. In hatchlings, the optical cavity contains processes of 12 sensory cells, each bearing a single cilium and various microvilli. The perikarya of these cells are located distally from the pigment cup. During further development the number of cells increases. Eye development starts with a small anlage situated underneath the epidermis, irrespective of whether this is the first eye or any additional one. The anlage consists of five unpigmented cells and three dendritic processes, each bearing apical microvilli and a single cilium. There is no evidence for an epidermal origin of the eyes. In L. viridis eye formation resembles that described in platyhelminths in which eyes also develop as cerebral derivatives. Although this result has the potential to influence the discussion on the position of Nemertea, the data have to be interpreted with care, since development of L. viridis is derived within the Nemertea. PMID:17913481

  5. Postotic and preotic cranial neural crest cells differently contribute to thyroid development.

    PubMed

    Maeda, Kazuhiro; Asai, Rieko; Maruyama, Kazuaki; Kurihara, Yukiko; Nakanishi, Toshio; Kurihara, Hiroki; Miyagawa-Tomita, Sachiko

    2016-01-01

    Thyroid development and formation vary among species, but in most species the thyroid morphogenesis consists of five stages: specification, budding, descent, bilobation and folliculogenesis. The detailed mechanisms of these stages have not been fully clarified. During early development, the cranial neural crest (CNC) contributes to the thyroid gland. The removal of the postotic CNC (corresponding to rhombomeres 6, 7 and 8, also known as the cardiac neural crest) results in abnormalities of the cardiovascular system, thymus, parathyroid glands, and thyroid gland. To investigate the influence of the CNC on thyroid bilobation process, we divided the CNC into two regions, the postotic CNC and the preotic CNC (from the mesencephalon to rhombomere 5) regions and examined. We found that preotic CNC-ablated embryos had a unilateral thyroid lobe, and confirmed the presence of a single lobe or the absence of lobes in postotic CNC-ablated chick embryos. The thyroid anlage in each region-ablated embryos was of a normal size at the descent stage, but at a later stage, the thyroid in preotic CNC-ablated embryos was of a normal size, conflicting with a previous report in which the thyroid was reduced in size in the postotic CNC-ablated embryos. The postotic CNC cells differentiated into connective tissues of the thyroid in quail-to-chick chimeras. In contrast, the preotic CNC cells did not differentiate into connective tissues of the thyroid. We found that preotic CNC cells encompassed the thyroid anlage from the specification stage to the descent stage. Finally, we found that endothelin-1 and endothelin type A receptor-knockout mice and bosentan (endothelin receptor antagonist)-treated chick embryos showed bilobation anomalies that included single-lobe formation. Therefore, not only the postotic CNC, but also the preotic CNC plays an important role in thyroid morphogenesis. PMID:26506449

  6. Effect of serotonin receptor 2A gene polymorphism on mirtazapine response in major depression.

    PubMed

    Kang, Rhee-Hun; Choi, Myoung-Jin; Paik, Jong-Woo; Hahn, Sang-Woo; Lee, Min-Soo

    2007-01-01

    The 5-HTR2A gene is a candidate gene for influencing the clinical response to treatment with antidepressants. The purpose of this study was to determine the relationship between the -1438A/G polymorphism of the 5-HTR2A gene and the response to mirtazapine in a Korean population with major depressive disorder. Mirtazapine was administered for eight weeks to the 101 patients who completed the study, during which we evaluated the clinical outcome using repeated-measures ANCOVA. A main effect of genotype or an effect of genotype-time interactions on the decrease in HAMD score during the eight-week follow-up was not found, which suggests that the 5-HTR2A -1438A/G polymorphism does not affect the clinical outcome to mirtazapine administration. However, significant effects of genotype and allele carriers on the decrease in the sleep score over the eight weeks were found (genotype: F = 4.093, p = 0.017; allele: F = 4.371, p = 0.037), whereas no effect of genotype-time interactions on the decrease in the HAMD score over the eight-week follow-up was found. These observations suggest that the -1438A/G polymorphism on the sleep improvement at each time period revealed significant differences in the sleep scores after two weeks of mirtazapine administration. The sleep scores were lower for carriers of the A+ allele than of the A- allele after two weeks of mirtazapine administration (p = 0.041), which means that the -1438GG genotype is associated with less improvement in sleep, and suggests that the effect of mirtazapine on improving the sleep quality differs with the 5-HTR2A -1438A/G polymorphism within two weeks of mirtazapine treatment. In conclusion, although the -1438A/G polymorphism affects the sleep improvement resulting from the administration of mirtazapine to Korean patients with major depressive disorder, our results do not support the hypothesis that this polymorphism of the 5-HTR2A gene is involved in the therapeutic response to mirtazapine. PMID:18314859

  7. Extravillous trophoblast cells-derived exosomes promote vascular smooth muscle cell migration

    PubMed Central

    Salomon, Carlos; Yee, Sarah; Scholz-Romero, Katherin; Kobayashi, Miharu; Vaswani, Kanchan; Kvaskoff, David; Illanes, Sebastian E.; Mitchell, Murray D.; Rice, Gregory E.

    2014-01-01

    Background: Vascular smooth muscle cells (VSMCs) migration is a critical process during human uterine spiral artery (SpA) remodeling and a successful pregnancy. Extravillous trophoblast cells (EVT) interact with VSMC and enhance their migration, however, the mechanisms by which EVT remodel SpA remain to be fully elucidated. We hypothesize that exosomes released from EVT promote VSMC migration. Methods: JEG-3 and HTR-8/SVneo cell lines were used as models for EVT. Cells were cultured at 37°C and humidified under an atmosphere of 5% CO2-balanced N2 to obtain 8% O2. Cell-conditioned media were collected, and exosomes (exo-JEG-3 and exo- HTR-8/SVneo) isolated by differential and buoyant density centrifugation. The effects of exo-EVT on VSMC migration were established using a real-time, live-cell imaging system (Incucyte™). Exosomal proteins where identified by mass spectrometry and submitted to bioinformatic pathway analysis (Ingenuity software). Results: HTR-8/SVneo cells were significantly more (~30%) invasive than JEG-3 cells. HTR-8/SVneo cells released 2.6-fold more exosomes (6.39 × 108 ± 2.5 × 108 particles/106 cells) compared to JEG-3 (2.86 × 108 ± 0.78 × 108 particles/106 cells). VSMC migration was significantly increased in the presence of exo-JEG-3 and exo-HTR-8/SVneo compared to control (−exosomes) (21.83 ± 0.49 h and 15.57 ± 0.32, respectively, vs. control 25.09 ± 0.58 h, p < 0.05). Sonication completely abolished the effect of exosomes on VSMC migration. Finally, mass spectrometry analysis identified unique exosomal proteins for each EVT cell line-derived exosomes. Conclusion: The data obtained in this study are consistent with the hypothesis that the release, content, and bioactivity of exosomes derived from EVT-like cell lines is cell origin-dependent and differentially regulates VSMC migration. Thus, an EVT exosomal signaling pathway may contribute to SpA remodeling by promoting the migration of VSMC out of the vessel walls. PMID:25157233

  8. Darmtrakt

    NASA Astrophysics Data System (ADS)

    Starck, Matthias

    Anatomie und Funktion des Verdauungssystems der Cranioten sind so divers und vielfältig wie deren Lebens- und Ernährungsweisen. Im Prinzip ist der Verdauungstrakt ein schlauchförmiges Organ, das den Körper von vorne nach hinten durchzieht und in Zonen verschiedener Funktion untergliedert ist. Er beginnt mit der Mundhöhle, die der Aufnahme und Zerkleinerung der Nahrung dient (Abb. 141). Schlund (Pharynx) und Speiseröhre (Oesophagus) sind "Transportstrecken" zum Magen, können aber auch als Speicherorgane zur temporären Aufbewahrung von Nahrung ausdifferenziert werden (Abb. 145). Im Magen (Gaster) wird die Nahrung mechanisch, chemisch und gegebenenfalls symbiontisch aufgeschlossen (Verdauung). Im anschließenden Dünndarm (Intestinum tenue) findet eine enzymatische Verdauung und die Absorption der Nährstoffe statt. Einfache oder paarige Blinddärme (Caeca) markieren meist den Übergang zum Dickdarm (Intestinum crassum).

  9. Sind die klassischen Methoden zur mykologischen Diagnostik noch "State-of-the-Art"?

    PubMed

    Wiegand, Cornelia; Bauer, Andrea; Brasch, Jochen; Nenoff, Pietro; Schaller, Martin; Mayser, Peter; Hipler, Uta-Christina; Elsner, Peter

    2016-05-01

    Die Labordiagnose einer Pilzinfektion der Haut basiert traditionell auf dem Nativpräparat und der Anzucht des Erregers aus dem klinischen Material. Auch der dermato- histologischer Nachweis von Pilzelementen ist möglich. Diese Methoden sind, sofern sie korrekt ausgeführt werden, in der Regel zum Pilznachweis geeignet. Im Zuge der personalisierten Medizin und den daraus erwachsenden Aufgaben werden jedoch neue Verfahren erforderlich, welche einfach, spezifisch und schnell sind. Der zusätzliche Einsatz von DNA-basierten molekularen Methoden erhöht die Empfindlichkeit sowie die diagnostische Spezifität und reduziert die zum Teil wochenlange Durchführungszeit der konventionellen mykologischen Diagnostik auf 24 bis 48 Stunden. Im Zuge der stetigen Weiterentwicklung im Bereich der personalisierten Medizin sind einfache Analysensysteme auf PCR-Basis denkbar, die in der Hautarztpraxis eine Dermatophyten-Sofort-Diagnostik erlauben (Point-of-Care-Tests). PMID:27119469

  10. Unentbehrlich in Natur, Technik und Forschung: Flüssigkristalle im Überblick

    NASA Astrophysics Data System (ADS)

    Mathelitsch, Leopold; Repnik, Robert; Bradac, Zlatko; Vilfan, Mojca; Kralj, Samo

    2003-05-01

    Flüssigkristalle können wie eine Flüssigkeit fließen und zugleich eine innere Ordnung besitzen, die an Festkörper erinnert. Sie begegnen uns im Alltag in vielen technischen Anwendungen, beispielsweise in Displays von elektronischen Geräten. Seit Millionen von Jahren sind sie schon zentrale Bausteine von biologischen Systemen. Dazu zählen zum Beispiel die DNS, viele Proteine und die Membran, die lebende Zellen umschließt. Wegen ihrer besonderen Eigenschaften eignen sich Flüssigkristalle gut als Analogien für andere physikalische Systeme: zum Beispiel die Teilchen-Antiteilchen-Annihilation oder kosmologische Modelle des Universums kurz nach dem Urknall.

  11. Von der Prägeometrie zur Topologischen Komplexität.

    NASA Astrophysics Data System (ADS)

    Kurth, D.

    Der Autor macht in seinem Beitrag gegen das vorherrschende reduktionistische Selbstverständnis der modernen Physik geltend, daß eine umfassende Theorie von Allem (TOE) nicht schon durch eine Alles vereinheitlichende Theorie als Abschluß des reduktionistischen Programms der Elementarteilchenphysik gegeben sein kann. Zum einen muß der initialen Kontingenz unseres Universums durch eine entsprechende quantenkosmologische Theorie Rechnung getragen werden, zum anderen muß auch die in dieser Kontingenz begründete Geschichtlichkeit unseres Universums, d.h. die Emergenz von Komplexität, von einer angemessenen TOE erklärt werden können. Der Autor zeigt, daß ein solcher Anspruch nicht mit den üblichen Komplexitätsmaßen der heutigen Komplexitätstheorien eingelöst werden kann, und schlägt als Alternative einen unmittelbar emergenztheoretisch begründeten Komplexitätsbegriff, den der Topologischen Komplexität vor.

  12. Renaturierung von Salzgrasländern bzw. Salzwiesen der Küsten

    NASA Astrophysics Data System (ADS)

    Seiberling, Stefan; Stock, Martin

    Die deutschen Meeresküsten werden im übergang vom Land zum Meer weitgehend von zwei ökosystemtypen geprägt. Auf die augenfälligeren, die Dünen, gehen wir hier nicht ein (siehe v. a.Grootjans et al. 2001, 2002, Rozé und Lemauviel 2004, Ketner-Oostra et al. 2006, Aptroot et al. 2007, Bossuyt et al. 2007). Gegenstand dieses Kapitels sind vielmehr die Salzwiesen, die im Wattenmeer der Nordsee als natürlicher Lebensraum auftreten und an der Ostseeküste — hier werden sie Salzgrasländer genannt — zu den ältesten Bestandteilen der Kulturlandschaft zählen. Naturnahe Küstensalzwiesen sind nicht nur Lebensraum für speziell angepasste Pflanzenund Tierarten, sondern tragen auch zur Regulation des marinen Stoffhaushalts und zum Küstenschutz bei.

  13. Wie alles begann

    NASA Astrophysics Data System (ADS)

    Steger, Almut

    An deutschen Universitäten entstand die Statistik als selbständige Wissenschaft vor gut 250 Jahren. Sie war zunächst reine Staatenbeschreibung. Erst im 19. Jahrhundert bildete sich der heutige Begriff von Statistik heraus. In mehreren Ländern gründete man damals statistische Vereine und länderübergreifend das Internationale Statistische Institut (ISI). Die deutschen Statistiker waren zwar ebenfalls national und international sehr aktiv, doch zur Gründung der Deutschen Statistischen Gesellschaft kam es erst 1911. Das Kapitel beschreibt diese Entwicklung, besonders ausführlich den Gründungsprozess. Danach wird über die schon mit der Gründung beginnenden, äußerst regen und zum Teil kontrovers ausgetragenen wissenschaftlichen Diskussionen berichtet, die jedoch mit dem Kriegsausbruch 1914 weitgehend zum Erliegen kamen.

  14. Historisches Rätsel Der rastlose Amerikaner

    NASA Astrophysics Data System (ADS)

    Loos, Andreas

    2004-09-01

    In der Schule, die er mit acht Jahren zum ersten Mal von innen sah, hielt man ihn nicht für allzu helle - schließlich hinkte der Kleine oft hinter der Klasse her. Und es hat etwas Tragisches, wenn der wohl berühmteste Erfinder aller Zeiten und Halter von 2000 Patenten im Alter über seinen Vater sagt: Er dachte, ich sei dumm. Und ich meinte schon fast selbst, ich sei ein Dummkopf.

  15. Windenergie

    NASA Astrophysics Data System (ADS)

    Zahoransky, Richard; Allelein, Hans-Josef; Bollin, Elmar; Oehler, Helmut; Schelling, Udo

    Die Griechen bauten wahrscheinlich schon im ersten Jahrhundert unserer Zeitrechnung Windmühlen. Ab dem Jahr 600 n. Chr. sind sie mit vertikalen Drehachsen in Persien bekannt. Weit früher wurde die Windenergie zum Antrieb von Schiffen verwendet. Die Niederlande nutzten im 17. und 18. Jahrhundert Windmühlen, um ihre Landflächen durch Leerpumpen eingedeichter Flächen zu vergrößern.

  16. Von Humboldt bis Einstein. Berlin als Weltzentrum der exakten Wissenschaften.

    NASA Astrophysics Data System (ADS)

    Meschkowski, H.

    Contents: 1. Die Anfänge. 2. Die Ära Dirichlet-Jacobi. 3. Der Ausbau der experimentellen Naturwissenschaften. 4. Alexander von Humboldt. 5. Berlin wird "Weltzentrum" der Mathematik. 6. Die Ära Helmholtz. 7. Neue Arbeitsweisen der Astronomie. 8. Chemie: Forschung und Industrie. 9. Max Planck. 10. Ins technische Zeitalter. 11. Zur Mathematik der zwanziger Jahre. 12. Albert Einstein. 13. Fortschritte der Grundlagenforschung. 14. Erwin Schrödinger: Physiker, Philosoph und Poet. 15. Zum Schluß.

  17. Bewertung der Informationsqualität im Enterprise 2.0

    NASA Astrophysics Data System (ADS)

    Ahlheid, Sven; Graefe, Gernot; Krebs, Alexander; Schuster, Dirk

    Die Entwicklungen zum Web 2.0 haben das World Wide Web (WWW) grundlegend verändert. Nachdem die meisten Nutzer im WWW zunächst "nur" nach Informationen suchten stellen Nutzer inzwischen sehr ausgiebig Informationen über sich selbst oder ihnen vertraute Themen in Blogs und Communities bereit. Facebook und Wikipedia sind zwei prominente Webseiten. Ihre Attraktivität entstammt allein den Informationen, welche die Nutzer selber zur Verfügung stellen.

  18. Johannes Kepler

    NASA Astrophysics Data System (ADS)

    Bialas, Volker

    Johannes Kepler (1571 - 1630) gilt zurecht als einer der bedeutendsten Mathematiker und Astronomen der frühen Neuzeit, doch wurde das Philosophische in seinem Werk bislang kaum in angemessener Weise gewürdigt. Volker Bialas legt eine fundierte und anregende Einführung in Leben, Werk und Weltanschauung Keplers vor und setzt dabei durch die Akzentuierung des philosophisch-ganzheitlichen Denkens bewußt einen Kontrapunkt zum herkömmlichen Kepler-Bild.

  19. [Isotope nephrographic studies during hormonal contraception using Depositon].

    PubMed

    Voigt, R; Klinger, G; Stoll, W; Arndt, J

    1978-01-01

    By means of isotope nephrograms of a total of 29 renally healthy women who had been taken for more than 1 year the drug Deposiston, the renal function is investigated. Checking is done by using the semiquantitative evaluation parameters according to Zum Winkel, Pabst and Hör and to own criteria. Our results show that the highly dosed application of estrogens does not induce significant changes of renal function in the isotope nephrogram. PMID:726732

  20. Umsetzung der Unternehmensstrategie mit der Balanced Scorecard

    NASA Astrophysics Data System (ADS)

    Crespo, Isabel; Bergmann, Lars; Portmann, Stefan; Lacker, Thomas; Lacker, Michael; Fleischmann, Jürgen; Kozó, Hans

    Die Balanced Scorecard (BSC) ist ein Ansatz zum strategischen Management, der neben der Ausrichtung des Unternehmens auf finanzielle Zielwerte ebenso großes Gewicht auf so genannte weiche Faktoren legt, die den wirtschaftlichen Erfolg eines Unternehmens erst ermöglichen. Das entscheidende Merkmal der Balanced Scorecard ist dabei, dass sie ein ausgewogenes System strategischer Ziele herstellt, welches das Unternehmen hinsichtlich der vier Perspektiven Finanzen, Kunden, interne Prozesse und Mitarbeiter und Potenziale strategisch ausrichtet (Kaplan u. Norton 1997).

  1. Ab initio vel ex eventu. II

    NASA Astrophysics Data System (ADS)

    Thiessen, P. A.; Treder, H.-J.

    Jedes initium wird durch experimenta crucis zum eventus. Jedes theoretisch interpretierbare ex-eventu-Resultat führt auf ein neues Initium. Gerade dies ist die gemeinsame Aussage von Atomistik, Quantenmechanik und Relativitätstheorie.Translated AbstractAb initio vel ex eventu. IIEvery initium becomes an eventus by experimenta crucis. Every theoretically interpretable ex-eventu result leads to a new initium. Right this is the joint assertion of atomism, quantum mechanics, and relativity.

  2. Dentalwerkstoffe und Dentalimplantate - Teil 2

    NASA Astrophysics Data System (ADS)

    Faltermeier, Andreas

    Wie in allen Bereichen der Medizin findet auch in der Zahnmedizin eine kontinuierliche Weiterentwicklung der verwendeten Werkstoffe statt. Gerade für Zahnersatz werden Werkstoffe gesucht, die zum einen ästhetisch, zum anderen haltbar und darüber hinaus auch körperverträglich sind. Auch steigt immer mehr der Wunsch der Patienten nach ästhetischen und zugleich biokompatiblen Materialien. Wurde früher fast ausschließlich als Füllungsmaterial im Seitenzahngebiet quecksilberhaltiges Amalgam verwendet, hat der Zahnarzt heutzutage eine große Auswahl an verschiedenen zahnfarbenen Materialien: zum einen werden sog. Komposite verwendet, das aus einer Polymermatrix mit eingebetteten Füllstoffen besteht, zum anderen können diverse Dentalkeramiken verwendet werden. Besonders die Verwendung von Hochleistungskeramiken, wie beispielsweise Zirkonoxid, das sich bereits als Bremsscheiben für Sportwägen, Hitzeschilde im Space Shuttle und als Kugelköpfe künstlicher Hüftgelenke bewährt hat, spielt heutzutage eine große Rolle bei der Verdrängung des Metalls aus der Mundhöhle. War es früher nur möglich, einen verloren gegangen Zahn mittels einer Brücke, die ein Beschleifen der Nachbarzähne zur Folge hat, oder durch herausnehmbaren Zahnersatz zu ersetzen, ist es heutzutage mit der modernen Implantologie möglich, Zahnersatz zahnschonend einzugliedern. Auch kann mittels Dentalimplantaten dem Wunsch vieler Patienten nach festem Zahnersatz anstelle eines herausnehmbaren Zahnersatzes entsprochen werden. So kann mit Hilfe neuer biokompatiblen Werkstoffe sowohl der ästhetische Anspruch befriedigt als auch das Selbstwertgefühl vieler Patienten angehoben werden.

  3. Maschinenelemente

    NASA Astrophysics Data System (ADS)

    Böge, Alfred; Böge, Wolfgang; Borutzki, Ulrich; Labisch, Susanna; Linke, Petra; Weidermann, Frank

    Der konstruktive Entwicklungsprozess eines Produkts kann nicht losgelöst von den einzelnen Phasen betrachtet werden, die es während seines Bestehens durchläuft. Jede Phase beeinflusst mehr oder weniger die Ziele der Produktentwicklung. Diese Wechselwirkungen müssen Entwickler und Konstrukteur berücksichtigen. Zum Teil spiegeln sich diese Verbindungen in Anforderungen und Gestaltungshinweisen wider (siehe Kapitel 1.4). Im Folgenden wird der Produktlebenszyklus mit seinen einzelnen Phasen näher vorgestellt.

  4. Glucocorticoid Receptors, Brain-Derived Neurotrophic Factor, Serotonin and Dopamine Neurotransmission are Associated with Interferon-Induced Depression

    PubMed Central

    Udina, M; Navinés, R; Egmond, E; Oriolo, G; Langohr, K; Gimenez, D; Valdés, M; Gómez-Gil, E; Grande, I; Gratacós, M; Kapczinski, F; Artigas, F; Vieta, E; Solà, R

    2016-01-01

    Background: The role of inflammation in mood disorders has received increased attention. There is substantial evidence that cytokine therapies, such as interferon alpha (IFN-alpha), can induce depressive symptoms. Indeed, proinflammatory cytokines change brain function in several ways, such as altering neurotransmitters, the glucocorticoid axis, and apoptotic mechanisms. This study aimed to evaluate the impact on mood of initiating IFN-alpha and ribavirin treatment in a cohort of patients with chronic hepatitis C. We investigated clinical, personality, and functional genetic variants associated with cytokine-induced depression. Methods: We recruited 344 Caucasian outpatients with chronic hepatitis C, initiating IFN-alpha and ribavirin therapy. All patients were euthymic at baseline according to DSM-IV-R criteria. Patients were assessed at baseline and 4, 12, 24, and 48 weeks after treatment initiation using the Patient Health Questionnaire (PHQ), the Hospital Anxiety and Depression Scale (HADS), and the Temperament and Character Inventory (TCI). We genotyped several functional polymorphisms of interleukin-28 (IL28B), indoleamine 2,3-dioxygenase (IDO-1), serotonin receptor-1A (HTR1A), catechol-O-methyl transferase (COMT), glucocorticoid receptors (GCR1 and GCR2), brain-derived neurotrophic factor (BDNF), and FK506 binding protein 5 (FKBP5) genes. A survival analysis was performed, and the Cox proportional hazards model was used for the multivariate analysis. Results: The cumulative incidence of depression was 0.35 at week 24 and 0.46 at week 48. The genotypic distributions were in Hardy-Weinberg equilibrium. Older age (p = 0.018, hazard ratio [HR] per 5 years = 1.21), presence of depression history (p = 0.0001, HR = 2.38), and subthreshold depressive symptoms at baseline (p = 0.005, HR = 1.13) increased the risk of IFN-induced depression. So too did TCI personality traits, with high scores on fatigability (p = 0.0037, HR = 1.17), impulsiveness (p = 0.0200 HR = 1

  5. High-resolution chromosome ideogram representation of recognized genes for bipolar disorder.

    PubMed

    Douglas, Lindsay N; McGuire, Austen B; Manzardo, Ann M; Butler, Merlin G

    2016-07-15

    Bipolar disorder (BPD) is genetically heterogeneous with a growing list of BPD associated genes reported in recent years resulting from increased genetic testing using advanced genetic technology, expanded genomic databases, and better awareness of the disorder. We compiled a master list of recognized susceptibility and genes associated with BPD identified from peer-reviewed medical literature sources using PubMed and by searching online databases, such as OMIM. Searched keywords were related to bipolar disorder and genetics. Our compiled list consisted of 290 genes with gene names arranged in alphabetical order in tabular form with source documents and their chromosome location and gene symbols plotted on high-resolution human chromosome ideograms. The identified genes impacted a broad range of biological pathways and processes including cellular signaling pathways particularly cAMP and calcium (e.g., CACNA1C, CAMK2A, CAMK2D, ADCY1, ADCY2); glutamatergic (e.g., GRIK1, GRM3, GRM7), dopaminergic (e.g., DRD2, DRD4, COMT, MAOA) and serotonergic (e.g., HTR1A, HTR2A, HTR3B) neurotransmission; molecular transporters (e.g., SLC39A3, SLC6A3, SLC8A1); and neuronal growth (e.g., BDNF, IGFBP1, NRG1, NRG3). The increasing prevalence of BPD calls for better understanding of the genetic etiology of this disorder and associations between the observed BPD phenotype and genes. Visual representation of genes for bipolar disorder becomes a tool enabling clinical and laboratory geneticists, genetic counselors, and other health care providers and researchers easy access to the location and distribution of currently recognized BPD associated genes. Our study may also help inform diagnosis and advance treatment developments for those affected with this disorder and improve genetic counseling for families. PMID:27063557

  6. Complete mitochondrial DNA sequence of the ark shell Scapharca broughtonii: an ultra-large metazoan mitochondrial genome.

    PubMed

    Liu, Yun-Guo; Kurokawa, Tadahide; Sekino, Masashi; Tanabe, Toru; Watanabe, Kazuhito

    2013-03-01

    The complete mitochondrial (mt) genome of the ark shell Scapharca broughtonii was determined using long PCR and a genome walking sequencing strategy with genus-specific primers. The S. broughtonii mt genome (GenBank accession number AB729113) contained 12 protein-coding genes (the atp8 gene is missing, as in most bivalves), 2 ribosomal RNA genes, and 42 transfer tRNA genes, in a length of 46,985 nucleotides for the size of mtDNA with only one copy of the heteroplasmic tandem repeat (HTR) unit. Moreover the S. broughtonii mt genome shows size variation; these genomes ranged in size from about 47 kb to about 50 kb because of variation in the number of repeat sequences in the non-coding region. The mt-genome of S. broughtonii is, to date, the longest reported metazoan mtDNA sequence. Sequence duplication in non-coding region and the formation of HTR arrays were two of the factors responsible for the ultra-large size of this mt genome. All the tRNA genes were found within the S. broughtonii mt genome, unlike the other bivalves usually lacking one or more tRNA genes. Twelve additional specimens were used to analyze the patterns of tandem repeat arrays by PCR amplification and agarose electrophoresis. Each of the 12 specimens displayed extensive heteroplasmy and had 8-10 length variants. The motifs of the HTR arrays are about 353-362 bp and the number of repeats ranges from 1 to 11. PMID:23291309

  7. Composition and proteolytic processing of corneal deposits associated with mutations in the TGFBI gene

    PubMed Central

    Karring, Henrik; Runager, Kasper; Thøgersen, Ida B.; Klintworth, Gordon K.; Højrup, Peter; Enghild, Jan J.

    2012-01-01

    Different types of granular corneal dystrophy (GCD)1 and lattice corneal dystrophy (LCD) are associated with mutations in the transforming growth factor beta induced gene (TGFBI). These dystrophies are characterized by the formation of non-amyloid granular deposits (GCDs) and amyloid (LCD type 1 and its variants) in the cornea. Typical corneal non-amyloid deposits from GCD type 2 (R124H), amyloid from a variant of LCD type 1 (V624M) and disease-free tissue controls were procured by laser capture microdissection and analyzed by tandem mass spectrometry. Label-free quantitative comparisons of deposits and controls suggested that the non-amyloid sample (R124H) specifically accumulated transforming growth factor beta induced protein (TGFBIp/keratoepithelin/βig-h3), serum amyloid P-component, clusterin, type III collagen, keratin 3, and histone H3-like protein. The amyloid (V624M) similarly accumulated serum amyloid P-component and clusterin but also a C-terminal fragment of TGFBIp containing residues Y571-R588 derived from the fourth fasciclin-1 domain (FAS1-4), apolipoprotein E and apolipoprotein A-IV. Significantly, analyses of the amyloid sample also revealed the presence of the serine protease Htr (High-temperature requirement) A1 and a number of proteolytic cleavage sites in the FAS1-4 domain of TGFBIp. These cleavage sites were consistent with the ligand binding and proteolytic activity of HtrA1 suggesting that it plays a role in the proteolytic processing of the amyloidogenic FAS1-4 domain. Taken together, the data suggest that the amyloidogenic-prone region of the fourth FAS1 domain of TGFBIp encompasses the Y571-R588 peptide and that HtrA1 is involved in the proteolytic processing of TGFBIp-derived amyloid in vivo. PMID:22155582

  8. Detection of Endometrial Cancer via Molecular Analysis of DNA Collected with Vaginal Tampons

    PubMed Central

    Bakkum-Gamez, Jamie N.; Wentzensen, Nicolas; Maurer, Matthew J.; Hawthorne, Kieran M.; Voss, Jesse S.; Kroneman, Trynda N.; Famuyide, Abimbola O.; Clayton, Amy C.; Halling, Kevin C.; Kerr, Sarah E.; Cliby, William A.; Dowdy, Sean C.; Kipp, Benjamin R.; Mariani, Andrea; Oberg, Ann L.; Podratz, Karl C.; Shridhar, Viji; Sherman, Mark E.

    2015-01-01

    Objective We demonstrate the feasibility of detecting EC by combining minimally-invasive specimen collection techniques with sensitive molecular testing. Methods Prior to hysterectomy for EC or benign indications, women collected vaginal pool samples with intravaginal tampons and underwent endometrial brushing. Specimens underwent pyrosequencing for DNA methylation of genes reported to be hypermethylated in gynecologic cancers and recently identified markers discovered by profiling over 200 ECs. Methylation was evaluated individually across CpGs and averaged across genes. Differences between EC and benign endometrium (BE) were assessed using two-sample t-tests and area under the curve (AUC). Results Thirty-eight ECs and 28 BEs were included. We evaluated 97 CpGs within 12 genes, including previously reported markers (RASSF1, HSP2A, HOXA9, CDH13, HAAO, and GTF2A1) and those identified in discovery work (ASCL2, HTR1B, NPY, HS3ST2, MME, ADCYAP1, and additional CDH13 CpG sites). Mean methylation was higher in tampon specimens from EC v. BE for 9 of 12 genes (ADCYAP1, ASCL2, CDH13, HS3ST2, HTR1B, MME, HAAO, HOXA9, and RASSF1) (all p<0.05). Among these genes, relative hypermethylation was observed in EC v. BE across CpGs. Endometrial brush and tampon results were similar. Within tampon specimens, AUC was highest for HTR1B (0.82), RASSF1 (0.75), and HOXA9 (0.74). This is the first report of HOXA9 hypermethylation in EC. Conclusion DNA hypermethylation in EC tissues can also be identified in vaginal pool DNA collected via intravaginal tampon. Identification of additional EC biomarkers and refined collection methods are needed to develop an early detection tool for EC. PMID:25677060

  9. Tolerance and Cross-Tolerance to Head Twitch Behavior Elicited by Phenethylamine- and Tryptamine-Derived Hallucinogens in Mice

    PubMed Central

    Smith, Douglas A.; Bailey, Jessica M.; Williams, Diarria

    2014-01-01

    The serotonin 5-hydroxytryptamine 2A (5-HT2A) receptor is a potential therapeutic target to a host of neuropsychiatric conditions, but agonist actions at this site are linked to abuse-related hallucinogenic effects that may limit therapeutic efficacy of chronic drug administration. Tolerance to some effects of hallucinogens has been observed in humans and laboratory animals, but the understanding of tolerance and cross-tolerance between distinct structural classes of hallucinogens is limited. Here, we used the drug-elicited head twitch response (HTR) in mice to assess the development of tolerance and cross-tolerance with two phenethylamine-derived [DOI (2,5-dimethoxy-4-iodoamphetamine) and 2C-T-7 (2,5-dimethoxy-4-propylthiophenethylamine)] and two tryptamine-derived [DPT (N,N-dipropyltryptamine) and DIPT (N,N-diisopropyltryptamine)] drugs with agonist affinity for 5-HT2A receptors. Tolerance developed to HTR elicited by daily DOI or 2C-T-7, but not to HTR elicited by DPT or DIPT. DOI-elicited tolerance was not surmountable with dose, and a similar insurmountable cross-tolerance was evident when DOI-tolerant mice were tested with various doses of 2C-T-7 or DPT. These studies suggest that the use of phenethylamine-derived hallucinogens as therapeutic agents may be limited not only by their abuse potential, but also by the rapid development of tolerance that would likely be maintained even if a patient were switched to a different 5-HT2A agonist medication from a distinct structural class. However, these experiments also imply that tryptamine-derived hallucinogens might have a reduced potential for tolerance development, compared with phenethylamine-derived 5-HT2A agonists, and might therefore be more suitable for chronic administration in a therapeutic context. PMID:25271256

  10. Review of Current Experience on Intermediate Heat Exchanger (IHX) and A Recommended Code Approach

    SciTech Connect

    Duane Spencer; Kevin McCoy

    2010-02-02

    The purpose of the ASME/DOE Gen IV Task 7 Part I is to review the current experience on various high temperature reactor intermediate heat exchanger (IHX) concepts. There are several different IHX concepts that could be envisioned for HTR/VHTR applications in a range of temperature from 850C to 950C. The concepts that will be primarily discussed herein are: (1) Tubular Helical Coil Heat Exchanger (THCHE); (2) Plate-Stamped Heat Exchanger (PSHE); (3) Plate-Fin Heat Exchanger (PFHE); and (4) Plate-Machined Heat Exchanger (PMHE). The primary coolant of the NGNP is potentially subject to radioactive contamination by the core as well as contamination from the secondary loop fluid. To isolate the radioactivity to minimize radiation doses to personnel, and protect the primary circuit from contamination, intermediate heat exchangers (IHXs) have been proposed as a means for separating the primary circuit of the NGNP (Next Generation Nuclear Plant) or other process heat application from the remainder of the plant. This task will first review the different concepts of IHX that could be envisioned for HTR/VHTR applications in a range of temperature from 850 to 950 C. This will cover shell-and-tube and compact designs (including the platefin concept). The review will then discuss the maturity of the concepts in terms of design, fabricability and component testing (or feedback from experience when applicable). Particular attention will be paid to the feasibility of developing the IHX concepts for the NGNP with operation expected in 2018-2021. This report will also discuss material candidates for IHX applications and will discuss specific issues that will have to be addressed in the context of the HTR design (thermal aging, corrosion, creep, creep-fatigue, etc). Particular attention will be paid to specific issues associated with operation at the upper end of the creep regime.

  11. Aspirin inhibits expression of sFLT1 from human cytotrophoblasts induced by hypoxia, via cyclo-oxygenase 1

    PubMed Central

    Li, Chao; Raikwar, Nandita S; Santillan, Mark K; Santillan, Donna A; Thomas, Christie P.

    2015-01-01

    Introduction Elevated circulating soluble FLT1 (sFLT1) levels in preeclampsia may play a role in its development. Aspirin is recommended for prevention of preeclampsia. We hypothesized that aspirin may inhibit the production of sFlt1. Methods Placentas from women with and without preeclampsia were collected. Primary cytotrophoblasts (CTBs) were cultured from normal placentas and treated with aspirin, sc-560, a COX1 inhibitor or celecoxib, a COX-2 inhibitor. The expression of sFLT1, FLT1, COX1, COX2 was studied. The effect of aspirin on sFlt1 expression was also studied in HEK293 cells and in HTR-8/SVNeo cells. Results The expression of sFLT1 was increased in preeclamptic placentas compared to control placentas and the expression and release of sFLT1 increased in CTBs exposed to 2% O2 compared to controls. Aspirin at 3 and 12 mM concentration reduced the expression and release of sFLT1 in CTBs. Aspirin also inhibited sFlt1 expression from HTR-8/SVNeo and HEK293 cells. Sc-560, but not celecoxib, reduced sFLT1 expression and release from CTBs. Aspirin and sc-560 also reduced hypoxia-induced FLT1 mRNA expression and inhibited COX1 mRNA in CTBs. Discussion This study confirms that sFLT1 expression is increased in preeclamptic placentas and in CTBs exposed to hypoxia. Aspirin inhibits the production sFLT1 in CTBs and in HTR-8/SVNeo. Sc-560 recapitulated the effects of aspirin on sFLT1 expression and release in CTBs suggesting that the aspirin effect may be mediated via inhibition of COX1. The study increases our understanding of the mechanisms regulating sFlt1 expression and provides a plausible explanation for the effect of aspirin to prevent preeclampsia. PMID:25638730

  12. Up-regulation of serotonin receptor 2B mRNA and protein in the peri-infarcted area of aged rats and stroke patients.

    PubMed

    Buga, Ana-Maria; Ciobanu, Ovidiu; Bădescu, George Mihai; Bogdan, Catalin; Weston, Ria; Slevin, Mark; Di Napoli, Mario; Popa-Wagner, Aurel

    2016-04-01

    Despite the fact that a high proportion of elderly stroke patients develop mood disorders, the mechanisms underlying late-onset neuropsychiatric and neurocognitive symptoms have so far received little attention in the field of neurobiology. In rodents, aged animals display depressive symptoms following stroke, whereas young animals recover fairly well. This finding has prompted us to investigate the expression of serotonin receptors 2A and 2B, which are directly linked to depression, in the brains of aged and young rats following stroke. Although the development of the infarct was more rapid in aged rats in the first 3 days after stroke, by day 14 the cortical infarcts were similar in size in both age groups i.e. 45% of total cortical volume in young rats and 55.7% in aged rats. We also found that the expression of serotonin receptor type B mRNA was markedly increased in the perilesional area of aged rats as compared to the younger counterparts. Furthermore, histologically, HTR2B protein expression in degenerating neurons was closely associated with activated microglia both in aged rats and human subjects. Treatment with fluoxetine attenuated the expression of Htr2B mRNA, stimulated post-stroke neurogenesis in the subventricular zone and was associated with an improved anhedonic behavior and an increased activity in the forced swim test in aged animals. We hypothesize that HTR2B expression in the infarcted territory may render degenerating neurons susceptible to attack by activated microglia and thus aggravate the consequences of stroke. PMID:27013593

  13. Nuclear Safeguards Considerations For The Pebble Bed Modular Reactor (PBMR)

    SciTech Connect

    Phillip Casey Durst; David Beddingfield; Brian Boyer; Robert Bean; Michael Collins; Michael Ehinger; David Hanks; David L. Moses; Lee Refalo

    2009-10-01

    High temperature reactors (HTRs) have been considered since the 1940s, and have been constructed and demonstrated in the United Kingdom (Dragon), United States (Peach Bottom and Fort Saint Vrain), Japan (HTTR), Germany (AVR and THTR-300), and have been the subject of conceptual studies in Russia (VGM). The attraction to these reactors is that they can use a variety of reactor fuels, including abundant thorium, which upon reprocessing of the spent fuel can produce fissile U-233. Hence, they could extend the stocks of available uranium, provided the fuel is reprocessed. Another attractive attribute is that HTRs typically operate at a much higher temperature than conventional light water reactors (LWRs), because of the use of pyrolytic carbon and silicon carbide coated (TRISO) fuel particles embedded in ceramic graphite. Rather than simply discharge most of the unused heat from the working fluid in the power plant to the environment, engineers have been designing reactors for 40 years to recover this heat and make it available for district heating or chemical conversion plants. Demonstrating high-temperature nuclear energy conversion was the purpose behind Fort Saint Vrain in the United States, THTR-300 in Germany, HTTR in Japan, and HTR-10 and HTR-PM, being built in China. This resulted in nuclear reactors at least 30% or more thermodynamically efficient than conventional LWRs, especially if the waste heat can be effectively utilized in chemical processing plants. A modern variant of high temperature reactors is the Pebble Bed Modular Reactor (PBMR). Originally developed in the United States and Germany, it is now being redesigned and marketed by the Republic of South Africa and China. The team examined historical high temperature and high temperature gas reactors (HTR and HTGR) and reviewed safeguards considerations for this reactor. The following is a preliminary report on this topic prepared under the ASA-100 Advanced Safeguards Project in support of the NNSA Next

  14. Additive genetic risk from five serotonin system polymorphisms interacts with interpersonal stress to predict depression.

    PubMed

    Vrshek-Schallhorn, Suzanne; Stroud, Catherine B; Mineka, Susan; Zinbarg, Richard E; Adam, Emma K; Redei, Eva E; Hammen, Constance; Craske, Michelle G

    2015-11-01

    Behavioral genetic research supports polygenic models of depression in which many genetic variations each contribute a small amount of risk, and prevailing diathesis-stress models suggest gene-environment interactions (G×E). Multilocus profile scores of additive risk offer an approach that is consistent with polygenic models of depression risk. In a first demonstration of this approach in a G×E predicting depression, we created an additive multilocus profile score from 5 serotonin system polymorphisms (1 each in the genes HTR1A, HTR2A, HTR2C, and 2 in TPH2). Analyses focused on 2 forms of interpersonal stress as environmental risk factors. Using 5 years of longitudinal diagnostic and life stress interviews from 387 emerging young adults in the Youth Emotion Project, survival analyses show that this multilocus profile score interacts with major interpersonal stressful life events to predict major depressive episode onsets (hazard ratio [HR] = 1.815, p = .007). Simultaneously, there was a significant protective effect of the profile score without a recent event (HR = 0.83, p = .030). The G×E effect with interpersonal chronic stress was not significant (HR = 1.15, p = .165). Finally, effect sizes for genetic factors examined ignoring stress suggested such an approach could lead to overlooking or misinterpreting genetic effects. Both the G×E effect and the protective simple main effect were replicated in a sample of early adolescent girls (N = 105). We discuss potential benefits of the multilocus genetic profile score approach and caveats for future research. PMID:26595467

  15. Role of HLA-G1 in trophoblast cell proliferation, adhesion and invasion

    SciTech Connect

    Jiang, Feng; Zhao, Hongxi; Wang, Li; Guo, Xinyu; Wang, Xiaohong; Yin, Guowu; Hu, Yunsheng; Li, Yi; Yao, Yuanqing

    2015-02-27

    Trophoblast cells are important in embryo implantation and fetomaternal tolerance. HLA-G is specifically expressed at the maternal–fetal interface and is a regulator in pregnancy. The aim of the present study was to detect the effect of HLA-G1 on trophoblast cell proliferation, adhesion, and invasion. Human trophoblast cell lines (JAR and HTR-8/SVneo cells) were infected with HLA-G1-expressing lentivirus. After infection, HLA-G1 expression of the cells was detected by western blotting. Cell proliferation was detected by the BrdU assay. The cell cycle and apoptosis of JAR and HTR-8/SVneo cells was measured by flow cytometry (FCM). The invasion of the cells under different conditions was detected by the transwell invasion chamber assay. HLA-G1 didn't show any significant influence on the proliferation, apoptosis, adhesion, and invasion of trophocytes in normal culture conditions. However, HLA-G1 inhibited JAR and HTR-8/SVneo cells invasion induced by hepatocyte growth factor (HGF) under normal oxygen conditions. In conditions of hypoxia, HLA-G1 couldn't inhibit the induction of cell invasion by HGF. HLA-G1 is not an independent factor for regulating the trophocytes. It may play an indirect role in embryo implantation and formation of the placenta. - Highlights: • HLA-G1 could not influence trophocytes under normal conditions. • HLA-G1 inhibited cell invasion induced by HGF under normal oxygen condition. • HLA-G1 could not influence cell invasion under hypoxia conditions.

  16. Rs6295 promoter variants of the serotonin type 1A receptor are differentially activated by c-Jun in vitro and correlate to transcript levels in human epileptic brain tissue.

    PubMed

    Pernhorst, Katharina; van Loo, Karen M J; von Lehe, Marec; Priebe, Lutz; Cichon, Sven; Herms, Stefan; Hoffmann, Per; Helmstaedter, Christoph; Sander, Thomas; Schoch, Susanne; Becker, Albert J

    2013-03-01

    Many brain disorders, including epilepsy, migraine and depression, manifest with episodic symptoms that may last for various time intervals. Transient alterations of neuronal function such as related to serotonin homeostasis generally underlie this phenomenon. Several nucleotide polymorphisms (SNPs) in gene promoters associated with these diseases have been described. For obvious reasons, their regulatory roles on gene expression particularly in human brain tissue remain largely enigmatic. The rs6295 G-/C-allelic variant is located in the promoter region of the human HTR1a gene, encoding the G-protein-coupled receptor for 5-hydroxytryptamine (5HT1AR). In addition to reported transcriptional repressor binding, our bioinformatic analyses predicted a reduced binding affinity of the transcription factor (TF) c-Jun for the G-allele. In vitro luciferase transfection assays revealed c-Jun to (a) activate the rs6295 C- significantly stronger than the G-allelic variant and (b) antagonize efficiently the repressive effect of Hes5 on the promoter. The G-allele of rs6295 is known to be associated with aspects of major depression and migraine. In order to address a potential role of rs6295 variants in human brain tissue, we have isolated DNA and mRNA from fresh frozen hippocampal tissue of pharmacoresistant temporal lobe epilepsy (TLE) patients (n=140) after epilepsy surgery for seizure control. We carried out SNP genotyping studies and mRNA analyses in order to determine HTR1a mRNA expression in human hippocampal samples stratified according to the rs6295 allelic variant. The mRNA expression of HTR1a was significantly more abundant in hippocampal mRNA of TLE patients homozygous for the rs6295 C-allele as compared to those with the GG-genotype. These data may point to a novel, i.e., rs6295 allelic variant and c-Jun dependent transcriptional 5HT1AR 'receptoropathy'. PMID:23333373

  17. Up-regulation of serotonin receptor 2B mRNA and protein in the peri-infarcted area of aged rats and stroke patients

    PubMed Central

    Bădescu, George Mihai; Bogdan, Catalin; Weston, Ria; Slevin, Mark; Di Napoli, Mario; Popa-Wagner, Aurel

    2016-01-01

    Despite the fact that a high proportion of elderly stroke patients develop mood disorders, the mechanisms underlying late-onset neuropsychiatric and neurocognitive symptoms have so far received little attention in the field of neurobiology. In rodents, aged animals display depressive symptoms following stroke, whereas young animals recover fairly well. This finding has prompted us to investigate the expression of serotonin receptors 2A and 2B, which are directly linked to depression, in the brains of aged and young rats following stroke. Although the development of the infarct was more rapid in aged rats in the first 3 days after stroke, by day 14 the cortical infarcts were similar in size in both age groups i.e. 45% of total cortical volume in young rats and 55.7% in aged rats. We also found that the expression of serotonin receptor type B mRNA was markedly increased in the perilesional area of aged rats as compared to the younger counterparts. Furthermore, histologically, HTR2B protein expression in degenerating neurons was closely associated with activated microglia both in aged rats and human subjects. Treatment with fluoxetine attenuated the expression of Htr2B mRNA, stimulated post-stroke neurogenesis in the subventricular zone and was associated with an improved anhedonic behavior and an increased activity in the forced swim test in aged animals. We hypothesize that HTR2B expression in the infarcted territory may render degenerating neurons susceptible to attack by activated microglia and thus aggravate the consequences of stroke. PMID:27013593

  18. Analysis of Resistance to Antimicrobials and Presence of Virulence/Stress Response Genes in Campylobacter Isolates from Patients with Severe Diarrhoea

    PubMed Central

    Ghunaim, Haitham; Behnke, Jerzy M.; Aigha, Idil; Sharma, Aarti; Doiphode, Sanjay H.; Deshmukh, Anand; Abu-Madi, Marawan M.

    2015-01-01

    Campylobacter infections are a major cause of diarrhoea world-wide and two of the antimicrobials used for their control (erythromycin and ciprofloxacin) have been losing efficacy in recent years. In a sample of 174 genotyped isolates from the stools of patients with severe diarrhoea in Qatar, collected between 2005 and 2012, 63.2% showed resistance to ciprofloxacin, 8.6% to erythromycin, 0.57% to chloramphenicol and all were sensitive to gentamycin. While 33.9% of isolates were sensitive to all four antimicrobials, 59.8% were resistant to at least one, 6.3% were resistant to two and none showed resistance to three antimicrobials. There was no host sex- or age-dependence among isolates resistant to ciprofloxacin and erythromycin and no significant variation was found with the region of origin of the patients. All isolates were screened for the presence of 3 virulence factors (ciaB, cadF and cdtB) and two stress-response factors (htrB and clpP), all of which were present in more than 50% of the isolates. Host sex-, age- and region of origin-dependent variations in prevalence were found for some of these factors. Data analysis for the combination of virulence factors and their effect on antimicrobial resistance indicated that the prevalence of resistance to both erythromycin and ciprofloxacin was higher in isolates harbouring ciaB but not clpP. Prevalence of resistance to ciprofloxacin was similar in clpP positive and negative isolates also possessing htrB, while for htrB-negative isolates prevalence was higher in the absence of clpP. These results are discussed and their implications are highlighted. PMID:25781009

  19. Progesterone-induced blocking factor differentially regulates trophoblast and tumor invasion by altering matrix metalloproteinase activity.

    PubMed

    Halasz, Melinda; Polgar, Beata; Berta, Gergely; Czimbalek, Livia; Szekeres-Bartho, Julia

    2013-12-01

    Invasiveness is a common feature of trophoblast and tumors; however, while tumor invasion is uncontrolled, trophoblast invasion is strictly regulated. Both trophoblast and tumor cells express high levels of the immunomodulatory progesterone-induced blocking factor (PIBF), therefore, we aimed to test the possibility that PIBF might be involved in invasion. To this aim, we used PIBF-silenced or PIBF-treated trophoblast (HTR8/Svneo, and primary trophoblast) and tumor (HT-1080, A549, HCT116, PC3) cell lines. Silencing of PIBF increased invasiveness as well as MMP-2,-9 secretion of HTR8/SVneo, and decreased those of HT-1080 cells. PIBF induced immediate STAT6 activation in both cell lines. Silencing of IL-4Rα abrogated all the above effects of PIBF, suggesting that invasion-related signaling by PIBF is initiated through the IL-4Rα/PIBF-receptor complex. In HTR-8/SVneo, PIBF induced fast, but transient Akt and ERK phosphorylation, whereas in tumor cells, PIBF triggered sustained Akt, ERK, and late STAT3 activation. The late signaling events might be due to indirect action of PIBF. PIBF induced the expression of EGF and HB-EGF in HT-1080 cells. The STAT3-activating effect of PIBF was reduced in HB-EGF-deficient HT-1080 cells, suggesting that PIBF-induced HB-EGF contributes to late STAT3 activation. PIBF binds to the promoters of IL-6, EGF, and HB-EGF; however, the protein profile of the protein/DNA complex is different in the two cell lines. We conclude that in tumor cells, PIBF induces proteins, which activate invasion signaling, while-based on our previous data-PIBF might control trophoblast invasion by suppressing proinvasive genes. PMID:23807209

  20. Maintaining effective mass drug administration for lymphatic filariasis through in-process monitoring in Sierra Leone

    PubMed Central

    2012-01-01

    Background Since 2007 Sierra Leone has conducted mass drug administration (MDA) for the elimination of lymphatic filariasis (LF) implemented by unpaid community health volunteers (CHVs). Other health campaigns such as Mother and Child Health Weeks (MCHW) pay for services to be implemented at community level and these persons are then known as community health workers (CHWs). In 2010, the LF MDA in the 12 districts of the Southern, Northern and Eastern Provinces un-expectantly coincided with universal distribution of Long Lasting Insecticide Treated Nets (LLITNs) during the MCHW. In-process monitoring of LF MDA was performed to ensure effective coverage was attained in hard to reach sites (HTR) in both urban and rural locations where vulnerable populations reside. Methods Independent monitors interviewed individuals eligible for LF MDA and tallied those who recalled having taken ivermectin and albendazole, calculated program coverage and reported results daily by phone. Monitoring of coverage in HTR sites in the 4 most rapidly urbanizing towns was performed after 4 weeks of LF MDA and again after 8 weeks throughout all 12 districts. End process monitoring was performed in randomly selected HTR sites not previously sampled throughout all 12 districts and compared to coverage calculated from the pre-MDA census and reported treatments. Results Only one town had reached effective program coverage (≥80%) after 4 weeks following which CHWs were recruited for LF MDA in all district headquarter towns. After 8 weeks only 4 of 12 districts had reached effective coverage so LF MDA was extended for a further month in all districts. By 12 weeks effective program coverage had been reached in all districts except Port Loko and there was no significant difference between those interviewed in communities versus households or by sex. Effective epidemiological coverage (≥65%) was reported in all districts and overall was significantly higher in males versus females. Conclusions

  1. SV40 Tag transformation of the normal invasive trophoblast results in a premalignant phenotype. I. Mechanisms responsible for hyperinvasiveness and resistance to anti-invasive action of TGFbeta.

    PubMed

    Khoo, N K; Bechberger, J F; Shepherd, T; Bond, S L; McCrae, K R; Hamilton, G S; Lala, P K

    1998-07-29

    Invasion of the uterus by first trimester human placental extravillous trophoblast (EVT) cells depends on mechanisms shared by malignant cells. However, unlike tumor invasion, trophoblast invasion of the uterus is stringently controlled in situ by local molecules such as transforming growth factor (TGF)beta. Since EVT cells possess active invasion-associated genes but are nontumorigenic, our objective was to induce premalignant and then malignant phenotype into a normal EVT cell line in order to identify the molecular basis of tumor progression. Simian virus 40 large T antigen (SV40 Tag) was introduced into a normal human first trimester invasive EVT cell line, HTR8, established in our laboratory. Since the HTR8 line has a limited in vitro lifespan of 12-15 passages, SV40 Tag-transformed cells were selected on the basis of extended lifespan. A long-lived line, RSVT-2, was produced and an immortalized subclone, RSVT2/C, was further derived under a forced crisis regimen. We examined transformation-induced alterations in proliferative and invasive abilities, responses to the invasion and proliferation-regulating growth factor TGFbeta and changes in gene expression for invasion-associated enzymes or enzyme inhibitors. RSVT-2 and RSVT2/C cell lines were hyperproliferative and hyperinvasive when compared with the parental HTR8 cell line. They were also variably resistant to the anti-proliferative and anti-invasive signals from TGFbeta. Since both cell lines remained non-tumorigenic in nude mice, these properties indicate that they attained a premalignant phenotype. Both cell lines showed reduced expression of tissue inhibitor of metalloproteases (TIMP)-1, while TIMP-2 and plasminogen activator inhibitor (PAI)-I expression was was also reduced in RSVT2/C cells, thus contributing to their hyperinvasiveness. Their resistance to the anti-invasive action of TGFbeta was explained by the failure of TGFbeta to upregulate TIMPs and PAI-I, in contrast to the TGFbeta

  2. Emergence of extended-spectrum β-lactam resistance among Escherichia coli at a US academic children’s hospital is clonal at the sequence type level for CTX-M-15, but not for CMY-2

    PubMed Central

    Weissman, Scott J.; Adler, Amanda; Qin, Xuan; Zerr, Danielle M.

    2013-01-01

    Resistance to extended-spectrum β-lactams is increasing worldwide among Escherichia coli and has been linked to a small number of emergent clones (e.g. ST38, ST131 and ST405) recovered from extraintestinal infections in community and hospital settings. There are, however, limited data about the relative contributions of bacterial strains, plasmids and β-lactamase genes to extended-spectrum β-lactam resistance in paediatric infections. We performed an extensive molecular analysis of phylogenetic, virulence and antibiotic resistance-related properties of 49 previously reported serial E. coli isolates recovered during 1999–2007 at Seattle Children’s Hospital (Seattle, WA). Class C enzyme CMY-2 and class A enzyme CTX-M-15 were the most prominent extended-spectrum β-lactam resistance enzymes in the collection, first appearing in this patient population in 2001 and 2003, respectively, and then steadily increasing in frequency over the remainder of the study period. Among 19 CMY-2-positive isolates, 16 distinct STs were detected (D = 98.25%, 95% CI 96–100.25%), indicating that CMY spread is non-clonal at the host strain level. In contrast, among ten CTX-M-15-positive isolates, three STs were detected (D = 37.78%, 95% CI 2.36–73.20%), of which eight represented the worldwide-disseminated ST131 lineage, consistent with clonal spread of CTX-M-15-associated resistance. fimHTR subtyping of ten ST131 isolates (including two CTX-M-negative isolates) revealed that, within ST131, carriage of allele fimHTR30 correlated with CTX-M-15 positivity, whilst carriage of non-fimHTR30 alleles correlated with carriage of non-CTX-M enzymes. Thus, spread of CMY-2 is non-clonal at the ST level, but clonal spread of CTX-M-15 may be associated with a specific fimHTR-defined sublineage of ST131. PMID:23434250

  3. Rickettsia amblyommii infecting Amblyomma sculptum in endemic spotted fever area from southeastern Brazil.

    PubMed

    Nunes, Emília de Carvalho; Vizzoni, Vinicius Figueiredo; Navarro, Daniel Leal; Iani, Felipe Campos de Melo; Durães, Liliane Silva; Daemon, Erik; Soares, Carlos Augusto Gomes; Gazeta, Gilberto Salles

    2015-12-01

    The Rickettsia bacteria include the aetiological agents for the human spotted fever (SF) disease. In the present study, a SF group Rickettsia amblyommii related bacterium was detected in a field collected Amblyomma sculptum (Amblyomma cajennense species complex) tick from a Brazilian SF endemic site in southeastern Brazil, in the municipality of Juiz de Fora, state of Minas Gerais. Genetic analysis based on genes ompA,ompB and htrA showed that the detected strain, named R. amblyommii str. JF, is related to the species R. amblyommii. PMID:26676317

  4. Raman characterization of monolayers formed from mixtures of sodium 2-mercaptoethanesulfonate and various aromatic mercapto-derivative bases.

    PubMed

    Kudelski, Andrzej

    2010-04-22

    Metal electrodes covered with organic (mono)layers containing pi-delocalized structures have many potential applications, for example, in construction of bioelectronic elements with high efficiency of electron transfer. In this contribution, a silver surface was modified with mixed monolayers formed from sodium 2-mercaptoethanesulfonate (MES) and four model (stable and easily available) aromatic thiols with strong basic properties: 4,6-diamino-2-mercaptopyrimidine (APY), 1H-1,2,4-triazole-3-thiol (HTR), 4-methyl-1,2,4-triazole-3-thiol (MTR), and 3-amino-1,2,4-triazole-5-thiol (ATR). The structure of the formed monolayers was determined from surface-enhanced Raman scattering (SERS) measurements. These studies showed that, despite significant differences in the molecular structures, MES is a very promising candidate for making mixed monolayers with mercapto-derivative aromatic bases that are relatively homogeneous (without large one-component domains) in broad pH range. At high pH, in a one-component ATR monolayer, a significant amount of molecules are in the anionic form and adopt a flat orientation versus the metal surface. At the same pH, in mixed ATR+MES monolayers, a significantly larger part of ATR molecules than for the respective one-component monolayer is adsorbed in the neutral form with the aromatic ring(s) oriented perpendicularly to the metal surface. Also in the mixed APY+MES and HTR+MES monolayers, a significantly smaller part of HTR or APY molecules than for the respective one-component HTR and APY monolayers is deprotonated. The structure of the MTR monolayer practically does not depend on the pH of the surrounding solution. Increase of the ratio of acidic dissociation and reorientation of ATR molecules from the perpendicular to the parallel orientation is also observed during storage of the respective one-component and mixed monolayers in water, phosphorus buffers, and in the solutions of model peptides (bovine serum albumin or laccase). In some

  5. Return of the lysergamides. Part I: Analytical and behavioural characterization of 1-propionyl-d-lysergic acid diethylamide (1P-LSD).

    PubMed

    Brandt, Simon D; Kavanagh, Pierce V; Westphal, Folker; Stratford, Alexander; Elliott, Simon P; Hoang, Khoa; Wallach, Jason; Halberstadt, Adam L

    2016-09-01

    1-Propionyl-d-lysergic acid diethylamide hemitartrate (1P-LSD) has become available as a 'research chemical' in the form of blotters and powdered material. This non-controlled derivative of d-lysergic acid diethylamide (LSD) has previously not been described in the published literature despite being closely related to 1-acetyl-LSD (ALD-52), which was developed in the 1950s. This study describes the characterization of 1P-LSD in comparison with LSD using various chromatographic and mass spectrometric methods, infrared and nuclear magnetic resonance spectroscopy. An important feature common to LSD and other serotonergic hallucinogens is that they produce 5-HT2A -receptor activation and induce the head-twitch response (HTR) in rats and mice. In order to assess whether 1P-LSD displays LSD-like properties and activates the 5-HT2A receptor, male C57BL/6 J mice were injected with vehicle (saline) or 1P-LSD (0.025-0.8 mg/kg, IP) and HTR assessed for 30 min using magnetometer coil recordings. It was found that 1P-LSD produced a dose-dependent increase in HTR counts, and that it had ~38% (ED50  = 349.6 nmol/kg) of the potency of LSD (ED50  = 132.8 nmol/kg). Furthermore, HTR was abolished when 1P-LSD administration followed pretreatment with the selective 5-HT2A receptor antagonist M100907 (0.1 mg/kg, SC), which was consistent with the concept that the behavioural response was mediated by activation of the 5-HT2A receptor. These results indicate that 1P-LSD produces LSD-like effects in mice, consistent with its classification as a serotonergic hallucinogen. Nevertheless, the extent to which 1P-LSD might show psychoactive effects in humans similar to LSD remains to be investigated. Copyright © 2015 John Wiley & Sons, Ltd. PMID:26456305

  6. Hydrogen Gas Production from Nuclear Power Plant in Relation to Hydrogen Fuel Cell Technologies Nowadays

    NASA Astrophysics Data System (ADS)

    Yusibani, Elin; Kamil, Insan; Suud, Zaki

    2010-06-01

    Recently, world has been confused by issues of energy resourcing, including fossil fuel use, global warming, and sustainable energy generation. Hydrogen may become the choice for future fuel of combustion engine. Hydrogen is an environmentally clean source of energy to end-users, particularly in transportation applications because without release of pollutants at the point of end use. Hydrogen may be produced from water using the process of electrolysis. One of the GEN-IV reactors nuclear projects (HTGRs, HTR, VHTR) is also can produce hydrogen from the process. In the present study, hydrogen gas production from nuclear power plant is reviewed in relation to commercialization of hydrogen fuel cell technologies nowadays.

  7. Hydrogen Gas Production from Nuclear Power Plant in Relation to Hydrogen Fuel Cell Technologies Nowadays

    SciTech Connect

    Yusibani, Elin; Kamil, Insan; Suud, Zaki

    2010-06-22

    Recently, world has been confused by issues of energy resourcing, including fossil fuel use, global warming, and sustainable energy generation. Hydrogen may become the choice for future fuel of combustion engine. Hydrogen is an environmentally clean source of energy to end-users, particularly in transportation applications because without release of pollutants at the point of end use. Hydrogen may be produced from water using the process of electrolysis. One of the GEN-IV reactors nuclear projects (HTGRs, HTR, VHTR) is also can produce hydrogen from the process. In the present study, hydrogen gas production from nuclear power plant is reviewed in relation to commercialization of hydrogen fuel cell technologies nowadays.

  8. [Evidenzbasierte Leitlinien, Anspruch und Wirklichkeit].

    PubMed

    Gutsch, Johannes; Reif, Marcus; Müller-Hübenthal, Boris; Matthiessen, Peter F

    2016-01-01

    Mit der Konzeption der «Evidenzbasierten Medizin» und den «Evidenzbasierten Leitlinien» soll mithilfe von Formalisierungsprozeduren die ärztliche Irrtumsanfälligkeit kalkulierbar gemacht werden. Quantifizierte objektive Aussagen über die therapeutische Wirksamkeit einer Behandlung sollen die individuelle ärztliche Beurteilung der therapeutischen Wirksamkeit überflüssig machen. Damit kommt der Befolgung von formalen Regeln die entscheidende Rolle bei der Beantwortung der Frage nach dem Wahrheitsgehalt und dem Wirklichkeitsbezug zu. Im Rahmen evidenzbasierter Leitlinien werden vorrangig die Ergebnisse randomisierter kontrollierter Studien (RCT) oder Meta-Analysen solcher Studien herangezogen. Am Beispiel der S3-Leitlinie «Malignes Melanom» wird hier eine evidenzbasierte Urteilsbildung zur Wirksamkeit einer unkonventionellen Therapie - hier mit einem Mistelpräparat - analytisch nachvollzogen. Die für die Beurteilung dieser unkonventionellen Therapie herangezogene randomisierte Studie wird genauer methodisch analysiert. Obwohl sie keine statistisch basierte Aussage zulässt, wurde eine Leitlinienempfehlung auf Basis dieser Studie abgeleitet. Es wird gezeigt, dass 1) allein die Existenz einer einzigen RCT mit hoher Evidenz gleichgesetzt wird, 2) die Ergebnisse trotz beträchtlicher Fehlinterpretationen in eine S3-Leitlinie einfließen und 3) Meinungen anstelle kritischer wissenschaftlicher Analysen verarbeitet werden. Unsere Untersuchung zeigt, dass noch so ausgefeilte epistemologische und methodologische Formalien den Arzt nicht von der Pflicht entbinden, auf Basis seiner ärztlichen Erfahrung und professionellen Kompetenz den Realitätswert der ihm zur Verfügung stehenden Information zu beurteilen. PMID:27161555

  9. Zivilisationsdynamik: Treiber Technik, Folgen und Konsequenzen. Civilisation dynamics: driving force technology, results and consequences

    NASA Astrophysics Data System (ADS)

    Jischa, Michael F.

    2010-11-01

    Die Menschheitsgeschichte ist untrennbar mit der Nutzung von Materie, Energie und Information verbunden. Im Laufe der Geschichte sind Produktivität, Bevölkerung und Ressourcenverbrauch ständig angestiegen, seit dem vergangenen Jahrhundert mit zunehmender Beschleunigung. In den früh industrialisierten Ländern entwickelte sich vor wenigen Jahrzehnten eine Bewusstseinswende, die Segnungen der Technik wurden zunehmend kritisch beurteilt. Das führte zur Formulierung des Leitbildes Nachhaltigkeit und unterschiedlichen Ansätzen, dieses zu operationalisieren, aus Sicht der Ingenieure mit dem Konzept Technikbewertung. Nach den Natur- und den Ingenieurwissenschaften haben die Gesellschaftswissenschaften diese Themen aufgegriffen, was zu einer teilweisen Annäherung der Zwei Kulturen geführt hat. Weiter sind Überlegungen entstanden, Lehr- und Forschungsinhalte zu überdenken, um auf die Weltprobleme (in der Sprache des Club of Rome) angemessen reagieren zu können. In jüngerer Zeit wurden Energieszenarien vorgestellt, deren Kernaussage unmissverständlich lautet: Die Zukunft gehört den erneuerbaren Energien.

  10. Tillage Effects on Selected Soil Physical Properties in a Maize-Bean Intercropping System in Mwala District, Kenya

    PubMed Central

    Karuma, Anne; Mtakwa, Peter; Amuri, Nyambilila; Gachene, Charles K.; Gicheru, Patrick

    2014-01-01

    A field study was carried out to evaluate the effects of tillage practices on soil physical properties in Mwala district, Eastern Kenya, during the long rains (LR) and short rains (SR) of 2012/13. The treatments were disc ploughing (DP), disc ploughing and harrowing (DPH), ox-ploughing (OX), subsoiling-ripping (SSR), hand hoeing with tied ridges (HTR), hand hoeing only (H). These were investigated under three cropping systems of sole maize, sole bean, and maize-bean intercrop in a split-plot design with four replications. Soil physical properties were monitored at different weeks after planting (WAP) throughout the growing seasons. A four-season average shows that soil moisture content was significantly (P < 0.05) higher in OX > SSR > DPH > H > HTR > DP with values ranging from 13.1 to 14.1%. Soil surface roughness and crust strength varied significantly (P < 0.05) over time within the growing seasons, between the tillage practices, and across the different seasons with values ranging from 26 to 66% and 1.21 to 1.31 MPa, respectively. Tillage practices and cropping systems did not significantly affect bulk density, porosity, or Ksat values. It is apparent that long term tillage experiment (>4 seasons) would be required to detect changes in soil physical properties as a result of the soil management practices. PMID:27379288

  11. A novel serotonin-secreting cell type regulates ciliary motility in the mucociliary epidermis of Xenopus tadpoles.

    PubMed

    Walentek, Peter; Bogusch, Susanne; Thumberger, Thomas; Vick, Philipp; Dubaissi, Eamon; Beyer, Tina; Blum, Martin; Schweickert, Axel

    2014-04-01

    The embryonic skin of Xenopus tadpoles serves as an experimental model system for mucociliary epithelia (MCE) such as the human airway epithelium. MCEs are characterized by the presence of mucus-secreting goblet and multiciliated cells (MCCs). A third cell type, ion-secreting cells (ISCs), is present in the larval skin as well. Synchronized beating of MCC cilia is required for directional transport of mucus. Here we describe a novel cell type in the Xenopus laevis larval epidermis, characterized by serotonin synthesis and secretion. It is termed small secretory cell (SSC). SSCs are detectable at early tadpole stages, unlike MCCs and ISCs, which are specified at early neurulation. Subcellularly, serotonin was found in large, apically localized vesicle-like structures, which were entirely shed into the surrounding medium. Pharmacological inhibition of serotonin synthesis decreased the velocity of cilia-driven fluid flow across the skin epithelium. This effect was mediated by serotonin type 3 receptor (Htr3), which was expressed in ciliated cells. Knockdown of Htr3 compromised flow velocity by reducing the ciliary motility of MCCs. SSCs thus represent a distinct and novel entity of the frog tadpole MCE, required for ciliary beating and mucus transport across the larval skin. The identification and characterization of SSCs consolidates the value of the Xenopus embryonic skin as a model system for human MCEs, which have been known for serotonin-dependent regulation of ciliary beat frequency. PMID:24598162

  12. Evidence for PDZ domains in bacteria, yeast, and plants.

    PubMed Central

    Ponting, C. P.

    1997-01-01

    Several dozen signaling proteins are now known to contain 80-100 residue repeats, called PDZ (or DHR or GLGF) domains, several of which interact with the C-terminal tetrapeptide motifs X-Ser/Thr-X-Val-COO- of ion channels and/or receptors. PDZ domains have previously been noted only in mammals, flies, and worms, suggesting that the primordial PDZ domain arose relatively late in eukaryotic evolution. Here, techniques of sequence analysis-including local alignment, profile, and motif database searches-indicate that PDZ domain homologues are present in yeast, plants, and bacteria. It is suggested that two PDZ domains occur in bacterial high-temperature requirement A (htrA) and one in tail-specific protease (tsp) homologues, and that a yeast htrA homologue contains four PDZ domains. Sequence comparisons suggest that the spread of PDZ domains in these diverse organisms may have occurred via horizontal gene transfer. The known affinity of Escherichia coli tsp for C-terminal polypeptides is proposed to be mediated by its PDZ-like domain, in a similar manner to the binding of C-terminal polypeptides by animal PDZ domains. PMID:9041651

  13. CCAAT displacement protein (CDP/cut) binds a negative regulatory element in the human tryptophan hydroxylase gene.

    PubMed

    Teerawatanasuk, N; Skalnik, D G; Carr, L G

    1999-01-01

    Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the biosynthesis of serotonin, a neurotransmitter that has been implicated in many psychiatric illnesses. The mechanism of transcriptional regulation of the human TPH gene is largely unknown. We have identified a negative regulatory element located between nucleotides -310 and -220 in the human TPH (hTPH) gene. Electromobility shift analyses performed with the -310/-220 hTPH probe and nuclear extract from P815-HTR (a TPH-expressing cell line) revealed two slow migrating protein-DNA complexes, designated I and II. CCAAT displacement protein (CDP/Cut) is involved in complex I formation as shown in electromobility shift analysis, using consensus oligonucleotide competitor and antibody. Mutations in the CDP/Cut binding site not only disrupted the CDP-DNA complex but also disrupted the second complex, suggesting that the core binding sequences of the two proteins are overlapping. The functional importance of these protein-DNA interactions was assessed by transiently transfecting wild-type and mutant pTPH/luciferase reporter constructs into P815-HTR cells. Mutations in the core CDP/Cut site resulted in an approximately fourfold increase in relative luciferase activities. Because CDP/Cut has been shown to repress transcription of many target genes, we speculate that disruption of the CDP/Cut binding was responsible, at least in part, for the activation of hTPH gene. PMID:9886051

  14. NF-Y activates mouse tryptophan hydroxylase transcription.

    PubMed

    Reed, G E; Kirchner, J E; Carr, L G

    1995-06-01

    Tryptophan hydroxylase catalyses the rate-limiting step in the biosynthesis of serotonin, a neurotransmitter which has been implicated in the etiologies of clinically important psychiatric illnesses. Tryptophan hydroxylase is expressed in a tissue-specific manner, but little is known about its transcriptional regulation. By analysing transcriptional activities of a set 5'-deletion constructs of promoter-reporter plasmids in P815-HTR mastocytoma cells, we found that transcription was activated by sequences between nucleotides -343 and -21. DNase I footprint analysis, using nuclear protein extracts from P815-HTR cells, revealed a protein-DNA interaction between nucleotides -77 and -46. A double stranded oligonucleotide, representing this binding site, specifically bound nuclear protein in a gel shift assay. Methylation interference analysis of this complex revealed that nuclear protein interacted with an inverted GGCCAAT element, which is a high-affinity binding motif for the transcription factor NF-Y (also known as CP1 or CBF). An NF-Y specific antibody abolished protein binding in a gel shift assay. Mutagenesis of specific base pairs abolished protein binding in vitro, and mutagenesis of the same base pairs in a reporter gene construct resulted in a 65% decrease in transcriptional activity. Our results suggest that the transcription factor NF-Y binds to a GGCCAAT motif in the tph proximal promoter and activates transcription. PMID:7552299

  15. Molecular genetics of attention-deficit/hyperactivity disorder: an overview

    PubMed Central

    Becker, Katja; Scherag, Susann; Franke, Barbara; Coghill, David

    2010-01-01

    As heritability is high in attention-deficit/hyperactivity disorder (ADHD), genetic factors must play a significant role in the development and course of this disorder. In recent years a large number of studies on different candidate genes for ADHD have been published, most have focused on genes involved in the dopaminergic neurotransmission system, such as DRD4, DRD5, DAT1/SLC6A3, DBH, DDC. Genes associated with the noradrenergic (such as NET1/SLC6A2, ADRA2A, ADRA2C) and serotonergic systems (such as 5-HTT/SLC6A4, HTR1B, HTR2A, TPH2) have also received considerable interest. Additional candidate genes related to neurotransmission and neuronal plasticity that have been studied less intensively include SNAP25, CHRNA4, NMDA, BDNF, NGF, NTF3, NTF4/5, GDNF. This review article provides an overview of these candidate gene studies, and summarizes findings from recently published genome-wide association studies (GWAS). GWAS is a relatively new tool that enables the identification of new ADHD genes in a hypothesis-free manner. Although these latter studies could be improved and need to be replicated they are starting to implicate processes like neuronal migration and cell adhesion and cell division as potentially important in the aetiology of ADHD and have suggested several new directions for future ADHD genetics studies. PMID:20145962

  16. Antiadhesive effects of GRN163L--an oligonucleotide N3'->P5' thio-phosphoramidate targeting telomerase.

    PubMed

    Jackson, Shalmica R; Zhu, Chun-Hong; Paulson, Vera; Watkins, Linda; Dikmen, Z Gunnur; Gryaznov, Sergei M; Wright, Woodring E; Shay, Jerry W

    2007-02-01

    We determined previously that a novel human telomerase RNA (hTR) antagonist, GRN163L, inhibited the tumorigenic potential of A549-luciferase (A549-luc) lung cancer cells in vitro and in vivo. Further studies revealed that A549-luc cells were also morphologically altered by GRN163L. A549-luc cells treated before cell attachment with a single dose of GRN163L only weakly attached to the substrate and remained rounded, whereas control mismatch-treated cells exhibited typical epitheloid appearance and adhesion properties. These morphologic changes were independent of hTR expression and telomerase inhibition and were unrelated to telomere length. This effect is dependent on the molecular properties of the lipid moiety, the phosphorothioate backbone, and the presence of triplet-G sequences within the GRN163L structure. Altered adhesion was manifested by a 50% reduction in rapid cellular attachment and a 3-fold decrease in total cell spreading surface area. Administration of a single dose of GRN163L (15 mg/kg) at the time of cell inoculation, using an in vivo model of lung cancer metastasis, resulted in significant reductions in tumor burden at days 13, 20, and 27 of tumor progression. Thus, the potent antimetastatic effects of GRN163L may be related, in part, to the antiadhesive effects of this novel cancer therapeutic conferred via specific structural determinants and that these effects are independent of telomerase inhibition or telomere shortening. PMID:17283146

  17. Reservoir technology research at the INEL

    SciTech Connect

    Renner, J.L.; Shook, G.M.; Faulder, D.D.

    1996-05-01

    Reservoir engineering research at INEL was aimed at developing a better understanding of The Geysers and developing better tools with which to study flow in fractured geothermal reservoirs in general. Two specific topics were studies in the last year: matrix fracture interactions and decline curve analysis. A third project, revisiting the behavior of the `high-temperature reservoir` (HTR), was started near the end of 1995. These projects are being conducted in collaboration with other researchers and/or private industry. For example, our HTR studies are motivated in part because of new isotopic analyses conducted elsewhere (Walters et al., in preparation). The ultimate goal of these projects is to improve predictive capabilities and reservoir management practices and to extend the commercial life of The Geysers. In addition to conducting engineering research for the Reservoir Technology Program, INEL also continued to assist the Geothermal Technology Organization (GTO) with the development and execution of cooperative research projects. In support of the overall mission of the Reservoir Technology program, INEL also entered into a broad program of subcontracts with industrial groups and universities. These programs support the Reservoir Technology mission by providing support for research topics considered particularly important by the geothermal industry. The GTO projects are summarized below.

  18. [Brain neurotransmitter systems gene Polymorphism: the Search for pharmacogenetic markers of efficacy of haloperidol in Russians and Tatars].

    PubMed

    Gareeva, A E; Kinyasheva, K O; Galaktionova, D Yu; Sabirov, E T; Valinourov, R G; Chudinov, A V; Zasedatelev, A S; Nasedkina, T V; Khusnutdinova, E K

    2015-01-01

    Antipsychotics are the main drugs for the treatment of severe mental illness--schizophrenia affects about 1% of the population. The mechanism of action of neuroleptics is still up to the end. Several studies in the field of pharmacogenetics confirm enourmous influence of several neurotransmitter systems in the brain on the efficiency and the development of side effects. In this paper, we analyzed the association of nine polymorphic variants of five genes of dopaminergic and serotonergic systems DRD4, HTR2A, TPH1, SLC18A1, COMT in Russian and Tatars patients living in the Republic of Bashkortostan (RB) with the efficiency of a typical antipsychotic haloperidol on the scale of positive and negative systems of PANSS. The study established pharmacogenetic markers of increased and decreased effectiveness of therapy with haloperidol in the treatment groups. The results of this study confirm the importance of changes in the nucleotide sequences of the studied genes of the serotoninergic and dopaminergic systems (HTR2A, TPH1, SLC18A1 COMT, DRD4) in the formation of individual sensitivity to haloperidol. The results of our work considered as preliminary contact, requires an increase in the number of samples studied. PMID:26710776

  19. Reactivation of Tert in the medial prefrontal cortex and hippocampus rescues aggression and depression of Tert−/− mice

    PubMed Central

    Zhou, Q-G; Wu, H-Y; Zhou, H; Liu, M-Y; Lee, H-W; Liu, X; Devkota, S; Ro, E J; Zhu, D-Y; Suh, H

    2016-01-01

    The role of telomerase reverse transcriptase (TERT) has been extensively investigated in the contexts of aging and cancer. Interestingly, Tert−/− mice exhibit additional but unexpected aggressive and depressive behaviors, implying the potential involvement of TERT function in mood control. Our conditional rescue experiments revealed that the depressive and aggressive behaviors of Tert−/− mice originate from Tert deficiency in two distinct brain structures. Reactivation of Tert in the hippocampus was sufficient to normalize the depressive but not the aggressive behaviors of Tert−/− mice. Conversely, re-expression of Tert in the medial prefrontal cortex (mPFC) reversed the aggressive but not the depressive behavior of Tert−/− mice. Mechanistically, decreased serotonergic signaling and increased nitric oxide (NO) transmission in the hippocampus transduced Tert deficiency into depression as evidenced by our observation that the infusion of a pharmacological agonist for serotonin receptor 1a (5-HTR1A) and a selective antagonist for neuronal NO synthase into the hippocampus successfully normalized the depressive behavior of Tert−/− mice. In addition, increased serotonergic transmission by the 5-HTR1A agonist in the mPFC was sufficient to rescue the aggressive behavior of Tert−/− mice. Thus, our studies revealed a novel function of TERT in the pathology of depression and aggression in a brain structure-specific manner, providing direct evidence for the contribution of TERT to emotional control. PMID:27300262

  20. Serotonin system gene polymorphisms are associated with impulsivity in a context dependent manner.

    PubMed

    Stoltenberg, Scott F; Christ, Christa C; Highland, Krista B

    2012-10-01

    Impulsivity is a risk factor for adverse outcomes and characterizes several psychiatric disorders and risk for suicide. There is strong evidence that genetic variation influences individual differences in impulsivity, but the details are not yet understood. There is growing interest in better understanding the context dependency of genetic effects that is reflected in studies examining gender specificity, gene×environment interaction and epistasis (gene-gene interaction). In a cross-sectional study we examined whether polymorphisms in six serotonin system candidate genes and the experience of early life trauma (age 0-12) were associated with individual differences in impulsivity in a non-clinical sample of Caucasian university students (N=424). We specifically tested potential gender specific, gene-gene, and gene×environment (early life trauma) effects. In our main analyses with Barratt Impulsiveness Scale (BIS-11) total score, there were significant (i.e. p<.01 and False Discovery Rate <.10) interactions between (1) gender and TPH2 (rs1386483) genotype; (2) gender and HTR2A (rs6313) genotype; and epistatic interactions among (3) 5-HTTLPR and MAOA uVNTR; (4) 5-HTTLPR and rs6313 and (5) HTR1B (rs6296) and rs6313 genotypes. Our results strongly support the explicit investigation of context dependent genetic effects on impulsivity and may help to resolve some of the conflicting reports in the literature. PMID:22735397

  1. Inconformity of CXCL3 plasma level and placenta expression in preeclampsia and its effect on trophoblast viability and invasion.

    PubMed

    Gui, Shunping; Ni, Shanshan; Jia, Jin; Gong, Yunhui; Gao, Linbo; Zhang, Lin; Zhou, Rong

    2014-01-01

    As a member of the chemokine family, CXCL3 was previously known to participate in many pathophysiological events. However, whether CXCL3 stimulates trophoblast invasion as a key process of preeclampsia pathogenesis remains largely unknown. Therefore, the aim of this study was to investigate this hypothesis and determine the effect of CXCL3 on the first trimester trophoblast. Seventy gravidas were included in this study. ELISA was used to detect CXCL3 plasma levels on preeclampsia and normal pregnant groups. CXCL3 protein and mRNA levels were detected via Western blot and real-time quantitative PCR analysis after immunolocalized in human placenta. Moreover, the CXCL3 function in HTR-8/Svneo was analyzed via WST-1 assay, flow cytometry and invasion test. The plasma CXCL3 level in preeclampsia was significantly higher than that in normal pregnancy. CXCL3 expression was observed in the cytoplasm of placental trophoblasts and vascular endothelium in all groups without significant difference between maternal and fetal sides. In addition, placenta CXCL3 expression in severe preeclampsia was significantly lower than those in normal and mild PE groups. Moreover, exogenous CXCL3 can promote the proliferation and invasion of HTR-8/Svneo; however, its effect on apoptosis remains unclear. In summary, a significant abnormality of plasma CXCL3 level and placental CXCL3 expression was discovered in severe preeclampsia; CXCL3 had a function in trophoblast invasion, which indicated its participation in shallow implantation. Therefore CXCL3 might be involved in severe preeclampsia pathogenesis. PMID:25485631

  2. Pandemics and vaccines: perceptions, reactions, and lessons learned from hard-to-reach Latinos and the H1N1 campaign.

    PubMed

    Cassady, Diana; Castaneda, Xochitl; Ruelas, Magdalena Ruiz; Vostrejs, Meredith Miller; Andrews, Teresa; Osorio, Liliana

    2012-08-01

    This paper examines knowledge, risk perception, and attitudes around the H1N1 pandemic among Latino hard-to-reach (HTR) populations in the United States. Ten focus groups were conducted throughout California (N=90), representing Latino immigrants disproportionately affected by H1N1: farmworkers, indigenous Mexicans, pregnant women, and children. Overall, participants were aware of the H1N1 epidemic and common prevention practices. However, many expressed doubts that the H1N1 outbreak constituted an epidemic because the U.S. media reports of the epidemic in Mexico did not match reports from participants' families in Mexico and because of participants' absence of personal experience with the disease. Participants mistrusted the H1N1 vaccine due to its novelty, conspiracy theories, and inconsistent information. Study findings confirm that vaccination campaign strategies should reflect the diversity of meaning, experiences, and socio-economic realities among target populations. Key findings inform future emergency response activities targeting HTR Latino communities. PMID:24212163

  3. Signaling and Adaptation Modulate the Dynamics of the Photosensoric Complex of Natronomonas pharaonis

    PubMed Central

    Mulkidjanian, Armen Y.; Shaitan, Konstantin V.; Engelhard, Martin; Klare, Johann P.; Steinhoff, Heinz-Jürgen

    2015-01-01

    Motile bacteria and archaea respond to chemical and physical stimuli seeking optimal conditions for survival. To this end transmembrane chemo- and photoreceptors organized in large arrays initiate signaling cascades and ultimately regulate the rotation of flagellar motors. To unravel the molecular mechanism of signaling in an archaeal phototaxis complex we performed coarse-grained molecular dynamics simulations of a trimer of receptor/transducer dimers, namely NpSRII/NpHtrII from Natronomonas pharaonis. Signaling is regulated by a reversible methylation mechanism called adaptation, which also influences the level of basal receptor activation. Mimicking two extreme methylation states in our simulations we found conformational changes for the transmembrane region of NpSRII/NpHtrII which resemble experimentally observed light-induced changes. Further downstream in the cytoplasmic domain of the transducer the signal propagates via distinct changes in the dynamics of HAMP1, HAMP2, the adaptation domain and the binding region for the kinase CheA, where conformational rearrangements were found to be subtle. Overall these observations suggest a signaling mechanism based on dynamic allostery resembling models previously proposed for E. coli chemoreceptors, indicating similar properties of signal transduction for archaeal photoreceptors and bacterial chemoreceptors. PMID:26496122

  4. Structural Features of the Telomerase RNA Gene in the Naked Mole Rat Heterocephalus glaber

    PubMed Central

    Evfratov, S. A.; Smekalova, E. M.; Golovin, A. V.; Logvina, N. A.; Zvereva, M. I.; Dontsova, O. A.

    2014-01-01

    Telomere length, an important feature of life span control, is dependent on the activity of telomerase (a key enzyme of the telomere-length-maintaining system). Telomerase RNA is a component of telomerase and, thus, is crucial for its activity. The structures of telomerase RNA genes and their promoter regions were compared for the long-living naked mole rat and different organisms. Two rare polymorphisms in Heterocephalus glaber telomerase RNA (hgTER) were identified: A→G in the first loop of pseudoknot P2b-p3 (an equivalent of 111nt in hTR) and G→A in the scaRNA domain CR7-p8b (an equivalent of 421nt in hTR). Analysis of TER promoter regions allowed us to identify two new transcription factor binding sites. The first one is the ETS family site, which was found to be a conserved element for all the analyzed TER promoters. The second site is unique for the promoter region of TER of the naked mole rat and is a binding site for the SOX17 transcription factor. The absence of one Sp1 site in the TER promoter region of the naked small rat is an additional specific feature of the promoter area of hgTER. Such variation in the hgTER transcription regulation region and hgTER itself could provide increased telomerase activity in stem cells and an extended lifespan to H. glaber. PMID:25093110

  5. Discovery of Ligands for a Novel Target, the Human Telomerase RNA, Based on Flexible-Target Virtual Screening and NMR

    PubMed Central

    Pinto, Irene Gómez; Guilbert, Christophe; Ulyanov, Nikolai B.; Stearns, Jay; James, Thomas L.

    2009-01-01

    The human ribonucleoprotein telomerase is a validated anticancer drug target, and hTRP2b is a part of the human telomerase RNA (hTR) essential for its activity. Interesting ligands that bind hTR-P2b were identified by iteratively using a tandem structure-based approach: docking of potential ligands from small databases to hTR-P2b via the program MORDOR, which permits flexibility in both ligand and target, with subsequent NMR screening of high-ranking compounds. A high percentage of the compounds tested experimentally were found via NMR to bind to the U-rich region of hTR-P2b; most have MW <500 daltons, are from different compound classes, and several possess a charge of 0 or +1. Of the 48 ligands identified, 24 exhibit a decided preference to bind hTR-P2b RNA rather than A-site rRNA and 10 do not bind A-site rRNA at all. Binding affinity was measured by monitoring RNA imino proton resonances for some of the compounds that showed hTR binding preference. PMID:18950148

  6. Rapid In Situ Hybridization using Oligonucleotide Probes on Paraformaldehyde-prefixed Brain of Rats with Serotonin Syndrome.

    PubMed

    Shokry, Ibrahim M; Callanan, John J; Sousa, John; Tao, Rui

    2015-01-01

    3,4-Methylenedioxymethamphetamine (MDMA; ecstasy) toxicity may cause region-specific changes in serotonergic mRNA expression due to acute serotonin (5-hydroxytryptamine; 5-HT) syndrome. This hypothesis can be tested using in situ hybridization to detect the serotonin 5-HT2A receptor gene htr2a. In the past, such procedures, utilizing radioactive riboprobe, were difficult because of the complicated workflow that needs several days to perform and the added difficulty that the technique required the use of fresh frozen tissues maintained in an RNase-free environment. Recently, the development of short oligonucleotide probes has simplified in situ hybridization procedures and allowed the use of paraformaldehyde-prefixed brain sections, which are more widely available in laboratories. Here, we describe a detailed protocol using non-radioactive oligonucleotide probes on the prefixed brain tissues. Hybridization probes used for this study include dapB (a bacterial gene coding for dihydrodipicolinate reductase), ppiB (a housekeeping gene coding for peptidylprolyl isomerase B), and htr2a (a serotonin gene coding for 5-HT2A receptors). This method is relatively simply, cheap, reproducible and requires less than two days to complete. PMID:26437182

  7. Continuous in-line gasification/vitrification process for thermal waste treatment: Process technology and current status of projects

    SciTech Connect

    Calaminus, B.; Stahlberg, R.

    1998-12-31

    The thermoselect High Temperature Recycling process has been developed in order to make available a thermal waste treatment technology avoiding major problems as known from traditional techniques like landfills or ashes, filter dust and emission producing processes. It combines slow degassing with fixed bed oxygen blown gasification and mineral and metal residue melting in a closed loop system. Municipal, industrial and other kinds of waste are compacted to less than one fifth of their original volume by means of an armored hydraulic press, and then periodically pushed into an indirectly heated degasification channel. As the waste plugs are pushed down the channel in an oxygen-free environment, waste humidity is evaporated and the organic components in the refuse are partially degasified and to a certain extent converted into a carbon-like product as the temperature increases. This flaky product and the enclosed inorganic components such as metals and minerals are continuously fed into a high-temperature reactor (HTR). Pure oxygen is added in controlled quantities and reacts with the material following exothermic oxidation reactions. Due to overall under-stoichiometric conditions, gasification products form a combustible synthesis gas. The heat of reaction leading to temperatures up to about 2,000 C in the core of the lower HTR section acts to also smelt the metal and mineral components of the waste. Chlorinated hydrocarbons such as dioxins and furans are reliably destroyed along with other organic compounds in the gaseous and the liquid phase.

  8. Rickettsia infection in Amblyomma tonelliae, a tick species from the Amblyomma cajennense complex.

    PubMed

    Tarragona, Evelina L; Cicuttin, Gabriel L; Mangold, Atilio J; Mastropaolo, Mariano; Nazarena De Salvo, M; Nava, Santiago

    2015-03-01

    The present study was performed to evaluate the Rickettsia infection in Amblyomma tonelliae ticks from Argentina. All ticks were subjected to DNA extraction and tested by a battery of PCRs to amplify fragments of four rickettsial genes, 23S-5S, gltA, ompA and htrA. Two ticks were positive. The Rickettsia detected in one tick represents a new lineage which is named Rickettsia sp. strain El Tunal. This new strain belongs to the canadensis group because it is closely related to Rickettsia monteiroi, Rickettsia canadensis and Candidatus "Rickettsia tarasevichiae". They clustered together on a high supported clade with both gltA and htrA genes. The other positive tick was infected with Candidatus "Rickettsia amblyommii". The results presented in this study constitute the first records of Rickettsia infection in A. tonelliae ticks. However, the medical relevance of these findings should be considered cautiously because the pathogenicity of Rickettsia sp. strain El Tunal and Candidatus "R. amblyommii" remains undetermined. PMID:25544308

  9. Expression of GALNT2 in human extravillous trophoblasts and its suppressive role in trophoblast invasion.

    PubMed

    Liao, W-C; Chen, C-H; Liu, C-H; Huang, M-J; Chen, C-W; Hung, J-S; Chou, C-H; Chen, C-H; Che, M-I; Chang, H-M; Lan, C-T; Huang, H-C; Tseng, G-F; Shyu, M-K; Huang, M-C

    2012-12-01

    Extravillus trophoblast (EVT) invasion plays a critical role in placental development. Integrins bind to extracellular matrix (ECM) proteins to mediate EVT cell adhesion, migration, and invasion. Changes in O-glycans on β1-integrin have been found to regulate cancer cell behavior. We hypothesize that O-glycosyltransferases can regulate EVT invasion through modulating the glycosylation and function of β1-integrin. Here, we found that the GALNT1 and GALNT2 mRNA were highly expressed in HTR8/SVneo and first trimester EVT cells. Immunohistochemstry and immunofluorescence staining showed that GALNT2 was expressed in subpopulations of EVT cells in deciduas, but not in syncytiotrophoblasts and cytotrophoblasts of placental villi. The percentage of GALNT2-positive EVT cells increased with gestational ages. Overexpression of GALNT2 in HTR8/SVneo cells significantly enhanced cell-collagen IV adhesion, but suppressed cell migration and invasion. Notably, we found that GALNT2 increased the expression of Tn antigen (GalNAc-Ser/Thr) on β1-integrin as revealed by Vicia Villosa agglutinin (VVA) binding. Furthermore, GALNT2 suppressed the phosphorylation of focal adhesion kinase (FAK), a crucial downstream signaling molecule of β1-integrin. Our findings suggest that GALNT2 is a critical initiating enzyme of O-glycosylation for regulating EVT invasion. PMID:23117232

  10. Discovery of ligands for a novel target, the human telomerase RNA, based on flexible-target virtual screening and NMR.

    PubMed

    Pinto, Irene Gómez; Guilbert, Christophe; Ulyanov, Nikolai B; Stearns, Jay; James, Thomas L

    2008-11-27

    The human ribonucleoprotein telomerase is a validated anticancer drug target, and hTR-P2b is a part of the human telomerase RNA (hTR) essential for its activity. Interesting ligands that bind hTR-P2b were identified by iteratively using a tandem structure-based approach: docking of potential ligands from small databases to hTR-P2b via the program MORDOR, which permits flexibility in both ligand and target, with subsequent NMR screening of high-ranking compounds. A high percentage of the compounds tested experimentally were found via NMR to bind to the U-rich region of hTR-P2b; most have MW < 500 Da and are from different compound classes, and several possess a charge of 0 or +1. Of the 48 ligands identified, 24 exhibit a decided preference to bind hTR-P2b RNA rather than A-site rRNA and 10 do not bind A-site rRNA at all. Binding affinity was measured by monitoring RNA imino proton resonances for some of the compounds that showed hTR binding preference. PMID:18950148

  11. Sertraline for the Treatment of Depression in Alzheimer Disease: Genetic Influences

    PubMed Central

    Peters, Matthew E.; Vaidya, Vijay; Drye, Lea T.; Rosenberg, Paul B.; Martin, Barbara K.; Porsteinsson, Anton P.; Frangakis, Constantine E.; Mintzer, Jacobo; Weintraub, Daniel; Schneider, Lon S.; Rabins, Peter V.; Munro, Cynthia A.; Meinert, Curtis L.; Lyketsos, Constantine G.; Dimitri, Avramopoulos

    2012-01-01

    Objective To assess the potential for genetic influences on sertraline treatment efficacy for depression of Alzheimer disease (dAD). Four functional genetic variants were studied: 2 serotonin receptors (HTR2A-T102C and HTR2C-Cys23Ser), the serotonin transporter (5HTT-LPR), and brain-derived neurotrophic factor (BDNF-Val66Met). Treatment response by genotype was measured by (1) the modified Alzheimer’s Disease Cooperative Study Clinical Global Impression of Change, (2) the Cornell scale for Depression in Dementia, and (3) remission of depression. Methods We utilized data from the Depression in Alzheimer’s Disease Study 2 (DIADS-2), a 24-week, randomized, multicenter trial showing no significant treatment effect of sertraline on dAD. Proportional odds logistic regression and mixed effects models were used to examine the above mentioned outcome measures. Results No significant interactions were seen between any of the genetic polymorphisms and the selected outcomes above at 12 or 24 weeks. Discussion Treatment outcomes in the DIADS-2 trial were not significantly influenced by genetic variation at the loci that were assessed. Future studies should continue to examine the interaction of depression-related genetic variants with antidepressant treatment in Alzheimer disease patients with depression. PMID:22228829

  12. Validation of SCALE for High Temperature Gas-Cooled Reactors Analysis

    SciTech Connect

    Ilas, Germina; Ilas, Dan; Kelly, Ryan P; Sunny, Eva E

    2012-08-01

    This report documents verification and validation studies carried out to assess the performance of the SCALE code system methods and nuclear data for modeling and analysis of High Temperature Gas-Cooled Reactor (HTGR) configurations. Validation data were available from the International Handbook of Evaluated Reactor Physics Benchmark Experiments (IRPhE Handbook), prepared by the International Reactor Physics Experiment Evaluation Project, for two different HTGR designs: prismatic and pebble bed. SCALE models have been developed for HTTR, a prismatic fuel design reactor operated in Japan and HTR-10, a pebble bed reactor operated in China. The models were based on benchmark specifications included in the 2009, 2010, and 2011 releases of the IRPhE Handbook. SCALE models for the HTR-PROTEUS pebble bed configuration at the PROTEUS critical facility in Switzerland have also been developed, based on benchmark specifications included in a 2009 IRPhE draft benchmark. The development of the SCALE models has involved a series of investigations to identify particular issues associated with modeling the physics of HTGRs and to understand and quantify the effect of particular modeling assumptions on calculation-to-experiment comparisons.

  13. Nuclear design of small-sized high temperature gas-cooled reactor for developing countries

    SciTech Connect

    Goto, M.; Seki, Y.; Inaba, Y.; Ohashi, H.; Sato, H.; Fukaya, Y.; Tachibana, Y.

    2012-07-01

    Japan Atomic Energy Agency (JAEA) has started a conceptual design of a small-sized HTGR with 50 MW thermal power (HTR50S), which is a first-of-a-kind commercial or demonstration plant of a small-sized HTGR to be deployed in developing countries such as Kazakhstan in the 2020's. The nuclear design of the HTR50S is performed by upgrading the proven technology of the High Temperature Engineering Test Reactor (HTTR) to reduce the cost for the construction. In the HTTR design, twelve kinds of fuel enrichment was used to optimize the power distribution, which is required to make the maximum fuel temperature below the thermal limitation during the burn-up period. However, manufacture of many kinds of fuel enrichment causes increase of the construction cost. To solve this problem, the present study challenges the nuclear design by reducing the number of fuel enrichment to as few as possible. The nuclear calculations were performed with SRAC code system whose validity was proven by the HTTR burn-up data. The calculation results suggested that the optimization of the power distribution was reasonably achieved and the maximum fuel temperature was kept below the limitation by using three kinds of fuel enrichment. (authors)

  14. Association between serotonin cumulative genetic score and the Behavioral Approach System (BAS): Moderation by early life environment

    PubMed Central

    Pearson, Rahel; McGeary, John E.; Beevers, Christopher G.

    2014-01-01

    The present study investigates if genetic variation in the serotonergic system interacts with early adversity to predict changes in the Behavioral Approach System (BAS), a system that taps into reward processing. In a sample of community adults (N= 236) the influence of single serotonergic candidate polymorphisms on BAS was analyzed, we also examined the aggregate contribution of these genetic variants by creating a Cumulative Genetic Score (CGS). A CGS quantifies an individual’s cumulative risk by aggregating the number of risk alleles across the candidate polymorphisms. After individual gene analysis, three candidate genes rs7305115 (TPH2), rs6311 (HTR2A), and rs6295 (HTR1A) were combined into the CGS. There were no significant interactions between individual candidate polymorphisms and childhood adversity, but the CGS interacted with childhood adversity to explain a significant amount of variance (11.6%) in the BAS. Findings suggest that genetic variations in the serotonergic system in combination with childhood adversity contribute to individual differences in reward sensitivity. PMID:25264393

  15. Common genetic variants and gene expression associated with white matter microstructure in the human brain

    PubMed Central

    Sprooten, Emma; Knowles, Emma E; McKay, D Reese; Göring, Harald HH; Curran, Joanne E; Kent, Jack W; Carless, Melanie A; Dyer, Thomas D; Drigalenko, Eugene I; Olvera, Rene L; Fox, Peter T; Almasy, Laura; Duggirala, Ravi; Kochunov, Peter; Blangero, John; Glahn, David C

    2014-01-01

    Identifying genes that contribute to white matter microstructure should provide insights into the neurobiological processes that regulate white matter development, plasticity and pathology. We detected five significant SNPs using genome-wide association analysis on a global measure of fractional anisotropy in 776 individuals from large extended pedigrees. Genetic correlations and genome-wide association results indicated that the genetic signal was largely homogeneous across white matter regions. Using RNA transcripts derived from lymphocytes in the same individuals, we identified two genes (GNA13 and CCDC91) that are likely to be cis-regulated by top SNPs, and whose expression levels were also genetically correlated with fractional anisotropy. A transcript of HTR7 was phenotypically associated with FA, and was associated with an intronic genome-wide significant SNP. These results encourage further research in the mechanisms by which GNA13, HTR7 and CCDC91 influence brain structure, and emphasize a role for g-protein signaling in the development and maintenance of white matter microstructure in health and disease. PMID:24736177

  16. Common genetic variants and gene expression associated with white matter microstructure in the human brain.

    PubMed

    Sprooten, Emma; Knowles, Emma E; McKay, D Reese; Göring, Harald H; Curran, Joanne E; Kent, Jack W; Carless, Melanie A; Dyer, Thomas D; Drigalenko, Eugene I; Olvera, Rene L; Fox, Peter T; Almasy, Laura; Duggirala, Ravi; Kochunov, Peter; Blangero, John; Glahn, David C

    2014-08-15

    Identifying genes that contribute to white matter microstructure should provide insights into the neurobiological processes that regulate white matter development, plasticity and pathology. We detected five significant SNPs using genome-wide association analysis on a global measure of fractional anisotropy in 776 individuals from large extended pedigrees. Genetic correlations and genome-wide association results indicated that the genetic signal was largely homogeneous across white matter regions. Using RNA transcripts derived from lymphocytes in the same individuals, we identified two genes (GNA13 and CCDC91) that are likely to be cis-regulated by top SNPs, and whose expression levels were also genetically correlated with fractional anisotropy. A transcript of HTR7 was phenotypically associated with FA, and was associated with an intronic genome-wide significant SNP. These results encourage further research in the mechanisms by which GNA13, HTR7 and CCDC91 influence brain structure, and emphasize a role for g-protein signaling in the development and maintenance of white matter microstructure in health and disease. PMID:24736177

  17. Genome-wide association study identifies five loci associated with lung function

    PubMed Central

    Repapi, Emmanouela; Sayers, Ian; Wain, Louise V; Burton, Paul R; Johnson, Toby; Obeidat, Ma’en; Zhao, Jing Hua; Ramasamy, Adaikalavan; Zhai, Guangju; Vitart, Veronique; Huffman, Jennifer E; Igl, Wilmar; Albrecht, Eva; Deloukas, Panos; Henderson, John; Granell, Raquel; McArdle, Wendy L; Rudnicka, Alicja R; Barroso, Inês; Loos, Ruth J F; Wareham, Nicholas J; Mustelin, Linda; Rantanen, Taina; Surakka, Ida; Imboden, Medea; Wichmann, H Erich; Grkovic, Ivica; Jankovic, Stipan; Zgaga, Lina; Hartikainen, Anna-Liisa; Peltonen, Leena; Gyllensten, Ulf; Johansson, Åsa; Zaboli, Ghazal; Campbell, Harry; Wild, Sarah H; Wilson, James F; Gläser, Sven; Homuth, Georg; Völzke, Henry; Mangino, Massimo; Soranzo, Nicole; Spector, Tim D; Polašek, Ozren; Rudan, Igor; Wright, Alan F; Heliövaara, Markku; Ripatti, Samuli; Pouta, Anneli; Naluai, Åsa Torinsson; Olin, Anna-Carin; Torén, Kjell; Cooper, Matthew N; James, Alan L; Palmer, Lyle J; Hingorani, Aroon D; Wannamethee, S Goya; Whincup, Peter H; Smith, George Davey; Ebrahim, Shah; McKeever, Tricia M; Pavord, Ian D; MacLeod, Andrew K; Morris, Andrew D; Porteous, David J; Cooper, Cyrus; Dennison, Elaine; Shaheen, Seif; Karrasch, Stefan; Schnabel, Eva; Schulz, Holger; Grallert, Harald; Bouatia-Naji, Nabila; Delplanque, Jérôme; Froguel, Philippe; Blakey, John D; Britton, John R; Morris, Richard W; Holloway, John W; Lawlor, Debbie A; Hui, Jennie; Nyberg, Fredrik; Jarvelin, Marjo-Riitta; Jackson, Cathy; Kähönen, Mika; Kaprio, Jaakko; Probst-Hensch, Nicole M; Koch, Beate; Hayward, Carol