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Sample records for alkenyldiarylmethane adam non-nucleoside

  1. Systematic evaluation of methyl ester bioisosteres in the context of developing alkenyldiarylmethanes (ADAMs) as non-nucleoside reverse transcriptase inhibitors (NNRTIs) for anti-HIV-1 chemotherapy.

    Science.gov (United States)

    Hoshi, Ayako; Sakamoto, Takeshi; Takayama, Jun; Xuan, Meiyan; Okazaki, Mari; Hartman, Tracy L; Buckheit, Robert W; Pannecouque, Christophe; Cushman, Mark

    2016-07-01

    The alkenyldiarylmethanes (ADAMs) are a class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) targeting HIV-1. Four chemically and metabolically stabilized ADAMs incorporating N-methoxyimidoyl halide replacements of the methyl esters of the lead compound were previously reported. In this study, twenty-five new ADAMs were synthesized in order to investigate the biological consequences of installing nine different methyl ester bioisosteres at three different locations. Attempts to define a universal rank order of methyl ester bioisosteres and discover the 'best' one in terms of inhibitory activity versus HIV-1 reverse transcriptase (RT) led to the realization that the potencies are critically dependent on the surrounding structure at each location, and therefore the definition of universal rank order is impossible. This investigation produced several new non-nucleoside reverse transcriptase inhibitors in which all three of the three methyl esters of the lead compound were replaced by methyl ester bioisosteres, resulting in compounds that are more potent as HIV-1 RT inhibitors and antiviral agents than the lead compound itself and are expected to also be more metabolically stable than the lead compound. PMID:27234889

  2. Functional non-nucleoside adenylyl cyclase inhibitors.

    Science.gov (United States)

    Lelle, Marco; Hameed, Abdul; Ackermann, Lisa-Maria; Kaloyanova, Stefka; Wagner, Manfred; Berisha, Filip; Nikolaev, Viacheslav O; Peneva, Kalina

    2015-05-01

    In this study, we describe the synthesis of novel functional non-nucleoside adenylyl cyclase inhibitors, which can be easily modified with thiol containing biomolecules such as tumour targeting structures. The linkage between inhibitor and biomolecule contains cleavable bonds to enable efficient intracellular delivery in the reductive milieu of the cytosol as well as in the acidic environment within endosomes and lysosomes. The suitability of this synthetic approach was shown by the successful bioconjugation of a poor cell-permeable inhibitor with a cell-penetrating peptide. Additionally, we have demonstrated the excellent inhibitory effect of the compounds presented here in a live-cell Förster resonance energy transfer-based assay in human embryonic kidney cells. PMID:25319071

  3. Novel indole-3-sulfonamides as potent HIV non-nucleoside reverse transcriptase inhibitors (NNRTIs)

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Zhijian; Wolkenberg, Scott E.; Lu, Meiqing; Munshi, Vandna; Moyer, Gregory; Feng, Meizhen; Carella, Anthony V.; Ecto, Linda T.; Gabryelski, Lori J.; Lai, Ming-Tain; Prasad, Sridar G.; Yan, Youwei; McGaughey, Georgia B.; Miller, Michael D.; Lindsley, Craig W.; Hartman, George D.; Vacca, Joseph P.; Williams, Theresa M. (Merck)

    2008-09-29

    This Letter describes the design, synthesis, and biological evaluation of novel 3-indole sulfonamides as potent non-nucleoside reverse transcriptase inhibitors (NNRTIs) with balanced profiles against common HIV RT mutants K103N and Y181C.

  4. Crystal structures of HIV-1 reverse transcriptase complexes with thiocarbamate non-nucleoside inhibitors

    International Nuclear Information System (INIS)

    O-Phthalimidoethyl-N-arylthiocarbamates (TCs) have been recently identified as a new class of potent HIV-1 reverse transcriptase (RT) non-nucleoside inhibitors (NNRTIs), by means of computer-aided drug design techniques [Ranise A. Spallarossa, S. Cesarini, F. Bondavalli, S. Schenone, O. Bruno, G. Menozzi, P. Fossa, L. Mosti, M. La Colla, et al., Structure-based design, parallel synthesis, structure-activity relationship, and molecular modeling studies of thiocarbamates, new potent non-nucleoside HIV-1 reverse transcriptase inhibitor isosteres of phenethylthiazolylthiourea derivatives, J. Med. Chem. 48 (2005) 3858-3873]. To elucidate the atomic details of RT/TC interaction and validate an earlier TC docking model, the structures of three RT/TC complexes were determined at 2.8-3.0 A resolution by X-ray crystallography. The conformations adopted by the enzyme-bound TCs were analyzed and compared with those of bioisosterically related NNRTIs

  5. Focus on Chirality of HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors

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    Valeria Famiglini

    2016-02-01

    Full Text Available Chiral HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs are of great interest since one enantiomer is often more potent than the corresponding counterpart against the HIV-1 wild type (WT and the HIV-1 drug resistant mutant strains. This review exemplifies the various studies made to investigate the effect of chirality on the antiretroviral activity of top HIV-1 NNRTI compounds, such as nevirapine (NVP, efavirenz (EFV, alkynyl- and alkenylquinazolinone DuPont compounds (DPC, diarylpyrimidine (DAPY, dihydroalkyloxybenzyloxopyrimidine (DABO, phenethylthiazolylthiourea (PETT, indolylarylsulfone (IAS, arylphosphoindole (API and trifluoromethylated indole (TFMI The chiral separation, the enantiosynthesis, along with the biological properties of these HIV-1 NNRTIs, are discussed.

  6. Biophysical Insights into the Inhibitory Mechanism of Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors

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    Nicolas Sluis-Cremer

    2013-11-01

    Full Text Available HIV-1 reverse transcriptase (RT plays a central role in HIV infection. Current United States Federal Drug Administration (USFDA-approved antiretroviral therapies can include one of five approved non-nucleoside RT inhibitors (NNRTIs, which are potent inhibitors of RT activity. Despite their crucial clinical role in treating and preventing HIV-1 infection, their mechanism of action remains elusive. In this review, we introduce RT and highlight major advances from experimental and computational biophysical experiments toward an understanding of RT function and the inhibitory mechanism(s of NNRTIs.

  7. Metabolic Abnormalities Associated with the Use of Protease Inhibitors and Non-nucleoside Reverse Transcriptase Inhibitors

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    Madhu N. Rao

    2006-01-01

    Full Text Available The use of protease inhibitors and non-nucleoside reverse transcriptase inhibitors for the treatment of HIV infection and AIDS has been associated with multiple abnormalities in glucose and lipid metabolism. Specifically, these abnormalities include insulin resistance, increased triglycerides and increased LDL cholesterol levels. The metabolic disturbances are due to a combination of factors, including the direct effect of medications, restoration to health and HIV disease, as well as individual genetic predisposition. Of the available anti-retroviral medications, indinavir has been associated with causing the most insulin resistance and ritonavir with causing the most hypertriglyceridemia.

  8. Substituted indoles as HIV-1 non-nucleoside reverse transcriptase inhibitors: a patent evaluation (WO2015044928).

    Science.gov (United States)

    Li, Xiao; Gao, Ping; Zhan, Peng; Liu, Xinyong

    2016-05-01

    The invention described in this patent (WO2015044928) is related to compounds based on the substituted indole scaffold, their synthetic process and application to inhibit HIV-1 replication as non-nucleoside reverse transcriptase inhibitors (NNRTIs). Some of the newly claimed compounds presented improved potency against wild-type (WT) HIV-1 strain in comparison to previously disclosed indole-based NNRTIs and were also shown to be effective against common resistant HIV-1 strains. In light of their novel structural characteristics, simple synthetic route and improved anti-HIV activity, these compounds deserve further study as promising NNRTIs. PMID:26742549

  9. Discovery, characterization, and lead optimization of 7-azaindole non-nucleoside HIV-1 reverse transcriptase inhibitors.

    Science.gov (United States)

    Stanton, Richard A; Lu, Xiao; Detorio, Mervi; Montero, Catherine; Hammond, Emily T; Ehteshami, Maryam; Domaoal, Robert A; Nettles, James H; Feraud, Michel; Schinazi, Raymond F

    2016-08-15

    A library of 585 compounds built off a 7-azaindole core was evaluated for anti-HIV-1 activity, and ten hits emerged with submicromolar potency and therapeutic index >100. Of these, three were identified as non-nucleoside reverse transcriptase (RT) inhibitors and were assayed against relevant resistant mutants. Lead compound 8 inhibited RT with submicromolar potency (IC50=0.73μM) and also maintained some activity against the clinically important RT mutants K103N and Y181C (IC50=9.2, 3.5μM) in cell-free assays. Free energy perturbation guided lead optimization resulted in the development of a compound with a two-fold increase in potency against RT (IC50=0.36μM). These data highlight the discovery of a unique scaffold with the potential to move forward as next-generation anti-HIV-1 agents. PMID:27390064

  10. Synthesis and HIV-1 Reverse Transcriptase Inhibitory Activity of Non-Nucleoside Phthalimide Derivatives

    Institute of Scientific and Technical Information of China (English)

    UNGWITAYATORN Jiraporn; WIWAT Chanpen; MATAYATSUK Chutima; PIMTHON Jutarat; PIYAVIRIYAKUL Suratsawadee

    2008-01-01

    A new type of non-nucleoside HIV-1 reverse transcriptase inhibitors in phthalimide series has been synthesized from either the reaction of N-carboethoxyphthalimide with amines or phthalimide with appropriate alkyl halides.The in vitro inhibitory activity of the synthesized compounds was studied by a radiometric assay at a concentration of 200 μg/mL using poly(rA)-oligo(dT) as a template-primer and methyl-[3H]dTTP as a substrate.The three most potent compounds, N-(m,p-dihydroxybenzyl)phthalimide (11), N-[2-(a-furyl)ethyl]phthalimide (29) and N-(5-methylpyrazin-2-ylmethyl)phthalimide (25) exhibited IC50 values of 60.90, 98.10 and 120.75 μg/mL, respecas a substrate).

  11. Novel phenyl(2-(phenylamino)pyrimidin-4-yl)methanones as potent non-nucleoside reverse transcriptase inhibitors

    Czech Academy of Sciences Publication Activity Database

    Šimon, Petr; Baszczyňski, Ondřej; Šaman, David; Bahador, G.; Stepan, G.; Hu, E.; Lansdon, E.; Jansa, P.; Janeba, Zlatko

    Rome: International Society for Antiviral Research (ISAR), 2015. s. 96. [International Conference on Antiviral Research /28./. 11.05.2015-15.05.2015, Rome] Institutional support: RVO:61388963 Keywords : non-nucleoside reverse transcriptase inhibitors * pyrimidine * HIV -1 Subject RIV: CC - Organic Chemistry

  12. Non-nucleoside reverse transcriptase inhibitors: a review on pharmacokinetics, pharmacodynamics, safety and tolerability

    Directory of Open Access Journals (Sweden)

    Iris Usach

    2013-09-01

    Full Text Available Introduction: Human immunodeficiency virus (HIV type-1 non-nucleoside and nucleoside reverse transcriptase inhibitors (NNRTIs are key drugs of highly active antiretroviral therapy (HAART in the clinical management of acquired immune deficiency syndrome (AIDS/HIV infection. Discussion: First-generation NNRTIs, nevirapine (NVP, delavirdine (DLV and efavirenz (EFV are drugs with a low genetic barrier and poor resistance profile, which has led to the development of new generations of NNRTIs. Second-generation NNRTIs, etravirine (ETR and rilpivirine (RPV have been approved by the Food and Drug Administration and European Union, and the next generation of drugs is currently being clinically developed. This review describes recent clinical data, pharmacokinetics, metabolism, pharmacodynamics, safety and tolerability of commercialized NNRTIs, including the effects of sex, race and age differences on pharmacokinetics and safety. Moreover, it summarizes the characteristics of next-generation NNRTIs: lersivirine, GSK 2248761, RDEA806, BILR 355 BS, calanolide A, MK-4965, MK-1439 and MK-6186. Conclusions: This review presents a wide description of NNRTIs, providing useful information for researchers interested in this field, both in clinical use and in research.

  13. Global Conformational Dynamics of HIV-1 Reverse Transcriptase Bound to Non-Nucleoside Inhibitors

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    Peter V. Coveney

    2012-07-01

    Full Text Available HIV-1 Reverse Transcriptase (RT is a multifunctional enzyme responsible for the transcription of the RNA genome of the HIV virus into DNA suitable for incorporation within the DNA of human host cells. Its crucial role in the viral life cycle has made it one of the major targets for antiretroviral drug therapy. The Non-Nucleoside RT Inhibitor (NNRTI class of drugs binds allosterically to the enzyme, affecting many aspects of its activity. We use both coarse grained network models and atomistic molecular dynamics to explore the changes in protein dynamics induced by NNRTI binding. We identify changes in the flexibility and conformation of residue Glu396 in the RNaseH primer grip which could provide an explanation for the acceleration in RNaseH cleavage rate observed experimentally in NNRTI bound HIV-1 RT. We further suggest a plausible path for conformational and dynamic changes to be communicated from the vicinity of the NNRTI binding pocket to the RNaseH at the other end of the enzyme.

  14. Exploring QSAR of Non-Nucleoside Reverse Transcriptase Inhibitors by Neural Networks: TIBO Derivatives

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    Driss Cherqaoui

    2004-01-01

    Full Text Available Abstract: Human Immunodeficiency Virus type 1 (HIV-1 reverse transcriptase is an important target for chemotherapeutic agents against the AIDS disease. 4,5,6,7-Tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H-ones (TIBO derivatives are potent non-nucleoside reverse transcriptase inhibitors (NNRTIs. In the present work, quantitative structure-activity relationship (QSAR analysis for a set of 82 TIBO derivatives has been investigated by means of a three-layered neural network (NN. It has been shown that NN can be a potential tool in the investigation of QSAR analysis compared with the models given in the literature. NN gave good statistical results both in fitting and prediction processes (0.861 ≤ r² ≤ 0.928, 0.839 ≤q² ≤ 0.845. The relevant factors controlling the anti-HIV-1 activity of TIBO derivatives have been identified. The results are along the same lines as those of our previous studies on HEPT derivatives and indicate the importance of the hydrophobic parameter in modeling the QSAR for TIBO derivatives.

  15. Non-nucleoside reverse transcriptase inhibitors (NNRTIs): past, present, and future.

    Science.gov (United States)

    De Clercq, Erik

    2004-01-01

    Non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) have become an inherent ingredient of the drug combination schemes that are currently used in the treatment of human immunodeficiency virus type 1 (HIV-1) infections. Starting from the 1-[(2-hydroxyethoxy)methyl]-6-(phenylsulfanyl)thymine (HEPT) and 4,5,6,7-tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one and -thione (TIBO) derivatives, numerous classes of compounds have been described as NNRTIs. Only three compounds have so far been approved for clinical use: nevirapine, delavirdine, and efavirenz. NNRTIs are notorious for rapidly leading to virus-drug resistance development, primarily based on the emergence of the K103N and Y181C mutations in the HIV-1 RT. Newer NNRTIs, such as capravirine, dapivirine (TMC 125), and DPC 083, are resilient to these 'NNRTI' mutations, and, therefore, offer considerable promise as future anti-HIV-1 drugs. NNRTIs are targeted at a specific 'pocket' binding site within the HIV-1 RT, that is distinct from, but both spatially and functionally related to, the catalytic site, where the nucleoside RT inhibitors (NRTIs) and nucleotide RT inhibitors (NtRTIs) interact. NNRTIs have acquired a definitive position, as part of a combination regimen with NRTIs and NtRTIs, in the first-line treatment of HIV-1 infections. PMID:17191775

  16. Searching for novel scaffold of triazole non-nucleoside inhibitors of HIV-1 reverse transcriptase.

    Science.gov (United States)

    Frączek, Tomasz; Paneth, Agata; Kamiński, Rafał; Krakowiak, Agnieszka; Paneth, Piotr

    2016-06-01

    Azoles are a promising class of the new generation of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). From thousands of reported compounds, many possess the same basic structure of an aryl substituted azole ring linked by a thioglycolamide chain with another aromatic ring. In order to find novel extensions for this basic scaffold, we explored the 5-position substitution pattern of triazole NNRTIs using molecular docking followed by the synthesis of selected compounds. We found that heterocyclic substituents in the 5-position of the triazole ring are detrimental to the inhibitory activity of compounds with four-membered thioglycolamide linker and this substitution seems to be viable only for compounds with shorter two-membered linker. Promising compound, N-(4-carboxy-2-chlorophenyl)-2-((4-benzyl-5-methyl-4H-1,2,4-triazol-3-yl)sulfanyl)acetamide, with potent inhibitory activity and acceptable aqueous solubility has been identified in this study that could serve as lead scaffold for the development of novel water-soluble salts of triazole NNRTIs. PMID:25942362

  17. Screening of new non-nucleoside reverse transcriptase inhibitors of HIV-1 based on traditional Chinese medicines database

    Institute of Scientific and Technical Information of China (English)

    Tao Liu; Ai Xiu Li; You Pan Miao; Ke Zhu Wu; Yi Ma

    2009-01-01

    HIV-1 RT is an important target for the treatment of AIDS. There are two major classes of antiviral agents that inhibit HIV-1 RT have been identified, nucleoside RT inhibitors (NRTIs) and non-nucleoside RT inhibitors (NNRTIs). In this report, a noval class of non-nucleoside compound with potential RT inhibitory activity were found from the traditional Chinese medicines database (TCMD) using a combination of virtual screening, docking, molecular dynamic simulations, where results were ranked by scoring function of the docking tool. The result indicates that M4753 (a compound derived from TCMD) has not only the lowest bonding energy but also the best match in geometric conformation with the forthcoming NNRTIs. Accordingly M4753 might possibly become a promising lead compound of NNRTIs for AIDS therapy.

  18. Influence of non-nucleoside reverse transcriptase inhibitors (efavirenz and nevirapine) on the pharmacodynamic activity of gliclazide in animal models

    OpenAIRE

    Mastan SK; Kumar K Eswar

    2009-01-01

    Abstract Background Type 2 diabetes may occur as a result of HIV infection and/or its treatment. Gliclazide is a widely used drug for the treatment of type 2 diabetes. Efavirenz and nevirapine are widely used non-nucleoside reverse transcriptase inhibitors for the treatment of HIV infection. The role of Efavirenz and nevirapine on the pharmacodynamic activity of gliclazide is not currently known. The objective of this study was to examine the effect of oral administration of efavirenz and nev...

  19. The HCV Non-Nucleoside Inhibitor Tegobuvir Utilizes a Novel Mechanism of Action to Inhibit NS5B Polymerase Function

    OpenAIRE

    Hebner, Christy M.; Han, Bin; Brendza, Katherine M.; Nash, Michelle; Sulfab, Maisoun; Tian, Yang; Hung, Magdeleine; Fung, Wanchi; Vivian, Randall W.; Trenkle, James; Taylor, James; Bjornson, Kyla; Bondy, Steven; Liu, Xiaohong; Link, John

    2012-01-01

    Tegobuvir (TGV) is a novel non-nucleoside inhibitor (NNI) of HCV RNA replication with demonstrated antiviral activity in patients with genotype 1 chronic HCV infection. The mechanism of action of TGV has not been clearly defined despite the identification of resistance mutations mapping to the NS5B polymerase region. TGV does not inhibit NS5B enzymatic activity in biochemical assays in vitro, suggesting a more complex antiviral mechanism with cellular components. Here, we demonstrate that TGV...

  20. What's an Adam's Apple?

    Science.gov (United States)

    ... Skating Crushes What's a Booger? What's an Adam's Apple? KidsHealth > For Kids > What's an Adam's Apple? Print A A A Text Size You're ... the throat. This is what's called an Adam's apple. Everyone's larynx grows during puberty, but a girl's ...

  1. Liver injury in HIV-1-infected patients receiving non-nucleosides reverse transcriptase inhibitors-based antiretroviral therapy

    Institute of Scientific and Technical Information of China (English)

    LI Zai-cun; LI Hong-jun; DAI Li-li; GAO Yan-qing; CAI Wei-ping; LI Hai-ying; HUANG Xiao-jie; ZHANG Tong; WU Hao

    2010-01-01

    Background Liver injury is one of the most important adverse effects of antiretroviral therapy, leading to therapy changing or discontinuation. Data on liver injury in human immunodeficiency virus-1-infected patients receiving antiretroviral therapy are limited in China. The purpose of this study was to investigate the features of liver injury in human immunodeficiency virus type 1-infected patients receiving non-nucleosides reverse transcriptase inhibitors-based antiretroviral therapy in China.Methods Seventy-five patients on antiretroviral therapy containing non-nucleosides reverse transcriptase inhibitors were retrospectively studied. The patients were divided into 2 groups: group 1 (with liver injury, n=45) and group 2(without liver injury, n=30). The features of liver injury were analyzed. The sex, age, baseline CD4 counts, hepatitis B virus (HBV) and/or hepatitis C virus (HCV) co-infection, hepatotoxic drug use and nevirapine or efavirenz use were compared between two groups.Results Forty-five patients (60.0%), 31 (68.9%) males and 14 (31.1%) females, aged 12 to 52 years (averaged (3g±9)years), experienced at least one episode of liver injury. Forty (53.3%) patients were co-infected with HBV and/or HCV, 42 (56%) patients had concomitant use of antituberculosis drugs or cotrimoxazole, 46 (61.3%) and 29 (38.7%) patients received regimen containing nevirapine and efavirenz, respectively. Grade 1 liver injuries were observed in 26 (57.8%)patients, grade 2 in 16 (35.6%), grade 3 in 2 (4.0%) and grade 4 in 1 (2.2%). Three (6.7%) patients discontinued highly active antiretroviral therapy (HAART) due to liver injury. In group 1, there were 29 (64.4%) patients co-infected with HBV and/or HCV, 32 (71.1%) patients received regimen containing nevirapine, and 30 (66.7%) patients had concomitant use of anti-tuberculosis drugs or cotrimoxazole, respectively, significantly higher than those in group 2 (11 (36.7%), 14 (46.7%)and 12 (40%), respectively; P=0.018, 0.033, 0

  2. The HCV non-nucleoside inhibitor Tegobuvir utilizes a novel mechanism of action to inhibit NS5B polymerase function.

    Directory of Open Access Journals (Sweden)

    Christy M Hebner

    Full Text Available Tegobuvir (TGV is a novel non-nucleoside inhibitor (NNI of HCV RNA replication with demonstrated antiviral activity in patients with genotype 1 chronic HCV infection. The mechanism of action of TGV has not been clearly defined despite the identification of resistance mutations mapping to the NS5B polymerase region. TGV does not inhibit NS5B enzymatic activity in biochemical assays in vitro, suggesting a more complex antiviral mechanism with cellular components. Here, we demonstrate that TGV exerts anti-HCV activity utilizing a unique chemical activation and subsequent direct interaction with the NS5B protein. Treatment of HCV subgenomic replicon cells with TGV results in a modified form of NS5B with a distinctly altered mobility on a SDS-PAGE gel. Further analysis reveals that the aberrantly migrating NS5B species contains the inhibitor molecule. Formation of this complex does not require the presence of any other HCV proteins. The intensity of the aberrantly migrating NS5B species is strongly dependent on cellular glutathione levels as well as CYP 1A activity. Furthermore analysis of NS5B protein purified from a heterologous expression system treated with TGV by mass spectrometry suggests that TGV undergoes a CYP- mediated intracellular activation step and the resulting metabolite, after forming a glutathione conjugate, directly and specifically interacts with NS5B. Taken together, these data demonstrate that upon metabolic activation TGV is a specific, covalent inhibitor of the HCV NS5B polymerase and is mechanistically distinct from other classes of the non-nucleoside inhibitors (NNI of the viral polymerase.

  3. The HCV non-nucleoside inhibitor Tegobuvir utilizes a novel mechanism of action to inhibit NS5B polymerase function.

    Science.gov (United States)

    Hebner, Christy M; Han, Bin; Brendza, Katherine M; Nash, Michelle; Sulfab, Maisoun; Tian, Yang; Hung, Magdeleine; Fung, Wanchi; Vivian, Randall W; Trenkle, James; Taylor, James; Bjornson, Kyla; Bondy, Steven; Liu, Xiaohong; Link, John; Neyts, Johan; Sakowicz, Roman; Zhong, Weidong; Tang, Hengli; Schmitz, Uli

    2012-01-01

    Tegobuvir (TGV) is a novel non-nucleoside inhibitor (NNI) of HCV RNA replication with demonstrated antiviral activity in patients with genotype 1 chronic HCV infection. The mechanism of action of TGV has not been clearly defined despite the identification of resistance mutations mapping to the NS5B polymerase region. TGV does not inhibit NS5B enzymatic activity in biochemical assays in vitro, suggesting a more complex antiviral mechanism with cellular components. Here, we demonstrate that TGV exerts anti-HCV activity utilizing a unique chemical activation and subsequent direct interaction with the NS5B protein. Treatment of HCV subgenomic replicon cells with TGV results in a modified form of NS5B with a distinctly altered mobility on a SDS-PAGE gel. Further analysis reveals that the aberrantly migrating NS5B species contains the inhibitor molecule. Formation of this complex does not require the presence of any other HCV proteins. The intensity of the aberrantly migrating NS5B species is strongly dependent on cellular glutathione levels as well as CYP 1A activity. Furthermore analysis of NS5B protein purified from a heterologous expression system treated with TGV by mass spectrometry suggests that TGV undergoes a CYP- mediated intracellular activation step and the resulting metabolite, after forming a glutathione conjugate, directly and specifically interacts with NS5B. Taken together, these data demonstrate that upon metabolic activation TGV is a specific, covalent inhibitor of the HCV NS5B polymerase and is mechanistically distinct from other classes of the non-nucleoside inhibitors (NNI) of the viral polymerase. PMID:22720059

  4. Viral resuppression and detection of drug resistance following interruption of a suppressive non-nucleoside reverse transcriptase inhibitor-based regimen

    DEFF Research Database (Denmark)

    Fox, Zoe; Phillips, Andrew; Cohen, Cal;

    2008-01-01

    BACKGROUND: Interruption of a non-nucleoside reverse transcriptase inhibitor (NNRTI)-regimen is often necessary, but must be performed with caution because NNRTIs have a low genetic barrier to resistance. Limited data exist to guide clinical practice on the best interruption strategy to use...

  5. Purification and Biochemical Characterisation of Rabbit Calicivirus RNA-Dependent RNA Polymerases and Identification of Non-Nucleoside Inhibitors

    Directory of Open Access Journals (Sweden)

    Nadya Urakova

    2016-04-01

    Full Text Available Rabbit haemorrhagic disease virus (RHDV is a calicivirus that causes acute infections in both domestic and wild European rabbits (Oryctolagus cuniculus. The virus causes significant economic losses in rabbit farming and reduces wild rabbit populations. The recent emergence of RHDV variants capable of overcoming immunity to other strains emphasises the need to develop universally effective antivirals to enable quick responses during outbreaks until new vaccines become available. The RNA-dependent RNA polymerase (RdRp is a primary target for the development of such antiviral drugs. In this study, we used cell-free in vitro assays to examine the biochemical characteristics of two rabbit calicivirus RdRps and the effects of several antivirals that were previously identified as human norovirus RdRp inhibitors. The non-nucleoside inhibitor NIC02 was identified as a potential scaffold for further drug development against rabbit caliciviruses. Our experiments revealed an unusually high temperature optimum (between 40 and 45 °C for RdRps derived from both a pathogenic and a non-pathogenic rabbit calicivirus, possibly demonstrating an adaptation to a host with a physiological body temperature of more than 38 °C. Interestingly, the in vitro polymerase activity of the non-pathogenic calicivirus RdRp was at least two times higher than that of the RdRp of the highly virulent RHDV.

  6. Purification and Biochemical Characterisation of Rabbit Calicivirus RNA-Dependent RNA Polymerases and Identification of Non-Nucleoside Inhibitors

    Science.gov (United States)

    Urakova, Nadya; Netzler, Natalie; Kelly, Andrew G.; Frese, Michael; White, Peter A.; Strive, Tanja

    2016-01-01

    Rabbit haemorrhagic disease virus (RHDV) is a calicivirus that causes acute infections in both domestic and wild European rabbits (Oryctolagus cuniculus). The virus causes significant economic losses in rabbit farming and reduces wild rabbit populations. The recent emergence of RHDV variants capable of overcoming immunity to other strains emphasises the need to develop universally effective antivirals to enable quick responses during outbreaks until new vaccines become available. The RNA-dependent RNA polymerase (RdRp) is a primary target for the development of such antiviral drugs. In this study, we used cell-free in vitro assays to examine the biochemical characteristics of two rabbit calicivirus RdRps and the effects of several antivirals that were previously identified as human norovirus RdRp inhibitors. The non-nucleoside inhibitor NIC02 was identified as a potential scaffold for further drug development against rabbit caliciviruses. Our experiments revealed an unusually high temperature optimum (between 40 and 45 °C) for RdRps derived from both a pathogenic and a non-pathogenic rabbit calicivirus, possibly demonstrating an adaptation to a host with a physiological body temperature of more than 38 °C. Interestingly, the in vitro polymerase activity of the non-pathogenic calicivirus RdRp was at least two times higher than that of the RdRp of the highly virulent RHDV. PMID:27089358

  7. Ligand similarity guided receptor selection enhances docking accuracy and recall for non-nucleoside HIV reverse transcriptase inhibitors.

    Science.gov (United States)

    Stanton, Richard A; Nettles, James H; Schinazi, Raymond F

    2015-11-01

    Non-nucleoside reverse transcriptase inhibitors (NNRTI) are allosteric inhibitors of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT), a viral polymerase essential to infection. Despite the availability of >150 NNRTI-bound RT crystal structures, rational design of new NNRTI remains challenging because of the variability of their induced fit, hydrophobic binding patterns. Docking NNRTI yields inconsistent results that vary markedly depending on the receptor structure used, as only 27% of the >20k cross-docking calculations we performed using known NNRTI were accurate. In order to determine if a hospitable receptor for docking could be selected a priori, we evaluated more than 40 chemical descriptors for their ability to pre-select a best receptor for NNRTI cross-docking. The receptor selection was based on similarity scores between the bound- and target-ligands generated by each descriptor. The top descriptors were able to double the probability of cross-docking accuracy over random receptor selection. Additionally, recall of known NNRTI from a large library of similar decoys was increased using the same approach. The results demonstrate the utility of pre-selecting receptors when docking into difficult targets. Graphical Abstract Cross-docking accuracy increases when using chemical descriptors to determine the NNRTI with maximum similarity to the new compound and then docking into its respective receptor. PMID:26450349

  8. Adam Smith: Critical Theorist?

    OpenAIRE

    Keith Tribe

    1999-01-01

    The bicentenary of Adam Smith's Wealth of Nations in 1976 was marked by the publication of a new complete edition of his works and correspondence, bringing together for the first time all extant published and unpublished writings. A basis was thereby provided for serious reconsideration of Adam Smith's work, and since the early 1980s many conventional assumptions concerning Smith's work and contemporary significance have been challenged. This paper surveys the foundations upon which this new,...

  9. Cross-validated stepwise regression for identification of novel non-nucleoside reverse transcriptase inhibitor resistance associated mutations

    Directory of Open Access Journals (Sweden)

    Van Houtte Margriet

    2011-10-01

    Full Text Available Abstract Background Linear regression models are used to quantitatively predict drug resistance, the phenotype, from the HIV-1 viral genotype. As new antiretroviral drugs become available, new resistance pathways emerge and the number of resistance associated mutations continues to increase. To accurately identify which drug options are left, the main goal of the modeling has been to maximize predictivity and not interpretability. However, we originally selected linear regression as the preferred method for its transparency as opposed to other techniques such as neural networks. Here, we apply a method to lower the complexity of these phenotype prediction models using a 3-fold cross-validated selection of mutations. Results Compared to standard stepwise regression we were able to reduce the number of mutations in the reverse transcriptase (RT inhibitor models as well as the number of interaction terms accounting for synergistic and antagonistic effects. This reduction in complexity was most significant for the non-nucleoside reverse transcriptase inhibitor (NNRTI models, while maintaining prediction accuracy and retaining virtually all known resistance associated mutations as first order terms in the models. Furthermore, for etravirine (ETR a better performance was seen on two years of unseen data. By analyzing the phenotype prediction models we identified a list of forty novel NNRTI mutations, putatively associated with resistance. The resistance association of novel variants at known NNRTI resistance positions: 100, 101, 181, 190, 221 and of mutations at positions not previously linked with NNRTI resistance: 102, 139, 219, 241, 376 and 382 was confirmed by phenotyping site-directed mutants. Conclusions We successfully identified and validated novel NNRTI resistance associated mutations by developing parsimonious resistance prediction models in which repeated cross-validation within the stepwise regression was applied. Our model selection

  10. The Lipid-Lowering Efficacy of Switching Within Non-Nucleoside Reverse Transcriptase Inhibitors in HIV-Infected Patients

    Directory of Open Access Journals (Sweden)

    A. M. Bain

    2008-01-01

    Full Text Available The objective of present research is to evaluate the lipid lowering efficacy and safety of switching within non-nucleoside reverse transcriptase inhibitors (NNRTI in HIV-infected patients. This is a multicenter, retrospective study utilizing a comprehensive electronic patient registry to identify all adult HIV-infected patients seen from October 1, 1998 through October 1, 2006, who substituted efavirenz for nevirapine (EFV→NVP or vice-versa (NVP→EFV, without change in other antiretrovirals. Lipid profiles before and after the switch were analyzed. A total of 124 patients were identified with 14 male (EFV→NVP, n = 9; NVP→EFV, n = 5 patients meeting the strict criteria for inclusion. An EFV→NVP switch resulted in significant reductions in TC -16% and non-HDL -25% (p≤0.02 and a trend towards a reduction in LDL-C -12%, TG -27%, TC/HDL -23%, TG/HDL -48% and an increase in HDL-C +15% without any changes to BMI, viral or immunological control. However, a NVP→EFV switch appeared to result in a non-significant worsening of LDL-C +29%, HDL-C -8%, TG +36%, non-HDL +28%, TC/HDL +57% and TG/HDL +46%. Lastly, more patients achieved their lipid goals when switched from EFV to NVP. These data suggest that switching from EFV to NVP-based HAART is associated with lipid improvement, however, switching from NVP to EFV-based HAART is associated with worsening of serum lipids.

  11. Efavirenz Has the Highest Anti-Proliferative Effect of Non-Nucleoside Reverse Transcriptase Inhibitors against Pancreatic Cancer Cells.

    Directory of Open Access Journals (Sweden)

    Markus Hecht

    Full Text Available Cancer prevention and therapy in HIV-1-infected patients will play an important role in future. The non-nucleoside reverse transcriptase inhibitors (NNRTI Efavirenz and Nevirapine are cytotoxic against cancer cells in vitro. As other NNRTIs have not been studied so far, all clinically used NNRTIs were tested and the in vitro toxic concentrations were compared to drug levels in patients to predict possible anti-cancer effects in vivo.Cytotoxicity was studied by Annexin-V-APC/7AAD staining and flow cytometry in the pancreatic cancer cell lines BxPC-3 and Panc-1 and confirmed by colony formation assays. The 50% effective cytotoxic concentrations (EC50 were calculated and compared to the blood levels in our patients and published data.The in vitro EC50 of the different drugs in the BxPC-3 pancreatic cancer cells were: Efavirenz 31.5 μmol/l (= 9944 ng/ml, Nevirapine 239 μmol/l (= 63,786 ng/ml, Etravirine 89.0 μmol/l (= 38,740 ng/ml, Lersivirine 543 μmol/l (= 168,523 ng/ml, Delavirdine 171 μmol/l (= 78,072 ng/ml, Rilpivirine 24.4 μmol/l (= 8941 ng/ml. As Efavirenz and Rilpivirine had the highest cytotoxic potential and Nevirapine is frequently used in HIV-1 positive patients, the results of these three drugs were further studied in Panc-1 pancreatic cancer cells and confirmed with colony formation assays. 205 patient blood levels of Efavirenz, 127 of Rilpivirine and 31 of Nevirapine were analyzed. The mean blood level of Efavirenz was 3587 ng/ml (range 162-15,363 ng/ml, of Rilpivirine 144 ng/ml (range 0-572 ng/ml and of Nevirapine 4955 ng/ml (range 1856-8697 ng/ml. Blood levels from our patients and from published data had comparable Efavirenz levels to the in vitro toxic EC50 in about 1 to 5% of all patients.All studied NNRTIs were toxic against cancer cells. A low percentage of patients taking Efavirenz reached in vitro cytotoxic blood levels. It can be speculated that in HIV-1 positive patients having high Efavirenz blood levels pancreatic

  12. Influence of non-nucleoside reverse transcriptase inhibitors (efavirenz and nevirapine on the pharmacodynamic activity of gliclazide in animal models

    Directory of Open Access Journals (Sweden)

    Mastan SK

    2009-10-01

    Full Text Available Abstract Background Type 2 diabetes may occur as a result of HIV infection and/or its treatment. Gliclazide is a widely used drug for the treatment of type 2 diabetes. Efavirenz and nevirapine are widely used non-nucleoside reverse transcriptase inhibitors for the treatment of HIV infection. The role of Efavirenz and nevirapine on the pharmacodynamic activity of gliclazide is not currently known. The objective of this study was to examine the effect of oral administration of efavirenz and nevirapine on blood glucose and investigate their effect on the activity of gliclazide in rats (normal and diabetic and rabbits to evaluate the safety and effectiveness of the combination. Methods Studies in normal and alloxan induced diabetic rats were conducted with oral doses of 2 mg/kg bd. wt. of gliclazide, 54 mg/kg bd. wt. of efavirenz or 18 mg/kg bd. wt. of nevirapine and their combination with adequate washout periods in between treatments. Studies in normal rabbits were conducted with 5.6 mg/1.5 kg bd. wt. of gliclazide, 42 mg/1.5 kg bd. wt. of efavirenz or 14 mg/1.5 kg bd. wt. of nevirapine and their combination given orally. Blood samples were collected at regular time intervals in rats from retro orbital puncture and by marginal ear vein puncture in rabbits. All the blood samples were analysed for blood glucose by GOD/POD method. Results Efavirenz and nevirapine alone have no significant effect on the blood glucose level in rats and rabbits. Gliclazide produced hypoglycaemic/antidiabetic activity in normal and diabetic rats with peak activity at 2 h and 8 h and hypoglycaemic activity in normal rabbits at 3 h. In combination, efavirenz reduced the effect of gliclazide in rats and rabbits, and the reduction was more significant with the single dose administration of efavirenz than multiple dose administration. In combination, nevirapine has no effect on the activity of gliclazide in rats and rabbits. Conclusion Thus, it can be concluded that the

  13. Sensitive assessment of the virologic outcomes of stopping and restarting non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy.

    Directory of Open Access Journals (Sweden)

    Anna Maria Geretti

    Full Text Available BACKGROUND: Non-nucleoside reverse transcriptase inhibitor (NNRTI-resistant mutants have been shown to emerge after interruption of suppressive NNRTI-based antiretroviral therapy (ART using routine testing. The aim of this study was to quantify the risk of resistance by sensitive testing and correlate the detection of resistance with NNRTI concentrations after treatment interruption and virologic responses after treatment resumption. METHODS: Resistance-associated mutations (RAMs and NNRTI concentrations were studied in plasma from 132 patients who interrupted suppressive ART within SMART. RAMs were detected by Sanger sequencing, allele-specific PCR, and ultra-deep sequencing. NNRTI concentrations were measured by sensitive high-performance liquid chromatography. RESULTS: Four weeks after NNRTI interruption, 19/31 (61.3% and 34/39 (87.2% patients showed measurable nevirapine (>0.25 ng/ml or efavirenz (>5 ng/ml concentrations, respectively. Median eight weeks after interruption, 22/131 (16.8% patients showed ≥1 NNRTI-RAM, including eight patients with NNRTI-RAMs detected only by sensitive testing. The adjusted odds ratio (OR of NNRTI-RAM detection was 7.62 (95% confidence interval [CI] 1.52, 38.30; p = 0.01 with nevirapine or efavirenz concentrations above vs. below the median measured in the study population. Staggered interruption, whereby nucleos(tide reverse transcriptase inhibitors (NRTIs were continued for median nine days after NNRTI interruption, did not prevent NNRTI-RAMs, but increased detection of NRTI-RAMs (OR 4.25; 95% CI 1.02, 17.77; p = 0.03. After restarting NNRTI-based ART (n = 90, virologic suppression rates <400 copies/ml were 8/13 (61.5% with NNRTI-RAMs, 7/11 (63.6% with NRTI-RAMs only, and 51/59 (86.4% without RAMs. The ORs of re-suppression were 0.18 (95% CI 0.03, 0.89 and 0.17 (95% CI 0.03, 1.15 for patients with NNRTI-RAMs or NRTI-RAMs only respectively vs. those without RAMs (p = 0.04. CONCLUSIONS

  14. Pharmacokinetics of the Experimental Non-Nucleosidic DNA Methyl Transferase Inhibitor N-Phthalyl-l-Tryptophan (RG 108) in Rats.

    Science.gov (United States)

    Schneeberger, Yvonne; Stenzig, Justus; Hübner, Florian; Schaefer, Andreas; Reichenspurner, Hermann; Eschenhagen, Thomas

    2016-05-01

    DNA methyl transferase (DNMT) inhibitors can re-establish the expression of tumour suppressor genes in malignant diseases, but might also be useful in other diseases. Inhibitors in clinical use are nucleosidic cytotoxic agents that need to be integrated into the DNA of dividing cells. Here, we assessed the in vivo kinetics of a non-nucleosidic inhibitor that is potentially free of cytotoxic effects and does not require cell division. The non-specific DNMT inhibitor N-phthalyl-l-tryptophan (RG 108) was injected subcutaneously in rats. Blood was drawn 0, 0.5, 1, 2, 4, 6, 8 and 24 hr after injection and RG 108 in plasma was measured by high-performance liquid chromatography coupled to mass spectrometry. Trough levels and area under the curve (AUC) were significantly higher with multiple-dose administration and cytochrome inhibition. In this group, time to maximal plasma concentration (tmax , mean ± S.D.) was 37.5 ± 15 min., terminal plasma half-life was approximately 3.7 h (60% CI: 2.1-15.6 h), maximal plasma concentration (Cmax ) was 61.3 ± 7.6 μM, and AUC was 200 ± 54 μmol·h/l. RG 108 peak levels were not influenced by cytochrome inhibition or multiple-dose administration regimens. Maximal tissue levels (Cmax in μmol/kg) were 6.9 ± 6.7, 1.6 ± 0.4 and 3.4 ± 1.1 in liver, skeletal and heart muscle, respectively. We conclude that despite its high lipophilicity, RG 108 can be used for in vivo experiments, appears safe and yields plasma and tissue levels in the range of the described 50% inhibitory concentration of around 1 to 5 μM. RG 108 can therefore be a useful tool for in vivo DNMT inhibition. PMID:26525153

  15. ADAM Proteases and Gastrointestinal Function.

    Science.gov (United States)

    Jones, Jennifer C; Rustagi, Shelly; Dempsey, Peter J

    2016-01-01

    A disintegrin and metalloproteinases (ADAMs) are a family of cell surface proteases that regulate diverse cellular functions, including cell adhesion, migration, cellular signaling, and proteolysis. Proteolytically active ADAMs are responsible for ectodomain shedding of membrane-associated proteins. ADAMs rapidly modulate key cell signaling pathways in response to changes in the extracellular environment (e.g., inflammation) and play a central role in coordinating intercellular communication within the local microenvironment. ADAM10 and ADAM17 are the most studied members of the ADAM family in the gastrointestinal tract. ADAMs regulate many cellular processes associated with intestinal development, cell fate specification, and the maintenance of intestinal stem cell/progenitor populations. Several signaling pathway molecules that undergo ectodomain shedding by ADAMs [e.g., ligands and receptors from epidermal growth factor receptor (EGFR)/ErbB and tumor necrosis factor α (TNFα) receptor (TNFR) families] help drive and control intestinal inflammation and injury/repair responses. Dysregulation of these processes through aberrant ADAM expression or sustained ADAM activity is linked to chronic inflammation, inflammation-associated cancer, and tumorigenesis. PMID:26667078

  16. The role of ADAMs in disease pathophysiology.

    LENUS (Irish Health Repository)

    Duffy, Michael J

    2012-02-01

    The ADAMs are a family of multidomain transmembrane and secreted proteins involved in both proteolysis and cell adhesion. Altered expression of specific ADAMs is implicated in the pathophysiology of several diseases including rheumatoid arthritis, Alzheimer\\'s disease, cardiac hypertrophy, asthma and cancer. Of these different diseases, it is in cancer where most research has been carried out. Multiple ADAMs, including ADAM-9, ADAM-10, ADAM-12, ADAM-15 and ADAM-17, have been shown to play a role in either cancer formation or progression. Consistent with these findings, increased expression of specific ADAMs in several cancer types was found to correlate with features of aggressive disease and poor prognosis. Currently, selective ADAM inhibitors against ADAM-10 and ADAM-17 are undergoing clinical trials for the treatment of cancer. Further work is required in order to establish a causative role for ADAMs in rheumatoid arthritis, Alzheimer\\'s disease, cardiac hypertrophy and asthma.

  17. Adam Smith's Invisible Hands

    OpenAIRE

    Persky, Joseph

    2004-01-01

    William Grampp’s JPE article on Adam Smith is creative and provocative. It errs, however, by disparaging the invisible hand’s importance as a symbol of various economic processes that help societies prosper in ways that individuals neither intend nor comprehend. Four specific problems stand out. First, Grampp unsoundly tries to limit the relevance of the invisible hand within the Wealth of Nations to situations in which a merchant increases domestic capital and strengthens national defens...

  18. John Adams in 1959

    CERN Document Server

    1959-01-01

    On 24 November 1959, the Proton Synchrotron accelerated particles to 24 GeV. John Adams, leader of the construction team, announced the achievement in the Main Auditorium. In his hand can be seen an empty vodka bottle, which he had received from Nikitin with the message that it was to be drunk when CERN passed Dubna's world record energy of 10 Gev. The bottle now contains a polaroid photograph of the 24 GeV pulse ready to be sent to the Soviet Union.

  19. QSAR Studies on 6-(1-Naphthylmethyl) Substituted S-DABO Derivatives as Novel Non-nucleoside HIV-1 Reverse Transcriptase Inhibitors

    Institute of Scientific and Technical Information of China (English)

    YIN Li-Qin; YU Shi-Wen; YAO Ling-Feng; HE Yan-Ping; XIE Xiao-Guang

    2008-01-01

    The AM1 and B3LYP methods were employed to calculate the structural pro- perties of 20 6-(1-naphthylmethyl) substituted S-DABO derivatives with β-carbonyl group on the C(2) side chain as novel potent non-nucleoside HIV-1 reverse transcriptase inhibitors. The correlation analysis (CA) and stepwise multiple regression analysis (SMR) were performed. The QSAR models indicate that the physicochemical parameters of QC9, MRR1, ELUMO, ∏R2 and μ have significant influence on the activities of these derivatives. The substitution of hydrophobic R2 and bulky aromatic R1 to form a conjugated system with the frame of those S-DABO series compounds should be considered to design new potent compounds for anti-HIV-1.

  20. Discovery of the Aryl-phospho-indole IDX899, a Highly Potent Anti-HIV Non-nucleoside Reverse Transcriptase Inhibitor.

    Science.gov (United States)

    Dousson, Cyril; Alexandre, François-René; Amador, Agnès; Bonaric, Séverine; Bot, Stéphanie; Caillet, Catherine; Convard, Thierry; da Costa, Daniel; Lioure, Marie-Pierre; Roland, Arlène; Rosinovsky, Elodie; Maldonado, Sébastien; Parsy, Christophe; Trochet, Christophe; Storer, Richard; Stewart, Alistair; Wang, Jingyang; Mayes, Benjamin A; Musiu, Chiara; Poddesu, Barbara; Vargiu, Luana; Liuzzi, Michel; Moussa, Adel; Jakubik, Jocelyn; Hubbard, Luke; Seifer, Maria; Standring, David

    2016-03-10

    Here, we describe the design, synthesis, biological evaluation, and identification of a clinical candidate non-nucleoside reverse transcriptase inhibitors (NNRTIs) with a novel aryl-phospho-indole (APhI) scaffold. NNRTIs are recommended components of highly active antiretroviral therapy (HAART) for the treatment of HIV-1. Since a major problem associated with NNRTI treatment is the emergence of drug resistant virus, this work focused on optimization of the APhI against clinically relevant HIV-1 Y181C and K103N mutants and the Y181C/K103N double mutant. Optimization of the phosphinate aryl substituent led to the discovery of the 3-Me,5-acrylonitrile-phenyl analogue RP-13s (IDX899) having an EC50 of 11 nM against the Y181C/K103N double mutant. PMID:26804933

  1. Discovery of Potent Non-Nucleoside Inhibitors of Dengue Viral RNA-Dependent RNA Polymerase from a Fragment Hit Using Structure-Based Drug Design.

    Science.gov (United States)

    Yokokawa, Fumiaki; Nilar, Shahul; Noble, Christian G; Lim, Siew Pheng; Rao, Ranga; Tania, Stefani; Wang, Gang; Lee, Gladys; Hunziker, Jürg; Karuna, Ratna; Manjunatha, Ujjini; Shi, Pei-Yong; Smith, Paul W

    2016-04-28

    The discovery and optimization of non-nucleoside dengue viral RNA-dependent-RNA polymerase (RdRp) inhibitors are described. An X-ray-based fragment screen of Novartis' fragment collection resulted in the identification of a biphenyl acetic acid fragment 3, which bound in the palm subdomain of RdRp. Subsequent optimization of the fragment hit 3, relying on structure-based design, resulted in a >1000-fold improvement in potency in vitro and acquired antidengue activity against all four serotypes with low micromolar EC50 in cell-based assays. The lead candidate 27 interacts with a novel binding pocket in the palm subdomain of the RdRp and exerts a promising activity against all clinically relevant dengue serotypes. PMID:26984786

  2. Virological and immunological outcomes at 3 years after starting antiretroviral therapy with regimens containing non-nucleoside reverse transcriptase inhibitor, protease inhibitor, or both in INITIO: open-label randomised trial

    DEFF Research Database (Denmark)

    Yeni, P; Cooper, DA; Aboulker, J-P;

    2006-01-01

    antiretroviral therapy with two nucleoside analogue reverse transcriptase inhibitors (didanosine+stavudine) plus either a non-nucleoside reverse transcriptase inhibitor (efavirenz, EFV) or a protease inhibitor (nelfinavir, NFV), or both (EFV/NFV), in patients with HIV-1 infection who had not previously received...

  3. Adam Smith's contribution to secularisation

    OpenAIRE

    Petrus Simons

    2013-01-01

    This article examined several crucial themes in Adam Smith’s philosophy with the purpose of highlighting and assessing his contribution to the secularisation of Western society. The article, written from the perspective of reformational philosophy, begins with a brief biography and sketch of Adam Smith’s influence on modern society, followed by a summary of Ponti Venter’s view on Smith. This sets the scene for a discussion of Adam Smith’s project, his method of tackling it, and his views on s...

  4. Adam Smith and dependency.

    Science.gov (United States)

    Ozler, Sule

    2012-06-01

    The focus of this paper is the works and life of Adam Smith, who is widely recognized as the father and founder of contemporary economics. Latent content analysis is applied to his seminal text in economics, An Inquiry into the Nature and Causes of the Wealth of Nations (1776). The results reveal that Smith considers dependence on others a problem and sees the solution to this problem in impersonalized interdependence. In addition, his views on social dependency and personal dependency, reflected in his Lectures on Jurisprudence (1963) and The Theory of Moral Sentiments (1759), are analyzed. This analysis suggests a central tension between dependence and independence in Smith's writings. The personal dependency patterns he exhibited in his life, which also suggest a tension between dependence and independence, are identified through a reading of his biographies. Based on insights from psychoanalytic literature, this paper proposes that developing the ideas in the Wealth of Nations was part of Smith's creative solution to this tension. In particular, his solution to one individual's dependence on another was through a system of impersonalized interdependence. In other words, Smith defended against his personal dependence through his economic theorizing. PMID:22712591

  5. John Adams Lecture

    CERN Multimedia

    PH Department

    2010-01-01

    13 December 2010 14:30 - Council Chamber, Bldg.503-1-001 Accelerator Breakthroughs, Achievements and Lessons from the Tevatron Collider V. Shiltsev / Fermilab’s Accelerator Physics Centre This year we celebrate the 25th anniversary of the first proton-antiproton collisions in the Tevatron. For two and a half decades the Tevatron at Fermilab (Batavia, IL, USA) was a centerpiece of the US and world’s High Energy Physics as the world’s highest energy particle collider at 1.8 TeV center of mass energy. While funding agencies are deciding on a 3-year extension of the Collider Run II operation through 2014, we – in this 2010 John Adams Lecture - will take a look in exciting story of the Tevatron: the story of long preparations, great expectations, numerous difficulties, years of “blood and sweat”, continuous upgrades, exceeding original goals (by a factor of 400) and high emotions. An accelerator scientist prospective will be given on a wide spectrum o...

  6. The case for addressing primary resistance mutations to non-nucleoside reverse transcriptase inhibitors to treat children born from mothers living with HIV in sub-Saharan Africa

    Directory of Open Access Journals (Sweden)

    Khady Kébé

    2014-01-01

    Full Text Available The prevalence of human immunodeficiency virus (HIV drug resistance mutations (DRMs was estimated in 25 untreated infants who were living with HIV-1, younger than 13 months and living in Senegal. Antiretroviral DRMs were detected in 8 of 25 (32% children. Non-nucleoside reverse transcriptase inhibitor (NNRTI DRMs were present in all (100% children whose viruses harboured DRMs: K103N in 43%; Y181C, K101E and V106M each in 29%; and Y188L in 14%. The D67N thymidine-analogue mutation was observed in only two children whose mothers had received chemoprophylaxis of mother-to-child transmission (MTCT. The proportion of children whose viruses harboured DRMs was then 6.5-fold higher in children whose mother–child couples had received nevirapine (NVP-based chemoprophylaxis than in other couples without prophylaxis [7 of 13 (53.8% vs. 1 of 12 (8.3%]. These findings point to the absolute need to address primary resistance mutations in case of virological failure in young children treated by antiretroviral drugs, and to make more effective treatment regimens available to NVP-exposed infants living with HIV-1 in Senegal.

  7. Structure-based optimization and derivatization of 2-substituted quinolone-based non-nucleoside HCV NS5B inhibitors with submicromolar cellular replicon potency.

    Science.gov (United States)

    Cheng, Yu; Shen, Jian; Peng, Run-Ze; Wang, Gui-Feng; Zuo, Jian-Ping; Long, Ya-Qiu

    2016-06-15

    HCV NS5B polymerase is an attractive and validated target for anti-HCV therapy. Starting from our previously identified 2-aryl quinolones as novel non-nucleoside NS5B polymerase inhibitors, structure-based optimization furnished 2-alkyl-N-benzyl quinolones with improved antiviral potency by employing privileged fragment hybridization strategy. The N-(4-chlorobenzyl)-2-(methoxymethyl)quinolone derivative 5f proved to be the best compound of this series, exhibiting a selective sub-micromolar antiviral effect (EC50=0.4μM, SI=10.8) in Huh7.5.1 cells carrying a HCV genotype 2a. Considering the undesirable pharmacokinetic property of the highly substituted quinolones, a novel chemotype of 1,6-naphthyridine-4,5-diones were evolved via scaffold hopping, affording brand new structure HCV inhibitors with compound 6h (EC50 (gt2a)=2.5μM, SI=7.2) as a promising hit. Molecular modeling studies suggest that both of 2-alkyl quinolones and 1,6-naphthyridine-4,5-diones function as HCV NS5B thumb pocket II inhibitors. PMID:27133482

  8. Design, Synthesis, and Evaluation of Thiophene[3,2-d]pyrimidine Derivatives as HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors with Significantly Improved Drug Resistance Profiles.

    Science.gov (United States)

    Kang, Dongwei; Fang, Zengjun; Li, Zhenyu; Huang, Boshi; Zhang, Heng; Lu, Xueyi; Xu, Haoran; Zhou, Zhongxia; Ding, Xiao; Daelemans, Dirk; De Clercq, Erik; Pannecouque, Christophe; Zhan, Peng; Liu, Xinyong

    2016-09-01

    We designed and synthesized a series of human immunodeficiency virus type 1 (HIV-1) non-nucleoside reverse transcriptase inhibitors (NNRTIs) with a piperidine-substituted thiophene[3,2-d]pyrimidine scaffold, employing a strategy of structure-based molecular hybridization and substituent decorating. Most of the synthesized compounds exhibited broad-spectrum activity with low (single-digit) nanomolar EC50 values toward a panel of wild-type (WT), single-mutant, and double-mutant HIV-1 strains. Compound 27 was the most potent; compared with ETV, its antiviral efficacy was 3-fold greater against WT, 5-7-fold greater against Y181C, Y188L, E138K, and F227L+V106A, and nearly equipotent against L100I and K103N, though somewhat weaker against K103N+Y181C. Importantly, 27 has lower cytotoxicity (CC50 > 227 μM) and a huge selectivity index (SI) value (ratio of CC50/EC50) of >159101. 27 also showed favorable, drug-like pharmacokinetic and safety properties in rats in vivo. Molecular docking studies and the structure-activity relationships provide important clues for further molecular elaboration. PMID:27541578

  9. Synthesis, structure-activity relationship and molecular docking of cyclohexenone based analogous as potent non-nucleoside reverse-transcriptase inhibitors

    Science.gov (United States)

    Nazar, Muhammad Faizan; Abdullah, Muhammad Imran; Badshah, Amir; Mahmood, Asif; Rana, Usman Ali; Khan, Salah Ud-Din

    2015-04-01

    The chalcones core in compounds is advantageously chosen effective synthons, which offer exciting perspectives in biological and pharmacological research. The present study reports the successful development of eight new cyclohexenone based anti-reverse transcriptase analogous using rational drug design synthesis principles. These new cyclohexenone derivatives (CDs) were synthesized by following a convenient route of Robinson annulation, and the molecular structure of these CDs were later confirmed by various analytical techniques such as 1H NMR, 13C NMR, FT-IR, UV-Vis spectroscopy and mass spectrometry. All the synthesized compounds were screened theoretically and experimentally against reverse transcriptase (RT) and found potentially active reverse transcriptase (RT) inhibitors. Of the compounds studied, the compound 2FC4 showed high interaction with RT at non-nucleoside binding site, contributing high free binding energy (ΔG -8.01 Kcal) and IC50 (0.207 μg/ml), respectively. Further results revealed that the compounds bearing more halogen groups, with additional hydrophobic character, offered superior anti-reverse transcriptase activity as compared to rest of compounds. It is anticipate that the present study would be very useful for the selection of potential reverse transcriptase inhibitors featuring inclusive pharmacological profiles.

  10. Effects of the protonation state in the interaction of an HIV-1 reverse transcriptase (RT) amino acid, Lys101, and a non nucleoside RT inhibitor, GW420867X.

    Science.gov (United States)

    Galembeck, Sérgio E; Bickelhaupt, F Matthias; Fonseca Guerra, Célia; Galembeck, Eduardo

    2014-07-01

    Interactions between an inhibitor and amino acids from a binding pocket could help not only to understand the nature of these interactions, but also to support the design of new inhibitors. In this paper, we explore the key interaction between a second generation non-nucleoside reverse transcriptase inhibitor (NNRTI), GW420867X, and HIV-1 RT amino acid Lys101 (K101), by quantum mechanical methods. The neutral, protonated, and zwitterionic complexes of GW420867X-K101 were studied. The interaction energies were determined by SCS-MP2/def2-cc-pVQZ, and the electron density was analyzed by natural bond orbital (NBO), atoms in molecules (AIM) and reduced gradient analysis. A large increase in the interaction was observed with the tautomerization of neutral or neutral protonated species. The monomers interact by two medium-strength hydrogen bonds, one partially covalent and another noncovalent. There are some van der Waals intramolecular interactions that are topologically unstable. The nature of the intermolecular interactions was also analyzed using quantitative molecular orbital (MO) theory in combination with an energy decomposition analysis (EDA) based on dispersion-corrected density functional theory (DFT) at BLYP-D/TZ2P. PMID:24965933

  11. Bookshelf. John Adams biography

    International Nuclear Information System (INIS)

    Full text: When John Bertram Adams died on 3 March 1984, CERN lost one of its principal architects. The late Sir John Adams was a very private person who rarely confided in his colleagues. This made the job of his biographer particularly difficult. Michael Crowley- Milling has succeeded admirably, and has performed a very important service. Is it a potted history of CERN, or the story of the building of the PS, or of the SPS? Yes, all of these, but most of all it is a thoughtful and discerning biography and a fitting tribute to a veritable giant of European science and technology. The sub-title,' Engineer Extraordinary' refers not only to John's outstanding ability as a builder of accelerators, but perhaps even more importantly, as a builder of teams and an 'engineer of opinions'. The book describes how John's attention to detail and intuitive engineering skills developed during the early part of his career, when working in radar research, and how he emerged as a natural leader in the building of the CERN PS. Then later, how his statesmanship enabled him to ''...rescue it (the 300 GeV Programme) from seeming political disaster and nurse it through technical problems to a successful conclusion.'' One crucial part of this process described is the visit to CERN in 1970 by Margaret Thatcher, at that time UK Secretary of State for Education and Science, and her subsequent letters of thanks, not only to Bernard Gregory as Director General, but also to John. It is interesting to speculate to what extent the good impression made on that occasion helped many years later, when as Prime Minister Mrs Thatcher decided that Britain should stay in CERN! After the successful commissioning of the SPS, the book goes on to describe the period when the two CERN Laboratories were merged under two Directors General. Unfortunately I found this part a little too low key, given that John and Leon van Hove presided over what was undoubtedly

  12. Adams inequalities on measure spaces

    CERN Document Server

    Fontana, Luigi

    2009-01-01

    In 1988 Adams obtained sharp Moser-Trudinger inequalities on bounded domains of R^n. The main step was a sharp exponential integral inequality for convolutions with the Riesz potential. In this paper we extend and improve Adams' results to functions defined on arbitrary measure spaces with finite measure. The Riesz fractional integral is replaced by general integral operators, whose kernels satisfy suitable and explicit growth conditions, given in terms of their distribution functions; natural conditions for sharpness are also given. Most of the known results about Moser-Trudinger inequalities can be easily adapted to our unified scheme. We give some new applications of our theorems, including: sharp higher order Moser-Trudinger trace inequalities, sharp Adams/Moser-Trudinger inequalities for general elliptic differential operators (scalar and vector-valued), for sums of weighted potentials, and for operators in the CR setting.

  13. Valproic acid inhibits the release of soluble CD40L induced by non-nucleoside reverse transcriptase inhibitors in human immunodeficiency virus infected individuals.

    Directory of Open Access Journals (Sweden)

    Donna C Davidson

    Full Text Available Despite the use of highly active antiretroviral therapies (HAART, a majority of Human Immunodeficiency Virus Type 1 (HIV infected individuals continually develop HIV - Associated Neurocognitive Disorders (HAND, indicating that host inflammatory mediators, in addition to viral proteins, may be contributing to these disorders. Consistent with this notion, we have previously shown that levels of the inflammatory mediator soluble CD40 ligand (sCD40L are elevated in the plasma and cerebrospinal fluid (CSF of HIV infected, cognitively impaired individuals, and that excess sCD40L can contribute to blood brain barrier (BBB permeability in vivo, thereby signifying the importance of this inflammatory mediator in the pathogenesis of HAND. Here we demonstrate that the non-nucleoside reverse transcriptase inhibitor (NNRTI efavirenz (EFV induces the release of circulating sCD40L in both HIV infected individuals and in an in vitro suspension of washed human platelets, which are the main source of circulating sCD40L. Additionally, EFV was found to activate glycogen synthase kinase 3 beta (GSK3β in platelets, and we now show that valproic acid (VPA, a known GSK3β inhibitor, was able to attenuate the release of sCD40L in HIV infected individuals receiving EFV, and in isolated human platelets. Collectively these results have important implications in determining the pro-inflammatory role that some antiretroviral regimens may have. The use of antiretrovirals remains the best strategy to prevent HIV-associated illnesses, including HAND, however these drugs have clear limitations to this end, and thus, these results underscore the need to develop adjunctive therapies for HAND that can also minimize the undesired negative effects of the antiretrovirals.

  14. The prevalence of transmitted resistance to first-generation non-nucleoside reverse transcriptase inhibitors and its potential economic impact in HIV-infected patients.

    Directory of Open Access Journals (Sweden)

    Sonya J Snedecor

    Full Text Available Non-nucleoside reverse transcriptase inhibitor (NNRTI-based highly active antiretroviral therapy (HAART including efavirenz is recommended as a 1(st-line treatment choice in international HIV guidelines, and it is one of the most common components of initial therapy. Resistance to 1(st-generation NNRTIs is found among treated and untreated HIV-infected individuals creating a subpopulation of HIV-infected individuals in whom efavirenz is not fully effective. This analysis reviewed published articles and conference abstracts to examine the prevalence of 1(st-generation NNRTI resistance in Europe, the United States (US, and Canada and to identify published evidence of the economic consequences of resistance. The reported prevalence of NNRTI resistance was generally higher in US/Canada than in Europe and increased in both regions from their introduction in the late 1990s until the early 2000s. The most recent time-based trends suggest that NNRTI-resistance prevalence may be stable or decreasing. These estimates of resistance may be understated as resistance estimates using ultra-sensitive genotypic testing methods, which identify low-frequency mutations undetected by standard testing methods, showed increased prevalence of resistance by more than two-fold. No studies were identified that explicitly investigated the costs of drug resistance. Rather, most studies reported costs of treatment change, failure, or disease progression. Among those studies, annual HIV medical costs of those infected with HIV increased 1 as CD4 cells decreased, driven in part by hospitalization at lower CD4 cell counts; 2 for treatment changes, and 3 for each virologic failure. The possible erosion of efficacy or of therapy choices through resistance transmission or selection, even when present with low frequency, may become a barrier to the use of 1(st-generation NNRTIs and the increased costs associated with regimen failure and disease progression underlie the importance

  15. Inhibitory activity of 9-phenylcyclohepta[d]pyrimidinedione derivatives against different strains of HIV-1 as non-nucleoside reverse transcriptase inhibitors

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    Shao Yiming

    2011-05-01

    Full Text Available Abstract Background The non-nucleoside reverse transcriptase inhibitor (NNRTI, as a major component of the highly active antiretroviral therapy (HAART to HIV-1 (human immunodeficiency virus type 1 infected patients, required the development of new NNRTIs with improved resistance profile and decreased toxicity. Therefore, a series of novel compounds, 9-phenylcyclohepta[d]pyrimidinedione derivatives (PCPs, were designed based on the chemical structure of TNK-651, to detect anti-HIV-1 activity. Results 1-[(benzyloxymethyl]-9-phenyl-cyclohepta[d] pyrimidinedione (BmPCP among four PCPs has antiviral activity on laboratory-adapted HIV strains (HIV-1 SF33. The results showed 50% inhibition concentrations (IC50s of BmPCP were 0.34 μM, 1.72 μM and 1.96 μM on TZM-bl, peripheral blood mononuclear cells (PBMCs and MT4, respectively. It was also effective against infection by the predominant HIV-1 isolates in China, with IC50s at low μM levels. Its selectivity index (SI ranged from 67 to 266 in different cells. The results of time-of-addition assay demonstrated that BmPCP inhibited HIV-1 infection by targeting the post entry of the HIV-1 replication cycle. For inhibition of HIV-1 reverse transcriptase activity, the IC50 values of BmPCP and NVP were 1.51 and 3.67 μM, respectively. Conclusions BmPCP with a novel structure acts as a NNRTI to inhibit HIV-1 replication and can serve as a lead compound for further development of new anti-HIV-1 drugs.

  16. Rapid CD4 decline after interruption of non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy in a resource-limited setting

    Directory of Open Access Journals (Sweden)

    Watcharananan Siriorn

    2007-11-01

    Full Text Available Abstract Background Non-nucleoside reverse transcriptase inhibitor (NNRTI with stavudine and lamivudine is widely used as the first-line antiretroviral therapy (ART in resource-limited settings. Lipodystrophy is common and options for switching ART regimen are limited; this situation can lead to patients' poor adherence and antiretroviral resistance. Treatment interruption (TI in patients with high CD4 cell counts, lipodystrophy, and limited options may be an alternative in resource-limited settings. This study aimed to determine time to resume ART after TI and predictors for early resumption of ART in a resource-limited setting. Methods A prospective study was conducted in January 2005 to December 2006 and enrolled HIV-infected patients with HIV-1 RNA 350 cells/mm3, and willing to interrupt ART. CD4 cell count, HIV-1 RNA, lipid profile, and lipodystrophy were assessed at baseline and every 3 months. ART was resumed when CD4 declined to 3 or developed HIV-related symptoms. Patients were grouped based on ART regimens [NNRTI or protease inhibitor (PI] prior to TI. Results There were 99 patients, 85 in NNRTI group and 14 in PI group. Mean age was 40.6 years; 46% were males. Median duration of ART was 47 months. Median nadir CD4 and baseline CD4 were 151 and 535 cells/mm3, respectively. Median CD4 change at 3 months after TI were -259 (NNRTI and -105 (PI cells/mm3 (p = 0.038. At 13-month median follow-up, there was no AIDS-defining illness; 38% (NNRTI and 29% (PI of patients developed HIV-related symptoms. ART was resumed in 51% (NNRTI and 36% (PI of patients (p = 0.022. By Kaplan-Meier analysis, median time to resume ART was 5.5 (NNRTI and 14.2 (PI months (log rank test, p = 0.026. By Cox's regression analysis, NNRTI-based ART (HR 4.9; 95%CI, 1.5–16.3, nadir CD4 3 (HR 2.7; 95%CI 1.4–5.3 and baseline CD4 3 (HR 1.6; 95%CI, 1.2–3.1 were predictors for early ART resumption. Conclusion TI of NNRTI-based ART leads to rapid CD4 decline and high

  17. Stability of the resistance to the thiosemicarbazone derived from 5,6-dimethoxy-1-indanone, a non-nucleoside polymerase inhibitor of bovine viral diarrhea virus.

    Directory of Open Access Journals (Sweden)

    Eliana F Castro

    Full Text Available Bovine viral diarrhea virus (BVDV is the prototype Pestivirus. BVDV infection is distributed worldwide and causes serious problems for the livestock industry. The thiosemicarbazone of 5,6-dimethoxy-1-indanone (TSC is a non-nucleoside polymerase inhibitor (NNI of BVDV. All TSC-resistant BVDV variants (BVDV-TSCr T1-5 present an N264D mutation in the NS5B gene (RdRp whereas the variant BVDV-TSCr T1 also presents an NS5B A392E mutation. In the present study, we carried out twenty passages of BVDV-TSCr T1-5 in MDBK cells in the absence of TSC to evaluate the stability of the resistance. The viral populations obtained (BVDV R1-5 remained resistant to the antiviral compound and conserved the mutations in NS5B associated with this phenotype. Along the passages, BVDV R2, R3 and R5 presented a delay in the production of cytopathic effect that correlated with a decrease in cell apoptosis and intracellular accumulation of viral RNA. The complete genome sequences that encode for NS2 to NS5B, Npro and Erns were analyzed. Additional mutations were detected in the NS5B of BVDV R1, R3 and R4. In both BVDV R2 and R3, most of the mutations found were localized in NS5A, whereas in BVDV R5, the only mutation fixed was NS5A V177A. These results suggest that mutations in NS5A could alter BVDV cytopathogenicity. In conclusion, the stability of the resistance to TSC may be due to the fixation of different compensatory mutations in each BVDV-TSCr. During their replication in a TSC-free medium, some virus populations presented a kind of interaction with the host cell that resembled a persistent infection: decreased cytopathogenicity and viral genome synthesis. This is the first report on the stability of antiviral resistance and on the evolution of NNI-resistant BVDV variants. The results obtained for BVDV-TSCr could also be applied for other NNIs.

  18. Selective killing of human immunodeficiency virus infected cells by non-nucleoside reverse transcriptase inhibitor-induced activation of HIV protease

    Directory of Open Access Journals (Sweden)

    Smeulders Liesbeth

    2010-10-01

    Full Text Available Abstract Background Current antiretroviral therapy against human immunodeficiency virus (HIV-1 reduces viral load and thereby prevents viral spread, but it cannot eradicate proviral genomes from infected cells. Cells in immunological sanctuaries as well as cells producing low levels of virus apparently contribute to a reservoir that maintains HIV persistence in the presence of highly active antiretroviral therapy. Thus, accelerated elimination of virus producing cells may represent a complementary strategy to control HIV infection. Here we sought to exploit HIV protease (PR related cytotoxicity in order to develop a strategy for drug induced killing of HIV producing cells. PR processes the viral Gag and Gag-Pol polyproteins during virus maturation, but is also implicated in killing of virus producing cells through off-target cleavage of host proteins. It has been observed previously that micromolar concentrations of certain non-nucleoside reverse transcriptase inhibitors (NNRTIs can stimulate intracellular PR activity, presumably by enhancing Gag-Pol dimerization. Results Using a newly developed cell-based assay we compared the degree of PR activation displayed by various NNRTIs. We identified inhibitors showing higher potency with respect to PR activation than previously described for NNRTIs, with the most potent compounds resulting in ~2-fold increase of the Gag processing signal at 250 nM. The degree of enhancement of intracellular Gag processing correlated with the compound's ability to enhance RT dimerization in a mammalian two-hybrid assay. Compounds were analyzed for their potential to mediate specific killing of chronically infected MT-4 cells. Levels of cytotoxicity on HIV infected cells determined for the different NNRTIs corresponded to the relative degree of drug induced intracellular PR activation, with CC50 values ranging from ~0.3 μM to above the tested concentration range (10 μM. Specific cytotoxicity was reverted by addition

  19. Efficacy of Pravastatin in Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI and Protease Inhibitor (PI-based HAART in HIV-Infected Patients

    Directory of Open Access Journals (Sweden)

    Susan A. Eaton

    2008-01-01

    Full Text Available Pravastatin has generally been considered a safe and effective option for HIV-infected patients on highly active antiretroviral therapy (HAART. However, pravastatin concentrations are known to significantly decrease with concomitant efavirenz (EFV use. Currently there are no studies determining if these reductions in pravastatin possibly translate into an attenuation of its lipid lowering efficacy when used in HIV-infected patients on non-nucleoside reverse transcriptase inhibitor (NNRTI-based HAART. To evaluate the differences in the lipid lowering efficacy of pravastatin for the treatment of dyslipidemia in HIV-infected patients on NNRTI-based HAART compared to protease inhibitor (PI-based regimens. A single center, retrospective evaluation of a comprehensive electronic HIV registry that identified HIV-infected, Veterans Affairs (VA patients who received pravastatin 20 mg plus NNRTI or PI-based HAART from January 1997 to November 2006 who met the strict criteria for inclusion. A total of 18 patients [NNRTI (n = 7 and PI (n = 11] met the strict criteria for inclusion. In HIV-infected patients taking NNRTI-based HAART there was a reduction in TC by -10.1%, LDL by -12% and non-HDL by -12.2% within 6 months after starting pravastatin 20 mg. In HIV-infected patients taking PI-based HAART, there was a reduction in TC by -10.1%, in LDL by -21.1% and in non-HDL by -13.8% within 6 months after starting pravastatin 20 mg. In both groups, only one additional patient achieved their patient specific lipid goals. In either group these reductions were seen without any apparent adverse drug events or compromise to virologic or immunologic control. This initial evaluation suggests that pravastatin’s efficacy may be attenuated with NNRTIs versus PI-based HAART, possibly due to known reductions in pravastatin concentrations when administered with NNRTI-based regimens. These effects were seen without any apparent compromises to safety and should be validated in

  20. Stability of the resistance to the thiosemicarbazone derived from 5,6-dimethoxy-1-indanone, a non-nucleoside polymerase inhibitor of bovine viral diarrhea virus.

    Science.gov (United States)

    Castro, Eliana F; Campos, Rodolfo H; Cavallaro, Lucía V

    2014-01-01

    Bovine viral diarrhea virus (BVDV) is the prototype Pestivirus. BVDV infection is distributed worldwide and causes serious problems for the livestock industry. The thiosemicarbazone of 5,6-dimethoxy-1-indanone (TSC) is a non-nucleoside polymerase inhibitor (NNI) of BVDV. All TSC-resistant BVDV variants (BVDV-TSCr T1-5) present an N264D mutation in the NS5B gene (RdRp) whereas the variant BVDV-TSCr T1 also presents an NS5B A392E mutation. In the present study, we carried out twenty passages of BVDV-TSCr T1-5 in MDBK cells in the absence of TSC to evaluate the stability of the resistance. The viral populations obtained (BVDV R1-5) remained resistant to the antiviral compound and conserved the mutations in NS5B associated with this phenotype. Along the passages, BVDV R2, R3 and R5 presented a delay in the production of cytopathic effect that correlated with a decrease in cell apoptosis and intracellular accumulation of viral RNA. The complete genome sequences that encode for NS2 to NS5B, Npro and Erns were analyzed. Additional mutations were detected in the NS5B of BVDV R1, R3 and R4. In both BVDV R2 and R3, most of the mutations found were localized in NS5A, whereas in BVDV R5, the only mutation fixed was NS5A V177A. These results suggest that mutations in NS5A could alter BVDV cytopathogenicity. In conclusion, the stability of the resistance to TSC may be due to the fixation of different compensatory mutations in each BVDV-TSCr. During their replication in a TSC-free medium, some virus populations presented a kind of interaction with the host cell that resembled a persistent infection: decreased cytopathogenicity and viral genome synthesis. This is the first report on the stability of antiviral resistance and on the evolution of NNI-resistant BVDV variants. The results obtained for BVDV-TSCr could also be applied for other NNIs. PMID:24950191

  1. Smith, Adam (1723-90)

    DEFF Research Database (Denmark)

    Bouchet, Dominique

    2015-01-01

    Adam Smith is often said to have been the founder of the science of economics and the father of liberalism in the sphere of economics. In fact he was neither. He lived at a turning point in western economic and political history, one that was littered with disruptive developments. He came up...... with a masterful synthesis of the economic knowledge of his period and emphasized both the relative autonomy of these phenomena and their importance in terms of generating wealth from, and in the interests of, everyone. Nevertheless, Smith never denied the moral foundation of economic behavior....

  2. Role of ADAM10 and ADAM17 in CD16b Shedding Mediated by Different Stimulators

    Institute of Scientific and Technical Information of China (English)

    Sha Guo; Min Peng; Qing Zhao; Wei Zhang

    2012-01-01

    Objective To investigate the main proteinases responsible for CD16b shedding under different stimulators.Methods HEK293 cell line stably expressing CD16b was constructed by lentivirus system.The cell line was then overexpressed with a disintegrin and metalloproteinase 10 (ADAM10) or ADAM17,suppressed with short hairpin RNA of ADAM10 or ADAM17,and reconstituted with ADAMi0 or ADAM17,respectively.After each treatment,the cell line was stimulated with ionomycin or phorbol 12-myristate13-acetate (PMA) for 12 hours.The soluble CD 16b released from cell membrane was detected by immunoprecipition and immtmoblot.Quantitation was then implemented to compare the amount of soluble CD 16b in cell supernatant after stimulation.Results HEK293 cell line stably expressing CD16b was successfully established.When CD16b expressing cell line was overexpressed with ADAM1 0,shedding of CD 16b was increased after stimulation with ionomycin but not PMA; when the cell line overexpressed with ADAM 17,shedding of CD 16b was increased after stimulation with PMA but not ionomycin.Similarly,when ADAM10 was suppressed by short hairpin RNA,CD16b shedding was decreased after stimulation with ionomycin; when ADAM17 was suppressed by short hairpin RNA,CD16b shedding was decreased after stimulation with PMA.The shedding of CD16b was increased again when CD16b expressing cell line was reconstituted with ADAM10 and stimulated by ionomycin or reconstituted with ADAM 17 and stimulated by PMA.Conclusions Both ADAM10 and ADAM17 could shed CD16b,but they possess differed preferences.ADAM10 is the main sheddase under stimulation of ionomycin,while ADAM17 is the main sheddase under stimulation of PMA.

  3. ADAM 12 protease induces adipogenesis in transgenic mice

    DEFF Research Database (Denmark)

    Kawaguchi, Nobuko; Xu, Xiufeng; Tajima, Rie; Kronqvist, Pauliina; Sundberg, Christina; Loechel, Frosty; Albrechtsen, Reidar; Wewer, Ulla M

    2002-01-01

    ADAM 12 (meltrin-alpha) is a member of the ADAM (a disintegrin and metalloprotease) family. ADAM 12 functions as an active metalloprotease, supports cell adhesion, and has been implicated in myoblast differentiation and fusion. Human ADAM 12 exists in two forms: the prototype membrane-anchored pr...... adipogenic phenotype, suggesting a requirement for ADAM 12 protease activity. This is the first in vivo demonstration that an ADAM protease is involved in adipogenesis....

  4. Activation of ADAM 12 protease by copper

    DEFF Research Database (Denmark)

    Loechel, F; Wewer, Ulla M.

    2001-01-01

    Conversion of latent proteases to the active form occurs by various mechanisms characteristic for different protease families. Here we report that the disintegrin metalloprotease ADAM 12-S is activated by Cu(II). Copper activation is distinct from the cysteine switch component of latency......: elimination of the ADAM 12 cysteine switch by a point mutation in the propeptide had no effect on copper activation, whereas mutation of an unpaired cysteine residue in the catalytic domain resulted in a mutant form of ADAM 12-S that was insensitive to copper. This suggests a multi-step activation mechanism...

  5. Adam Smith’s contribution to secularisation

    Directory of Open Access Journals (Sweden)

    Petrus Simons

    2013-06-01

    Full Text Available This article examined several crucial themes in Adam Smith’s philosophy with the purpose of highlighting and assessing his contribution to the secularisation of Western society. The article, written from the perspective of reformational philosophy, begins with a brief biography and sketch of Adam Smith’s influence on modern society, followed by a summary of Ponti Venter’s view on Smith. This sets the scene for a discussion of Adam Smith’s project, his method of tackling it, and his views on systems, philosophy of history and the concept of philosophy.

  6. Cleavage Site Localization Differentially Controls Interleukin-6 Receptor Proteolysis by ADAM10 and ADAM17.

    Science.gov (United States)

    Riethmueller, Steffen; Ehlers, Johanna C; Lokau, Juliane; Düsterhöft, Stefan; Knittler, Katharina; Dombrowsky, Gregor; Grötzinger, Joachim; Rabe, Björn; Rose-John, Stefan; Garbers, Christoph

    2016-01-01

    Limited proteolysis of the Interleukin-6 Receptor (IL-6R) leads to the release of the IL-6R ectodomain. Binding of the cytokine IL-6 to the soluble IL-6R (sIL-6R) results in an agonistic IL-6/sIL-6R complex, which activates cells via gp130 irrespective of whether the cells express the IL-6R itself. This signaling pathway has been termed trans-signaling and is thought to mainly account for the pro-inflammatory properties of IL-6. A Disintegrin And Metalloprotease 10 (ADAM10) and ADAM17 are the major proteases that cleave the IL-6R. We have previously shown that deletion of a ten amino acid long stretch within the stalk region including the cleavage site prevents ADAM17-mediated cleavage, whereas the receptor retained its full biological activity. In the present study, we show that deletion of a triple serine (3S) motif (Ser-359 to Ser-361) adjacent to the cleavage site is sufficient to prevent IL-6R cleavage by ADAM17, but not ADAM10. We find that the impaired shedding is caused by the reduced distance between the cleavage site and the plasma membrane. Positioning of the cleavage site in greater distance towards the plasma membrane abrogates ADAM17-mediated shedding and reveals a novel cleavage site of ADAM10. Our findings underline functional differences in IL-6R proteolysis by ADAM10 and ADAM17. PMID:27151651

  7. Kellwood Company Finalizes Acquisition of ADAM

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    The Town and Country-based apparel company Kellwood Company announced its acquisition of ADAM according to Michael Kramer,Chief Executive Officer and President of Kellwood.This acquisition is the first in

  8. Adam Smith om språket

    OpenAIRE

    Sandelin, Bo

    2009-01-01

    Adam Smith on language. Like most 18th century scholars, Adam Smith was not restricted to one field. One of his interests, besides economics, was language, which may partly be a consequence of his Scottish origin and the low standing of the Scottish dialect. Smith's Lectures on Rhetoric and Belles Lettres deals with various aspects of language. Smith appears to be a purist, critical of French influence on the English language. Concerning rhetoric, different rules prevail for different kinds o...

  9. ADAM SMITH'S OPTIMISTIC TELEOLOGICAL VIEW OF HISTORY

    OpenAIRE

    Alvey, James E.

    2003-01-01

    Adam Smith's four-stage theory provides the framework for his writings on history. The fourth stage is the commercial epoch; the culmination of history in this stage is a key component in the conventional interpretation of Adam Smith as a prophet of commercialism. In two historical case studies Smith shows the capacity of commercial society to regenerate itself. This potent capacity suggests that commercial society is inevitable. At a certain point in time it also overcomes the major obstacle...

  10. ADAM9 Is a Novel Product of Polymorphonuclear Neutrophils

    DEFF Research Database (Denmark)

    Roychaudhuri, Robin; Hergrueter, Anja H; Polverino, Francesca;

    2014-01-01

    A disintegrin and a metalloproteinase domain (ADAM) 9 is known to be expressed by monocytes and macrophages. In this study, we report that ADAM9 is also a product of human and murine polymorphonuclear neutrophils (PMNs). ADAM9 is not synthesized de novo by circulating PMNs. Rather, ADAM9 protein is...... stored in the gelatinase and specific granules and the secretory vesicles of human PMNs. Unstimulated PMNs express minimal quantities of surface ADAM9, but activation of PMNs with degranulating agonists rapidly (within 15 min) increases PMN surface ADAM9 levels. Human PMNs produce small quantities of...... soluble forms of ADAM9. Surprisingly, ADAM9 degrades several extracellular matrix (ECM) proteins, including fibronectin, entactin, laminin, and insoluble elastin, as potently as matrix metalloproteinase-9. However, ADAM9 does not degrade types I, III, or IV collagen or denatured collagens in vitro. To...

  11. ADAM 12 Protease Induces Adipogenesis in Transgenic Mice

    OpenAIRE

    Kawaguchi, Nobuko; Xu, Xiufeng; Tajima, Rie; Kronqvist, Pauliina; Sundberg, Christina; Loechel, Frosty; Albrechtsen, Reidar; Wewer, Ulla M.

    2002-01-01

    ADAM 12 (meltrin-α) is a member of the ADAM (a disintegrin and metalloprotease) family. ADAM 12 functions as an active metalloprotease, supports cell adhesion, and has been implicated in myoblast differentiation and fusion. Human ADAM 12 exists in two forms: the prototype membrane-anchored protein, ADAM 12-L, and a shorter secreted form, ADAM 12-S. Here we report the occurrence of adipocytes in the skeletal muscle of transgenic mice in which overexpression of either form is driven by the musc...

  12. Differential gene expression in ADAM10 and mutant ADAM10 transgenic mice

    Directory of Open Access Journals (Sweden)

    Postina Rolf

    2009-02-01

    Full Text Available Abstract Background In a transgenic mouse model of Alzheimer disease (AD, cleavage of the amyloid precursor protein (APP by the α-secretase ADAM10 prevented amyloid plaque formation, and alleviated cognitive deficits. Furthermore, ADAM10 overexpression increased the cortical synaptogenesis. These results suggest that upregulation of ADAM10 in the brain has beneficial effects on AD pathology. Results To assess the influence of ADAM10 on the gene expression profile in the brain, we performed a microarray analysis using RNA isolated from brains of five months old mice overexpressing either the α-secretase ADAM10, or a dominant-negative mutant (dn of this enzyme. As compared to non-transgenic wild-type mice, in ADAM10 transgenic mice 355 genes, and in dnADAM10 mice 143 genes were found to be differentially expressed. A higher number of genes was differentially regulated in double-transgenic mouse strains additionally expressing the human APP[V717I] mutant. Overexpression of proteolytically active ADAM10 affected several physiological pathways, such as cell communication, nervous system development, neuron projection as well as synaptic transmission. Although ADAM10 has been implicated in Notch and β-catenin signaling, no significant changes in the respective target genes were observed in adult ADAM10 transgenic mice. Real-time RT-PCR confirmed a downregulation of genes coding for the inflammation-associated proteins S100a8 and S100a9 induced by moderate ADAM10 overexpression. Overexpression of the dominant-negative form dnADAM10 led to a significant increase in the expression of the fatty acid-binding protein Fabp7, which also has been found in higher amounts in brains of Down syndrome patients. Conclusion In general, there was only a moderate alteration of gene expression in ADAM10 overexpressing mice. Genes coding for pro-inflammatory or pro-apoptotic proteins were not over-represented among differentially regulated genes. Even a decrease of

  13. LRP1 shedding in human brain: roles of ADAM10 and ADAM17

    Directory of Open Access Journals (Sweden)

    Reiss Karina

    2009-04-01

    Full Text Available Abstract Background The low-density lipoprotein receptor-related protein 1 (LRP1 plays critical roles in lipid metabolism, cell survival, and the clearance of amyloid-β (Aβ peptide. Functional soluble LRP1 (sLRP1 has been detected in circulating human placenta; however, whether sLRP1 is also present in the central nervous system is unclear. Results Here we show that abundant sLRP1 capable of binding its ligands is present in human brain tissue and cerebral spinal fluid (CSF. Interestingly, the levels of sLRP1 in CSF are significantly increased in older individuals, suggesting that either LRP1 shedding is increased or sLRP1 clearance is decreased during aging. To examine potential effects of pathological ligands on LRP1 shedding, we treated MEF cells with Aβ peptide and found that LRP1 shedding was increased. ADAM10 and ADAM17 are key members of the ADAM family that process membrane-associated proteins including amyloid precursor protein and Notch. We found that LRP1 shedding was significantly decreased in MEF cells lacking ADAM10 and/or ADAM17. Furthermore, forced expression of ADAM10 increased LRP1 shedding, which was inhibited by ADAM-specific inhibitor TIMP-3. Conclusion Our results demonstrate that LRP1 is shed by ADAM10 and ADAM17 and functional sLRP1 is abundantly present in human brain and CSF. Dysregulated LRP1 shedding during aging could alter its function and may contribute to the pathogenesis of AD.

  14. Novel HIV-1 Non-nucleoside Reverse Transcriptase Inhibitor Agents: Optimization of Diarylanilines with High Potency against Wild-Type and Rilpivirine-Resistant E138K Mutant Virus.

    Science.gov (United States)

    Liu, Na; Wei, Lei; Huang, Li; Yu, Fei; Zheng, Weifan; Qin, Bingjie; Zhu, Dong-Qin; Morris-Natschke, Susan L; Jiang, Shibo; Chen, Chin-Ho; Lee, Kuo-Hsiung; Xie, Lan

    2016-04-28

    Three series (6, 13, and 14) of new diarylaniline (DAAN) analogues were designed, synthesized, and evaluated for anti-HIV potency, especially against the E138K viral strain with a major mutation conferring resistance to the new-generation non-nucleoside reverse transcriptase inhibitor drug rilpivirine (1b). Promising new compounds were then assessed for physicochemical and associated pharmaceutical properties, including aqueous solubility, log P value, and metabolic stability, as well as predicted lipophilic parameters of ligand efficiency, ligand lipophilic efficiency, and ligand efficiency-dependent lipophilicity indices, which are associated with ADME property profiles. Compounds 6a, 14c, and 14d showed high potency against the 1b-resistant E138K mutated viral strain as well as good balance between anti-HIV-1 activity and desirable druglike properties. From the perspective of optimizing future NNRTI compounds as clinical trial candidates, computational modeling results provided valuable information about how the R(1) group might provide greater efficacy against the E138K mutant. PMID:27070547

  15. ADAM10 negatively regulates neuronal differentiation during spinal cord development.

    Directory of Open Access Journals (Sweden)

    Xin Yan

    Full Text Available Members of the ADAM (a disintegrin and metalloprotease family are involved in embryogenesis and tissue formation via their proteolytic function, cell-cell and cell-matrix interactions. ADAM10 is expressed temporally and spatially in the developing chicken spinal cord, but its function remains elusive. In the present study, we address this question by electroporating ADAM10 specific morpholino antisense oligonucleotides (ADAM10-mo or dominant-negative ADAM10 (dn-ADAM10 plasmid into the developing chicken spinal cord as well as by in vitro cell culture investigation. Our results show that downregulation of ADAM10 drives precocious differentiation of neural progenitor cells and radial glial cells, resulting in an increase of neurons in the developing spinal cord, even in the prospective ventricular zone. Remarkably, overexpression of the dn-ADAM10 plasmid mutated in the metalloprotease domain (dn-ADAM10-me mimics the phenotype as found by the ADAM10-mo transfection. Furthermore, in vitro experiments on cultured cells demonstrate that downregulation of ADAM10 decreases the amount of the cleaved intracellular part of Notch1 receptor and its target, and increases the number of βIII-tubulin-positive cells during neural progenitor cell differentiation. Taken together, our data suggest that ADAM10 negatively regulates neuronal differentiation, possibly via its proteolytic effect on the Notch signaling during development of the spinal cord.

  16. Role of ADAMs in cancer formation and progression.

    LENUS (Irish Health Repository)

    Duffy, Michael J

    2012-02-01

    The ADAMs (a disintegrin and metalloproteinase) comprise a family of multidomain transmembrane and secreted proteins. One of their best-established roles is the release of biologically important ligands, such as tumor necrosis factor-alpha, epidermal growth factor, transforming growth factor-alpha, and amphiregulin. Because these ligands have been implicated in the formation and progression of tumors, it might be expected that the specific ADAMs involved in their release would also be involved in malignancy. Consistent with this hypothesis, emerging data from model systems suggest that ADAMs, such as ADAM-9, ADAM-12, ADAM-15, and ADAM-17, are causally involved in tumor formation\\/progression. In human cancer, specific ADAMs are up-regulated, with levels generally correlating with parameters of tumor progression and poor outcome. In preclinical models, selective ADAM inhibitors against ADAM-10 and ADAM-17 have been shown to synergize with existing therapies in decreasing tumor growth. The ADAMs are thus a new family of potential targets for the treatment of cancer, especially malignancies that are dependent on human epidermal growth factor receptor ligands or tumor necrosis factor-alpha.

  17. J. B. Adams Acting Director-General

    CERN Multimedia

    1960-01-01

    After the tragic death of Prof. C. J. Bakker, the Council of CERN held an emergency meeting on May 3, 1960. Following this session, Mr. F. de Rose, President of the Council of the European Organization for Nuclear Research, announced the appointment of Mr. J. B. Adams, Director of the PS division to the post of acting Director-General.

  18. MBS Analysis Of Kinetic Structures Using ADAMS

    DEFF Research Database (Denmark)

    Kirkegaard, Poul Henning; Nielsen, Søren R.K.

    2009-01-01

    The present paper considers multibody system (MBS) analysis of kinetic structures using the software package ADAMS. Deployable, foldable, expandable and reconfigurable kinetic structures can provide a change in the geometric morphology of the envelope by contributing to making it adaptable to e.g...

  19. Adam Smith and the Rhetoric of Style.

    Science.gov (United States)

    Moran, Michael G.

    Historians of rhetoric have generally accepted the view that Adam Smith rejected the principles of classical rhetoric. However, while there can be no doubt that Smith greatly truncated the five classical arts of rhetoric (invention, arrangement, style, memory, and delivery) by reducing his concerns largely to style and arrangement, he did not…

  20. Adam Smith, Religion, and Tuition Tax Credits.

    Science.gov (United States)

    Alexander, Kern

    1983-01-01

    Examines tuition tax credit programs in framework of Adam Smith's ideas on the economic impact of established churches. Finds that tuition tax credits would amount to state expenditures to relieve the financial burden of parochial school parents and would allow churches to invest commercially to maintain their charitable functions. (JW)

  1. Regulation und Transport der Disintegrin und Metalloproteinasen ADAM10 und ADAM17

    OpenAIRE

    Groth, Esther

    2016-01-01

    By mediating proteolytic shedding of several transmembrane proteins like growth factors, cytokines, adhesion molecules, and receptors on cell surface, the disintegrin and metalloproteinases ADAM10 and ADAM17 function as critical regulators of different diseases like Alzheimer, asthma, cardiovascular disease, cancer, and inflammation. Furthermore, they play a pivotal role in the regulation of embryogenesis and the development of an organism. Their own regulation is subject to several mechanism...

  2. ADAM "sequence" part II: hypothesis and speculation.

    Science.gov (United States)

    Opitz, John M; Johnson, Dennis R; Gilbert-Barness, Enid F

    2015-03-01

    Noted for centuries in humans, a relatively hairless mammal [e.g., Hallero, 1766; Hohl, 1828 in Klunker, 2003], the so-called amniotic deformities, adhesions, mutilations (ADAM) sequence remains causally and pathogenetically incognito. In 1930 Streeter stated " apodictically" that no evidence has been found that intra-uterine amputation is due to amniotic bands or adhesions …" and that his 16 cases provided (histological) evidence for a "germinal origin." He concluded that an amniotic cord was "not an adhesion or inflammatory product but … an anomalous developmental structure and present from the outset." In survivors the "traces" of damaged limb-buds "reveal the scars of poor germ-plasm." In 1958, Willis, in dismissing the amniotic origin of the ADAM defects (or "Streeter" or "Simonart" bands) quoted Keith [1940] to the effect that "(a)mniotic adhesions … are always produced by … the fetus – as a result of dysplasia in foetal tissues. They are the result, not the cause, of foetal malformations." Streeter [1930] mentions a potential familial case (56-year-old man and his mother), not controlled by photographs or other records and concluded "that the (ADAM) deformity is not easily transmissible," but "due to the constitution of the germ-plasm." Torpin [1968] concluded, as apodictically as Streeter and Willis, that "… proof of amnion rupture without damage to the chorionic sac is no longer "in question." Considering Torpin's decades-long study of the ADAM phenomenon and review of 494 references (missing many) it is surprising that he does not discuss the relationship between the apparent ADAM defects and other, internal anomalies that maybe present in an affected fetus or infant not evidently caused by the amniotic disruptions, adhesions or mutilations, unless his mind was made up. Our review of these internal and other presumed primary malformations in ADAM is ongoing. However, on a preliminary basis, it seems likely to us that: (1) there is an increased

  3. Cellular roles of ADAM12 in health and disease

    DEFF Research Database (Denmark)

    Kveiborg, Marie; Albrechtsen, Reidar; Couchman, John R; Wewer, Ulla M

    2008-01-01

    and it is a potential biomarker for breast cancer. It is therefore important to understand ADAM12's functions. Many cellular roles for ADAM12 have been suggested. It is an active metalloprotease, and has been implicated in insulin-like growth factor (IGF) receptor signaling, through cleavage of IGF...... transmitting signals to or from the cell interior. These ADAM12-mediated cellular effects appear to be critical events in both biological and pathological processes. This review presents current knowledge on ADAM12 functions gained from in vitro and in vivo observations, describes ADAM12's role in both normal...... physiology and pathology, particularly in cancer, and discusses important areas for future investigation....

  4. Catalytic properties of ADAM12 and its domain deletion mutants

    DEFF Research Database (Denmark)

    Jacobsen, Jonas; Visse, Robert; Sørensen, Hans Peter; Enghild, Jan J; Brew, Keith; Wewer, Ulla M; Nagase, Hideaki

    2008-01-01

    affinity (9-44 nM). However, TIMP-1 is a much weaker inhibitor. N-TIMP-3 variants that lack MMP inhibitory activity but retained the ability to inhibit ADAM17/TACE failed to inhibit ADAM12. These results indicate unique enzymatic properties of ADAM12 among the members of the ADAM family of......Human ADAM12 (a disintegrin and metalloproteinase) is a multidomain zinc metalloproteinase expressed at high levels during development and in human tumors. ADAM12 exists as two splice variants: a classical type 1 membrane-anchored form (ADAM12-L) and a secreted splice variant (ADAM12-S) consisting...... active on this substrate. It was also observed that NaCl inhibits ADAM12. Among the tissue inhibitors of metalloproteinases (TIMP) examined, the N-terminal domain of TIMP-3 (N-TIMP-3) inhibits ADAM12-S and ADAM12-PC with low nanomolar Ki(app) values while TIMP-2 inhibits them with a slightly lower...

  5. Molecular profiling of ADAM12 in human bladder cancer

    DEFF Research Database (Denmark)

    Frolich, Camilla; Albrechtsen, Reidar; Andersen, Lars Dyrskjøt; Rudkjær, Lise; Ørntoft, Torben Falck; Wewer, Ulla M.

    2006-01-01

    PURPOSE: We have previously found ADAM12, a disintegrin and metalloprotease, to be an interesting biomarker for breast cancer. The purpose of this study was to determine the gene and protein expression profiles of ADAM12 in different grades and stages of bladder cancer. EXPERIMENTAL DESIGN: ADAM12...... staining on tissue arrays of bladder cancers. The presence and relative amount of ADAM12 in the urine of cancer patients were determined by Western blotting and densitometric measurements, respectively. RESULTS: ADAM12 mRNA expression was significantly up-regulated in bladder cancer, as determined by...... could be detected in the urine by Western blotting; ADAM12 was present in higher levels in the urine from patients with bladder cancer compared with urine from healthy individuals. Significantly, following removal of tumor by surgery, in most bladder cancer cases examined, the level of ADAM12 in the...

  6. ADAM (Affordable Desktop Application Manager): a Unix desktop application manager

    International Nuclear Information System (INIS)

    ADAM stands for Affordable Desktop Application Manager. It is a GUI developed at CERN with the aim to ease access to applications. The motivation to develop ADAM came from the unavailability of environments like COSE/CDE and their heavy resource consumption. ADAM has proven to be user friendly: new users are able to customize it to their needs in few minutes. Groups of users may share through ADAM a common application environment. ADAM also integrates the Unix and the PC world. PC users can excess Unix applications in the same way as their usual Windows applications. This paper describes all the ADAM features, how they are used at CERN Public Services, and the future plans for ADAM. (author)

  7. Induction with lopinavir-based treatment followed by switch to nevirapine-based regimen versus non-nucleoside reverse transcriptase inhibitors-based treatment for first line antiretroviral therapy in HIV infected children three years and older.

    Directory of Open Access Journals (Sweden)

    Gerardo Alvarez-Uria

    Full Text Available The World Health Organization recommends non-nucleoside reverse transcriptase inhibitors (NNRTIs-based antiretroviral therapy (ART for children three years and older. In younger children, starting ART with lopinavir boosted with ritonavir (LPVr results in lower risk of virological failure, but data in children three years and older are scarce, and long-term ART with LPVr is problematic in resource-poor settings.Retrospective cohort of children three years and older who started triple ART including LPVr or a NNRTI between 2007 and 2013 in a rural setting in India. Children who started LPVr were switched to nevirapine-based ART after virological suppression. We analysed two outcomes, virological suppression (HIV-RNA 1000 copies/ml after virological suppression using Cox proportional hazard regression. A sensitivity analysis was performed using inverse probability of treatment weighting (IPTW based of propensity score methods.Of 325 children having a viral load during the first year of ART, 74/83 (89.2% in the LPVr group achieved virological suppression versus 185/242 (76.5% in the NNRTI group. In a multivariable analysis, the use of LPVr-based ART was associated with higher probability of virological suppression (adjusted odds ratio 3.19, 95% confidence interval [CI] 1.11-9.13. After IPTW, the estimated risk difference was 12.2% (95% CI, 2.9-21.5. In a multivariable analysis including 292 children who had virological suppression and available viral loads after one year of ART, children switched from LPVr to nevirapine did not have significant higher risk of virological failure (adjusted hazard ratio 1.18, 95% CI 0.36-3.81.In a cohort of HIV infected children three years and older in a resource-limited setting, an LPVr induction- nevirapine maintenance strategy resulted in more initial virological suppression and similar incidence of virological failure after initial virological suppression than NNRTI-based regimens.

  8. Estudio Teórico Preliminar de Fármacos Anti-VIH, Inhibidores No Nucleosídicos de la Transcriptasa Reversa Preliminary Theoretical Study on HIV-1, Non-Nucleoside Reverse Transcriptase Inhibitors

    Directory of Open Access Journals (Sweden)

    Martín A Dragonetti

    2008-01-01

    Full Text Available Una serie de compuestos derivados de quinoxalina, benzoxazina y benzodiazepina fue utilizada para realizar un estudio teórico preliminar que permita plantear un potencial grupo farmacóforo que conduzca a la síntesis de posibles inhibidores no-nucleosídicos de la transcriptasa reversa del virus del SIDA. El estudio teórico se llevó a cabo utilizando modelado molecular asistido por computadora. Se analizaron las conformaciones obtenidas para los compuestos en estudio (densidad atómica de carga y del arreglo espacial de los grupos atómicos. Los resultados se compararon con la información aportada por los complejos cristalográficos (fármaco-transcriptasa reversa extraídos de una base de datos de proteínas. Este estudio permitió establecer los requerimientos esenciales para que un compuesto se comporte como inhibidor de la transcriptasa reversa del VIH-1 y encontrar el potencial farmacóforo común a este tipo de fármacos.A series of quinoxaline, benzooxazine and benzodiazepine derivatives was selected to perform a preliminary theoretical study tending to find a potential pharmacophoric group that could lead to the synthesis of non nucleoside inhibitors of the HIV-1 reverse transcriptase. The theoretical study was performed using computer-assisted molecular modeling. The achieved final conformations of the selected compounds were compared and analyzed in terms of the atomic charge density and the atomic groups arrangements. The results were compared with information extracted from the crystallographic complexes (drug-reverse transcriptase reported in a protein data bank. This analysis enables to establish the essential requirements for a compound inhibition behavior of the HIV-1 reverse transcriptase and to find a potential pharmacophore common to this type of compounds.

  9. Long-term effectiveness of initiating non-nucleoside reverse transcriptase inhibitor- versus ritonavir-boosted protease inhibitor-based antiretroviral therapy: implications for first-line therapy choice in resource-limited settings

    Directory of Open Access Journals (Sweden)

    Viviane D Lima

    2016-08-01

    Full Text Available Introduction: In many resource-limited settings, combination antiretroviral therapy (cART failure is diagnosed clinically or immunologically. As such, there is a high likelihood that patients may stay on a virologically failing regimen for a substantial period of time. Here, we compared the long-term impact of initiating non-nucleoside reverse transcriptase inhibitor (NNRTI- versus boosted protease inhibitor (bPI-based cART in British Columbia (BC, Canada. Methods: We followed prospectively 3925 ART-naïve patients who started NNRTIs (N=1963, 50% or bPIs (N=1962; 50% from 1 January 2000 until 30 June 2013 in BC. At six months, we assessed whether patients virologically failed therapy (a plasma viral load (pVL >50 copies/mL, and we stratified them based on the pVL at the time of failure ≤500 versus >500 copies/mL. We then followed these patients for another six months and calculated their probability of achieving subsequent viral suppression (pVL 500 copies/mL, they had a 20% lower probability of suppressing at 12 months than pVL-matched bPI initiators (0.37 (0.29–0.45 vs. 0.46 (0.38–0.54. In terms of evolving HIV drug resistance, those who failed on NNRTI performed worse than bPI in all scenarios, especially if they failed with a viral load >500 copies/mL. Conclusions: Our results show that patients who virologically failed at six months on NNRTI and continued on the same regimen had a lower probability of subsequently achieving viral suppression and a higher chance of evolving HIV drug resistance. These results suggest that improving access to regular virologic monitoring is critically important, especially if NNRTI-based cART is to remain a preferred choice for first-line therapy in resource-limited settings.

  10. Residue-Ligand Interaction Energy (ReLIE on a Receptor-Dependent 3D-QSAR Analysis of S- and NH-DABOs as Non-Nucleoside Reverse Transcriptase Inhibitors

    Directory of Open Access Journals (Sweden)

    Monique Araújo de Brito

    2012-06-01

    Full Text Available A series of 74 dihydroalkoxybenzyloxopyrimidines (DABOs, a class of highly potent non-nucleoside reverse transcriptase inhibitors (NNRTIs, was retrieved from the literature and studied by receptor-dependent (RD three-dimensional quantitative structure-activity relationship (3D-QSAR analysis to derive RD-3D-QSAR models. The descriptors in this new method are the steric and electrostatic interaction energies of the protein-ligand complexes (per residue simulated by molecular dynamics, an approach named Residue-Ligand Interaction Energy (ReLIE. This study was performed using a training set of 59 compounds and the MKC-442/RT complex structure as reference. The ReLIE-3D-QSAR models were constructed and evaluated by genetic algorithm (GA and partial least squares (PLS. In the best equations, at least one term is related to one of the amino acid residues of the p51 subunit: Asn136, Asn137, Glu138, and Thr139. This fact implies the importance of interchain interaction (p66-p51 in the equations that best describe the structure-activity relationship for this class of compounds. The best equation shows q2 = 0.660, SEcv = 0.500, r2 = 0.930, and SEE = 0.226. The external predictive ability of this best model was evaluated using a test set of 15 compounds. In order to design more potent DABO analogues as anti-HIV/AIDS agents, substituents capable of interactions with residues like Ile94, Lys101, Tyr181, and Tyr188 should be selected. Also, given the importance of the conserved Asn136, this residue could become an attractive target for the design of novel NNRTIs with improved potency and increased ability to avoid the development of drug-resistant viruses.

  11. 3d-tuotekuva Case Adams Oy

    OpenAIRE

    Dergaeva, Marija

    2010-01-01

    Tässä toiminnallisessa opinnäytetyössä tutkittiin tuotevisualisoinnin haasteita ja tavoitteita käyttäen esimerkkeinä työnäytteitä mainostoimisto Adams OY:lle sekäsen asiakkaille Altialle ja Olville tehtävistä visualisoinneista. Visualisointitehtäviin kuuluivat pääasiassa juomia sisältävät tuotteet ja pakkaukset. Työssä keskityttiin tutkimaan still-kuvia, sillä ne ovat Adams Oy:llä tärkein osa. Tavoitteena oli luoda tuotekuva tehokkaasti ja toimivasti selventäen samalla työprosessia sekä tekni...

  12. SOBRE A FILOSOFIA MORAL DE ADAM SMITH

    OpenAIRE

    Hugo E. A. da Gama Cerqueira

    2006-01-01

    This article examines Adam Smith’s Theory of moral sentiments. Taking as its point of departure the moral philosophy of the Scottish enlightenment, the paper presents the central argument of Smith’s Theory. It analyses the concepts of “sympathy” and “impartial spectator” and points to the originality of Smith’s argument on the relationship between morality and sociality.

  13. Adam Smith: Anthropology and Moral Philosophy

    OpenAIRE

    Lázaro-Cantero, R. (Raquel)

    2010-01-01

    Adam Smith was a moral philosopher. His economic and legal thought can't be separated from his moral psychology which frames his anthropological and social proposal. Experimental Newtonian methodology and Hume's empirism feed his approximation to the reality of human being. In this new context the traditional categories of society are defined and combined in a new way. In this paper I try to argue that the assumed optimism which sometimes is attributed to Smith about the proper functioning of...

  14. Reduction of the disintegrin and metalloprotease ADAM12 in preeclampsia

    DEFF Research Database (Denmark)

    Laigaard, Jennie; Sørensen, Tina; Placing, Sophie; Holck, Peter; Frohlich, Camilla; Wøjdemann, Karen R; Sundberg, Karin; Shalmi, Anne-Cathrine; Tabor, Ann; Nørgaard-Pedersen, Bent; Ottesen, Bent; Christiansen, Michael; Wewer, Ulla M

    2005-01-01

    OBJECTIVES: The secreted form of ADAM12 is a metalloprotease that may be involved in placental and fetal growth. We examined whether the concentration of ADAM12 in first-trimester maternal serum could be used as a marker for preeclampsia. METHODS: We developed a semiautomated, time-resolved, immu......OBJECTIVES: The secreted form of ADAM12 is a metalloprotease that may be involved in placental and fetal growth. We examined whether the concentration of ADAM12 in first-trimester maternal serum could be used as a marker for preeclampsia. METHODS: We developed a semiautomated, time......-resolved, immunofluorometric assay for the quantification of ADAM12 in serum. The assay detected ADAM12 in a range of 78-1248 microg/L. Serum samples derived from women in the first trimester of a normal pregnancy (n = 324) and from women who later developed preeclampsia during pregnancy (n = 160) were obtained from the First...... Trimester Copenhagen Study. ADAM12 levels were assayed in these serum samples. Serum levels of ADAM12 were converted to multiples of the median (MoM) after log-linear regression of concentration versus gestational age. RESULTS: Serum ADAM12 levels in women who developed preeclampsia during pregnancy had a...

  15. Effectiveness of non-nucleoside reverse-transcriptase inhibitor-based antiretroviral therapy in women previously exposed to a single intrapartum dose of nevirapine: a multi-country, prospective cohort study.

    Directory of Open Access Journals (Sweden)

    Jeffrey S A Stringer

    2010-02-01

    Full Text Available BACKGROUND: Intrapartum and neonatal single-dose nevirapine (NVP reduces the risk of mother-to-child HIV transmission but also induces viral resistance to non-nucleoside reverse transcriptase inhibitor (NNRTI drugs. This drug resistance largely fades over time. We hypothesized that women with a prior single-dose NVP exposure would have no more than a 10% higher cumulative prevalence of failure of their NNRTI-containing antiretroviral therapy (ART over the first 48 wk of therapy than would women without a prior exposure. METHODS AND FINDINGS: We enrolled 355 NVP-exposed and 523 NVP-unexposed women at two sites in Zambia, one site in Kenya, and two sites in Thailand into a prospective, non-inferiority cohort study and followed them for 48 wk on ART. Those who died, discontinued NNRTI-containing ART, or had a plasma viral load >or=400 copies/ml at either the 24 wk or 48 wk study visits and confirmed on repeat testing were characterized as having failed therapy. Overall, 114 of 355 NVP-exposed women (32.1% and 132 of 523 NVP-unexposed women (25.2% met criteria for treatment failure. The difference in failure rates between the exposure groups was 6.9% (95% confidence interval [CI] 0.8%-13.0%. The failure rates of women stratified by our predefined exposure interval categories were as follows: 47 of 116 women in whom less than 6 mo elapsed between exposure and starting ART failed therapy (40%; p<0.001 compared to unexposed women; 25 of 67 women in whom 7-12 mo elapsed between exposure and starting ART failed therapy (37%; p = 0.04 compared to unexposed women; and 42 of 172 women in whom more than 12 mo elapsed between exposure and starting ART failed therapy (24%; p = 0.82 compared to unexposed women. Locally weighted regression analysis also indicated a clear inverse relationship between virologic failure and the exposure interval. CONCLUSIONS: Prior exposure to single-dose NVP was associated with an increased risk of treatment failure; however, this

  16. From Adam Swift to Adam Smith: How the "Invisible Hand" Overcomes Middle Class Hypocrisy

    Science.gov (United States)

    Tooley, James

    2007-01-01

    This paper challenges Richard Pring's suggestion that parents using private education may be undermining the desire for social justice and equality, using recent arguments of Adam Swift as a springboard. Swift's position on the banning of private schools, which uses a Rawlsian "veil of ignorance" argument, is explored, and it is suggested that, if…

  17. Para ler Adam Smith: novas abordagens [Reading Adam Smith: new approaches

    OpenAIRE

    Hugo E. A. da Gama Cerqueira

    2003-01-01

    A new comprehension of Adam Smith's writings arose in the last years. These studies emphasized the political and ethical dimensions of his work and its connection with the eighteenth-century context. This article reviews the historical reception of Smith's works and discusses the recent literature about the relation between his moral philosophy and political economy.

  18. Adam Michnik: kriisis Euroopat ohustab rahvuslik egoism / Adam Michnik ; interv. Külli-Riin Tigasson

    Index Scriptorium Estoniae

    Michnik, Adam, 1946-

    2009-01-01

    Poola suurima kvaliteetlehe Gazeta Wyborczka petoimetaja Adam Michnik vastab küsimustele, mis puudutavad 2008. aastal alanud majanduskriisi, protektsionismi ja egoismi levikut, Ida-Euroopas levinud poliitilise ja majandusliku mudeli ümber hindamist, ladinaameerikalikku putinismi ja antikommunistlikku autoritaarsust ning trükiajakirjanduse tulevikku internetiajastul. Vt. samas: Elulugu

  19. Kisah Adam dalam Literatur Muslim Indonesia

    Directory of Open Access Journals (Sweden)

    Ismatu Ropi

    2014-03-01

    Full Text Available Buku yang ditulis oleh Steenbrink kali ini berupaya membuktikan sebuah hipotesis bahwa betapapun berasal dari sumber yang sama, Al-Qur'an dan Hadits, kisah Adam dalam tradisi Islam di Asia Tenggara mengalami proses pengkayaan orang sangat luar biasa dan tentunya dalam beberapa hal sangat berbeda dengan apa yang dipotret oleh kedua sumber ajaran Islam itu sendiri. Selain itu, sebagaimana terungkap dalam pendahuluan buku, karya ini berupaya mengklarifikasi kemungkinan adanya persamaan dan kesinambungan antara Yahudi, Kristen, dan Islam sebagai agama-agama Ibrahim (Abrahamic religions.Copyright (c 2014 by SDI. All right reserved.DOI: 10.15408/sdi.v6i2.735

  20. ADAM SMITH: THE INVISIBLE HAND OR CONFIDENCE

    OpenAIRE

    Fernando Luis, Gache; Dino, Otero

    2010-01-01

    In 1776 Adam Smith raised the matter that an invisible hand was the one which moved the markets to obtain its efficiency. Despite in the present paper we are going to raise the hypothesis, that this invisible hand is in fact the confidence that each person feels when he is going to do business. That in addition it is unique, because it is different from the confidence of the others and that is a variable nonlinear that essentially is ligatured to respective personal histories. For that we are...

  1. Adam Smith et la banque libre

    OpenAIRE

    Le Maux, Laurent

    2002-01-01

    Smith is the forerunner of the free banking theory. Smith develop the law of reflux which asserts that private banks cannot over-issue because the convertibility rule and the market mechanism induce banks to supply just the amount of money that public want to hold. The real bills doctrine of Adam Smith has been misinterpreted and just propose a solution to the law of reflux. Smith is a forerunner too of information asymmetry theory. He shows that banks are confronted with information asymmetr...

  2. ADAM SMITH, UN LIBERALISMO BIEN TEMPERADO

    OpenAIRE

    Roland Pfefferkorn

    2008-01-01

    Gracias a la inmensa fortuna que ha conocido Enquiry into the Nature and Causes of the Wealth of Nations, Adam Smith es considerado como el "padre fundador" de la economía política clásica. Una lectura rápida de la obra ha permitido a veces hacer del célebre economista un pensador simplemente liberal, en una acepción parcial de la palabra. La Riqueza de las naciones merece una lectura cuidadosa. Aunque Smith es conocido principalmente como economista político, no hay que olvidar que fue titul...

  3. 50 Years of synchrotrons Adams' Memorial lecture

    CERN Document Server

    Lawson, J D; CERN. Geneva

    1996-01-01

    Fifty years ago Frank Goward of the Atomic Energy Research Establishment Group at Malvern converted a small American betatron to make the worldÕs first synchrotron. At the same time Marcus Oliphant was planning to build at Birmingham a large proton machine with a ring magnet and variable magnetic field. Ideas for this had come to him during night-shifts tending the electromagnetic separators at Oak Ridge during the war. Some seven years later, in 1953, a group gathered together in Geneva to build the PS. A major contributor to the design work which had made this possible was John Adams. An account of some of the achievements in these eventful years will be presented. CERN has built nine synchrotrons/colliders and two temporary test rings. Eight machines are still running. The review will start with the PS, the first proton synchrotron based on the alternating gradient principle invented in 1952 at BNL. The design work of the PS team, under the enlightened leadership of J.B. Adams, and the construction of the...

  4. The Failed Educations of John Stuart Mill and Henry Adams.

    Science.gov (United States)

    Crossley, Robert

    1979-01-01

    Analyzes and contrasts Mill's "Autobiography" and Adams'"The Education of Henry Adams" in order to present two approaches to the nature of education and of failure. Maintains that their perspectives may serve as catalysts and cautions for contemporary theories of education and its utility and relevance. (CAM)

  5. A brief critique of the Adam-Gibbs entropy model

    DEFF Research Database (Denmark)

    Dyre, J. C.; Hecksher, Tina; Niss, Kristine

    This paper critically discusses the entropy model proposed by Adam and Gibbs in 1965 for the dramatic temperature dependence of glass-forming liquids' average relaxation time, which is one of the most influential models during the last four decades. We discuss the Adam-Gibbs model's theoretical b...

  6. Targeting ADAM12 in human disease: head, body or tail?

    DEFF Research Database (Denmark)

    Jacobsen, J; Wewer, U M

    2009-01-01

    insulin-like growth factor receptor signaling. The body of the protein (consisting of the disintegrin, cysteine-rich, and EGF-like domains) is involved in contacts with the extracellular matrix and other cells through interactions with integrins and syndecans. Finally, the tail of the protein (consisting......ADAM12/meltrin alpha is a type I transmembrane multidomain protein involved in tumor progression and other severe diseases, including osteoarthritis, and as such could be considered as a potential drug target. In addition to protease activity, ADAM12 possesses cell binding and cell signaling...... of the cytoplasmic domain) is engaged in interactions with intracellular signaling molecules. In many studies, ADAM12 overexpression has been correlated with disease, and ADAM12 has been shown to promote tumor growth and progression in cancer. On the other hand, protective effects of ADAM12 in...

  7. Helping Eve Overcome ADAM: G-Quadruplexes in the ADAM-15 Promoter as New Molecular Targets for Breast Cancer Therapeutics

    Directory of Open Access Journals (Sweden)

    Robert V. Brown

    2013-12-01

    Full Text Available ADAM-15, with known zymogen, secretase, and disintegrin activities, is a catalytically active member of the ADAM family normally expressed in early embryonic development and aberrantly expressed in various cancers, including breast, prostate and lung. ADAM-15 promotes extracellular shedding of E-cadherin, a soluble ligand for the HER2/neu receptor, leading to activation, increased motility, and proliferation. Targeted downregulation of both ADAM-15 and HER2/neu function synergistically kills breast cancer cells, but to date there are no therapeutic options for decreasing ADAM-15 function or expression. In this vein, we have examined a unique string of guanine-rich DNA within the critical core promoter of ADAM-15. This region of DNA consists of seven contiguous runs of three or more consecutive guanines, which, under superhelical stress, can relax from duplex DNA to form an intrastrand secondary G-quadruplex (G4 structure. Using biophysical and biological techniques, we have examined the G4 formation within the entire and various truncated regions of the ADAM-15 promoter, and demonstrate strong intrastrand G4 formation serving to function as a biological silencer element. Characterization of the predominant G4 species formed within the ADAM-15 promoter will allow for specific drug targeting and stabilization, and the further development of novel, targeted therapeutics.

  8. Human and Murine Interleukin 23 Receptors Are Novel Substrates for A Disintegrin and Metalloproteases ADAM10 and ADAM17.

    Science.gov (United States)

    Franke, Manuel; Schröder, Jutta; Monhasery, Niloufar; Ackfeld, Theresa; Hummel, Thorben M; Rabe, Björn; Garbers, Christoph; Becker-Pauly, Christoph; Floss, Doreen M; Scheller, Jürgen

    2016-05-13

    IL-23 (interleukin 23) regulates immune responses against pathogens and plays a major role in the differentiation and maintenance of TH17 cells and the development of autoimmune diseases and cancer. The IL-23 receptor (IL-23R) complex consists of the unique IL-23R and the common IL-12 receptor β1 (IL-12Rβ1). Differential splicing generates antagonistic soluble IL-23R (sIL-23R) variants, which might limit IL-23-mediated immune responses. Here, ectodomain shedding of human and murine IL-23R was identified as an alternative pathway for the generation of sIL-23R. Importantly, proteolytically released sIL-23R has IL-23 binding activity. Shedding of IL-23R was induced by stimulation with the phorbol ester phorbol 12-myristate 13-acetate (PMA), but not by ionomycin. PMA-induced shedding was abrogated by an ADAM (A disintegrin and metalloprotease) 10 and 17 selective inhibitor, but not by an ADAM10 selective inhibitor. ADAM17-deficient but not ADAM10-deficient HEK293 cells failed to shed IL-23R after PMA stimulation, demonstrating that ADAM17 but not ADAM10 cleaves the IL-23R. Constitutive shedding was, however, inhibited by an ADAM10 selective inhibitor. Using deletions and specific amino acid residue exchanges, we identified critical determinants of ectodomain shedding within the stalk region of the IL-23R. Finally, interaction studies identified domains 1 and 3 of the IL-23R as the main ADAM17 binding sites. In summary, we describe human and murine IL-23R as novel targets for protein ectodomain shedding by ADAM10 and ADAM17. PMID:26961870

  9. John Adams and CERN: Personal Recollections

    CERN Document Server

    Brianti, Giorgio

    2013-01-01

    By any standards, John Adams had a most remarkable career. He was involved in three important, emerging technologies, radar, particle accelerators and controlled fusion, and had an outstanding impact on the last two. Without a university education, he attained hierarchical positions of the highest level in prestigious national and international organizations. This article covers the CERN part of his career, by offering some personal insights into the different facets of his contributions to major accelerator projects, from the first strong-focusing synchrotron, the PS, to the SPS and its conversion to a proton–antiproton collider. In particular, it outlines his abilities as a leader of an international collaboration, which has served as an example for international initiatives in other disciplines.

  10. Luhmann Receives 2007 John Adam Fleming Medal

    Science.gov (United States)

    Russell, Christopher T.; Luhmann, Janet G.

    2008-02-01

    This year's John Adam Fleming medalist quickly established a reputation as an innovative and productive scientist with a broad range of interests. She made early and seminal contributions to aeronomy, cosmic rays, and magnetospheric and planetary physics. She contributed importantly to the understanding of the interaction of the solar wind with the atmosphere and magnetic fields of Mercury, Venus, Earth, and Mars. She has examined the behavior of planetary rings, the interaction of interstellar neutrals with heliospheric plasmas, as well as the interaction of planetary neutrals with the heliosphere. She has led in the study of the interaction of the moon Titan with the Saturn magnetosphere, and most recently she developed a vigorous solar physics effort, leading the implementation of the IMPACT particle and field package on the twin STEREO mission, now entering its second year of successful operation.

  11. Human ADAM 12 (meltrin alpha) is an active metalloprotease

    DEFF Research Database (Denmark)

    Loechel, F; Gilpin, B J; Engvall, E; Albrechtsen, R; Wewer, U M

    1998-01-01

    in a latent form, probably by means of a cysteine switch. The zymogen could be activated chemically by alkylation with N-ethylmaleimide. Cleavage of the prodomain at a site for a furin-like endopeptidase resulted in an ADAM 12 protein with proteolytic activity. The protease activity was sensitive to...... 12 is catalytically active. We used the trapping mechanism of alpha2-macroglobulin to assay for protease activity of wild-type and mutant ADAM 12 proteins produced in a COS cell transfection system. We found that ADAM 12 is synthesized as a zymogen, with the prodomain maintaining the metalloprotease...

  12. Adam Smith and the Invisible Hand: From Metaphor to Myth

    OpenAIRE

    Gavin Kennedy

    2009-01-01

    Adam Smith and the ‘invisible hand’ are nearly synonymous in modern economic thinking. Adam Smith is strongly associated with the invisible hand, understood as a general rule that people in realising their self-interests unintentionally benefit the public good. The attribution to Smith is challengeable. Adam Smith’s use of the metaphor was much more modest; it was re-invented in the 1930s and 1940s onwards to bolster mathematical treatments of capitalism (Samuelson, Friedman) and to sup...

  13. Molecular profiling of ADAM12 in human bladder cancer

    DEFF Research Database (Denmark)

    Albrechtsen, Reidar; Dyrskjøt, Lars; Rudkjaer, Lise;

    2006-01-01

    gene expression was evaluated in tumors from 96 patients with bladder cancer using a customized Affymetrix GeneChip. Gene expression in bladder cancer was validated using reverse transcription-PCR, quantitative PCR, and in situ hybridization. Protein expression was evaluated by immunohistochemical...... microarray analysis, and the level of ADAM12 mRNA correlated with disease stage. Reverse transcription-PCR, quantitative PCR, and in situ hybridization validated the gene expression results. Using immunohistochemistry, we found ADAM12 protein expression correlated with tumor stage and grade. Finally, ADAM12...

  14. ADAM15 expression is downregulated in melanoma metastasis compared to primary melanoma

    International Nuclear Information System (INIS)

    Research highlights: → Strong ADAM15 expression is found in normal melanocytes. → ADAM15 expression is significantly downregulated in patients with melanoma metastasis. → TGF-β can downregulate ADAM15 expression in melanoma cells. → Overexpression of ADAM15 in melanoma cells inhibits migration, proliferation and invasion of melanoma cells. → Conclusion: ADAM15 represents an tumor suppressor protein in melanoma. -- Abstract: In a mouse melanoma metastasis model it has been recently shown that ADAM15 overexpression in melanoma cells significantly reduced the number of metastatic nodules on the lung. Unfortunately, the expression of ADAM15 in human melanoma tissue has not been determined so far. In our study, we characterized the expression of ADAM15 in tissue micro-arrays of patients with primary melanoma with melanoma metastasis. ADAM15 was expressed in melanocytes and endothelial cells of benign nevi and melanoma tissue. Importantly, ADAM15 was significantly downregulated in melanoma metastasis compared to primary melanoma. We further demonstrate that IFN-γ and TGF-β downregulate ADAM15 protein levels in melanoma cells. To investigate the role of ADAM15 in melanoma progression, we overexpressed ADAM15 in melanoma cells. Importantly, overexpression of ADAM15 in melanoma cells reduced the migration, invasion and the anchorage dependent and independent cell growth of melanoma cells. In summary, the downregulation of ADAM15 plays an important role in melanoma progression and ADAM15 act as a tumorsuppressor in melanoma.

  15. ADAM12 and alpha9beta1 integrin are instrumental in human myogenic cell differentiation

    DEFF Research Database (Denmark)

    Lafuste, Peggy; Sonnet, Corinne; Chazaud, Bénédicte; Dreyfus, Patrick A; Gherardi, Romain K; Wewer, Ulla M; Authier, François-Jérôme

    2005-01-01

    of alpha9 parallels that of ADAM12 and culminates at time of fusion. alpha9 and ADAM12 coimmunoprecipitate and participate to mpc adhesion. Inhibition of ADAM12/alpha9beta1 integrin interplay, by either ADAM12 antisense oligonucleotides or blocking antibody to alpha9beta1, inhibited overall mpc...

  16. ADAM15 expression is downregulated in melanoma metastasis compared to primary melanoma

    Energy Technology Data Exchange (ETDEWEB)

    Ungerer, Christopher; Doberstein, Kai [Pharmazentrum Frankfurt/ZAFES, University Hospital Goethe University Frankfurt, Frankfurt am Main (Germany); Buerger, Claudia; Hardt, Katja; Boehncke, Wolf-Henning [Department of Dermatology, Clinic of the Goethe-University, Theodor-Stern-Kai, Frankfurt (Germany); Boehm, Beate [Division of Rheumatology, Goethe University, Frankfurt am Main (Germany); Pfeilschifter, Josef [Pharmazentrum Frankfurt/ZAFES, University Hospital Goethe University Frankfurt, Frankfurt am Main (Germany); Dummer, Reinhard [Department of Pathology, Institute of Surgical Pathology, University Hospital, Zurich (Switzerland); Mihic-Probst, Daniela [Department of Dermatology, University Hospital Zurich (Switzerland); Gutwein, Paul, E-mail: p.gutwein@med.uni-frankfurt.de [Pharmazentrum Frankfurt/ZAFES, University Hospital Goethe University Frankfurt, Frankfurt am Main (Germany)

    2010-10-22

    Research highlights: {yields} Strong ADAM15 expression is found in normal melanocytes. {yields} ADAM15 expression is significantly downregulated in patients with melanoma metastasis. {yields} TGF-{beta} can downregulate ADAM15 expression in melanoma cells. {yields} Overexpression of ADAM15 in melanoma cells inhibits migration, proliferation and invasion of melanoma cells. {yields} Conclusion: ADAM15 represents an tumor suppressor protein in melanoma. -- Abstract: In a mouse melanoma metastasis model it has been recently shown that ADAM15 overexpression in melanoma cells significantly reduced the number of metastatic nodules on the lung. Unfortunately, the expression of ADAM15 in human melanoma tissue has not been determined so far. In our study, we characterized the expression of ADAM15 in tissue micro-arrays of patients with primary melanoma with melanoma metastasis. ADAM15 was expressed in melanocytes and endothelial cells of benign nevi and melanoma tissue. Importantly, ADAM15 was significantly downregulated in melanoma metastasis compared to primary melanoma. We further demonstrate that IFN-{gamma} and TGF-{beta} downregulate ADAM15 protein levels in melanoma cells. To investigate the role of ADAM15 in melanoma progression, we overexpressed ADAM15 in melanoma cells. Importantly, overexpression of ADAM15 in melanoma cells reduced the migration, invasion and the anchorage dependent and independent cell growth of melanoma cells. In summary, the downregulation of ADAM15 plays an important role in melanoma progression and ADAM15 act as a tumorsuppressor in melanoma.

  17. TspanC8 tetraspanins differentially regulate the cleavage of ADAM10 substrates, Notch activation and ADAM10 membrane compartmentalization.

    Science.gov (United States)

    Jouannet, Stéphanie; Saint-Pol, Julien; Fernandez, Laurent; Nguyen, Viet; Charrin, Stéphanie; Boucheix, Claude; Brou, Christel; Milhiet, Pierre-Emmanuel; Rubinstein, Eric

    2016-05-01

    The metalloprotease ADAM10 mediates the shedding of the ectodomain of various cell membrane proteins, including APP, the precursor of the amyloid peptide Aβ, and Notch receptors following ligand binding. ADAM10 associates with the members of an evolutionary conserved subgroup of tetraspanins, referred to as TspanC8, which regulate its exit from the endoplasmic reticulum. Here we show that 4 of these TspanC8 (Tspan5, Tspan14, Tspan15 and Tspan33) which positively regulate ADAM10 surface expression levels differentially impact ADAM10-dependent Notch activation and the cleavage of several ADAM10 substrates, including APP, N-cadherin and CD44. Sucrose gradient fractionation, single molecule tracking and quantitative mass-spectrometry analysis of the repertoire of molecules co-immunoprecipitated with Tspan5, Tspan15 and ADAM10 show that these two tetraspanins differentially regulate ADAM10 membrane compartmentalization. These data represent a unique example where several tetraspanins differentially regulate the function of a common partner protein through a distinct membrane compartmentalization. PMID:26686862

  18. Adam Podin ja pan-evangeelne vaimulaad / Toivo Pilli

    Index Scriptorium Estoniae

    Pilli, Toivo, 1962-

    2013-01-01

    Adam Podini elust ja tööst: Keila baptistikoguduse vaimulikuna, vanglamisjonäri ja pidalitõbiste abistajana, baptistide teoloogilise seminari direktorina, Evangeelse Alliansi kontaktisikuna Eestis

  19. Siim Nestor soovitab : Ugly Duckling. Adam F / Siim Nestor

    Index Scriptorium Estoniae

    Nestor, Siim, 1974-

    2006-01-01

    Ameerika hip-hop-ansambli Ugly Duckling'i heliplaadi "Bang for the Buck"esitluskontserdist 9. nov. Tallinna klubis Hollywood. Inglise diskor Adam F drum'n'bass-üritusel "Sin City" 10. nov. Tartu linna klubis Tallinn

  20. ADAM10 as a target for anti-cancer therapy.

    Science.gov (United States)

    Moss, Marcia L; Stoeck, Alexander; Yan, Wenbo; Dempsey, Peter J

    2008-02-01

    There is a great unmet medical need in the area of cancer treatment. A potential therapeutic target for intervention in cancer is ADAM10. ADAM10 is a disintegrin-metalloproteinase that processes membrane bound proteins from the cell surface to yield soluble forms. Pharmaceutical companies are actively seeking out inhibitors of ADAM10 for treatments in cancer as the enzyme is known to release the ErbB receptor, HER2/ErbB2 from the cell membrane, an event that is necessary for HER2 positive tumor cells to proliferate. ADAM10 is also capable of processing betacellulin indicating that an inhibitor could be used against EGFR/ErbB1 and/or HER4/ErbB4 receptor positive tumor cells that are betacellulin-dependent. ADAM10 is the principle sheddase for several other molecules associated with cancer proliferation, differentiation, adhesion and migration such as Notch, E-cadherin, CD44 and L1 adhesion molecule indicating that targeting ADAM10 with specific inhibitors could be beneficial. PMID:18289051

  1. ADAM SMITH: THE INVISIBLE HAND OR CONFIDENCE

    Directory of Open Access Journals (Sweden)

    Fernando Luis, Gache

    2010-01-01

    Full Text Available In 1776 Adam Smith raised the matter that an invisible hand was the one which moved the markets to obtain its efficiency. Despite in the present paper we are going to raise the hypothesis, that this invisible hand is in fact the confidence that each person feels when he is going to do business. That in addition it is unique, because it is different from the confidence of the others and that is a variable nonlinear that essentially is ligatured to respective personal histories. For that we are going to take as its bases the paper by Leopoldo Abadía (2009, with respect to the financial economy crisis that happened in 2007-2008, to evidence the form in which confidence operates. Therefore the contribution that we hope to do with this paper is to emphasize that, the level of confidence of the different actors, is the one which really moves the markets, (therefore the economy and that the crisis of the subprime mortgages is a confidence crisis at world-wide level.

  2. Who taught Adam to speak?1

    Directory of Open Access Journals (Sweden)

    Arthur C. Custance

    1994-03-01

    Full Text Available It is taken for granted that the first man, being half-ape, 'spoke’ by copying them. Research shows that such grunts and cries cannot ‘evolve' into cultured speech because the speech organs and brain structure required for human language are entirety different from those needed for of animal communication. The difference in animal and human thinking processes is not merely one of degree but rather of kind. This difference is seen in the use of signs vs. symbols, of emotional and situational language v.v. conceptual, objective language. No animal communication system can account for the human one. Perhaps, then, speech is instinctive? No, for people, however primitive, have been found without a language. Yet unless spoken to, one does not learn to speak as demonstrated by feral (wild children and deaf-mutes(like Helen Keller. So the question is - who spoke to the first human being - Adam to teach him? About all that scientific investigation can do is to demonstrate what cannot be the origin of this extraordinary trait of human nature. The only light we have is from revelation. The first two chapters of Genesis not only tell us Who spoke first but also how the process of language was acquired. But the implications of the necessity of this unique faculty in terms of his humanity and the purpose of his very creation are profound.

  3. Case study: adams mine landfill proposal

    International Nuclear Information System (INIS)

    I have been asked to comment on 'how to address social concerns' in my capacity as the project manager for the City of Toronto's Toronto Integrated Solid Waste Resource Management (TIRM) Process, which was initiated in 1997 and concluded in the Fall of 2000. Inherent in this request is the goal of learning from a non-nuclear procurement process in order to offer insights for those working in the field on the short- and long-term management of nuclear waste. In particular, I have been asked to comment on the learning experience from the proposed engagement of the Adams Mine Landfill that became the focus of an intense four-day debate before Toronto's City Council and was propelled into international news linked to Toronto's Olympic bid. I would like to extend my thanks to Natural Resources Canada for their support of my participation in the NEA Conference. The opinions in this paper are those of the author and not those of the City of Toronto. (author)

  4. Discovery of 3-{5-[(6-Amino-1H-pyrazolo[3,4-b]pyridine-3-yl)methoxy]-2-chlorophenoxy}-5-chlorobenzonitrile (MK-4965): A Potent, Orally Bioavailable HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitor with Improved Potency against Key Mutant Viruses

    Energy Technology Data Exchange (ETDEWEB)

    Tucker, Thomas J.; Sisko, John T.; Tynebor, Robert M.; Williams, Theresa M.; Felock, Peter J.; Flynn, Jessica A.; Lai, Ming-Tain; Liang, Yuexia; McGaughey, Georgia; Liu, Meiquing; Miller, Mike; Moyer, Gregory; Munshi, Vandna; Perlow-Poehnelt, Rebecca; Prasad, Sridhar; Reid, John C.; Sanchez, Rosa; Torrent, Maricel; Vacca, Joseph P.; Wan, Bang-Lin; Yan, Youwei (Merck)

    2009-07-10

    Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have been shown to be a key component of highly active antiretroviral therapy (HAART). The use of NNRTIs has become part of standard combination antiviral therapies producing clinical outcomes with efficacy comparable to other antiviral regimens. There is, however, a critical issue with the emergence of clinical resistance, and a need has arisen for novel NNRTIs with a broad spectrum of activity against key HIV-1 RT mutations. Using a combination of traditional medicinal chemistry/SAR analyses, crystallography, and molecular modeling, we have designed and synthesized a series of novel, highly potent NNRTIs that possess broad spectrum antiviral activity and good pharmacokinetic profiles. Further refinement of key compounds in this series to optimize physical properties and pharmacokinetics has resulted in the identification of 8e (MK-4965), which has high levels of potency against wild-type and key mutant viruses, excellent oral bioavailability and overall pharmacokinetics, and a clean ancillary profile.

  5. The ADAMs family of proteases: new biomarkers and therapeutic targets for cancer?

    LENUS (Irish Health Repository)

    Duffy, Michael J

    2011-06-09

    Abstract The ADAMs are transmembrane proteins implicated in proteolysis and cell adhesion. Forty gene members of the family have been identified, of which 21 are believed to be functional in humans. As proteases, their main substrates are the ectodomains of other transmembrane proteins. These substrates include precursor forms of growth factors, cytokines, growth factor receptors, cytokine receptors and several different types of adhesion molecules. Although altered expression of specific ADAMs has been implicated in different diseases, their best-documented role is in cancer formation and progression. ADAMs shown to play a role in cancer include ADAM9, ADAM10, ADAM12, ADAM15 and ADAM17. Two of the ADAMs, i.e., ADAM10 and 17 appear to promote cancer progression by releasing HER\\/EGFR ligands. The released ligands activate HER\\/EGFR signalling that culminates in increased cell proliferation, migration and survival. Consistent with a causative role in cancer, several ADAMs are emerging as potential cancer biomarkers for aiding cancer diagnosis and predicting patient outcome. Furthermore, a number of selective ADAM inhibitors, especially against ADAM10 and ADAM17, have been shown to have anti-cancer effects. At least one of these inhibitors is now undergoing clinical trials in patients with breast cancer.

  6. Adam Smith et les passions musicales

    Directory of Open Access Journals (Sweden)

    Marc Parmentier

    2012-02-01

    Full Text Available Dans sa Théorie des sentiments moraux (1759, Adam Smith classe les passions en trois catégories : passions sociales, asociales, égoïstes. Cette classification résulte directement de leur capacité à susciter ou non la sympathie. Les passions sociales apparaissent ainsi comme les plus propres à susciter un écho sympathique. La question à laquelle tente de répondre l'article est de savoir pourquoi ces mêmes passions sociales sont qualifiées par A. Smith de « naturellement musicales ». L'utilisation du concept de sympathie dans le domaine musical est fréquente aux XVIIème et XVIIIème siècles, mais l'hypothèse avancée ici est que le lien est plus profond chez A. Smith. La sympathie met en effet en évidence une qualité d'ordre à la fois esthétique et morale inhérente à certaines passions, leur « convenance » (propriety par opposition aux passions « discordantes ». Ces passions, produisant une superposition d'échos sympathiques comparables aux harmoniques d'un ton fondamental, sont les plus susceptibles d'être imitées par la musique, si l'on tient compte de la théorie esthétique originale formulée par A. Smith, pour qui la beauté des arts imitatifs ne tient pas à l'illusion mais au contraire à l'écart entre l'imitation et son objet.In his Theory of Moral Sentiments, Adam Smith distinguishes three types of passions: social passions, unsocial passions and selfish passions. This classification relies on their capacity to evoke sympathy. Social passions are the most apt to arouse a sympathetic echo in their observers. This article tries to answer the question why A. Smith describes social passions as « naturally musical ». In 17th and 18th centuries sympathy is often mentioned in connection with musical topics, but the link established by A. Smith is more profound. In fact, sympathy reveals an esthetic and moral quality of « convenient », vs « discordant », passions. These passions, that produce

  7. Characterization of Mammalian ADAM2 and Its Absence from Human Sperm.

    Directory of Open Access Journals (Sweden)

    Heejin Choi

    Full Text Available The members of the ADAM (a disintegrin and metalloprotease family are membrane-anchored multi-domain proteins that play prominent roles in male reproduction. ADAM2, which was one of the first identified ADAMs, is the best studied ADAM in reproduction. In the male germ cells of mice, ADAM2 and other ADAMs form complexes that contribute to sperm-sperm adhesion, sperm-egg interactions, and the migration of sperm in the female reproductive tract. Here, we generated specific antibodies against mouse and human ADAM2, and investigated various features of ADAM2 in mice, monkeys and humans. We found that the cytoplasmic domain of ADAM2 might enable the differential association of this protein with other ADAMs in mice. Western blot analysis with the anti-human ADAM2 antibodies showed that ADAM2 is present in the testis and sperm of monkeys. Monkey ADAM2 was found to associate with chaperone proteins in testis. In humans, we identified ADAM2 as a 100-kDa protein in the testis, but failed to detect it in sperm. This is surprising given the results in mice and monkeys, but it is consistent with the failure of ADAM2 identification in the previous proteomic analyses of human sperm. These findings suggest that the reproductive functions of ADAM2 differ between humans and mice. Our protein analysis showed the presence of potential ADAM2 complexes involving yet-unknown proteins in human testis. Taken together, our results provide new information regarding the characteristics of ADAM2 in mammalian species, including humans.

  8. Characterization of Mammalian ADAM2 and Its Absence from Human Sperm

    Science.gov (United States)

    Choi, Heejin; Jin, Sora; Kwon, Jun Tae; Kim, Jihye; Jeong, Juri; Kim, Jaehwan; Jeon, Suyeon; Park, Zee Yong; Jung, Kang-Jin; Park, Kwangsung; Cho, Chunghee

    2016-01-01

    The members of the ADAM (a disintegrin and metalloprotease) family are membrane-anchored multi-domain proteins that play prominent roles in male reproduction. ADAM2, which was one of the first identified ADAMs, is the best studied ADAM in reproduction. In the male germ cells of mice, ADAM2 and other ADAMs form complexes that contribute to sperm-sperm adhesion, sperm-egg interactions, and the migration of sperm in the female reproductive tract. Here, we generated specific antibodies against mouse and human ADAM2, and investigated various features of ADAM2 in mice, monkeys and humans. We found that the cytoplasmic domain of ADAM2 might enable the differential association of this protein with other ADAMs in mice. Western blot analysis with the anti-human ADAM2 antibodies showed that ADAM2 is present in the testis and sperm of monkeys. Monkey ADAM2 was found to associate with chaperone proteins in testis. In humans, we identified ADAM2 as a 100-kDa protein in the testis, but failed to detect it in sperm. This is surprising given the results in mice and monkeys, but it is consistent with the failure of ADAM2 identification in the previous proteomic analyses of human sperm. These findings suggest that the reproductive functions of ADAM2 differ between humans and mice. Our protein analysis showed the presence of potential ADAM2 complexes involving yet-unknown proteins in human testis. Taken together, our results provide new information regarding the characteristics of ADAM2 in mammalian species, including humans. PMID:27341348

  9. Structural Characterization of the Ectodomain of a Disintegrin and Metalloproteinase-22 (ADAM22), a Neural Adhesion Receptor Instead of Metalloproteinase INSIGHTS ON ADAM FUNCTION

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Heli; Shim, Ann H.R.; He, Xiaolin; (NWU)

    2009-12-01

    ADAMs (adisintegrin and metalloproteinases) are a family of multidomain transmembrane glycoproteins with diverse roles in physiology and diseases, with several members being drug targets for cancer and inflammation therapies. The spatial organization of the ADAM extracellular segment and its influence on the function of ADAMs have been unclear. Although most members of the ADAM family are active zinc metalloproteinases, 8 of 21 ADAMs lack functional metalloproteinase domains and are implicated in protein-protein interactions instead of membrane protein ectodomain shedding. One of such non-proteinase ADAMs, ADAM22, acts as a receptor on the surface of the postsynaptic neuron to regulate synaptic signal transmission. The crystal structure of the full ectodomain of mature human ADAM22 shows that it is a compact four-leaf clover with the metalloproteinase-like domain held in the concave face of a rigid module formed by the disintegrin, cysteine-rich, and epidermal growth factor-like domains. The loss of metalloproteinase activity is ensured by the absence of critical catalytic residues, the filling of the substrate groove, and the steric hindrance by the cysteine-rich domain. The structure, combined with calorimetric experiments, suggests distinct roles of three putative calcium ions bound to ADAM22, with one in the metalloproteinase-like domain being regulatory and two in the disintegrin domain being structural. The metalloproteinase-like domain contacts the rest of ADAM22 with discontinuous, hydrophilic, and poorly complemented interactions, suggesting the possibility of modular movement of ADAM22 and other ADAMs. The ADAM22 structure provides a framework for understanding how different ADAMs exert their adhesive function and shedding activities.

  10. Hierarchy of ADAM12 binding to integrins in tumor cells

    DEFF Research Database (Denmark)

    Thodeti, Charles Kumar; Fröhlich, Camilla; Nielsen, Christian Kamp;

    2005-01-01

    12. However, when alpha9beta1 integrin is not expressed--as in many carcinoma cells--other members of the beta1 integrin family can replace its ligand binding activity. In attachment assays, the recombinant disintegrin domain of ADAM12 only supported alpha9 integrin-dependent tumor cell attachment...... with a rounded morphology; attachment of cells with a spread morphology required further activation of the alpha9beta1 integrin. We demonstrated that phosphoinositide-3-kinase appears to be central in regulating alpha9beta1 integrin cell spreading activity in response to ADAM12....

  11. Adam Smith's account of self-deceit and informal institutions

    OpenAIRE

    Gerschlager, Caroline

    2007-01-01

    According to Adam Smith, self-deceit is essential to the economy. In this light the paper draws on the Theory of Moral Sentiments and revisits Adam Smith’s view of the self. The originality of Smith’s account of self-deceit is seen in his insights into self-regulating social forces. The paper illustrates how, in this view, informal institutions are important because they countervail self-deceit in markets. It suggests that Smith overestimated these countervailing forces for the reason that in...

  12. Foolishness and identity: Amartya Sen and Adam Smith

    OpenAIRE

    Gerschlager, Caroline

    2008-01-01

    Drawing on Amartya Sen the paper aims at a better understanding of the motivational foundation of the economic agent by analysing Adam Smith’s insights into the foolishness of human ambitions. It inquires whether there is another side to the pursuit of self-interest in Adam Smith and particularly accentuates his parable of the poor man’s son as a prototypical example. Complementing the standard views of the self and their recent extensions, the present analysis of the parable advances a descr...

  13. Harald Velner - insener üle poole sajandi / Harald-Adam Velner

    Index Scriptorium Estoniae

    Velner, Harald-Adam, 1923-2012

    2008-01-01

    Harald-Adam Velner on Eesti Inseneride Liidu esimene taasiseseisvumisjärgne president. Lisaks Liis Seili lühiartikkel Harald-Adam Velneri isast August Velnerist: Teedeinsenerist isa juhtis inseneride ühendust enne sõda

  14. Preliminarily functional analysis of a cloned novel human gene ADAM29

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    ADAM is a family of type I integral membrane proteins which are characterized by sharing a disintegrin and metalloprotease domain and involved in many important physiological processes such as fertilization, neurogenesis and inflammatory response. A novel human ADAM gene--ADAM29, which was cloned in our laboratory, is exclusively expressed in human testis and contains a potential fusion domain. A full-length cDNA of ADAM29 was obtained by using multiple-step PCR. Phylogenetic tree of known mammalian ADAMs specifically expressed in testis was reconstructed. Polyclonal antiserum was raised by immunizing the rabbits with sub-peptide of ADAM29 (Leu268-Asp374) as immunogen. The result of immunohistochemical test on human testis showed that ADAM29 is expressed in different stages of spermatogenesis and in interstitial cells. ADAM29 may play a certain role in the signal transduction during the maturation of testis-associated cells.

  15. A Functional Role for ADAM10 in Human Immunodeficiency Virus Type-1 Replication

    Directory of Open Access Journals (Sweden)

    Rubin Donald H

    2011-05-01

    Full Text Available Abstract Background Gene trap insertional mutagenesis was used as a high-throughput approach to discover cellular genes participating in viral infection by screening libraries of cells selected for survival from lytic infection with a variety of viruses. Cells harboring a disrupted ADAM10 (A Disintegrin and Metalloprotease 10 allele survived reovirus infection, and subsequently ADAM10 was shown by RNA interference to be important for replication of HIV-1. Results Silencing ADAM10 expression with small interfering RNA (siRNA 48 hours before infection significantly inhibited HIV-1 replication in primary human monocyte-derived macrophages and in CD4+ cell lines. In agreement, ADAM10 over-expression significantly increased HIV-1 replication. ADAM10 down-regulation did not inhibit viral reverse transcription, indicating that viral entry and uncoating are also independent of ADAM10 expression. Integration of HIV-1 cDNA was reduced in ADAM10 down-regulated cells; however, concomitant 2-LTR circle formation was not detected, suggesting that HIV-1 does not enter the nucleus. Further, ADAM10 silencing inhibited downstream reporter gene expression and viral protein translation. Interestingly, we found that while the metalloprotease domain of ADAM10 is not required for HIV-1 replication, ADAM15 and γ-secretase (which proteolytically release the extracellular and intracellular domains of ADAM10 from the plasma membrane, respectively do support productive infection. Conclusions We propose that ADAM10 facilitates replication at the level of nuclear trafficking. Collectively, our data support a model whereby ADAM10 is cleaved by ADAM15 and γ-secretase and that the ADAM10 intracellular domain directly facilitates HIV-1 nuclear trafficking. Thus, ADAM10 represents a novel cellular target class for development of antiretroviral drugs.

  16. ADAM 12 as a second-trimester maternal serum marker in screening for Down syndrome

    DEFF Research Database (Denmark)

    Christiansen, Michael; Spencer, Kevin; Laigaard, Jennie;

    2007-01-01

    ADAM 12 is a placenta-derived glycoprotein that is involved in growth and differentiation. The maternal serum concentration of ADAM 12 is a potential first-trimester maternal serum marker of Down syndrome (DS). Here we examine the potential of ADAM 12 as a second-trimester maternal serum marker of...

  17. Engineering graduate student Tiffany Adams honored by Oregon State University

    OpenAIRE

    Gilbert, Karen

    2006-01-01

    Tiffany Adams, a Ph.D. candidate in Charles E. Via, Jr. Department of Civil and Environmental Engineering in the College of Engineering at Virginia Tech, has been named to Oregon State University's Council of Early Career Engineers, one of three categories of awards for the university's outstanding engineering alumni.

  18. Father Knows Best: Using Adam Smith to Teach Transactions Costs

    Science.gov (United States)

    Dupont, Brandon

    2014-01-01

    Adam Smith's moral philosophy can be used to introduce economics students to the important idea of transactions costs. The author provides a brief background in this article to Smith's moral philosophy and connects it to the costs of transacting in a way that fits easily into the standard principles of microeconomics classroom. By doing…

  19. Adam Smith and the Moral Economy of the Classroom System.

    Science.gov (United States)

    Hamilton, D.

    1980-01-01

    Traces the development of mass schooling to its origins in 19th-century Glasgow. Its importance as an intellectual and economic center enabled Glasgow to invent a solution to the problem of urban schooling, while the association of scholars like Adam Smith with Glasgow University made Scottish educational theories acceptable around the world. (DB)

  20. Adam Smith and the Teaching of English Literature.

    Science.gov (United States)

    Court, Franklin E.

    1985-01-01

    Adam Smith used selections from English literature in his classroom during the eighteenth century because he believed that vernacular literature could provide a ready context for the teaching of ideological, social, and moral lessons. He believed that higher education should prepare students for the real business of the real world. (RM)

  1. Adams operations on higher arithmetic K-theory

    DEFF Research Database (Denmark)

    Feliu, Elisenda

    2010-01-01

    We construct Adams operations on the rational higher arithmetic K-groups of a proper arithmetic variety. The de¿nition applies to the higher arithmetic K-groups given by Takeda as well as to the groups suggested by Deligne and Soulé, by means of the homotopy groups of the homotopy ¿ber of the reg......We construct Adams operations on the rational higher arithmetic K-groups of a proper arithmetic variety. The de¿nition applies to the higher arithmetic K-groups given by Takeda as well as to the groups suggested by Deligne and Soulé, by means of the homotopy groups of the homotopy ¿ber...... of the regulator map. They are compatible with the Adams operations on algebraic K-theory. The de¿nition relies on the chain morphism representing Adams operations in higher algebraic K-theory given previously by the author. It is shown that this chain morphism commutes strictly with the representative...

  2. Increased B Cell ADAM10 in Allergic Patients and Th2 Prone Mice.

    Directory of Open Access Journals (Sweden)

    Lauren Folgosa Cooley

    Full Text Available ADAM10, as the sheddase of the low affinity IgE receptor (CD23, promotes IgE production and thus is a unique target for attenuating allergic disease. Herein, we describe that B cell levels of ADAM10, specifically, are increased in allergic patients and Th2 prone WT mouse strains (Balb/c and A/J. While T cell help augments ADAM10 expression, Balb WT B cells exhibit increased ADAM10 in the naïve state and even more dramatically increased ADAM10 after anti-CD40/IL4 stimulation compared C57 (Th1 prone WT B cells. Furthermore, ADAM17 and TNF are reduced in allergic patients and Th2 prone mouse strains (Balb/c and A/J compared to Th1 prone controls. To further understand this regulation, ADAM17 and TNF were studied in C57Bl/6 and Balb/c mice deficient in ADAM10. C57-ADAM10B-/- were more adept at increasing ADAM17 levels and thus TNF cleavage resulting in excess follicular TNF levels and abnormal secondary lymphoid tissue architecture not noted in Balb-ADAM10B-/-. Moreover, the level of B cell ADAM10 as well as Th context is critical for determining IgE production potential. Using a murine house dust mite airway hypersensitivity model, we describe that high B cell ADAM10 level in a Th2 context (Balb/c WT is optimal for disease induction including bronchoconstriction, goblet cell metaplasia, mucus, inflammatory cellular infiltration, and IgE production. Balb/c mice deficient in B cell ADAM10 have attenuated lung and airway symptoms compared to Balb WT and are actually most similar to C57 WT (Th1 prone. C57-ADAM10B-/- have even further reduced symptomology. Taken together, it is critical to consider both innate B cell levels of ADAM10 and ADAM17 as well as Th context when determining host susceptibility to allergic disease. High B cell ADAM10 and low ADAM17 levels would help diagnostically in predicting Th2 disease susceptibility; and, we provide support for the use ADAM10 inhibitors in treating Th2 disease.

  3. Trafficking of human ADAM 12-L: retention in the trans-Golgi network

    DEFF Research Database (Denmark)

    Hougaard, S; Loechel, F; Xu, X;

    2000-01-01

    We have investigated the trafficking of the membrane-anchored form of human ADAM 12 (ADAM 12-L) fused to a green fluorescence protein tag. Subcellular localization of the protein in transiently transfected cells was determined by fluorescence microscopy and trypsin sensitivity. Full-length ADAM 12...... cytoplasmic and transmembrane domains, but not the Src homology 3 domain (SH3) binding sites. These results raise the possibility that a trafficking checkpoint in the trans-Golgi network is one of the cellular mechanisms for regulation of ADAM 12-L function, by allowing a rapid release of ADAM 12-L to the...

  4. ADAM8 in squamous cell carcinoma of the head and neck: a retrospective study

    International Nuclear Information System (INIS)

    A disintegrin and metalloproteinase (ADAMs) have been associated with multiple malignancies. ADAMs are involved in cell fusion, cell migration, membrane protein shedding and proteolysis. ADAM8 has been found to be overexpressed in squamous cell carcinomas of the lung. A new study showed that ADAM8 is significantly overexpressed in metastasis of squamous cell carcinomas of the head and neck (HNSCC). We determined ADAM8 levels in the serum of 79 HNSCC patients at the time of diagnosis, in 35 patients 3 months after treatment and in 10 patients 1 year after therapy and compared the results to the sera of 31 healthy volunteers. We also constructed tissue microarrays to detect ADAM8 immunohistochemically in 100 patients. The results were correlated with the survival data of the patients to determine the diagnostic and prognostic value. The data demonstrated that patients with high ADAM8 expression in the tumor have worse survival rates. We found that high ADAM8 serum levels correlated with high ADAM8 expression in tumor samples. Soluble ADAM8 levels did not show any prognostic or diagnostic properties. In summary ADAM8 expression is a prognostic factor for survival of patients with head and neck squamous cell carcinoma

  5. The interaction between ADAM22 and 14-3-3β

    Institute of Scientific and Technical Information of China (English)

    ZHU; Pengcheng(朱鹏程); SANG; Yingying(桑瑛颖); XU; Rener(徐人尔); ZHAO; Jing(赵璟); LI; Changben(李昌本); ZHAO; Shouyuan(赵寿元)

    2002-01-01

    ADAM family consists of a number of transmembrane proteins that contain a disintegrin and metalloprotease domain. ADAMs are involved in a highly diverse set of biological processes, including fertilization, neurogenesis, myogenesis and inflammatory response. The ADAM proteins have both cell adhesion and protease activities. Adam22 is highly expressed in human brain. The adam22-/- mice presented severe ataxia and died before weaning, but the function of ADAM22 is still unknown. 14-3-3β interacting with ADAM22 was detected by using yeast two-hybrid assay. The specificity of interaction between ADAM22 and 14-3-3β was proved by in vitro binding assay and immunoprecipitation. The major 14-3-3β binding site was located in the last 28 amino acid residues of ADAM22 cytoplasmic tail. Protein 14-3-3β is abundant and plays an important role in mediating cell diffusion, migration and cell cycle control. The interaction of ADAM22 and 14-3-3β suggests that the ADAM22 may play a crucial role in neural function and development.

  6. ADAM12 produced by tumor cells rather than stromal cells accelerates breast tumor progression

    DEFF Research Database (Denmark)

    Frohlich, Camilla; Nehammer, Camilla; Albrechtsen, Reidar;

    2011-01-01

    ADAM12 deficiency reduces breast tumor progression in the PyMT model. However, the catalytic activity of ADAM12 appears to be dispensable for its tumor-promoting effect. Interestingly, we demonstrate that ADAM12 endogenously expressed in tumor-associated stroma in the PyMT model does not influence......Expression of ADAM12 is low in most normal tissues, but is markedly increased in numerous human cancers, including breast carcinomas. We have previously shown that overexpression of ADAM12 accelerates tumor progression in a mouse model of breast cancer (PyMT). In the present study, we found that...... tumor progression, but that ADAM12 expression by tumor cells is necessary for tumor progression in these mice. This finding is consistent with our observation that in human breast carcinoma ADAM12 is almost exclusively located in tumor cells and only rarely seen in the tumor-associated stroma. We...

  7. Cell-surface metalloprotease ADAM12 is internalized by a clathrin- and Grb2-dependent mechanism

    DEFF Research Database (Denmark)

    Hansen, Dorte Stautz; Leyme, Anthony; Grandal, Michael Vibo;

    2012-01-01

    -surface are possibly crucial in these contexts. We here investigated internalization and subsequent recycling or degradation of ADAM12 as a potentially important regulatory mechanism. Our results show that ADAM12 is constitutively internalized primarily via the clathrin-dependent pathway and is subsequently......ADAM12 (A Disintegrin And Metalloprotease 12), a member of the ADAMs family of transmembrane proteins, is involved in ectodomain shedding, cell-adhesion and signaling, with important implications in cancer. Therefore, mechanisms that regulate the levels and activity of ADAM12 at the cell...... detected in both early and recycling endosomes. The protease activity of ADAM12 does not influence this internalization mechanism. Analysis of essential elements for internalization established that proline-rich regions in the cytoplasmic domain of ADAM12, previously shown to interact with Src-homology 3...

  8. Synthesis and comparison of 4-[18F]F-ADAM, 2-[18F]F-ADAM, N-Desmethyl-4-[18F]F-ADAM and [18F]F-AFM as serotonin transporter imaging agents

    International Nuclear Information System (INIS)

    4-[18F]F-ADAM (1a), 2-[18F]F-ADAM (2a), N-Desmethyl-4-[18F]F-ADAM (3a) and [18F]F-AFM (4a ) were synthesized in 1.7, 3.9, 2.9 and 0.6% yield (EOS), respectively, in a synthesis time of ∼120 min from EOB. PET studies in rats showed that the maximum specific uptake ratios of 1a, 2a, 3a and 4a in midbrain were 3.86, 0.73, 0.35 and 2.23, respectively. Thus, in terms of radiochemical yield, specific binding and in vivo stability, 4-[18F]F-ADAM may be the most appropriate SERT imaging agent for human studies. - Highlights: ► Four 18F-labeled radioligands were synthesized and evaluated as SERT imaging agents. ► 4-[18F]F-ADAM and [18F]F-AFM had high specific uptake in SERT-rich brain regions. ► 2-[18F]F-ADAM and N-Desmethyl-4-[18F]F-ADAM had low specific uptake in brain. ► 4-[18F]F-ADAM may be the most appropriate SERT imaging agent for human studies.

  9. Adams-Based Rover Terramechanics and Mobility Simulator - ARTEMIS

    Science.gov (United States)

    Trease, Brian P.; Lindeman, Randel A.; Arvidson, Raymond E.; Bennett, Keith; VanDyke, Lauren P.; Zhou, Feng; Iagnemma, Karl; Senatore, Carmine

    2013-01-01

    The Mars Exploration Rovers (MERs), Spirit and Opportunity, far exceeded their original drive distance expectations and have traveled, at the time of this reporting, a combined 29 kilometers across the surface of Mars. The Rover Sequencing and Visualization Program (RSVP), the current program used to plan drives for MERs, is only a kinematic simulator of rover movement. Therefore, rover response to various terrains and soil types cannot be modeled. Although sandbox experiments attempt to model rover-terrain interaction, these experiments are time-intensive and costly, and they cannot be used within the tactical timeline of rover driving. Imaging techniques and hazard avoidance features on MER help to prevent the rover from traveling over dangerous terrains, but mobility issues have shown that these methods are not always sufficient. ARTEMIS, a dynamic modeling tool for MER, allows planned drives to be simulated before commands are sent to the rover. The deformable soils component of this model allows rover-terrain interactions to be simulated to determine if a particular drive path would take the rover over terrain that would induce hazardous levels of slip or sink. When used in the rover drive planning process, dynamic modeling reduces the likelihood of future mobility issues because high-risk areas could be identified before drive commands are sent to the rover, and drives planned over these areas could be rerouted. The ARTEMIS software consists of several components. These include a preprocessor, Digital Elevation Models (DEMs), Adams rover model, wheel and soil parameter files, MSC Adams GUI (commercial), MSC Adams dynamics solver (commercial), terramechanics subroutines (FORTRAN), a contact detection engine, a soil modification engine, and output DEMs of deformed soil. The preprocessor is used to define the terrain (from a DEM) and define the soil parameters for the terrain file. The Adams rover model is placed in this terrain. Wheel and soil parameter files

  10. HIV-1逆转录酶抑制剂的合成及活性评价%Synthesis and anti-HIV-1 activity evaluation of N-1-alkyl-5-halogeno-6-alkylamino uracils as novel non-nucleoside HIV-1 reverse transcriptase inhibitors

    Institute of Scientific and Technical Information of China (English)

    闫寒; 王孝伟; 郭盈; 张志丽; 刘俊义

    2011-01-01

    N-1-alkyl-5-halogeno-6-alkylamino uracils, which are novel 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT)analogues, were synthesized as the selective and potent non-nucleoside human immunodeficiency virus(HIV)-1 reverse transcriptase inhibitors. Some of the compounds showed potent inhibitory activity against HIV-1 reverse transcriptase. For instance, compounds ld, lm and In exhibited potent anti-HIV-1 activity with the ICso values of 13.3, 11.7 and 3.15 gM, respectively,which are comparable to that of nevirapinc(IC5O 8.38 μM).%本研究以HIV-1逆转录酶为靶点,设计了一类具有HEPT类结构的化合物:1-乙氧基甲基/苄氧基甲基-5-卤代-6-脂肪胺尿嘧啶作为抑制剂,并对合成的目标化合物进行了生物活性测定,一些化合物显示出较强的抗HIV生物活性,与对照物奈韦拉平相比(IC50 8.30μM)化合物1d,1m和1n的IC50 值分别达到了13.3,11.7和3.15 μM.

  11. Systematic substrate identification indicates a central role for the metalloprotease ADAM10 in axon targeting and synapse function

    OpenAIRE

    Kuhn, P.-H.; Colombo, A.V.; Schusser, B.; Dreymueller, D.; Wetzel, S.; Schepers, U.; Herber, J.; Ludwig, A.; Kremmer, E; Montag, D.; Müller, U; Schweizer, M.; Saftig, P; Bräse, S.; Lichtenthaler, S.F.

    2016-01-01

    Metzincin metalloproteases have major roles in intercellular communication by modulating the function of membrane proteins. One of the proteases is the a-disintegrin-and-metalloprotease 10 (ADAM10) which acts as alpha-secretase of the Alzheimer's disease amyloid precursor protein. ADAM10 is also required for neuronal network functions in murine brain, but neuronal ADAM10 substrates are only partly known. With a proteomic analysis of Adam10-deficient neurons we identified 91, mostly novel ADAM...

  12. The Book That Adam Smith Did Not Write

    OpenAIRE

    Immanuel Wallerstein

    1996-01-01

    [fre] Analyse de pourquoi Adam Smith définit le marché parfait au niveau de la « nation » et non pas au niveau du monde entier. Il s'avère clair que Smith voit de justifications nombreuses pour les États à restreindre le marché une fois qu'on traverse les frontières étatiques. Il est également favorable à l'élargissement des frontières étatiques. [eng] An analysis of why Adam Smith's perfect market is not defined at the levai of the whole world but rather at the levai of the « nation ». It be...

  13. Adam Smith's concept of sympathy and contemporary research on empathy

    OpenAIRE

    2009-01-01

    Abstract In this paper, I explain and analyse the concept of sympathy as Adam Smith describes it, then I present relevant research on empathy from the fields of social psychology and behavioural biology in order to compare the two concepts. I argue that this comparison shows that Smith’s theory is consistent with modern scientific research and thus a realistic account of human psychology, which renders his moral theory even more appealing. First, I introduce Smith by reference to his ...

  14. Circulating ADAM17 Level Reflects Disease Activity in Proteinase-3 ANCA-Associated Vasculitis.

    Science.gov (United States)

    Bertram, Anna; Lovric, Svjetlana; Engel, Alissa; Beese, Michaela; Wyss, Kristin; Hertel, Barbara; Park, Joon-Keun; Becker, Jan U; Kegel, Johanna; Haller, Hermann; Haubitz, Marion; Kirsch, Torsten

    2015-11-01

    ANCA-associated vasculitides are characterized by inflammatory destruction of small vessels accompanied by enhanced cleavage of membrane-bound proteins. One of the main proteases responsible for ectodomain shedding is disintegrin and metalloproteinase domain-containing protein 17 (ADAM17). Given its potential role in aggravating vascular dysfunction, we examined the role of ADAM17 in active proteinase-3 (PR3)-positive ANCA-associated vasculitis (AAV). ADAM17 concentration was significantly increased in plasma samples from patients with active PR3-AAV compared with samples from patients in remission or from other controls with renal nonvascular diseases. Comparably, plasma levels of the ADAM17 substrate syndecan-1 were significantly enhanced in active AAV. We also observed that plasma-derived ADAM17 retained its specific proteolytic activity and was partly located on extracellular microparticles. Transcript levels of ADAM17 were increased in blood samples of patients with active AAV, but those of ADAM10 or tissue inhibitor of metalloproteinases 3, which inhibits ADAMs, were not. We also performed a microRNA (miR) screen and identified miR-634 as significantly upregulated in blood samples from patients with active AAV. In vitro, miR-634 mimics induced a proinflammatory phenotype in monocyte-derived macrophages, with enhanced expression and release of ADAM17 and IL-6. These data suggest that ADAM17 has a prominent role in AAV and might account for the vascular complications associated with this disease. PMID:25788529

  15. ADAM9 is highly expressed in renal cell cancer and is associated with tumour progression

    Directory of Open Access Journals (Sweden)

    Johannsen Manfred

    2008-06-01

    Full Text Available Abstract Background A Disintegrin And Metalloprotease (ADAM 9 has been implicated in tumour progression of various solid tumours, however, little is known about its role in renal cell carcinoma. We evaluated the expression of ADAM9 on protein and transcript level in a clinico-pathologically characterized renal cell cancer cohort. Methods 108 renal cancer cases were immunostained for ADAM9 on a tissue-micro-array. For 30 additional cases, ADAM9 mRNA of microdissected tumour and normal tissue was analyzed via quantitative RT-PCR. SPSS 14.0 was used to apply crosstables (Fisher's exact test and χ2-test, correlations and univariate as well as multivariate survival analyses. Results ADAM9 was significantly up-regulated in renal cancer in comparison to the adjacent normal tissue on mRNA level. On protein level, ADAM9 was significantly associated with higher tumour grade, positive nodal status and distant metastasis. Furthermore, ADAM9 protein expression was significantly associated with shortened patient survival in the univariate analysis. Conclusion ADAM9 is strongly expressed in a large proportion of renal cell cancers, concordant with findings in other tumour entities. Additionally, ADAM9 expression is significantly associated with markers of unfavourable prognosis. Whether the demonstrated prognostic value of ADAM9 is independent from other tumour parameters will have to be verified in larger study cohorts.

  16. ADAM9 is highly expressed in renal cell cancer and is associated with tumour progression

    International Nuclear Information System (INIS)

    A Disintegrin And Metalloprotease (ADAM) 9 has been implicated in tumour progression of various solid tumours, however, little is known about its role in renal cell carcinoma. We evaluated the expression of ADAM9 on protein and transcript level in a clinico-pathologically characterized renal cell cancer cohort. 108 renal cancer cases were immunostained for ADAM9 on a tissue-micro-array. For 30 additional cases, ADAM9 mRNA of microdissected tumour and normal tissue was analyzed via quantitative RT-PCR. SPSS 14.0 was used to apply crosstables (Fisher's exact test and χ2-test), correlations and univariate as well as multivariate survival analyses. ADAM9 was significantly up-regulated in renal cancer in comparison to the adjacent normal tissue on mRNA level. On protein level, ADAM9 was significantly associated with higher tumour grade, positive nodal status and distant metastasis. Furthermore, ADAM9 protein expression was significantly associated with shortened patient survival in the univariate analysis. ADAM9 is strongly expressed in a large proportion of renal cell cancers, concordant with findings in other tumour entities. Additionally, ADAM9 expression is significantly associated with markers of unfavourable prognosis. Whether the demonstrated prognostic value of ADAM9 is independent from other tumour parameters will have to be verified in larger study cohorts

  17. ADAM33, a new candidate for psoriasis susceptibility.

    Directory of Open Access Journals (Sweden)

    Fabienne Lesueur

    Full Text Available Psoriasis is a chronic skin disorder with multifactorial etiology. In a recent study, we reported results of a genome-wide scan on 46 French extended families presenting with plaque psoriasis. In addition to unambiguous linkage to the major susceptibility locus PSORS1 on Chromosome 6p21, we provided evidence for a susceptibility locus on Chromosome 20p13. To follow up this novel psoriasis susceptibility locus we used a family-based association test (FBAT for an association scan over the 17 Mb candidate region. A total of 85 uncorrelated SNP markers located in 65 genes of the region were initially investigated in the same set of large families used for the genome wide search, which consisted of 295 nuclear families. When positive association was obtained for a SNP, candidate genes nearby were explored more in detail using a denser set of SNPs. Thus, the gene ADAM33 was found to be significantly associated with psoriasis in this family set (The best association was on a 3-SNP haplotype P = 0.00004, based on 1,000,000 permutations. This association was independent of PSORS1. ADAM33 has been previously associated with asthma, which demonstrates that immune system diseases may be controlled by common susceptibility genes with general effects on dermal inflammation and immunity. The identification of ADAM33 as a psoriasis susceptibility gene identified by positional cloning in an outbred population should provide insights into the pathogenesis and natural history of this common disease.

  18. ADAM17 deletion in thymic epithelial cells alters aire expression without affecting T cell developmental progression.

    Directory of Open Access Journals (Sweden)

    David M Gravano

    Full Text Available BACKGROUND: Cellular interactions between thymocytes and thymic stromal cells are critical for normal T cell development. Thymic epithelial cells (TECs are important stromal niche cells that provide essential growth factors, cytokines, and present self-antigens to developing thymocytes. The identification of genes that mediate cellular crosstalk in the thymus is ongoing. One candidate gene, Adam17, encodes a metalloprotease that functions by cleaving the ectodomain of several transmembrane proteins and regulates various developmental processes. In conventional Adam17 knockout mice, a non-cell autonomous role for ADAM17 in adult T cell development was reported, which strongly suggested that expression of ADAM17 in TECs was required for normal T cell development. However, knockdown of Adam17 results in multisystem developmental defects and perinatal lethality, which has made study of the role of Adam17 in specific cell types difficult. Here, we examined T cell and thymic epithelial cell development using a conditional knockout approach. METHODOLOGY/PRINCIPAL FINDINGS: We generated an Adam17 conditional knockout mouse in which floxed Adam17 is deleted specifically in TECs by Cre recombinase under the control of the Foxn1 promoter. Normal T cell lineage choice and development through the canonical αβ T cell stages was observed. Interestingly, Adam17 deficiency in TECs resulted in reduced expression of the transcription factor Aire. However, no alterations in the patterns of TEC phenotypic marker expression and thymus morphology were noted. CONCLUSIONS/SIGNIFICANCE: In contrast to expectation, our data clearly shows that absence of Adam17 in TECs is dispensable for normal T cell development. Differentiation of TECs is also unaffected by loss of Adam17 based on phenotypic markers. Surprisingly, we have uncovered a novel genetic link between Adam17and Aire expression in vivo. The cell type in which ADAM17 mediates its non-cell autonomous impact and

  19. Levatiracetam for the management of Lance-Adams syndrome

    Directory of Open Access Journals (Sweden)

    Faik ILIK*

    2014-04-01

    Full Text Available How to Cite This Article: Ilik F, Ilik MK, Çöven I. Levatiracetam for the management of Lance-Adams syndrome. Iran J Child Neurol. 2014 Spring 8(2:57-59. Chronic post-hypoxic myoclonus, also known as Lance-Adams syndrome (LAS is a neurological complication characterized by uncontrolled myoclonic jerks following cardiac arrest. In this article, clinical manifestation and symptomatic treatment options are discussed especially concerning the rationale of use of levatiracetam in patients with Lance-Adams syndrome. Clinical presentation is action myoclonus associated with cerebellar ataxia, postural imbalance, and very mild intellectual deficit.An 18-year-old female patient was admitted to our intensive care unit in a coma. She had a cardiorespiratory arrest after a splenectomy in a local hospital. Then, myoclonic movements were continuously observed over the entire body, including the face.On day 14 of hospitalization, we started levatiracetam 1000 mg daily. The frequency of convulsion movements was reduced. The patient level of consciousness was 15 on the Glasgow coma scale (GCS on the Mini-Mental State Examination (MMSE score was 23 out of 30. She was later transferred to the rehabilitation department.Vigilance is required to ensure early diagnosis and timely intervention for the myoclonic jerks. In conclusion, we would like to emphasize that LAS should be considered in patients with the myoclonic jerks following cardiac arrest and that levatiracetam therapy may be useful as treatment.References1. Lance JW, Adams RD. The syndrome of intention or action myoclonus as a sequel to hypoxic encephalopathy. Brain 1963; 86: 111-136.2. Guo XH, Yu SY, Liu J, Wu WP, Pu CQ, Zhu K. Posthypoxic myoclonus treated with 5-hydroxytryptophan: a case report. J Clin Neurol 2002; 15: 313-6.3. Arpesella R, Dallocchio C, Arbasino C, Imberti R, Martinotti R, Frucht SJ. A patient with intractable posthypoxic myoclonus (Lance-Adams syndrome treated with sodium oxybate

  20. ADAM 12 cleaves extracellular matrix proteins and correlates with cancer status and stage

    DEFF Research Database (Denmark)

    Roy, Roopali; Wewer, Ulla M; Zurakowski, David; Pories, Susan E; Moses, Marsha A

    2004-01-01

    ADAM 12 is a member of a family of disintegrin-containing metalloproteases that have been implicated in a variety of diseases including Alzheimer's disease, arthritis, and cancer. We purified ADAM 12 from the urine of breast cancer patients via Q-Sepharose anion exchange and gelatin-Sepharose aff...... diagnostic and prognostic tests for breast and perhaps other cancers.......ADAM 12 is a member of a family of disintegrin-containing metalloproteases that have been implicated in a variety of diseases including Alzheimer's disease, arthritis, and cancer. We purified ADAM 12 from the urine of breast cancer patients via Q-Sepharose anion exchange and gelatin...... in human urine, 117 urine samples from breast cancer patients and controls were analyzed by immunoblot. The majority of samples from cancer patients were positive for ADAM 12 (67 of 71, sensitivity 0.94) compared with urine from controls in which ADAM 12 was detected with significantly lower...

  1. ADAM 12, a disintegrin metalloprotease, interacts with insulin-like growth factor-binding protein-3

    DEFF Research Database (Denmark)

    Shi, Z; Xu, Wei; Loechel, F;

    2000-01-01

    yet the pregnancy-specific protease, or proteases, have not been identified. We utilized a yeast two-hybrid assay and a human placental cDNA library to investigate IGFBP-3-interacting proteins. A disintegrin and metalloprotease-12 (ADAM 12), a member of a family of metalloprotease disintegrins that is...... highly expressed in placental tissue, was identified as interacting with IGFBP-3. This interaction involved the cysteine-rich domain of ADAM 12. Unlike other members of this family of disintegrin metalloproteases that are membrane proteins, ADAM 12 exists as an alternatively spliced soluble secreted...... protein. To verify the interaction between ADAM 12 and IGFBP-3, an expression construct containing an ADAM 12-S cDNA was transfected into COS-1 cells. Co-precipitation was observed when conditioned medium was analyzed by immunoprecipitation with an antibody against either ADAM 12 or IGFBP-3 followed by...

  2. Regulation of ADAM12 cell-surface expression by protein kinase C epsilon

    DEFF Research Database (Denmark)

    Sundberg, Christina; Thodeti, Charles Kumar; Kveiborg, Marie;

    2004-01-01

    constitutively active protein. However, little is known about the regulation of ADAM12 cell-surface translocation. Here, we used human RD rhabdomyosarcoma cells, which express ADAM12 at the cell surface, in a temporal pattern. We report that protein kinase C (PKC) epsilon induces ADAM12 translocation to the cell......The ADAM (a disintegrin and metalloprotease) family consists of multidomain cell-surface proteins that have a major impact on cell behavior. These transmembrane-anchored proteins are synthesized as proforms that have (from the N terminus): a prodomain; a metalloprotease-, disintegrin......-immunoprecipitated from membrane-enriched fractions of PMA-treated cells, 3) RD cells transfected with EGFP-tagged, myristoylated PKCepsilon expressed more ADAM12 at the cell surface than did non-transfected cells, and 4) RD cells transfected with a kinase-inactive PKCepsilon mutant did not exhibit ADAM12 cell...

  3. A Functional Role for ADAM10 in Human Immunodeficiency Virus Type-1 Replication

    OpenAIRE

    Rubin Donald H; Hodge Thomas W; Sheng Jinsong; Li Guangyu; Murray James L; Friedrich Brian M; O'Brien William A; Ferguson Monique R

    2011-01-01

    Abstract Background Gene trap insertional mutagenesis was used as a high-throughput approach to discover cellular genes participating in viral infection by screening libraries of cells selected for survival from lytic infection with a variety of viruses. Cells harboring a disrupted ADAM10 (A Disintegrin and Metalloprotease 10) allele survived reovirus infection, and subsequently ADAM10 was shown by RNA interference to be important for replication of HIV-1. Results Silencing ADAM10 expression ...

  4. Transgenic Overexpression of ADAM12 Suppresses Muscle Regeneration and Aggravates Dystrophy in Aged mdx Mice

    OpenAIRE

    Jørgensen, Louise Helskov; Jensen, Charlotte Harken; Wewer, Ulla M.; Schrøder, Henrik Daa

    2007-01-01

    Muscular dystrophies are characterized by insufficient restoration and gradual replacement of the skeletal muscle by fat and connective tissue. ADAM12 has previously been shown to alleviate the pathology of young dystrophin-deficient mdx mice, a model for Duchenne muscular dystrophy. The observed effect of ADAM12 was suggested to be mediated via a membrane-stabilizing up-regulation of utrophin, α7B integrin, and dystroglycans. Ectopic ADAM12 expression in normal mouse skeletal muscle also imp...

  5. Adam Olearius ja kultuuriline Teine teekonnal Oktsidendist Orienti / Aigi Heero, Maris Saagpakk

    Index Scriptorium Estoniae

    Heero, Aigi, 1971-

    2013-01-01

    Erinevate rahvaste kujutamisest 1656. aastal ilmunud Adam Oleariuse tuntud varauusaegses reisikirjas "Vermehrte Newe Beschreibung Der Muscowitischen vnd Persischen Reyse". Eestlaste kujutamisest võrdluses teiste rahvastega

  6. ADAM SMITH: LA MANO INVISIBLE O LA CONFIANZA

    OpenAIRE

    Gache, Fernando Luis; Otero, Dino

    2010-01-01

    En 1776 Adam Smith planteó que una mano invisible era quien movía a los mercados para obtener su eficiencia. No obstante en el presente trabajo vamos a plantear la hipótesis, que dicha mano invisible, es en realidad la confianza que cada persona siente en el momento de hacer un negocio. Que además es única, pues es distinta a la confianza de los demás y que se trata de una variable no lineal que fundamentalmente está ligada a las respectivas historias personales. Para ello vamos a tomar como ...

  7. Adam Curle : Radical Peacemaker and Pioneer of Peace Studies

    OpenAIRE

    Woodhouse, Tom

    2010-01-01

    Peer reviewed Aquest article presenta un relat biogràfic d'Adam Curle, amb un èmfasi especial en el desenvolupament de les seves idees sobre la pau i els estudis per la pau i en l'impacte que aquestes idees van tenir sobre el desenvolupament d'aquest camp en els aspectes teòric i pràctic. Curle va ser el professor fundador del Departament d'Estudis per la Pau a la Universitat de Bradford al Regne Unit. Nomenat catedràtic l'any 1973, el Departament va iniciar els seus programes d'ensenyamen...

  8. Introduction: REVIEW SYMPOSIUM ON GIOVANNI ARRIGHIS ADAM SMITH IN BEIJING

    OpenAIRE

    Thomas D. Hall

    2015-01-01

    About sixteen months ago we began discussing commissioning a series of review essays on Arrighis Adam Smith in Beijing. The original idea was to publish a collection of essays from various world-systems scholars, and have Arrighi respond. As we all know, Giovanni became ill and sadly passed in summer of 2009. In commissioning the essays as book review editor I faced a special challenge. Some likely writers had already committed to essays for other venues (e.g., Janet Abo-Lughod 2008; Chris Ch...

  9. Research on Fault Evaluation of Armament Equipment Based on ADAMS

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    The levels of simulation are introduced, and the importance of virtual prototyping of armament equipment is discussed and steps of virtual prototyping are outlined. The faults that affect firing performance are discussea, ADAMS is first to be introduced to armament equipment,and a virtual prototyping model of artillery is established with the help of Fortran language based on analysis of topology of artillery and forces applied on it. The plan of fault evaluation is brought forward, the modules are analyzed, and the concept of fault evaluation function is introduced Finally, the perspective of virtual technology is presented.

  10. Adam Smith et le “républicanisme”

    Directory of Open Access Journals (Sweden)

    Alexandra HYARD

    2003-10-01

    Full Text Available Je remercie Pierre Lurbe et Ann Thomson pour leurs remarques. Je tiens également à remercier Thierry Demals pour son aide précieuse. Néanmoins, je reste seule responsable des éventuelles erreurs contenues dans ce travail.Introduction Smith semble avoir toujours été en théorie un républicain, et il a sûrement eu le vrai esprit d’un républicain dans son amour de toute liberté rationnelle. (Rae 124 Par cette phrase, Rae nous livre son opinion sur une des questions relatives à Adam Smith (1723-1...

  11. Adam Smith et le “républicanisme”

    OpenAIRE

    Alexandra HYARD

    2011-01-01

    Je remercie Pierre Lurbe et Ann Thomson pour leurs remarques. Je tiens également à remercier Thierry Demals pour son aide précieuse. Néanmoins, je reste seule responsable des éventuelles erreurs contenues dans ce travail.Introduction Smith semble avoir toujours été en théorie un républicain, et il a sûrement eu le vrai esprit d’un républicain dans son amour de toute liberté rationnelle. (Rae 124) Par cette phrase, Rae nous livre son opinion sur une des questions relatives à Adam Smith (1723-1...

  12. Adam Smith on Monopoly Theory. Making good a lacuna

    OpenAIRE

    Salvadori, Neri; Signorino, Rodolfo

    2012-01-01

    The paper analyzes Adam Smith’s views on monopoly focusing on Book IV and V of The Wealth of Nations and argues that Smith has left his analysis of monopoly in an embryonic form while the majority of scholars have assessed it starting from premises different from those, actually though implicitly, used by Smith to approach this subject. We show that Smith makes use of the word ‘monopoly’ to refer to a heterogeneous collection of market outcomes, besides that of a single seller market, and tha...

  13. ADAM33 gene silencing by promoter hypermethylation as a molecular marker in breast invasive lobular carcinoma

    Directory of Open Access Journals (Sweden)

    de Souza Emanuel M

    2009-03-01

    Full Text Available Abstract Background ADAM33 protein is a member of the family of transmembrane glycoproteins composed of multidomains. ADAM family members have different activities, such as proteolysis and adhesion, making them good candidates to mediate the extracellular matrix remodelling and changes in cellular adhesion that characterise certain pathologies and cancer development. It was reported that one family member, ADAM23, is down-regulated by promoter hypermethylation. This seems to correlate with tumour progression and metastasis in breast cancer. In this study, we explored the involvement of ADAM33, another ADAM family member, in breast cancer. Methods First, we analysed ADAM33 expression in breast tumour cell lines by RT-PCR and western blotting. We also used 5-aza-2'-deoxycytidine (5azadCR treatment and DNA bisulphite sequencing to study the promoter methylation of ADAM33 in breast tumour cell lines. We evaluated ADAM33 methylation in primary tumour samples by methylation specific PCR (MSP. Finally, ADAM33 promoter hypermethylation was correlated with clinicopathological data using the chi-square test and Fisher's exact test. Results The expression analysis of ADAM33 in breast tumour cell lines by RT-PCR revealed gene silencing in 65% of tumour cell lines. The corresponding lack of ADAM33 protein was confirmed by western blotting. We also used 5-aza-2'-deoxycytidine (5-aza-dCR demethylation and bisulphite sequencing methodologies to confirm that gene silencing is due to ADAM33 promoter hypermethylation. Using MSP, we detected ADAM33 promoter hypermethylation in 40% of primary breast tumour samples. The correlation between methylation pattern and patient's clinicopathological data was not significantly associated with histological grade; tumour stage (TNM; tumour size; ER, PR or ERBB2 status; lymph node status; metastasis or recurrence. Methylation frequency in invasive lobular carcinoma (ILC was 76.2% compared with 25.5% in invasive ductal carcinoma

  14. Metalloproteinases ADAM12 and MMP-14 are associated with cavernous sinus invasion in pituitary adenomas.

    Science.gov (United States)

    Wang, Junwen; Voellger, Benjamin; Benzel, Julia; Schlomann, Uwe; Nimsky, Christopher; Bartsch, Jörg W; Carl, Barbara

    2016-09-15

    Invasion of tumor cells critically depends on cell-cell or cell-extracellular matrix interactions. Enzymes capable of modulating these interactions belong to the proteinase families of ADAM (a disintegrin and metalloprotease) and MMP (matrix metalloprotease) proteins. Our objective is to examine their expression levels and evaluate the relationship between expression levels and cavernous sinus invasion in pituitary adenomas. Tissue samples from 35 patients with pituitary adenomas were analyzed. Quantitative real-time polymerase chain reaction (qPCR) was employed to assess mRNA expression levels for ADAM and MMP genes. Protein levels were examined using immunohistochemistry and Western Blot. Correlation analyses between expression levels and clinical parameters were performed. By silencing ADAM12 and MMP-14 with siRNA in a mouse pituitary adenoma cell line (TtT/GF), their cellular effects were investigated. In our study, nine women and 26 men were included, with a mean age of 53.1 years (range 15-84 years) at the time of surgery. There were 19 cases with cavernous sinus invasion. The proteins ADAM12 and MMP-14 were significantly up-regulated in invasive adenomas compared to noninvasive adenomas. Both human isoforms of ADAM12 (ADAM12L and ADAM12s) were involved in tumor invasion; moreover, ADAM12L was found to correlate positively with Ki-67 proliferation index in pituitary adenomas. In TtT/GF pituitary adenoma cells, silencing of ADAM12 and MMP-14 significantly inhibited cell invasion and migration, respectively, whereas only silencing of ADAM12 suppressed cell proliferation. We conclude that ADAM12 and MMP-14 are associated with cavernous sinus invasion in pituitary adenomas, which qualifies these proteins in diagnosis and therapy. PMID:27144841

  15. ADAM15 Is Functionally Associated with the Metastatic Progression of Human Bladder Cancer.

    Directory of Open Access Journals (Sweden)

    Guadalupe Lorenzatti Hiles

    Full Text Available ADAM15 is a member of a family of catalytically active disintegrin membrane metalloproteinases that function as molecular signaling switches, shed membrane bound growth factors and/or cleave and inactivate cell adhesion molecules. Aberrant metalloproteinase function of ADAM15 may contribute to tumor progression through the release of growth factors or disruption of cell adhesion. In this study, we utilized human bladder cancer tissues and cell lines to evaluate the expression and function of ADAM15 in the progression of human bladder cancer. Examination of genome and transcriptome databases revealed that ADAM15 ranked in the top 5% of amplified genes and its mRNA was significantly overexpressed in invasive and metastatic bladder cancer compared to noninvasive disease. Immunostaining of a bladder tumor tissue array designed to evaluate disease progression revealed increased ADAM15 immunoreactivity associated with increasing cancer stage and exhibited significantly stronger staining in metastatic samples. About half of the invasive tumors and the majority of the metastatic cases exhibited high ADAM15 staining index, while all low grade and noninvasive cases exhibited negative or low staining. The knockdown of ADAM15 mRNA expression significantly inhibited bladder tumor cell migration and reduced the invasive capacity of bladder tumor cells through MatrigelTM and monolayers of vascular endothelium. The knockdown of ADAM15 in a human xenograft model of bladder cancer inhibited tumor growth by 45% compared to controls. Structural modeling of the catalytic domain led to the design of a novel ADAM15-specific sulfonamide inhibitor that demonstrated bioactivity and significantly reduced the viability of bladder cancer cells in vitro and in human bladder cancer xenografts. Taken together, the results revealed an undescribed role of ADAM15 in the invasion of human bladder cancer and suggested that the ADAM15 catalytic domain may represent a viable

  16. Adam Smith e Francis Ysidro Edgeworth: uma crítica do utilitarismo [Adam Smith and Francis Ysidro Edgeworth: a criticism to utilitarianism

    OpenAIRE

    Solange Regina Marin; André Marzulo Quintana

    2011-01-01

    We suggest, in this paper, the investigation of Adam Smith and Francis Ysidro Edgeworth's utilitarianism conceptions. Both conceptions were used in order to develop Economics as science. However, they presented the limitations of the economic theory, which boundaries recommended.

  17. The futility of utility: how market dynamics marginalize Adam Smith

    Science.gov (United States)

    McCauley, Joseph L.

    2000-10-01

    Economic theorizing is based on the postulated, nonempiric notion of utility. Economists assume that prices, dynamics, and market equilibria are supposed to be derived from utility. The results are supposed to represent mathematically the stabilizing action of Adam Smith's invisible hand. In deterministic excess demand dynamics I show the following. A utility function generally does not exist mathematically due to nonintegrable dynamics when production/investment are accounted for, resolving Mirowski's thesis. Price as a function of demand does not exist mathematically either. All equilibria are unstable. I then explain how deterministic chaos can be distinguished from random noise at short times. In the generalization to liquid markets and finance theory described by stochastic excess demand dynamics, I also show the following. Market price distributions cannot be rescaled to describe price movements as ‘equilibrium’ fluctuations about a systematic drift in price. Utility maximization does not describe equilibrium. Maximization of the Gibbs entropy of the observed price distribution of an asset would describe equilibrium, if equilibrium could be achieved, but equilibrium does not describe real, liquid markets (stocks, bonds, foreign exchange). There are three inconsistent definitions of equilibrium used in economics and finance, only one of which is correct. Prices in unregulated free markets are unstable against both noise and rising or falling expectations: Adam Smith's stabilizing invisible hand does not exist, either in mathematical models of liquid market data, or in real market data.

  18. ADAM12-mediated focal adhesion formation is differently regulated by beta1 and beta3 integrins

    DEFF Research Database (Denmark)

    Thodeti, Charles Kumar; Frohlich, Camilla; Nielsen, Christian Kamp;

    2005-01-01

    ADAM12, adisintegrin and metalloprotease, has been demonstrated to be upregulated in human malignant tumors and to accelerate the malignant phenotype in a mouse model for breast cancer. ADAM12 is a substrate for beta1 integrins and may affect tumor and stromal cell behavior through its binding to...

  19. At læse Adam Smith er både befriende og irriterende

    DEFF Research Database (Denmark)

    Larsen, Steen Nepper

    2014-01-01

    Anmeldelse af Adam Smith: "Teorien om de moralske følelser", oversat af Claus Bratt Østergaard, udg. på Informations Forlag......Anmeldelse af Adam Smith: "Teorien om de moralske følelser", oversat af Claus Bratt Østergaard, udg. på Informations Forlag...

  20. ADAM12 overexpression does not improve outcome in mice with laminin alpha2-deficient muscular dystrophy

    DEFF Research Database (Denmark)

    Guo, Ling T; Shelton, G Diane; Wewer, Ulla M;

    2005-01-01

    We have recently shown that overexpression of ADAM12 results in increased muscle regeneration and significantly reduced pathology in mdx, dystrophin deficient mice. In the present study, we tested the effect of overexpressing ADAM12 in dy(W) laminin-deficient mice. dy mice have a very severe clin...

  1. Deciphering the role of the ADAM17-dependent secretome in cell signaling.

    Science.gov (United States)

    Kawahara, Rebeca; Lima, Renato Niyama; Domingues, Romênia R; Pauletti, Bianca Alves; Meirelles, Gabriela V; Assis, Michelle; Figueira, Ana Carolina Migliorini; Paes Leme, Adriana Franco

    2014-04-01

    ADAM17 has been initially identified as the main sheddase responsible for releasing the soluble form of a variety of cell-surface proteins, including growth factors, cytokines, cell adhesion molecules, and receptors, most of which are associated with pathological processes, including cancer and inflammation. However, the function and composition of the ADAM17-dependent secretome on a proteome-wide scale is poorly understood. In this study, we observed that the ADAM17-dependent secretome plays an important role in promoting cell proliferation and migration. To further demonstrate the repertoire of proteins involved in this cross-talk, we employed mass-spectrometry-based proteomics using nonmetabolic and metabolic labeling approaches to explore the secretome composition of wild-type and ADAM17(-/-) knockout mouse embryonic fibroblast (mEF) cells. Bioinformatic analyses indicated the differential regulation of 277 soluble proteins in the ADAM17-dependent secretome as well as novel direct ADAM17 cleavage substrates, such as mimecan and perlecan. Furthermore, we found that the ADAM17-dependent secretome promoted an opposite regulation of ERK and FAK pathways as well as PPARγ downstream activation. These findings demonstrated fine-tuning of cell signaling rendered by the soluble molecules mediated by ADAM17. PMID:24625128

  2. DEVELOPMENT OF THE HUMAN LUNG MEASURED BY AEROSOL-DERIVED AIRWAY MORPHEMETRY (ADAM).

    Science.gov (United States)

    We measured, in vivo, the airspace calibers of the small airways and alveoli by ADAM in the lungs of children of ages 6 to 18 years and adults aged 18 to 80 years. ADAM utilizes the gravitational settling time of inhaled monodisperse particles to infer the vertical distance to th...

  3. ADAM12 in human liver cancers: TGF-beta-regulated expression in stellate cells is associated with matrix remodeling

    DEFF Research Database (Denmark)

    Le Pabic, Hélène; Bonnier, Dominique; Wewer, Ulla M;

    2003-01-01

    "A disintegrin and metalloproteinases" (ADAMs) form a family of cell-surface glycoproteins with potential protease and cell-adhesion activities. We have investigated ADAM expression in human liver cancers and their regulation by several cytokines involved in liver injury. Using degenerative RT...... carcinomas (up to 3- and 6-fold, respectively) and liver metastases from colonic carcinomas (up to 40- and 60-fold, respectively). The up-regulation of both ADAM9 and ADAM12 was correlated with an increase in matrix metalloproteinase 2 expression and activity. In conclusion, in liver cancers ADAM9 and ADAM12...... was associated with the transition from quiescent to activated state of rat HSCs and markedly increased in human livers with cirrhosis. ADAM12 but not ADAM9 expression was up-regulated by transforming growth factor beta (TGF-beta) in human activated HSCs. The PI3K inhibitor LY294002 and the mitogen...

  4. Adam Smith Problem ou problème des sciences sociales ? Détour par l'anthropologie d'Adam Smith

    OpenAIRE

    Jean-Daniel Boyer

    2009-01-01

    The point of this article is to define man?s universal character traits, as Adam Smith describes them in his work, in order to show that the Adam Smith Problem is in fact not grounded. It results more from an anachronistic understanding of his work, and bears witness to the issues raised by the separation of the social sciences branches. JEL classification ? B12

  5. Cysteine-rich domain of human ADAM 12 (meltrin alpha) supports tumor cell adhesion

    DEFF Research Database (Denmark)

    Iba, K; Albrechtsen, R; Gilpin, B J;

    1999-01-01

    tumor cell adhesion. We found that the disintegrin-like domain of human ADAM 15 supported adhesion of alphavbeta3-expressing A375 melanoma cells. In the case of human ADAM 12, however, recombinant polypeptides of the cysteine-rich domain but not the disintegrin-like domain supported cell adhesion of a...... panel of carcinoma cell lines. On attachment to recombinant polypeptides from the cysteine-rich domain of human ADAM 12, most tumor cell lines, such as MDA-MB-231 breast carcinoma cells, were rounded and associated with numerous actin-containing filopodia and used a cell surface heparan sulfate...... proteoglycan to attach. Finally, we demonstrated that authentic full-length human ADAM 12 could bind to heparin Sepharose. Together these results suggest a novel role of the cysteine-rich domain of ADAM 12 -- that of supporting tumor cell adhesion....

  6. The role of CXCL16 and its processing metalloproteinases ADAM10 and ADAM17 in the proliferation and migration of human mesangial cells

    International Nuclear Information System (INIS)

    In this study, we analyzed the regulation and functional role of CXCL16 in human mesangial cells (hMCs). We can show, that CXCL16 is constitutively expressed in hMCs and is further up-regulated by cytokine mix (IFNγ, TNFα, and IL1β). The constitutive release of CXCL16 from hMCs was rapidly induced by the stimulation with cytokines. We identified ADAM10 and ADAM17 as being responsible for the cytokine-induced shedding of CXCL16. Notably, targeting ADAM10 and ADAM17 in hMCs decreased the chemotaxis of T-Jurkat cells, whereas the inhibition of CXCL16 had no significant influence. This suggests that both proteases are important players in the recruitment of immune cells into the glomerulus, but other substrates than CXCL16 are involved in this process. Finally, we could show that the inhibition of CXCL16, ADAM10, and ADAM17 led to a strong reduction of cell proliferation and migration of hMCs. This finding could be important to develop novel diagnostic and therapeutic strategies to treat mesangial proliferative kidney diseases

  7. Aktivierung der alpha-Sekretase ADAM10 als neuer therapeutischer Ansatz zur Behandlung der Alzheimer-Erkrankung

    OpenAIRE

    Tippmann, Frank

    2008-01-01

    Die Stimulation der APP-prozessierenden α-Sekretase ADAM10 eröffnet eine vielversprechende Möglichkeit zur medizinischen Behandlung der Alzheimer-Krankheit. In dieser Arbeit wurden drei unterschiedliche Strategien zur therapeutischen Aktivierung von ADAM10 verfolgt: Die Aktivierung des G-Protein-gekoppelten Rezeptors PAC1 durch PACAP, die Gentherapie mit ADAM10-cDNA und die ADAM10-Promotorstimulation durch Retinoid-Rezeptor-Aktivierung. PACAP-38 stimuliert die α-Sekretase-vermittelte APPsα...

  8. A new species of Casmaria H. Adams & A. Adams, 1853 (Gastropoda, Cassidae from the Philippines identified by molecular data

    Directory of Open Access Journals (Sweden)

    Alexander Fedosov

    2014-03-01

    Full Text Available The genus Casmaria H. Adams & A. Adams, 1853 (family Cassidae is widespread in the tropical Indo-Pacific and has been documented from some Atlantic localities as well. Two Casmaria species, C. erinaceus (Linnaeus, 1758 and C. ponderosa (Gmelin, 1791, are common in Indo-Pacific shallow-water sandy bottom communities and are characterized by high morphological variability; both species encompass multiple, often sympatric forms of uncertain status. In the present study we carry out a phylogenetic analysis of some Philippine Casmaria morphs and demonstrate that one of the distinctive morphs earlier assigned to Casmaria ponderosa is in fact a different species, which we describe as Casmaria boblehmani sp. nov. The smooth form of Casmaria ponderosa, C. ponderosa ponderosa, and the solid nodulose form, widely called “form nodulosa” despite being strikingly different in shell morphology, are shown to be conspecific. Studied specimens of these two morphs even from different localities share the same haplotype of the CO1 gene. In light of these new data on the morphological variability of Casmaria species, we discuss criteria of species delimitation in the genus Casmaria and possible affinities of Casmaria boblehmani sp. nov. within the genus.

  9. The sorting protein PACS-2 promotes ErbB signalling by regulating recycling of the metalloproteinase ADAM17

    DEFF Research Database (Denmark)

    Dombernowsky, Sarah Louise; Samsøe-Petersen, Jacob; Petersen, Camilla Hansson;

    2015-01-01

    poorly understood. Here, through a functional genome-wide siRNA screen, we identify the sorting protein PACS-2 as a regulator of ADAM17 trafficking and ErbB signalling. PACS-2 loss reduces ADAM17 cell-surface levels and ADAM17-dependent ErbB ligand shedding, without apparent effects on related proteases...

  10. HIV-1非核苷类逆转录酶抑制剂药效团模型构建及新抑制剂的搜索%Pharmacophore model building of HIV-1 non-nucleoside reverse transcriptase inhibitors and searching for new inhibitors

    Institute of Scientific and Technical Information of China (English)

    肖泽云; 李凯; 李爱秀; 王晓辉; 刘勇庆

    2016-01-01

    [目的]构建Ⅰ型人类免疫缺陷病毒(human immunodeficiency virus type 1,HIV-1)非核苷类逆转录酶抑制剂(non-nucleoside reverse transcriptase inhibitors,NNRTIs)的药效团模型,通过对中药化学数据库(traditional Chinese medicine database,TCMD)的搜索,在中药中寻找新型抗耐药的NNRTIs.[方法]从已知的NNRTIs与逆转录酶复合物的晶体结构出发,通过构象分析和药效团识别等方法,构建NNRTIs的药效团模型并检验其可靠性;基于药效团模型对TCMD进行数据库搜索,发现新型潜在的NNRTIs.[结果]从PDB中检索出2010年至2014年RT与NNRTIs复合物的晶体结构30个,从中抽提出其活性配体,建立了一个包含30个活性配体的小分子数据库;通过对上市药物TMC278和TMC125及高活性抑制剂DJZ的构象叠合和药效特征基团分析构建了新的NNRTIs药效团模型,该模型包含了5个药效特征基团;以符合这5个药效特征基团中任意4个为条件,在活性配体小分子数据库中验证性搜索出18个化合物,检出率为60.0%;基于五点药效团模型对TCMD进行数据库搜索得到272个化合物.[结论]以TMC278、TMC 125和DJZ构建的五点药效团模型,以符合其中任意4个为条件,在活性配体小分子数据库中的检出率达到60.0%,表明所建药效团模型是可靠的.

  11. Establishment of pharmacological evaluation system for non-nucleoside reverse-transcriptase inhibitors resistant HIV-1%非核苷类逆转录酶抑制剂耐药型HIV-1药理评价体系的建立

    Institute of Scientific and Technical Information of China (English)

    曹颖莉; 李少雄; 陈虹; 郭颖

    2009-01-01

    建立9种临床常见的对非核苷类逆转录酶抑制剂(non-nucleoside reverse-transcriptase inhibitors,NNRTIs)耐药型HIV-1重组病毒药理评价模型.应用重叠PCR定点突变技术将耐药突变位点引入HIV-1核心基因(pNL4-3.Luc.R-E-),以水泡性口膜炎病毒的外壳糖蛋白(vesicular stomatitis virus glycoprotein,VSV-G)包装含耐药突变位点的HIV-1核心,形成耐药型HIV-1重组假病毒颗粒,简称VSVG/HIV-mut(包括VSVG/HIV-wt、VSVG/HIV-K103N、VSVG/HIV-Y181C、VSVG/HIV-L100I,K103N、VSVG/HIV.Y188L、VSVG/HIV-K103N,181C、VSVG/HIV-K103N,P225H、VSVG/HIV-K103N,Y188L、VSVG/HIV-K103N,G109A和VSVG/HIV-K103N,V1081).经验证9种NNRTIs耐药型HIV-1重组病毒颗粒均具有高感染能力,对核苷类阳性药物不耐药,而对非核苷类阳性药物呈现不同程度的耐药性(17~10 000倍),且耐药倍数与报道的数据基本一致.所建立的耐药型模型是针对NNRTIs耐药的HIV-1复制环节的细胞水平药效学评价体系,野生型和9种耐药型HIV-1模型的联合应用,可为新型非核苷类逆转录酶抑制剂的研发提供更全面药效学评价的安全平台.

  12. Nuclear trafficking of the HIV-1 pre-integration complex depends on the ADAM10 intracellular domain

    International Nuclear Information System (INIS)

    Previously, we showed that ADAM10 is necessary for HIV-1 replication in primary human macrophages and immortalized cell lines. Silencing ADAM10 expression interrupted the HIV-1 life cycle prior to nuclear translocation of viral cDNA. Furthermore, our data indicated that HIV-1 replication depends on the expression of ADAM15 and γ-secretase, which proteolytically processes ADAM10. Silencing ADAM15 or γ-secretase expression inhibits HIV-1 replication between reverse transcription and nuclear entry. Here, we show that ADAM10 expression also supports replication in CD4+ T lymphocytes. The intracellular domain (ICD) of ADAM10 associates with the HIV-1 pre-integration complex (PIC) in the cytoplasm and immunoprecipitates and co-localizes with HIV-1 integrase, a key component of PIC. Taken together, our data support a model whereby ADAM15/γ-secretase processing of ADAM10 releases the ICD, which then incorporates into HIV-1 PIC to facilitate nuclear trafficking. Thus, these studies suggest ADAM10 as a novel therapeutic target for inhibiting HIV-1 prior to nuclear entry. - Highlights: • Nuclear trafficking of the HIV-1 pre-integration complex depends on ADAM10. • ADAM10 associates with HIV-1 integrase in the pre-integration complex. • HIV-1 replication depends on the expression of ADAM15 and γ-secretase. • Silencing ADAM15 or γ-secretase expression inhibits nuclear import of viral cDNA. • ADAM10 is important for HIV-1 replication in human macrophages and CD4+ T lymphocytes

  13. Nuclear trafficking of the HIV-1 pre-integration complex depends on the ADAM10 intracellular domain

    Energy Technology Data Exchange (ETDEWEB)

    Endsley, Mark A., E-mail: maendsle@utmb.edu [Department Internal Medicine, Division of Infectious Diseases, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555 (United States); Somasunderam, Anoma D., E-mail: asomasun@utmb.edu [Department Internal Medicine, Division of Infectious Diseases, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555 (United States); Li, Guangyu, E-mail: LIG001@mail.etsu.edu [Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614 (United States); Oezguen, Numan, E-mail: numan.oezguen@bcm.edu [Department of Pathology and Immunology, Microbiome Center, Texas Children' s Hospital, Houston, TX 77030 (United States); Thiviyanathan, Varatharasa, E-mail: Varatharasa.Thiviyanathan@uth.tmc.edu [Institute of Molecular Medicine, University of Texas Health Science Center, Houston, TX 77030 (United States); Murray, James L., E-mail: jmurray100@yahoo.com [GeneTAG Technology, Inc., 3155 Northwoods Place, Norcross, GA 30071 (United States); Rubin, Donald H., E-mail: don.h.rubin@vanderbilt.edu [Research Medicine, VA Tennessee Valley Healthcare System, 1310 24th Ave. South, Nashville, TN 37212 (United States); Departments of Medicine, Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, 1161 21st Ave South, Nashville, TN 37232 (United States); Hodge, Thomas W., E-mail: twhodge3@gmail.com [Pre-clinical and Antiviral Research, Tamir Biotechnology, Inc., 12625 High Bluff Dr., Suite 113, San Diego, CA 92130 (United States); and others

    2014-04-15

    Previously, we showed that ADAM10 is necessary for HIV-1 replication in primary human macrophages and immortalized cell lines. Silencing ADAM10 expression interrupted the HIV-1 life cycle prior to nuclear translocation of viral cDNA. Furthermore, our data indicated that HIV-1 replication depends on the expression of ADAM15 and γ-secretase, which proteolytically processes ADAM10. Silencing ADAM15 or γ-secretase expression inhibits HIV-1 replication between reverse transcription and nuclear entry. Here, we show that ADAM10 expression also supports replication in CD4{sup +} T lymphocytes. The intracellular domain (ICD) of ADAM10 associates with the HIV-1 pre-integration complex (PIC) in the cytoplasm and immunoprecipitates and co-localizes with HIV-1 integrase, a key component of PIC. Taken together, our data support a model whereby ADAM15/γ-secretase processing of ADAM10 releases the ICD, which then incorporates into HIV-1 PIC to facilitate nuclear trafficking. Thus, these studies suggest ADAM10 as a novel therapeutic target for inhibiting HIV-1 prior to nuclear entry. - Highlights: • Nuclear trafficking of the HIV-1 pre-integration complex depends on ADAM10. • ADAM10 associates with HIV-1 integrase in the pre-integration complex. • HIV-1 replication depends on the expression of ADAM15 and γ-secretase. • Silencing ADAM15 or γ-secretase expression inhibits nuclear import of viral cDNA. • ADAM10 is important for HIV-1 replication in human macrophages and CD4{sup +} T lymphocytes.

  14. Adam Smith and the new era of China

    Directory of Open Access Journals (Sweden)

    Aníbal Carlos Zottele

    2013-01-01

    Full Text Available ural area has been the quiet main character of China’s economic development. The history of this thousand-year-old culture seems to be exempted from further comments about its role. Its importance has been strongly expressed during crisis which institutions of that great nation in XX century were shook. Agricultural sector was the key in modernization period initiated in 1980 even in the later phases. Agriculture preponderance as progress support of the nations is presented by Scottish thinker Adam Smith in his work An Inquiry into the Nature and Causes of the Wealth of Nations. The status of Chinese development in XVII y XVIII centuries has been characterized in this document as well as the natural order of progress against unnatural or retrograde order followed by the Netherlands, in that time the country that had achieved higher levels growth in Europe. Apparently, at present, China repeats its old experiences by concentrating on the path praised by Smith.

  15. Econophysical visualization of Adam Smith’s invisible hand

    Science.gov (United States)

    Cohen, Morrel H.; Eliazar, Iddo I.

    2013-02-01

    Consider a complex system whose macrostate is statistically observable, but yet whose operating mechanism is an unknown black-box. In this paper we address the problem of inferring, from the system’s macrostate statistics, the system’s intrinsic force yielding the observed statistics. The inference is established via two diametrically opposite approaches which result in the very same intrinsic force: a top-down approach based on the notion of entropy, and a bottom-up approach based on the notion of Langevin dynamics. The general results established are applied to the problem of visualizing the intrinsic socioeconomic force-Adam Smith’s invisible hand-shaping the distribution of wealth in human societies. Our analysis yields quantitative econophysical representations of figurative socioeconomic forces, quantitative definitions of “poor” and “rich”, and a quantitative characterization of the “poor-get-poorer” and the “rich-get-richer” phenomena.

  16. Virtuální prototyp robotu v ADAMS

    OpenAIRE

    Příleský, Libor

    2012-01-01

    Tato práce se zabývá vytvořením virtuálního modelu robotu v ADAMS a co-simulačním propojením tohoto modelu s návrhem řízení v Matlab/Simulink. Robotem je segway Pierot vytvořený v rámci předchozích závěrečných prací. Obsahem této práce je vytvoření multi-body modelu, volba pohonu vytvoření co-simulačního propojení a samotná co-simulace.

  17. Modeling and Simulating for TSHD's Swell Compensator by ADAMS

    Institute of Scientific and Technical Information of China (English)

    LIU Zhi; NI Fusheng; ZHOU Hong

    2007-01-01

    CHC Trailing suction hopper dredgers (TSHD) have been widely used in dredging industry. In order to simulate the dredging process accurately, a mathematical model for a swell compensator used in TSHD is proposed, and a friendly simulation model based on the Automated Dynamic Analysis of Mechanical Systems (ADAMS) is built to test and validate the mathematical model for the swell compensator. The factors influencing the dynamic behavior of the TSHD suction pipe system, such as the motion of the vessel in an unquiet situation with different water current velocities, seabed profiles, seabed soil hardness and the forces acting on the suction pipe system, have been taken into consideration. The simulation results show that they fit in with the operating practice qualitatively.

  18. A Disintegrin and Metalloprotease (ADAM): Historical Overview of Their Functions

    Science.gov (United States)

    Giebeler, Nives; Zigrino, Paola

    2016-01-01

    Since the discovery of the first disintegrin protein from snake venom and the following identification of a mammalian membrane-anchored metalloprotease-disintegrin implicated in fertilization, almost three decades of studies have identified additional members of these families and several biochemical mechanisms regulating their expression and activity in the cell. Most importantly, new in vivo functions have been recognized for these proteins including cell partitioning during development, modulation of inflammatory reactions, and development of cancers. In this review, we will overview the a disintegrin and metalloprotease (ADAM) family of proteases highlighting some of the major research achievements in the analysis of ADAMs’ function that have underscored the importance of these proteins in physiological and pathological processes over the years. PMID:27120619

  19. Parameterized Analysis of 2-DOF Motion Platform Based on ADAMS

    Directory of Open Access Journals (Sweden)

    Hu Hanyuan

    2015-01-01

    Full Text Available According to the functions of parametric modeling and analysis from ADAMS, this thesis was established a parametric simulation model in order to optimize the rated output power of electric cylinders according to the real field environment. First, the variable which could affect sensitivity of the output variables was chosen by the electric cylinder’s elongation which was obtained through loop vector method. Then this thesis tried to get the optimum optimization design parameters through the simulation, and the change of rated output power affected by the change of parameters, meanwhile, made a filter and calibration of parameters which have greater influence on sensibilities. The goal of design could meet the qualification with less work load and faster speed. It is concluded that the change of the location parameters affects the rated output power.

  20. ADAM10 is essential for cranial neural crest-derived maxillofacial bone development.

    Science.gov (United States)

    Tan, Yu; Fu, Runqing; Liu, Jiaqiang; Wu, Yong; Wang, Bo; Jiang, Ning; Nie, Ping; Cao, Haifeng; Yang, Zhi; Fang, Bing

    2016-07-01

    Growth disorders of the craniofacial bones may lead to craniofacial deformities. The majority of maxillofacial bones are derived from cranial neural crest cells via intramembranous bone formation. Any interruption of the craniofacial skeleton development process might lead to craniofacial malformation. A disintegrin and metalloprotease (ADAM)10 plays an essential role in organ development and tissue integrity in different organs. However, little is known about its function in craniofacial bone formation. Therefore, we investigated the role of ADAM10 in the developing craniofacial skeleton, particularly during typical mandibular bone development. First, we showed that ADAM10 was expressed in a specific area of the craniofacial bone and that the expression pattern dynamically changed during normal mouse craniofacial development. Then, we crossed wnt1-cre transgenic mice with adam10-flox mice to generate ADAM10 conditional knockout mice. The stereomicroscopic, radiographic, and von Kossa staining results showed that conditional knockout of ADAM10 in cranial neural crest cells led to embryonic death, craniofacial dysmorphia and bone defects. Furthermore, we demonstrated that impaired mineralization could be triggered by decreased osteoblast differentiation, increased cell death. Overall, these findings show that ADAM10 plays an essential role in craniofacial bone development. PMID:27221046

  1. Soluble ADAM33 initiates airway remodeling to promote susceptibility for allergic asthma in early life

    Science.gov (United States)

    Davies, Elizabeth R.; Kelly, Joanne F.C.; Howarth, Peter H.; Wilson, David I.; Holgate, Stephen T.; Davies, Donna E.; Whitsett, Jeffrey A.; Haitchi, Hans Michael

    2016-01-01

    Asthma is a chronic inflammatory airways disease that usually begins in early life and involves gene-environment interactions. Although most asthma exhibits allergic inflammation, many allergic individuals do not have asthma. Here, we report how the asthma gene a disintegrin and metalloprotease 33 (ADAM33) acts as local tissue susceptibility gene that promotes allergic asthma. We show that enzymatically active soluble ADAM33 (sADAM33) is increased in asthmatic airways and plays a role in airway remodeling, independent of inflammation. Furthermore, remodeling and inflammation are both suppressed in Adam33-null mice after allergen challenge. When induced in utero or added ex vivo, sADAM33 causes structural remodeling of the airways, which enhances postnatal airway eosinophilia and bronchial hyperresponsiveness following subthreshold challenge with an aeroallergen. This substantial gene-environment interaction helps to explain the end-organ expression of allergic asthma in genetically susceptible individuals. Finally, we show that sADAM33-induced airway remodeling is reversible, highlighting the therapeutic potential of targeting ADAM33 in asthma.

  2. Antibodies binding the ADAM10 substrate recognition domain inhibit Eph function.

    Science.gov (United States)

    Atapattu, Lakmali; Saha, Nayanendu; Llerena, Carmen; Vail, Mary E; Scott, Andrew M; Nikolov, Dimitar B; Lackmann, Martin; Janes, Peter W

    2012-12-15

    The ADAM10 transmembrane metalloprotease cleaves a variety of cell surface proteins that are important in disease, including ligands for receptor tyrosine kinases of the erbB and Eph families. ADAM10-mediated cleavage of ephrins, the ligands for Eph receptors, is suggested to control Eph/ephrin-mediated cell-cell adhesion and segregation, important during normal developmental processes, and implicated in tumour neo-angiogenesis and metastasis. We previously identified a substrate-binding pocket in the ADAM10 C domain that binds the EphA/ephrin-A complex thereby regulating ephrin cleavage. We have now generated monoclonal antibodies specifically recognising this region of ADAM10, which inhibit ephrin cleavage and Eph/ephrin-mediated cell function, including ephrin-induced Eph receptor internalisation, phosphorylation and Eph-mediated cell segregation. Our studies confirm the important role of ADAM10 in cell-cell interactions mediated by both A- and B-type Eph receptors, and suggest antibodies against the ADAM10 substrate-recognition pocket as promising therapeutic agents, acting by inhibiting cleavage of ephrins and potentially other ADAM10 substrates. PMID:23108669

  3. ADAM10-Notch signaling governs the recruitment of ovarian pregranulosa cells and controls folliculogenesis in mice.

    Science.gov (United States)

    Feng, Lizhao; Wang, Yijing; Cai, Han; Sun, Guanghong; Niu, Wanbao; Xin, Qiliang; Tang, Xiaofang; Zhang, Jiawei; Wang, Chao; Zhang, Hua; Xia, Guoliang

    2016-06-01

    Ovarian follicles are the basic functional units of female reproduction in the mammalian ovary. We show here that the protein a disintegrin and metalloproteinase domain 10 (ADAM10), a cell surface sheddase, plays an indispensable role in controlling primordial follicle formation by regulating the recruitment of follicle supporting cells in mice. We demonstrate that suppressing ADAM10 in vitro or deletion of Adam10 in vivo disrupts germline cyst breakdown and primordial follicle formation. Using a cell lineage tracing approach, we show that ADAM10 governs the recruitment of ovarian follicle cells by regulating the differentiation and proliferation of LGR5-positive follicle supporting progenitor cells. By detecting the development of FOXL2-positive pregranulosa cells, we found that inhibiting ADAM10 reduced the number of FOXL2-positive cells in perinatal ovaries. Furthermore, inhibiting ADAM10 suppressed the activation of Notch signaling, and blocking Notch signaling also disrupted the recruitment of follicle progenitor cells. Taken together, these results show that ADAM10-Notch signaling in ovarian somatic cells governs the primordial follicle formation by controlling the development of ovarian pregranulosa cells. The proper recruitment of ovarian follicle supporting cells is essential for establishment of the ovarian reserve in mice. PMID:27084580

  4. An improved fluorescent substrate for assaying soluble and membrane-associated ADAM family member activities.

    Science.gov (United States)

    Moss, Marcia L; Minond, Dmitriy; Yoneyama, Toshie; Hansen, Hinrich P; Vujanovic, Nikola; Rasmussen, Fred H

    2016-08-15

    A fluorescent resonance energy transfer substrate with improved sensitivity for ADAM17, -10, and -9 (where ADAM represents a disintegrin and metalloproteinase) has been designed. The new substrate, Dabcyl-Pro-Arg-Ala-Ala-Ala-Homophe-Thr-Ser-Pro-Lys(FAM)-NH2, has specificity constants of 6.3 (±0.3) × 10(4) M(-1) s(-1) and 2.4 (±0.3) × 10(3) M(-1) s(-1) for ADAM17 and ADAM10, respectively. The substrate is more sensitive than widely used peptides based on the precursor tumor necrosis factor-alpha (TNF-alpha) cleavage site, PEPDAB010 or Dabcyl-Ser-Pro-Leu-Ala-Gln-Ala-Val-Arg-Ser-Ser-Lys(FAM)-NH2 and Mca-Pro-Leu-Ala-Gln-Ala-Val-Dpa-Arg-Ser-Ser-Arg-NH2. ADAM9 also processes the new peptide more than 18-fold better than the TNF-alpha-based substrates. The new substrate has a unique selectivity profile because it is processed less efficiently by ADAM8 and MMP1, -2, -3, -8, -9, -12, and -14. This substrate provides a unique tool in which to assess ADAM17, -10, and -9 activities. PMID:27177841

  5. Selective inhibition of ADAM12 catalytic activity through engineering of tissue inhibitor of metalloproteinase 2 (TIMP-2)

    DEFF Research Database (Denmark)

    Kveiborg, Marie; Jacobsen, Jonas; Lee, Meng-Huee;

    2010-01-01

    -mediated ADAM12 inhibition. Intriguingly, we found that removal of the AB-loop in N-TIMP-2, which is known to impair its interaction with TACE, resulted in increased affinity to ADAM12. Importantly, using a cell-based epidermal growth factor-shedding assay, we demonstrated for the first time an inhibitory......The disintegrin and metalloprotease ADAM12 has important functions in normal physiology as well as in diseases, such as cancer. Little is known about how ADAM12 confers its pro-tumorigenic effect; however, its proteolytic capacity is probably a key component. Thus selective inhibition of ADAM12...

  6. ADAM12-directed ectodomain shedding of E-cadherin potentiates trophoblast fusion.

    Science.gov (United States)

    Aghababaei, M; Hogg, K; Perdu, S; Robinson, W P; Beristain, A G

    2015-12-01

    Trophoblasts, placental cells of epithelial lineage, undergo extensive differentiation to form the cellular components of the placenta. Trophoblast progenitor cell differentiation into the multinucleated syncytiotrophoblast is a key developmental process required for placental function, where defects in syncytiotrophoblast formation and turnover associate with placental pathologies and link to poor pregnancy outcomes. The cellular and molecular processes governing syncytiotrophoblast formation are poorly understood, but require the activation of pathways that direct cell fusion. The protease, A Disintegrin and Metalloproteinase 12 (ADAM12), controls cell fusion in myoblasts and is highly expressed in the placenta localizing to multiple trophoblast populations. However, the importance of ADAM12 in regulating trophoblast fusion is unknown. Here, we describe a function for ADAM12 in regulating trophoblast fusion. Using two distinct trophoblast models of cell fusion, we show that ADAM12 is dynamically upregulated and is under the transcriptional control of protein kinase A. siRNA-directed loss of ADAM12 impedes spontaneous fusion of primary cytotrophoblasts, whereas overexpression of the secreted variant, ADAM12S, potentiates cell fusion in the Bewo trophoblast cell line. Mechanistically, both ectopic and endogenous levels of ADAM12 were shown to control trophoblast fusion through E-cadherin ectodomain shedding and remodeling of intercellular boundaries. This study describes a novel role for ADAM12 in placental development, specifically highlighting its importance in controlling the differentiation of villous cytotrophoblasts into multinucleated cellular structures. Moreover, this work identifies E-cadherin as a novel ADAM12 substrate, and highlights the significance that cell adhesion molecule ectodomain shedding has in normal development. PMID:25909890

  7. Another Distortion of Adam Smith: The Case of the "Invisible Hand"

    OpenAIRE

    Michael Meeropol

    2004-01-01

    This paper addresses a major omission in the way textbook writers and journalists utilize Adam Smith’s concept of the “invisible hand” to make Adam Smith an intellectual precursor of modern neo-liberal economic policy. Specifically, the paper addresses the use of the concept of the “invisible hand” by Adam Smith to address two major issues in the debate over neo-liberal policy: the international flow of capital and its role in the location of investment projects and the inequality in the dist...

  8. Effects of [123I]ADAM, a serotonin transporter radiopharmaceutical, on pregnant Sprague–Dawley rats

    International Nuclear Information System (INIS)

    Serotonin transport abnormalities are implicated in neuropsychiatric disorders. [123I]ADAM ([123I]-2-([2-({dimethylamino}methyl)phenyl]thio)-5-iodophenylamine) is a novel radiotracer that targets serotonin transporters. We assessed the toxicity of [123I]ADAM (18.5 MBq) administered in early- and late-phases (8 and 14 day postfertilization, respectively) of pregnancy. The mortality, clinical status, and gross necropsy were measured in pregnant rats, and the fertility index was measured in rat offspring (weight, clinical observations). We found no dosing-related clinical signs. In conclusion, [123I]ADAM was not toxic in an animal pregnancy model.

  9. Transgenic overexpression of ADAM12 suppresses muscle regeneration and aggravates dystrophy in aged mdx mice

    DEFF Research Database (Denmark)

    Jørgensen, Louise Helskov; Jensen, Charlotte Harken; Wewer, Ulla M;

    2007-01-01

    ADAM12 could be a candidate for nonreplacement gene therapy of Duchenne muscular dystrophy. We therefore evaluated the long-term effect of ADAM12 overexpression in muscle. Surprisingly, we observed loss of skeletal muscle and accelerated fibrosis and adipogenesis in 1-year-old mdx mice transgenically......Muscular dystrophies are characterized by insufficient restoration and gradual replacement of the skeletal muscle by fat and connective tissue. ADAM12 has previously been shown to alleviate the pathology of young dystrophin-deficient mdx mice, a model for Duchenne muscular dystrophy. The observed...... regeneration as a possible factor in development of muscular dystrophy....

  10. A comment on Adams' measurements of the gravitational redshift of Sirius B

    International Nuclear Information System (INIS)

    The contention of Hetherington (1980. Q. J. R. Astro. Soc. 21,246) that Adams' determination (1925. Proc. natn. Acad. Sci. USA, 11,382) of the gravitational redshift of Sirius B is the result of a deliberate effort to reproduce the value predicted earlier on theoretical grounds is examined. It is emphasized that Adams' measurements may instead be the result of spectral contamination by scattered light from Sirius A, and the plausibility of that suggestion is confirmed by numerical simulations. There is thus, at present, no evidence to support the contention that Adams may not have acted objectively in this particular scientific endeavour. (author)

  11. Wydarzenia rewolucji amerykańskiej roku 1776 w oczach Abigail Adams

    OpenAIRE

    Stelmasiak, Katarzyna

    1999-01-01

    Abigail Adams played a unique role in the years leading up to the declaration of American independence. She was a highly intelligent person with a forceful and a colourful personality. She was the only woman in American history to be the wife of one president and the mother of another. When Abigail Adams married John Adams in 1764, she did not expect that her life would be changed by the Revolution. Her expectations of marriage were those established by the model of her pare...

  12. Differential expression of ADAM (a disintegrin and metalloproteinase) genes between human first trimester villous and extravillous trophoblast cells.

    Science.gov (United States)

    Takahashi, Hironori; Yuge, Kazuya; Matsubara, Shigeki; Ohkuchi, Akihide; Kuwata, Tomoyuki; Usui, Rie; Suzuki, Mitsuaki; Takizawa, Toshihiro

    2014-01-01

    A disintegrin and metalloproteinases (ADAMs) are members of the metzincin family of zinc-dependent metalloproteinases that play pivotal roles in the proteolytic degradation of the extracellular matrix for cell invasion. Few studies have investigated the ADAM subtypes that are expressed in first trimester trophoblast cells. The purpose of this study was to elucidate the differential expression profiles of ADAMs between first trimester villous trophoblast cells (VTs) and extravillous trophoblast cells (EVTs). We isolated EVTs from explanted human first trimester chorionic villi and investigated the mRNA expression levels of five members of the ADAM family (ADAMTS1, ADAMTS2, ADAM10, ADAM12, and ADAM17) using real-time PCR. Chorionic villous tips were defined as first trimester VTs. Of the differentially expressed ADAM genes between first trimester VTs and EVTs, ADAMTS1 was expressed at a significantly higher level in EVTs than in VTs. In contrast, both ADAM10 and ADAM12 were expressed at significantly higher levels in VTs than in EVTs. No differences were found in the mRNA levels of ADAMTS2 and ADAM17 between the two cell types. Moreover, we demonstrated that in VTs, the expression level of ADAM12 was significantly downregulated in the late first trimester (10-13 gestational weeks) compared to the middle first trimester (7-8 weeks). These results suggest that first trimester trophoblast cells express ADAM genes in cell type- and gestational age-dependent manners. Our data provide additional insight into the functions of ADAMs in the human placenta. PMID:24998958

  13. Molecular design and structural optimization of potent peptide hydroxamate inhibitors to selectively target human ADAM metallopeptidase domain 17.

    Science.gov (United States)

    Wang, Zhengting; Wang, Lei; Fan, Rong; Zhou, Jie; Zhong, Jie

    2016-04-01

    Human ADAMs (a disintegrin and metalloproteinases) have been established as an attractive therapeutic target of inflammatory disorders such as inflammatory bowel disease (IBD). The ADAM metallopeptidase domain 17 (ADAM17 or TACE) and its close relative ADAM10 are two of the most important ADAM members that share high conservation in sequence, structure and function, but exhibit subtle difference in regulation of downstream cell signaling events. Here, we described a systematic protocol that combined computational modeling and experimental assay to discover novel peptide hydroxamate derivatives as potent and selective inhibitors for ADAM17 over ADAM10. In the procedure, a virtual combinatorial library of peptide hydroxamate compounds was generated by exploiting intermolecular interactions involved in crystal and modeled structures. The library was examined in detail to identify few promising candidates with both high affinity to ADAM17 and low affinity to ADAM10, which were then tested in vitro with enzyme inhibition assay. Consequently, two peptide hydroxamates Hxm-Phe-Ser-Asn and Hxm-Phe-Arg-Gln were found to exhibit potent inhibition against ADAM17 (Ki=92 and 47nM, respectively) and strong selectivity for ADAM17 over ADAM10 (∼7-fold and ∼5-fold, S=0.86 and 0.71, respectively). The structural basis and energetic property of ADAM17 and ADAM10 interactions with the designed inhibitors were also investigated systematically. It is found that the exquisite network of nonbonded interactions involving the side chains of peptide hydroxamates is primarily responsible for inhibitor selectivity, while the coordination interactions and hydrogen bonds formed by the hydroxamate moiety and backbone of peptide hydroxamates confer high affinity to inhibitor binding. PMID:26709988

  14. ADAM 12-S cleaves IGFBP-3 and IGFBP-5 and is inhibited by TIMP-3

    DEFF Research Database (Denmark)

    Loechel, F; Fox, J W; Murphy, G;

    2000-01-01

    that it cleaves insulin-like growth factor binding protein-3 (IGFBP-3). This result supports a role for ADAM 12-S in the degradation of IGFBP-3 in the blood of pregnant women. Furthermore, we tested for proteolysis of other members of the IGF binding protein family and found that ADAM 12-S cleaves...... IGFBP-5 in addition to IGFBP-3, but does not cleave IGFBP-1, -2, -4, or -6. ADAM 12-S may therefore be the IGFBP-5 protease that is secreted by osteoblasts and other cells. Cleavage of both IGFBP-3 and -5 by ADAM 12-S was inhibited by TIMP-3, raising the possibility that TIMP-3 is a physiological...

  15. Paradise Lost: Difference between Adam and Eve’s Lament on Leaving Paradise - A Contrastive Analysis

    Directory of Open Access Journals (Sweden)

    Sara Torres Servín

    2013-01-01

    Full Text Available The difference between Adam and Eve’s lament on leaving Paradise in Milton’s Paradise Lost is striking in its contrastive content and depth. This paper analyzes the difference that exists between the feelings and spiritual attitudes that Adam and Eve express on the occasion when they are informed by the angel Michael that they have to abandon the Garden of Eden. It is a comparison of their lament in order to understand the contrast of the two attitudes that Milton wove in the tapestry that Paradise Lost is. The paper also explores male and female roles in Paradise Lost and concludes that Adam and Eve are equal yet different, that difference being the cause of their contrastive ways of expressing their sorrow. Adam and Eve manifest two contrastive worldviews in opposition, one spiritual (heavenly, and the other material (earthly.

  16. A delay differential equation solver based on the parallel Adams algorithms

    Institute of Scientific and Technical Information of China (English)

    ChengjianZHANG; HongbingYU

    2001-01-01

    This paper constructs a class of parallel Adams algorithms for the systems of delay differential equations.The results on convergence and stability are given.The theoretical analysis and numerical test shows that this algorithm is effect and comparable.

  17. Highlighting High Performance: Adam Joseph Lewis Center for Environmental Studies, Oberlin College, Oberlin, Ohio

    Energy Technology Data Exchange (ETDEWEB)

    None

    2002-11-01

    Oberlin College’s Adam Joseph Lewis Center for Environmental Studies is a high-performance building featuring an expansive photovoltaic system and a closed-loop groundwater heat pump system. Designers incorporated energy-efficient components and materials

  18. FlipADAM: a potential new SPECT imaging agent for the serotonin transporter

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Julie L.; Deutsch, Eric C. [Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 (United States); Oya, Shunichi [Department of Radiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 (United States); Kung, Hank F., E-mail: kunghf@gmail.co [Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 (United States); Department of Radiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 (United States)

    2010-07-15

    Introduction: Single photon emission computed tomography (SPECT) imaging of the serotonin transporter (SERT) in the brain is a useful tool for examining normal physiological functions and disease states involving the serotonergic system. The goal of this study was to develop an improved SPECT radiotracer with faster kinetics than the current leading SPECT tracer, [{sup 123}I]ADAM, for selective SERT imaging. Methods: The in vitro binding affinities of (2-(2'-((dimethylamino)methyl)-4'-iodophenylthio)benzenamine) (FlipADAM) (1c), were determined using Hampshire pig kidney cells stably overexpressing the serotonin, norepinephrine (NET) or dopamine transporter (DAT). Localization of [{sup 125}I]FlipADAM (1c) was evaluated through biodistribution and autoradiography in male Sprague Dawley rats, and the specificity of binding was assessed by injecting selective SERT or NET inhibitors prior to [{sup 125}I]FlipADAM (1c). Results: FlipADAM (1c) displayed a high binding affinity for SERT (K{sub i}=1.0 nM) and good selectivity over NET and DAT binding (43-fold and 257-fold, respectively). [{sup 125}I]FlipADAM (1c) successfully penetrated the blood brain barrier, as evidenced by the brain uptake at 2 min (1.75% dose/g). [{sup 125}I]FlipADAM(1c) also had a good target to non-target (hypothalamus/cerebellum) ratio of 3.35 at 60 min post-injection. In autoradiography studies, [{sup 125}I]FlipADAM (1c) showed selective localization in SERT-rich brain regions such as the thalamic nuclei, amygdala, dorsal raphe nuclei and other areas. Conclusion: [{sup 125}I]FlipADAM (1c) exhibited faster clearance from the brain and time to binding equilibrium when compared to [{sup 125}I]2-(2'-((dimethylamino)methyl)-phenylthio)-5-iodophenylamine [{sup 125}I]ADAM (1b) and a higher target to non-target ratio when compared to [{sup 125}I]5-iodo-2-(2'-((dimethylamino)methyl)-phenylthio)benzyl alcohol [{sup 125}I]IDAM (1a). Therefore, [{sup 123}I]FlipADAM (1c) may be an improved

  19. Automation of TL brick dating by ADAM-1

    International Nuclear Information System (INIS)

    Thermoluminescence has become an established dating method for ceramics and more recently for bricks. Based on the experiences of the work carried out since the late 1970's at the Rathgen-Forschungslabor in Berlin on the dating of bricks from historic architecture, and after evaluating all commercially available and some individually built automated and semi-automated TL-readers, a specially adapted machine for the fine grain dating of bricks was constructed in an interdisciplinary research project, undertaken by a team recruited from three faculties of the Czech Technical University in Prague. The result is the automated TL-reader ADAM-1 (Automated Dating Apparatus for Monuments) for the dating of historic architecture. Both the specific adaptation of the technique and the necessary optimal automation have influenced the design of this TL-reader. The principle advantage of brick as opposed to ceramic TL-dating emerges from the possibility of being able to obtain both a large number of samples and an above average quantity of datable material from each sample. This, together with the specific physical and chemical conditions in a brick wall, allowed a rethinking of the traditional error calculation and thus lower error margins as those obtained when dating ceramic shards. The TL-reader must therefore be able to measure and evaluate automatically numerous samples. The annular sample holder of ADAM-1 has 60 sample positions, which allow the irradiation and evaluation of samples taken from two locations. The thirty samples from one sampling point are divided into subgroups, which are processed in various ways. Three samples serve for a rough estimate of the TL sensitivity of the brick material. Nine samples are used for the measurement of 'natural TL' of the material. A further nine samples are used for testing the sensitivity of the material to beta radiation. The last nine samples serve for the testing of the sensitivity to alpha radiation. To determine the

  20. Dampak Pengolahan Limbah Padat Medis pada Petugas Incinerator di RSUP H. Adam Malik Tahun 2014

    OpenAIRE

    Darwin

    2016-01-01

    Adam Malik Central General Hospital causes some complaints from the incinerator operators such as wounded by spuit needles, wounded by broken glasses, and difficult to breathe because they inhale incinerator smoke or gas in the medical solid waste. Therefore, job safety and health in the hospital, especially in managing medical solid waste should be done. The research was qualitative which was aimed to analyze the effect of K3 (Job safety and health) n incinerator operators at H. Adam ...

  1. ADAM12 Alleviates the Skeletal Muscle Pathology in mdx Dystrophic Mice

    OpenAIRE

    Kronqvist, Pauliina; Kawaguchi, Nobuko; Albrechtsen, Reidar; Xu, Xiufeng; Schrøder, Henrik Daa; Moghadaszadeh, Behzad; Nielsen, Finn Cilius; Fröhlich, Camilla; Engvall, Eva; Wewer, Ulla M.

    2002-01-01

    Muscular dystrophy is characterized by muscle degeneration and insufficient regeneration and replacement of muscle fibers by connective tissue. New therapeutic strategies directed toward various forms of muscular dystrophy are needed to preserve muscle mass and promote regeneration. In this study we examined the role of the transmembrane ADAM12, a disintegrin and metalloprotease, which is normally associated with development and regeneration of skeletal muscle. We demonstrate that ADAM12 over...

  2. Insidensi Suspek Glaukoma Di RSUP H. Adam Malik Medan Tahun 2012

    OpenAIRE

    Wikaningtyas, Dian

    2016-01-01

    This research aimed to determine the incidence of new patients with glaucoma suspect in.H.Adam Malik Hospital in 2012. This study is a retrospective descriptive study. Subjects were patients with suspected glaucoma treatment in Poly Eyes RSUP.H.Adam Malik. Samples numbered 38 people with suspected diagnosis of glaucoma, then the sample data taken from the patient's medical record including the intra oculi pressure, visual acuity, systemic disease, age, gender, ethnicity, descent history, empl...

  3. An Arginine Stretch Limits ADAM10 Exit from the Endoplasmic Reticulum*

    OpenAIRE

    Marcello, Elena; Gardoni, Fabrizio; Di Luca, Monica; Pérez-Otaño, Isabel

    2010-01-01

    A disintegrin and metalloproteinase 10 (ADAM10) is a type I transmembrane glycoprotein responsible for the ectodomain shedding of a number of proteins implicated in the pathogenesis of diseases ranging from cancer to Alzheimer Disease. ADAM10 is synthesized in an inactive form, which is proteolytically activated during its forward transport along the secretory pathway and at the plasma membrane. Therefore, modulation of its trafficking could provide a mechanism to finely tune its shedding act...

  4. SAP97-mediated ADAM10 trafficking from Golgi outposts depends on PKC phosphorylation

    OpenAIRE

    Saraceno, C; Marcello, E; Di Marino, D.; Borroni, B.; Claeysen, S; Perroy, J; Padovani, A; Tramontano, A; Gardoni, F.; M.M.G. Di Luca

    2014-01-01

    International audience A disintegrin and metalloproteinase 10 (ADAM10) is the major α-secretase that catalyzes the amyloid precursor protein (APP) ectodomain shedding in the brain and prevents amyloid formation. Its activity depends on correct intracellular trafficking and on synaptic membrane insertion. Here, we describe that in hippocampal neurons the synapse-associated protein-97 (SAP97), an excitatory synapse scaffolding element, governs ADAM10 trafficking from dendritic Golgi outposts...

  5. ADAM: a general method for using various data types in asteroid reconstruction

    OpenAIRE

    Viikinkoski, Matti; Kaasalainen, Mikko; Durech, Josef

    2015-01-01

    We introduce ADAM, the All-Data Asteroid Modelling algorithm. ADAM is simple and universal since it handles all disk-resolved data types (adaptive optics or other images, interferometry, and range-Doppler radar data) in a uniform manner via the 2D Fourier transform, enabling fast convergence in model optimization. The resolved data can be combined with disk-integrated data (photometry). In the reconstruction process, the difference between each data type is only a few code lines defining the ...

  6. STUDI KOMPARATIF KONSEP KETUHANAN ISLAM DAN AGAMA ADAM PADA KOMUNITAS SAMIN

    Directory of Open Access Journals (Sweden)

    Mohammad Rosyid

    2015-03-01

    Full Text Available Abstract: One of the problems that disturb the harmony between religious communities is a lack of understanding of the majority (mainstream religion about the local religion, and vice versa. This article aims to develop such inter-religious understanding by comparing between Islam and the religion of Adam, a local religion of Samin community. The comparative study was made within the scope of the concept of God in both religions. This study found that the understanding between Islam the religion of Adam about the concept of God is essential in common. God called Allah (in Islam and Yai (in the religion of Adam are equally perceived as condescendent, an only single power, and the Almighty. Both communities also share Adam as the first man in the world. So, it is not proportional if the public ridicule Samin community with atheist stigma.Abstrak: Salah satu problem yang mengganggu keharmonisan antar komunitas beragama adalah kurangnya pemahaman pemeluk agama mayoritas (mainstream di suatu negara tentang agama lokal, dan demikian pula sebaliknya. Artikel ini bertujuan untuk membangun kesalingpahaman antar pemeluk agama itu dengan melakukan kaji banding antara agama Islam dengan agama Adam, sebuah agama lokal komunitas Samin. Kaji banding itu dilakukan dalam lingkup konsep ketuhanan dalam dua agama itu. Kajian ini menemukan bahwa pemahaman antara Islam dengan agama Adam tentang konsep Tuhan memiliki kesamaan secara esensial. Tuhan yang disebut dengan Allah (dalam Islam dan Yai (dalam agama Adam sama-sama dipersepsikan sebagai tempat berlindung, kekuatan tunggal, dan Zat Yang Maha segala-galanya. Kedua komunitas juga sama dalam memandang Adam sebagai manusia yang pertama di dunia. Dengan adanya pemahaman itu maka tidak proporsional lagi jika publik mengolok-olok komunitas Samin dengan stigma ateis.

  7. The Lack of ADAM17 Activity during Embryonic Development Causes Hemorrhage and Impairs Vessel Formation

    OpenAIRE

    Canault, Matthias; Certel, Kaan; Schatzberg, Daphne; Wagner, Denisa D.; Hynes, Richard O.

    2010-01-01

    Background ADAM17/TACE activity is important during embryonic development. We wished to investigate possible roles of this metalloprotease, focusing on vascular development. Methodology/Principal Findings Mice mutant in the enzymatic activity of ADAM17 were examined at various stages of embryonic development for vascular pattern and integrity using markers for vessel wall cells. We observed hemorrhage and edema starting at embryonic day E14.5 and becoming more severe as development...

  8. Prevalensi Katarak dengan Diabetes Melitus di RSUP H. Adam Malik Medan Tahun 2012

    OpenAIRE

    Bustami, Faisal

    2015-01-01

    • Purpose: The research aims to obtain the incidence of cataracts with diabetes mellitus in Adam Malik Medan hospital in 2012. • Method: This research is a descriptive study. Data subjects were taken from medical records of cataract patients with diabetes mellitus who seek treatment in the eyes of Adam Malik Medan Hospital. • Result: Data totaling 72 patients who were diagnosed with diabetes mellitus cataract, From the results obtained number of cataract patients with diabetes mellitus ...

  9. The sorting protein PACS-2 promotes ErbB signalling by regulating recycling of the metalloproteinase ADAM17

    Science.gov (United States)

    Dombernowsky, Sarah Louise; Samsøe-Petersen, Jacob; Petersen, Camilla Hansson; Instrell, Rachael; Hedegaard, Anne-Mette Bornhardt; Thomas, Laurel; Atkins, Katelyn Mae; Auclair, Sylvain; Albrechtsen, Reidar; Mygind, Kasper Johansen; Fröhlich, Camilla; Howell, Michael; Parker, Peter; Thomas, Gary; Kveiborg, Marie

    2015-01-01

    The metalloproteinase ADAM17 activates ErbB signalling by releasing ligands from the cell surface, a key step underlying epithelial development, growth, and tumour progression. However, mechanisms acutely controlling ADAM17 cell-surface availability to modulate the extent of ErbB ligand release are poorly understood. Here, through a functional genome-wide siRNA screen, we identify the sorting protein PACS-2 as a regulator of ADAM17 trafficking and ErbB signalling. PACS-2 loss reduces ADAM17 cell-surface levels and ADAM17-dependent ErbB ligand shedding, without apparent effects on related proteases. PACS-2 co-localizes with ADAM17 on early endosomes and PACS-2 knockdown decreases the recycling and stability of internalized ADAM17. Hence, PACS-2 sustains ADAM17 cell-surface activity by diverting ADAM17 away from degradative pathways. Interestingly, Pacs2-deficient mice display significantly reduced levels of phosphorylated EGFR and intestinal proliferation. We suggest that this mechanism controlling ADAM17 cell-surface availability and EGFR signalling may play a role in intestinal homeostasis, with potential implications for cancer biology. PMID:26108729

  10. A-Disintegrin-And-Metalloproteinase (ADAM) 10 Activity on Resting and Activated Platelets.

    Science.gov (United States)

    Facey, Adam; Pinar, Isaac; Arthur, Jane F; Qiao, Jianlin; Jing, Jing; Mado, Belden; Carberry, Josie; Andrews, Robert K; Gardiner, Elizabeth E

    2016-03-01

    The primary platelet collagen receptor, glycoprotein VI (GPVI), plays an important role in platelet activation and thrombosis. The ectodomain of human GPVI (sGPVI) is proteolytically shed from human platelets by a-disintegrin-and-metalloproteinase 10 (ADAM10). In this study, we used a novel ADAM10-sensitive fluorescence resonance energy transfer sensor to analyze ADAM10-mediated shedding of GPVI from human platelets in response to the exposure of GPVI ligands collagen-related peptide (10 μg/mL), collagen (10 μg/mL), and convulxin (0.1 μg/mL) to shear stress (1000-10000 s(-1), 5 min), or a generic activator of metalloproteinases, N-ethylmaleimide (NEM, 5 mM). Elevated shear, NEM, or ligand engagement of GPVI all induced shedding of GPVI, as detected by release of sGPVI; however, only shear or NEM significantly increased ADAM10 enzyme activity. ADAM10 activity was also detectable on the surface of thrombi formed on a collagen-coated surface under flow conditions. Our findings indicate different mechanisms regulate shear- and ligand-induced shedding and shear forces found within the vasculature can regulate ADAM10 activity. PMID:26840909

  11. In silico investigation of ADAM12 effect on TGF-β receptors trafficking

    Directory of Open Access Journals (Sweden)

    LeMeur Nolwenn

    2009-09-01

    Full Text Available Abstract Background The transforming growth factor beta is known to have pleiotropic effects, including differentiation, proliferation and apoptosis. However the underlying mechanisms remain poorly understood. The regulation and effect of TGF-β signaling is complex and highly depends on specific protein context. In liver, we have recently showed that the disintegrin and metalloproteinase ADAM12 interacts with TGF-β receptors and modulates their trafficking among membranes, a crucial point in TGF-β signaling and development of fibrosis. The present study aims to better understand how ADAM12 impacts on TGF-β receptors trafficking and TGF-β signaling. Findings We extracted qualitative biological observations from experimental data and defined a family of models producing a behavior compatible with the presence of ADAM12. We computationally explored the properties of this family of models which allowed us to make novel predictions. We predict that ADAM12 increases TGF-β receptors internalization rate between the cell surface and the endosomal membrane. It also appears that ADAM12 modifies TGF-β signaling shape favoring a permanent response by removing the transient component observed under physiological conditions. Conclusion In this work, confronting differential models with qualitative biological observations, we obtained predictions giving new insights into the role of ADAM12 in TGF-β signaling and hepatic fibrosis process.

  12. ADAMS/WT advanced development - version 1.4 and beyond

    Energy Technology Data Exchange (ETDEWEB)

    Elliott, A.S.; Depauw, T.R. [Mechanical Dynamics, Inc., Mesa, AZ (United States)

    1996-12-31

    ADAMS/WT is an wind-turbine-specific shell for the general-purpose mechanical system simulation package ADAMS5. It was developed under the guidance of the National Renewable Energy Laboratory to give engineers and analysts in the wind turbine community access to the analytical power of ADAMS, without having to become expert in its particular technology. The 1.4 version of ADAMS/WT is the most recent upgrade to the package, incorporating the most up-to-date version of the AeroDyn aerodynamic forcing subroutines from the University of Utah. It is also the first version to be made available on the Windows/NT platform. In version 1.4, ADAMS/WT has been significantly improved throughout and runs much faster. Automatic generation of standardized output has been added. The documentation has been extensively augmented with more detailed descriptions, more figures and more examples. ADAMS/WT remains the most powerful analytical tool available for horizontal-axis wind turbine development. 10 figs.

  13. Biodistribution and radiation dosimetry of [123I]ADAM in healthy human subjects: preliminary results

    International Nuclear Information System (INIS)

    [123I]ADAM [2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine (ADAM)] has recently been shown to be a very promising imaging ligand for the detection of serotonin transporters (SERT) in human brain, because of its high specificity for SERT. [123I]ADAM has previously been used only for animal studies. In this work, we investigated the radiation dosimetry and biodistribution of [123I]ADAM based on whole-body scans in healthy human volunteers. Following the administration of 196±20 MBq (range 157-220 MBq) [123I]ADAM, serial whole-body images were performed up to 24 h. Estimates of radiation absorbed dose were calculated using the MIRDOSE 3.0 program with a dynamic bladder model. Twelve source organs were considered in estimating absorbed radiation doses for organs of the body. The highest absorbed organ doses were found to the lower large intestine wall (8.3.10-2 mGy/MBq), kidneys (5.2.10-2 mGy/MBq), urinary bladder wall (4.9.10-2 mGy/MBq) and thyroid (4.3.10-2 mGy/MBq). The effective dose was estimated to be 2.2.10-2 mSv/MBq. The results suggest that [123I]ADAM is of potential value as a tracer for single-photon emission tomography imaging of serotonin receptors in humans, with acceptable dosimetry and high brain uptake. (orig.)

  14. ADAM and ADAMTS Family Proteins and Snake Venom Metalloproteinases: A Structural Overview

    Directory of Open Access Journals (Sweden)

    Soichi Takeda

    2016-05-01

    Full Text Available A disintegrin and metalloproteinase (ADAM family proteins constitute a major class of membrane-anchored multidomain proteinases that are responsible for the shedding of cell-surface protein ectodomains, including the latent forms of growth factors, cytokines, receptors and other molecules. Snake venom metalloproteinases (SVMPs are major components in most viper venoms. SVMPs are primarily responsible for hemorrhagic activity and may also interfere with the hemostatic system in envenomed animals. SVMPs are phylogenetically most closely related to ADAMs and, together with ADAMs and related ADAM with thrombospondin motifs (ADAMTS family proteinases, constitute adamalysins/reprolysins or the M12B clan (MEROPS database of metalloproteinases. Although the catalytic domain structure is topologically similar to that of other metalloproteinases such as matrix metalloproteinases, the M12B proteinases have a modular structure with multiple non-catalytic ancillary domains that are not found in other proteinases. Notably, crystallographic studies revealed that, in addition to the conserved metalloproteinase domain, M12B members share a hallmark cysteine-rich domain designated as the “ADAM_CR” domain. Despite their name, ADAMTSs lack disintegrin-like structures and instead comprise two ADAM_CR domains. This review highlights the current state of our knowledge on the three-dimensional structures of M12B proteinases, focusing on their unique domains that may collaboratively participate in directing these proteinases to specific substrates.

  15. ADAM SMITH: LA MANO INVISIBLE O LA CONFIANZA

    Directory of Open Access Journals (Sweden)

    Gache, Fernando Luis

    2010-12-01

    Full Text Available En 1776 Adam Smith planteó que una mano invisible era quien movía a los mercados para obtener su eficiencia. No obstante en el presente trabajo vamos a plantear la hipótesis, que dicha mano invisible, es en realidad la confianza que cada persona siente en el momento de hacer un negocio. Que además es única, pues es distinta a la confianza de los demás y que se trata de una variable no lineal que fundamentalmente está ligada a las respectivas historias personales. Para ello vamos a tomar como base el trabajo de Leopoldo Abadía (2009, respecto de la crisis económico financiera que se desató en el 2007-2008, para poner en evidencia la forma en que opera la confianza. Por lo tanto la contribución que esperamos hacer con este trabajo es destacar que, el nivel de confianza de los diferentes actores, es quien realmente mueve a los mercados, (por tanto la economía y que la crisis de las hipotecas subprime es una crisis de confianza a nivel mundial.

  16. Adam Smith om forholdet mellem moralske fornemmelser og naturen

    DEFF Research Database (Denmark)

    Huggler, Lise Oxenbøll

    2008-01-01

    I The Theory of Moral Sentiments giver Adam Smith en fremstilling af, hvordan mennesket i sam­fundslivet udvikler moralske fornemmelser og af den betydning, disse har for menneskers følelses- og handlingsliv. Her er synssansen afgørende, idet den sætter mennesket i stand til rumligt lokaliser......­bart at betragte andre menneskers opførsel såvel som andre menneskers reaktioner på ens egen opførsel. Den sætter derved på en entydig måde mennesket i stand til at forholde sig til sig selv og til andre mennesker. På dette grundlag opstiller Smith en række psykologiske reaktionsmønstre. Ikke desto mindre påkalder...... han jævnligt bl.a. naturen som en metafysisk entitet. Der skal her argumenteres for, at de metafysiske begreber har til opgave at skabe den sammenhæng i menneskelivet, som kausale reaktioner i sig selv ikke giver. I forlængelse af dette peges der på, at Smith synes at hævde, at mennesket i samfundet...

  17. Xerxes in Mikhail Bulgakov’s Play Adam and Eve

    Directory of Open Access Journals (Sweden)

    Souren A. Takhtajan

    2015-08-01

    Full Text Available In his Histories 8:118, Herodotus tells the dramatic story of Xerxes’ return to Asia from Greece by sea. The overcrowded ship was caught in a storm, and the captain advised the king to get rid of most of the passengers. Xerxes called on the Persians to prove their loyalty to the king, and they showed their obeisance by leaping into the sea. After his return, Xerxes awarded the captain of the ship with a golden crown for saving the king’s life—and cut off his head for causing the deaths of so many Persians. In the play Adam and Eve, Bulgakov depicts the outbreak of war between the Soviet Union and the Western world. Nearly everyone in Leningrad dies from a gas attack. But Efrosimov, a chemistry professor and a man of genius, has managed to save the lives of the other characters in the play, the Soviet fighter pilot Daragan included. Nevertheless, Daragan hates Efrosimov for his efforts to prevent the war and then to stop it. The fighter pilot imagines for the professor both an award for his merits and subsequent capital punishment for his alleged crime. In this article, I suggest that Bulgakov has borrowed the motif of award and execution from Herodotus.

  18. IOPY/ISPY类HIV-1逆转录酶抑制剂的定量构效关系研究%Quantitative Structure-Activity Relationship of IOPY/ISPY Analogues as HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors

    Institute of Scientific and Technical Information of China (English)

    朱瑞新; 王飞; 刘琦; 康廷国

    2011-01-01

    C-5修饰的3-碘-4-芳氧基/芳硫基吡啶酮(IOPY/ISPY)类化合物是一类潜在的HIV-1非核苷类逆转录酶抑制剂,特别是这类化合物因具有同时抑制野生型和突变型病毒株的特性,而受到更加广泛的关注.首先利用两套2D通用描述符同时构建了该类化合物的线性和非线性定量构效关系模型.结果表明这些模型都具有较好的预测能力,并且非线性模型较线性模型预测能力更好些.为了更好、更形象地描述逆转录酶抑制剂的特征,进一步结合三维定量构效关系(3D-QSAR)模型,以及SAReport分析对该类化合物同时抑制野生型和突变型病%A series of C-5 modified 3-iodo-4-aryloxypyridinones(IOPY’s) and 3-iodo-4-arylthio-pyridinones(ISPY’s) serves as a potential class of HIV-1 non-nucleoside reverse transcriptase inhibitors.These two pyridinone analogues are attracting more attentions mainly due to their potential abilities to si-multaneously inhibit wild type and mutant HIV-1 strains.In this study,two sets of traditional two-dimensional descriptors were applied respectively to create linear and binary QSAR models for these compounds.Our results indicated the well prediction ability of the obtained models.It is also indicated that binary model achieved a better prediction results than the linear one.Furthermore,in order to obtain a better description of the structure characteristics of the HIV-1 reverse transcriptase inhibitors,3D-QSAR models and SAReport analysis were used to explore the compound features which contribute to the inhibition of wild type as well as mutant HIV-1 strains.Our analysis reveals that there may existed three principles to follow when the compounds are modified:(i) the electrostatic potentials distribution of R-groups plays a key role in determining the biological activities of the compounds;(ii) an aromatic ring or aromatic heterocycle for R-groups is favorable to enhance the biological activity

  19. Loss of the Metalloprotease ADAM9 Leads to Cone-Rod Dystrophy in Humans and Retinal Degeneration in Mice

    OpenAIRE

    Parry, David A.; Toomes, Carmel; Bida, Lina; Danciger, Michael; Towns, Katherine V.; McKibbin, Martin; Jacobson, Samuel G.; Logan, Clare V.; Ali, Manir; Bond, Jacquelyn; Chance, Rebecca; Swendeman, Steven; Daniele, Lauren L.; Springell, Kelly; Adams, Matthew

    2009-01-01

    Cone-rod dystrophy (CRD) is an inherited progressive retinal dystrophy affecting the function of cone and rod photoreceptors. By autozygosity mapping, we identified null mutations in the ADAM metallopeptidase domain 9 (ADAM9) gene in four consanguineous families with recessively inherited early-onset CRD. We also found reduced photoreceptor responses in Adam9 knockout mice, previously reported to be asymptomatic. In 12-month-old knockout mice, photoreceptors appear normal, but the apical proc...

  20. Analysis of membrane proteome and secretome in cells over-expressing ADAM17 using quantitative proteomics

    International Nuclear Information System (INIS)

    Full text: A disintegrin and metalloproteinase (ADAM) protease is involved in proteolytic ectodomain shedding of several membrane-associated proteins and modulation of key cell signaling pathways in the tumor microenvironment. In this study, we examined the effect of over-expressing the full length human ADAM17 in membrane and secreted proteins. To this end, we constructed a stable Flp-In T-RExHEK293 cells expressing ADAM17 by tetracycline induction. These cells were grown in Dulbeccos modified Eagles medium containing light lysine, arginine or heavy, L-Arg-13C615N4 and L-Lys -13C615N2 (SILAC: stable isotope labeling with amino acid in cell culture) media and they were treated with an ADAM17 activator, phorbolester (PMA). Controls such as Flp-In T-RExHEK293 cell without PMA treatment and without ADAM17 cloned were cultivated in light medium. The ADAM17 overexpression was induced with tetracycline 500 ng/ml for 24 hours. Cells in a heavy condition were treated with PMA 50 ng/ml for 1 hour and vehicle DMSO was used as control in a light cell condition. The extracellular media were collected, concentrated and used to evaluate the secretome and a cell surface biotinylation-based approach was used to capture cell surface-associated proteins. The biotinylated proteins were eluted with dithiothreitol, alkylated with iodoacetamide and then digested with trypsin. The resulting peptides were subjected to LC-MS/MS analysis on an ETD enabled Orbitrap Velos instrument. The results showed different proteins up or down regulated in membrane and secretome analysis which might represent potential molecules involved in signaling or ADAM17 regulation events. (author)

  1. Analysis of membrane proteome and secretome in cells over-expressing ADAM17 using quantitative proteomics

    Energy Technology Data Exchange (ETDEWEB)

    Kawahara, R.; Simabuco, F.M. [Laboratorio Nacional de Biociencias - LNBIO, Campinas, SP (Brazil); Yokoo, S.; Paes Leme, A.F. [Laboratorio Nacional de Luz Sincrotron (LNLS), Campinas, SP (Brazil); Sherman, N. [University of Virginia, Charlottesville, VA (United States)

    2012-07-01

    Full text: A disintegrin and metalloproteinase (ADAM) protease is involved in proteolytic ectodomain shedding of several membrane-associated proteins and modulation of key cell signaling pathways in the tumor microenvironment. In this study, we examined the effect of over-expressing the full length human ADAM17 in membrane and secreted proteins. To this end, we constructed a stable Flp-In T-RExHEK293 cells expressing ADAM17 by tetracycline induction. These cells were grown in Dulbeccos modified Eagles medium containing light lysine, arginine or heavy, L-Arg-13C615N4 and L-Lys -13C615N2 (SILAC: stable isotope labeling with amino acid in cell culture) media and they were treated with an ADAM17 activator, phorbolester (PMA). Controls such as Flp-In T-RExHEK293 cell without PMA treatment and without ADAM17 cloned were cultivated in light medium. The ADAM17 overexpression was induced with tetracycline 500 ng/ml for 24 hours. Cells in a heavy condition were treated with PMA 50 ng/ml for 1 hour and vehicle DMSO was used as control in a light cell condition. The extracellular media were collected, concentrated and used to evaluate the secretome and a cell surface biotinylation-based approach was used to capture cell surface-associated proteins. The biotinylated proteins were eluted with dithiothreitol, alkylated with iodoacetamide and then digested with trypsin. The resulting peptides were subjected to LC-MS/MS analysis on an ETD enabled Orbitrap Velos instrument. The results showed different proteins up or down regulated in membrane and secretome analysis which might represent potential molecules involved in signaling or ADAM17 regulation events. (author)

  2. 2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine (ADAM): an improved serotonin transporter ligand

    Energy Technology Data Exchange (ETDEWEB)

    Oya, Shunichi; Choi, S.-R.; Hou, Catherine; Mu Mu; Kung, M.-P.; Acton, Paul D.; Siciliano, Michael; Kung, Hank F. E-mail: kunghf@sunmac.spect.upenn.edu

    2000-04-01

    Serotonin transporters (SERT) are target-sites for commonly used antidepressants, such as fluoxetine, paroxetine, sertraline, and so on. Imaging of these sites in the living human brain may provide an important tool to evaluate the mechanisms of action as well as to monitor the treatment of depressed patients. Synthesis and characterization of an improved SERT imaging agent, ADAM (2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine)(7) was achieved. The new compound, ADAM(7), displayed an extremely potent binding affinity toward SERT (K{sub i}=0.013 nM, in membrane preparations of LLC-PK{sub 1}-cloned cell lines expressing the specific monoamine transporter). ADAM(7) also showed more than 1,000-fold selectivity for SERT over norepinephrine transporter (NET) and dopamine transporter (DAT) (K{sub i}=699 and 840 nM, for NET and DAT, respectively). The radiolabeled compound [{sup 125}I]ADAM(7) showed an excellent brain uptake in rats (1.41% dose at 2 min post intravenous [IV] injection), and consistently displayed the highest uptake (between 60-240 min post IV injection) in hypothalamus, a region with the highest density of SERT. The specific uptake of [{sup 125}I]ADAM(7) in the hypothalamus exhibited the highest target-to-nontarget ratio ([hypothalamus - cerebellum]/cerebellum was 3.97 at 120 min post IV injection). The preliminary imaging study of [{sup 123}I]ADAM in the brain of a baboon by single photon emission computed tomography (SPECT) at 180-240 min post IV injection indicated a specific uptake in midbrain region rich in SERT. These data suggest that the new ligand [{sup 123}I]ADAM(7) may be useful for SPECT imaging of SERT binding sites in the human brain.

  3. Spiro K. Antiochos Receives 2013 John Adam Fleming Medal: Citation

    Science.gov (United States)

    Klimchuk, James A.

    2014-01-01

    The John Adam Fleming Medal is awarded for "original research and technical leadership in geomagnetism, atmospheric electricity, aeronomy, space physics, and related sciences." Originality and technical leadership are exactly the characteristics that distinguish the research of Spiro K. Antiochos. Spiro possesses a truly unique combination of physical insight, creativity, and mastery of the concepts and mathematical and numerical tools of space physics. These talents have allowed him to develop completely original theories for major observational problems and to test and refine those theories using sophisticated numerical simulation codes that he himself helped to develop. Spiro's physical insight is especially impressive. He has an uncanny ability to identify the fundamental aspects of complex problems and to see physical connections where others do not. This can sometimes involve ideas that may initially seem counterintuitive to those with less creativity. Many of Spiro's revolutionary advances have opened up whole new areas of study and shaped the course of space physics. Examples include the breakout model for coronal mass ejections (CMEs), the S-web model for the slow solar wind, and the thermal nonequilibrium model for solar prominences. The breakout model is of special significance to AGU as it strives to promote science for the betterment of humanity. CMEs are enormous explosions on the Sun that can have major "space weather" impacts here on Earth. They affect technologies ranging from communication and navigation systems to electrical power grids. Breakout is the leading theory for why CMEs occur and may one day be the foundation for more accurate space weather forecasting.

  4. "Mitochondrial Eve", "Y Chromosome Adam", testosterone, and human evolution.

    Science.gov (United States)

    Howard, James Michael

    2002-01-01

    I suggest primate evolution began as a consequence of increased testosterone in males which increased aggression and sexuality, therefore, reproduction and success. With time, negative effects of excessive testosterone reduced spermatogenesis and started a decline of the group. Approximately 30-40 million years ago, the gene DAZ (Deleted in AZoospermia) appeared on the Y chromosome, increased spermatogenesis, and rescued the early primates from extinction. (Note: DAZ is considered by some to specifically, positively affect spermatogenesis; others suggest it has no effect on spermatogenesis.) Hominid evolution continued with increasing testosterone. The advent of increased testosterone in females of Homo erectus (or Homo ergaster) increased the female-to-male body size ratio, and eventually produced another era of excessive testosterone. Excessive testosterone caused a reduction in population size (bottleneck) that produced the "Mitochondrial Eve" (ME) mechanism. (Only certain females continued during the bottleneck to transmit their mitochondrial DNA.) That is, the ME mechanism culminated, again, in excessive testosterone and reduced spermatogenesis in the hominid line. Approximately 50,000 to 200,000 years ago, a "doubling" of the DAZ gene occurred on the Y chromosome in hominid males which rescued the hominid line with increased spermatogenesis in certain males. This produced the "Y Chromosome Adam" event. The doubling of DAZ allowed further increases in testosterone in hominids that resulted in the increased size and development of the brain. Modern humans periodically fluctuate between the positive and negative consequences of increased levels of testosterone, currently identifiable as the secular trend, increased infections, and reduced spermatogenesis. PMID:12449688

  5. TGFβ induces proHB-EGF shedding and EGFR transactivation through ADAM activation in gastric cancer cells

    International Nuclear Information System (INIS)

    Research highlights: → TGFβ induces EGFR transactivation through proHB-EGF shedding by activated ADAM members in gastric cancer cells. → TGFβ induces nuclear translocation of HB-EGF-CTF cleaved by ADAM members. → TGFβ enhances cell growth by EGFR transactivation and HB-EGF-CTF nuclear translocation and ADAM inhibitors block these effects. → Silencing of ADAM17 also blocks EGFR transactivation, HB-EGF-CTF nuclear translocation and cancer cell growth by TGFβ. → ADAM17 may play a crucial role in this TGFβ-HB-EGF signal transduction. -- Abstract: Background and aims: Transforming growth factor-beta (TGFβ) is known to potently inhibit cell growth. Loss of responsiveness to TGFβ inhibition on cell growth is a hallmark of many types of cancer, yet its mechanism is not fully understood. Membrane-anchored heparin-binding EGF-like growth factor (proHB-EGF) ectodomain is cleaved by a disintegrin and metalloproteinase (ADAM) members and is implicated in epidermal growth factor receptor (EGFR) transactivation. Recently, nuclear translocation of the C-terminal fragment (CTF) of pro-HB-EGF was found to induce cell growth. We investigated the association between TGFβ and HB-EGF signal transduction via ADAM activation. Materials and methods: The CCK-8 assay in two gastric cancer cell lines was used to determine the effect for cell growth by TGFβ. The effect of two ADAM inhibitors was also evaluated. Induction of EGFR phosphorylation by TGFβ was analyzed and the effect of the ADAM inhibitors was also examined. Nuclear translocation of HB-EGF-CTF by shedding through ADAM activated by TGFβ was also analyzed. EGFR transactivation, HB-EGF-CTF nuclear translocation, and cell growth were examined under the condition of ADAM17 knockdown. Result: TGFβ-induced EGFR phosphorylation of which ADAM inhibitors were able to inhibit. TGFβ induced shedding of proHB-EGF allowing HB-EGF-CTF to translocate to the nucleus. ADAM inhibitors blocked this nuclear translocation. TGF

  6. ADAM10 is expressed in human podocytes and found in urinary vesicles of patients with glomerular kidney diseases

    Directory of Open Access Journals (Sweden)

    Weide Thomas

    2010-01-01

    Full Text Available Abstract Background The importance of the Notch signaling in the development of glomerular diseases has been recently described. Therefore we analyzed in podocytes the expression and activity of ADAM10, one important component of the Notch signaling complex. Methods By Western blot, immunofluorescence and immunohistochemistry analysis we characterized the expression of ADAM10 in human podocytes, human urine and human renal tissue. Results We present evidence, that differentiated human podocytes possessed increased amounts of mature ADAM10 and released elevated levels of L1 adhesion molecule, one well known substrate of ADAM10. By using specific siRNA and metalloproteinase inhibitors we demonstrate that ADAM10 is involved in the cleavage of L1 in human podocytes. Injury of podocytes enhanced the ADAM10 mediated cleavage of L1. In addition, we detected ADAM10 in urinary podocytes from patients with kidney diseases and in tissue sections of normal human kidney. Finally, we found elevated levels of ADAM10 in urinary vesicles of patients with glomerular kidney diseases. Conclusions The activity of ADAM10 in human podocytes may play an important role in the development of glomerular kidney diseases.

  7. The retinoic acid receptor agonist Am80 increases hippocampal ADAM10 in aged SAMP8 mice.

    Science.gov (United States)

    Kitaoka, Kazuyoshi; Shimizu, Noriyuki; Ono, Koji; Chikahisa, Sachiko; Nakagomi, Madoka; Shudo, Koichi; Ishimura, Kazunori; Séi, Hiroyoshi; Yoshizaki, Kazuo

    2013-09-01

    The retinoic acid (RA, a vitamin A metabolite) receptor (RAR) is a transcription factor. Vitamin A/RA administration improves the Alzheimer's disease (AD)- and age-related attenuation of memory/learning in mouse models. Recently, a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) was identified as a key molecule in RA-mediated anti-AD mechanisms. We investigated the effect of chronic administration of the RAR agonist Am80 (tamibarotene) on ADAM10 expression in senescence-accelerated mice (SAMP8). Moreover, we estimated changes in the expression of the amyloid precursor protein (APP), amyloid beta (Aβ), and hairy/enhancer of split (Hes), which are mediated by ADAM10. Spatial working memory and the levels of a hippocampal proliferation marker (Ki67) were also assessed in these mice. ADAM10 mRNA and protein expression was significantly reduced in the hippocampus of 13-month-old SAMP8 mice; their expression improved significantly after Am80 administration. Further, after Am80 administration, the expression levels of Hes5 and Ki67 were restored and the deterioration of working memory was suppressed, whereas APP and Aβ levels remained unchanged. Our results suggest that Am80 administration effectively improves dementia by activating the hippocampal ADAM10-Notch-Hes5 proliferative pathway. PMID:23624141

  8. ADAM17在恶性肿瘤中的研究及其进展%Researches and Advances of ADAM17 in Malignancy

    Institute of Scientific and Technical Information of China (English)

    刘爽; 马荣

    2013-01-01

    The disintegrin and metalloproteinase 17 (ADAM 17) is one newly discovered family members metalloproteinase disintegrin (ADAMs),which plays an important role in tumor development.ADAM17 is also called TACE.It has activities of disintegrin and metalloproteinase.Besides,it can separate inactive TNF-α from cell membrane and bind with its receptor,thus active downstream EGFR signal transduction of TNF-o.In addition,it can active many signal transduction pathways like Notch,then affect the biological behaviors of tumor cells such as adhesion,apoptosis,metastasis and proliferation.Taking a wide view of research in ADAM17,it has high expression in many malignant tumors,and the high expression levels are related with degree of tumor invasion and metastasis.With the gradual and further basic scientific research of ADAM17,its clinical potential is being increasingly developed.Based on its high expression levels in many malignant tumors,it can be used as tumor makers to help in the diagnosis,metastasis and prognosis judging in many tumors.Using EGFR as a research trigger point,many target drugs were successfully developed,which brought hopes to malignant tumor patients.ADAM17 plays an important role in ligand releasing step.This article gives a review on the function and mechanism of AMAM 17 in develop of malignant tumors and its application prospect in treatment of cancer.%去整合素-金属蛋白酶17(adisintegrin and metalloproteinase 17,ADAM17)是近年来发现的金属蛋白酶解聚素(adisintegrin and metalloproteinase,ADAMs)家族成员之一,参与肿瘤发生发展的重要过程.去整合素-金属蛋白酶17(ADAM17)又称为肿瘤坏死因子转换酶(TACE),因此除了具有解聚素和金属蛋白酶的活性,还可以将没有活性的肿瘤坏死因子(TNF-α)从细胞膜上切割下来,并与其受体相结合,从而激活TNF-α下游的EGFR信号传导,此外还可以激活多条信号传导途径如Notch传导通路等,进而影响肿瘤细胞的粘附

  9. ADAM12 alleviates the skeletal muscle pathology in mdx dystrophic mice

    DEFF Research Database (Denmark)

    Kronqvist, Pauliina; Kawaguchi, Nobuko; Albrechtsen, Reidar;

    2002-01-01

    Muscular dystrophy is characterized by muscle degeneration and insufficient regeneration and replacement of muscle fibers by connective tissue. New therapeutic strategies directed toward various forms of muscular dystrophy are needed to preserve muscle mass and promote regeneration. In this study...... evidenced by less muscle cell necrosis and inflammation, lower levels of serum creatine kinase, and less uptake of Evans Blue dye into muscle fibers. These studies demonstrate that ADAM12 directly or indirectly contributes to muscle cell regeneration, stability, and survival....... we examined the role of the transmembrane ADAM12, a disintegrin and metalloprotease, which is normally associated with development and regeneration of skeletal muscle. We demonstrate that ADAM12 overexpression in the dystrophin-deficient mdx mice alleviated the muscle pathology in these animals, as...

  10. Association of ADAM33 Gene Polymorphisms with Keloid Scars in a Northeastern Chinese Population

    Directory of Open Access Journals (Sweden)

    Jianyu Han

    2014-08-01

    Full Text Available Objective: To study the association between ADAM33 and keloid scars in the northeastern Chinese population. Methods: A total of 283 keloid scar patients and a control group of 290 healthy volunteers were recruited for this study. Six polymorphic loci (V4, T+1, T2, T1, S2 and Q-1 of ADAM33 were selected for genotyping. Genotypes were determined by using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP method. Results: We observed the frequency of the rs612709 A allele exhibited a significantly decreased frequency in cases than in controls(22 vs.39.6%, PP= 0.041. In contrast, the haplotype H8 (GGGAGG was more common in the control group than in the case group (P=0.022. Conclusions: Our data suggest that the ADAM33 polymorphisms may be associated with keloid scars in the northeastern Chinese population.

  11. Gender Ideology in the Diary of Adam and Eve By Mark Twain

    Directory of Open Access Journals (Sweden)

    Paramita Ayuningtyas

    2011-03-01

    Full Text Available This article aims to show that behind the new version of Genesis by Mark Twain in his novel The Diary of Adam and Eve, there are some patriarchal principles that appear in it. It can be seen from the characterizations of Adam and Eve. By using some concepts from feminism and also focusing on the context of the novel, the analysis shows that patriarchal stereotypes about gender are applied in constructing the characters of Adam and Eve. Not only the content, but the form of the diary is also analyzed with the same method, and the same result is found. Therefore, it can be concluded that in spite of his progressiveness, Mark Twain still held patriarchal values in re-interpreting the tale of human creation.

  12. Data preparation requirements for modeling wind turbines with ADAMS{reg_sign}

    Energy Technology Data Exchange (ETDEWEB)

    Buhl, M.L. Jr.

    1994-12-01

    This contains guidelines for the kind of information that designers need to model a complete wind turbine with ADAMS. The information here is not at all exhaustive. It does, however, represent the collective knowledge of two years of experience gained by National Renewable Energy Laboratory (NREL) engineers while using ADAMS to model wind turbines. If designers save the following information as they design a new turbine, they will have an excellent start on an ADAMS model. The more accurate the input data, the better the results will be. Designers will have to make the tradeoff between the required effort to improve their input data and the benefits of a more accurate simulation. The authors break the turbine into each of its major subsystems and describe them in detail. They attach a table of parameters to the end of the document to make it easier for one to keep track of data requirements.

  13. [An important son of Aub: the military surgeon and ophthalmologist Johann Adam Schmidt (1759-1809)].

    Science.gov (United States)

    Krogmann, Frank; Vollmuth, Ralf

    2009-01-01

    The following article gives you a review to the life and work of the military surgeon and ophthalmologist Johann Adam Schmidt who was born in Aub/Lower Franconia on the 12th of October 1759. He had got his surgical education in Würzburg and had worked as an Unterchirurgus in the War of the Bavarian succession. Later on he completed his education in Vienna where he, by joining different work places, had been appointed to a professorship at the Medico-Surgical Joseph's Academy and became a leading figure of the Austrian military medical service. Also as an ophthalmologist Johann Adam Schmidt obtained high credit for his practical activity and his academic work. Johann Adam Schmidt died on the 19th of February 1809 and left a multiplicity of publications. He got not least publicity as the doctor of Beethoven, who dedicated the trio for piano, clarinet or violin and violoncello (Es-major) Opus 38 to Schmidt. PMID:20509447

  14. Identification of binding peptides of the ADAM15 disintegrin domain using phage display

    Indian Academy of Sciences (India)

    Jing Wu; Min-Chen Wu; Lian-Fen Zhang; Jian-Yong Lei; Lei Feng; Jian Jin

    2009-06-01

    ADAM15 plays an important role in tumour development by interacting with integrins. In this study, we investigated the target peptides of the ADAM15 disintegrin domain. First, we successfully produced the recombinant human ADAM15 disintegrin domain (RADD) that could inhibit melanoma cell adhesion by using Escherichia coli. Second, four specific binding peptides (peptides A, B, C, and D) were selected using a phage display 12-mer peptide library. The screening protocol involved 4 rounds of positive panning on RADD and 2 rounds of subtractive selection with streptavidin. By using the BLAST software and a relevant protein database, integrin v3 was found to be homologous to peptide A. Synthetic peptide A had a highly inhibitory effect on RADD–integrin v3 binding. The results demonstrate the potential application of short peptides for disrupting high-affinity ADAM–integrin interactions.

  15. ADAM12 alleviates the skeletal muscle pathology in mdx dystrophic mice

    DEFF Research Database (Denmark)

    Kronqvist, Pauliina; Kawaguchi, Nobuko; Albrechtsen, Reidar; Xu, Xiufeng; Schrøder, Henrik Daa; Moghadaszadeh, Behzad; Nielsen, Finn Cilius; Frohlich, Camilla; Engvall, Eva; Wewer, Ulla M

    2002-01-01

    Muscular dystrophy is characterized by muscle degeneration and insufficient regeneration and replacement of muscle fibers by connective tissue. New therapeutic strategies directed toward various forms of muscular dystrophy are needed to preserve muscle mass and promote regeneration. In this study...... we examined the role of the transmembrane ADAM12, a disintegrin and metalloprotease, which is normally associated with development and regeneration of skeletal muscle. We demonstrate that ADAM12 overexpression in the dystrophin-deficient mdx mice alleviated the muscle pathology in these animals, as...

  16. Adam M. Reid: APA/APAGS Award for Distinguished Graduate Student in Professional Psychology.

    Science.gov (United States)

    2015-11-01

    The APA/APAGS Award for Distinguished Graduate Student in Professional Psychology is awarded on an annual basis by the APA Board of Professional Affairs (BPA) and the American Psychological Association of Graduate Students (APAGS) to a graduate student who has demonstrated outstanding practice and application of psychology. One of the 2015 award winners is Adam M. Reid, who received this award "for his community service, in which he has integrated the highest standards of professional psychological clinical practice and science." Adam's award citation, biography, and a selected bibliography are presented here. PMID:26618976

  17. A substrate-optimized electrophoretic mobility shift assay for ADAM12

    DEFF Research Database (Denmark)

    Kotzsch, Alexander; Skovgaard, Tine; Buus, Uwe;

    2014-01-01

    long been investigated as pharmaceutical drug targets; however, due to lack of potency and in vivo side effects, none of the small-molecule inhibitors discovered so far has made it beyond clinical testing. Ongoing research on novel selective inhibitors of ADAMs requires reliable biochemical assays to...... validate molecular probes from large-scale screening efforts. Here we describe an electrophoretic mobility shift assay for ADAM12 based on the identification of an optimized peptide substrate that is characterized by excellent performance and reproducibility....

  18. Higher Toda brackets and the Adams spectral sequence in triangulated categories

    OpenAIRE

    Christensen, J. Daniel; Frankland, Martin

    2015-01-01

    The Adams spectral sequence is available in any triangulated category equipped with a projective or injective class. Higher Toda brackets can also be defined in a triangulated category, as observed by B. Shipley based on J. Cohen's approach for spectra. We provide a family of definitions of higher Toda brackets, show that they are equivalent to Shipley's, and show that they are self-dual. Our main result is that the Adams differential $d_r$ can be expressed as an $(r+1)$-fold Toda bracket and...

  19. Regulation of human ADAM 12 protease by the prodomain. Evidence for a functional cysteine switch

    DEFF Research Database (Denmark)

    Loechel, F; Overgaard, M T; Oxvig, C;

    1999-01-01

    prodomain maintaining the protease in a latent form. We now provide evidence that the latency mechanism of ADAM 12 can be explained by the cysteine switch model, in which coordination of Zn2+ in the active site of the catalytic domain by a cysteine residue in the prodomain is critical for inhibition of the...... protease. Replacing Cys179 with other amino acids results in an ADAM 12 proform that is proteolytically active, but latency can be restored by placing cysteine at other positions in the propeptide. None of the amino acids adjacent to the crucial cysteine residue is essential for blocking activity of the...

  20. DYNAMIC ANALYSIS OF A CRIMPING DEVICE WITH MULTIPLE CAMS USING MSC ADAMS II

    Directory of Open Access Journals (Sweden)

    Gheorghe Popescu

    2012-05-01

    Full Text Available Through the present paper, the author presents the results of the dynamic analysis with MSC ADAMS of the mechanism with a crimping device with 12 tightening cams, designed and used in the technological process of assembly of the indigenous electrical detonators. In this sense, the mechanism with multiple cams is considered a mechanical system and is treated as an assembly of rigid bodies connected by mechanical connections and elastic elements. For shaping and simulation of the mechanism with multiple cams using ADAMS program, the author got through the following stages: construction of the pattern, its testing and simulation, validation, finishing, parametrization, optimization of the pattern.

  1. El sujeto económico y la racionalidad en Adam Smith

    Directory of Open Access Journals (Sweden)

    Vanesa Valeria D’Elia

    2009-12-01

    Full Text Available El supuesto de racionalidad es central en la teoría económica actual, es el pilar sobre el cual se construye el homo economicus de la teoría convencional. Este trabajo parte del enfoque de la racionalidad en Adam Smith, y busca aportar a la discusión de las características del sujeto racional y de sus implicaciones para el análisis económico. Reexamina el significado de la racionalidad a la luz de diversos autores y argumenta que los fundamentos de la obra de Adam Smith siguen vigentes.

  2. ANALYSIS WITH MSC ADAMS OF A 5-FINGER AND 3-PHALANX /FINGER UNDER-ACTUATEDMECHANICAL HAND

    Directory of Open Access Journals (Sweden)

    Gheorghe POPESCU

    2013-05-01

    Full Text Available This paper studies the analysis with MSC ADAMS of a 5-fingered and 3-phalanx/finger underactuatedmechanical hand, designed by the author to work on industrial robots. Moreover, in order to increasegrasping safety in the automated handling process, the author has fitted each finger with a locking sequence inthe final phase of grasping. Thus, the mechanism of mechanical hand is considered to be a mechanical systemand is treated like a set of rigid bodies connected by mechanical linkages and elastic elements. To model andsimulate this mechanism with MSC ADAMS programme, the author covered the following stages: constructionof the model, testing-simulation, validation, finishing, parameterization, and optimization

  3. ADAM12 is a four-leafed clover: the excised prodomain remains bound to the mature enzyme

    DEFF Research Database (Denmark)

    Wewer, Ulla M; Mörgelin, Matthias; Holck, Peter; Jacobsen, Jonas; Lydolph, Magnus C; Johnsen, Anders H; Kveiborg, Marie; Albrechtsen, Reidar

    2006-01-01

    soluble ADAM12-S. ADAM12 is synthesized as a zymogen with the prodomain keeping the metalloprotease inactive through a cysteine-switch mechanism. Maturation and activation of the protease involves the cleavage of the prodomain in the trans-Golgi or possibly at the cell surface by a furin-peptidase. The...

  4. ADAM12 is expressed in the tumour vasculature and mediates ectodomain shedding of several membrane-anchored endothelial proteins

    DEFF Research Database (Denmark)

    Frohlich, Camilla; Klitgaard, Marie; Noer, Julie B;

    2013-01-01

    ADAM (a disintegrin and metalloproteinase) 12 is a metalloprotease implicated in cancer progression. ADAM12 can activate membrane-anchored proteins, such as sonic hedgehog, Delta-like 1 and certain epidermal growth factor receptor ligands, through a process called ectodomain shedding. We screened...

  5. Problems with McAdams and Pals's (2006) Proposal of a Framework for an Integrative Theory of Personality

    Science.gov (United States)

    Epstein, Seymour

    2007-01-01

    Comments on the original article "A New Big Five: Fundamental Principles for an Integrative Science of Personality," by Dan P. McAdams and Jennifer L. Pals (see record 2006-03947-002). Here, the current author begins with a critique of McAdams and Pals's (April 2006) five principles for a framework for an integrative theory of personality. The…

  6. ADAM17-siRNA inhibits MCF-7 breast cancer through EGFR-PI3K-AKT activation.

    Science.gov (United States)

    Meng, Xiangchao; Hu, Baoshan; Hossain, Mohammad Monir; Chen, Guofu; Sun, Ying; Zhang, Xuepeng

    2016-08-01

    A disintegrin and metalloproteinase-17 (ADAM17) can cut and release a wide variety of epidermal growth factor receptor (EGFR) ligands to promote survival, invasion and proliferation of cancer cell, and therefore, is considered to be a potential therapeutic target for cancer. The main goal of the present study was to observe the effects of ADAM17 small interfering RNA (ADAM17-siRNA) on human MCF-7 breast cancer and investigate its activation pathway. In vitro, MCF-7 cells were divided into ADAM17-siRNA groups, nonsense siRNA groups, AG1478 (selective EGFR blocker) groups, LY294002 [phosphatidylinositol 3-kinase (PI3K) phosphorylation inhibitor] groups, PD0325901 [mitogen extracellular kinase (MEK) inhibitor] groups and control groups. In vivo, MCF-7 cells were implanted subcutaneously into nude mice and then these mice were randomly divided into ADAM17-siRNA groups, vector groups and control groups. Our data showed that compared with the control groups, ADAM17-siRNA, AG1478 and LY294002 could inhibit the migration and proliferation of MCF-7 cells, but PD0325901 and nonsense siRNA did not show this effect. Except that specific ADAM17-siRNA could inhibit the expression of ADAM17 mRNA, others did not change it. Western blot analysis further confirmed that EGFR-PI3K-AKT signaling pathway is involved in ADAM17-siRNA inhibiting migration and proliferation of MCF-7 cells. Similarly to the former, the growth of MCF-7 breast cancer in nude mice was significantly inhibited by ADAM17-siRNA. Compared with the control group and the vector group, the tumor volume was smaller in the ADAM17-siRNA group, the tissues developed large areas of necrosis, immunohistochemistry showed low expressions of ADAM17 and Ki-67 and western blot analysis proved that the expression of ADAM17 protein in the tissue was also reduced. The present study suggests that ADAM17-siRNA inhibits MCF-7 breast cancer and is activated through the EGFR-PI3K-AKT signaling pathway. PMID:27221510

  7. ADAM12 redistributes and activates MMP-14, resulting in gelatin degradation, reduced apoptosis and increased tumor growth

    DEFF Research Database (Denmark)

    Albrechtsen, Reidar; Hansen, Dorte Stautz; Vikeså, Jonas;

    2013-01-01

    activation, gelatin degradation was stimulated and tumor cell apoptosis was decreased, with reduced expression of the pro-apoptotic proteins BCL2L11 and BIK. The effect on gelatin degradation was abrogated by inhibition of the MMP-14 activity and appeared to be dependent on cell surface αVβ3 integrin......Matrix metalloproteinases (MMPs), in particular MMP-2, MMP-9 and MMP-14, play a key role in various aspects of cancer pathology. Likewise, ADAMs (a disintegrin and metalloproteinases), including ADAM12, are upregulated in malignant tumors and contribute to the pathology of cancers. Here, we show...... antibodies against ADAM12. Furthermore, orthotopic implantation of ADAM12-expressing MCF7 cells in nude mice produced tumors with increased levels of activated MMP-14 and confirmed that ADAM12 protects tumor cells against apoptosis, leading to increased tumor progression. In conclusion, our data suggest that...

  8. Knock-down of protein L-isoaspartyl O-methyltransferase increases β-amyloid production by decreasing ADAM10 and ADAM17 levels

    Institute of Scientific and Technical Information of China (English)

    Narkhyun BAE; Se Eun BYEON; Jihyuk SONG; Sang-Jin LEE; Moosik KWON; Inhee MOOK-JUNG; Jae Youl CHO; Sungyoul HONG

    2011-01-01

    Aim: To examine the role of protein L-isoaspartyl O-methyltransferase (PIMT; EC 2.1.1.77) on the secretion of Aβ peptides.Methods: HEK293 APPsw cells were treated with PIMT siRNA or adenosine dialdehyde (AdOX), a broad-spectrum methyltransferase inhibitor. Under the conditions, the level of Aβ secretion and regulatory mechanism by PIMT were examined.Results: Knock-down of PIMT and treatment with AdOX significantly increased Aβ40 secretion. Reductions in levels of PIMT decreased the secretion of soluble amyloid precursor protein alpha (sAPPα) without altering the total expression of APP or its membrane-bound C83 fragment. However, the levels of the C99 fragment generated by β-secretase were enhanced. Moreover, the decreased secretion of sAPPα resulting from PIMT knock-down seemed to be linked with the suppression of the expression of α-secretase gene products,α-disintegrin and metalloprotease 10 (ADAM10) and ADAM17, as indicated by Western blot analysis. In contrast, ADAM10 was not down-regulated in response to treatment with the protein arginine methyltransferase (PRMT) inhibitor, AMI-1.Conclusion: This study demonstrates a novel role for PIMT, but not PRMT, as a negative regulator of Aβ peptide formation and a potential protective factor in the pathogenesis of AD.

  9. ADAM17 is critical for multipolar exit and radial migration of neuronal intermediate progenitor cells in mice cerebral cortex.

    Directory of Open Access Journals (Sweden)

    Qingyu Li

    Full Text Available The radial migration of neuronal progenitor cells is critical for the development of cerebral cortex layers. They go through a critical step transforming from multipolar to bipolar before outward migration. A Disintegrin and Metalloprotease 17 (ADAM17 is a transmembrane protease which can process many substrates involved in cell-cell interaction, including Notch, ligands of EGFR, and some cell adhesion molecules. In this study, we used in utero electroporation to knock down or overexpress ADAM17 at embryonic day 14.5 (E14.5 in neuronal progenitor cells to examine the role of ADAM17 in cortical embryonic neurogenesis. Our results showed that the radial migration of ADAM17-knocked down cells were normal till E16.5 and reached the intermediate zone (IZ. Then most transfected cells stopped migration and stayed at the IZ to inner cortical plate (CP layer at E18.5, and there was higher percentage of multipolar cells at IZ layer in the ADAM17-knocked down group compared to the cells in control group. Marker staining revealed that those ADAM17-knocked down cells differentiated normally from neural stem cells (NSCs to neuronal intermediate progenitor cells (nIPCs but did not differentiate into mature neurons. The migration and multipolar exit defects caused by ADAM17 knockdown could be partially rescued by over-expressing an shRNA resistant ADAM17, while overexpressing ADAM17 alone did not affect the radial migration. Taken together, our results showed for the first time that, ADAM17 is critical in regulating the multipolar-stage exit and radial migration of the nIPCs during telencephalon cortex development in mice.

  10. ADAM17 is critical for multipolar exit and radial migration of neuronal intermediate progenitor cells in mice cerebral cortex.

    Science.gov (United States)

    Li, Qingyu; Zhang, Zhengyu; Li, Zengmin; Zhou, Mei; Liu, Bin; Pan, Le; Ma, Zhixing; Zheng, Yufang

    2013-01-01

    The radial migration of neuronal progenitor cells is critical for the development of cerebral cortex layers. They go through a critical step transforming from multipolar to bipolar before outward migration. A Disintegrin and Metalloprotease 17 (ADAM17) is a transmembrane protease which can process many substrates involved in cell-cell interaction, including Notch, ligands of EGFR, and some cell adhesion molecules. In this study, we used in utero electroporation to knock down or overexpress ADAM17 at embryonic day 14.5 (E14.5) in neuronal progenitor cells to examine the role of ADAM17 in cortical embryonic neurogenesis. Our results showed that the radial migration of ADAM17-knocked down cells were normal till E16.5 and reached the intermediate zone (IZ). Then most transfected cells stopped migration and stayed at the IZ to inner cortical plate (CP) layer at E18.5, and there was higher percentage of multipolar cells at IZ layer in the ADAM17-knocked down group compared to the cells in control group. Marker staining revealed that those ADAM17-knocked down cells differentiated normally from neural stem cells (NSCs) to neuronal intermediate progenitor cells (nIPCs) but did not differentiate into mature neurons. The migration and multipolar exit defects caused by ADAM17 knockdown could be partially rescued by over-expressing an shRNA resistant ADAM17, while overexpressing ADAM17 alone did not affect the radial migration. Taken together, our results showed for the first time that, ADAM17 is critical in regulating the multipolar-stage exit and radial migration of the nIPCs during telencephalon cortex development in mice. PMID:23755270

  11. ADAM12/syndecan-4 signaling promotes beta 1 integrin-dependent cell spreading through protein kinase Calpha and RhoA

    DEFF Research Database (Denmark)

    Thodeti, Charles Kumar; Albrechtsen, Reidar; Grauslund, Morten;

    2002-01-01

    The ADAMs (a disintegrin and metalloprotease) comprise a large family of multidomain proteins with cell-binding and metalloprotease activities. The ADAM12 cysteine-rich domain (rADAM12-cys) supports cell attachment using syndecan-4 as a primary cell surface receptor that subsequently triggers bet...

  12. ADAM12: a potential target for the treatment of chronic wounds

    DEFF Research Database (Denmark)

    Harsha, Asheesh; Stojadinovic, Olivera; Brem, Harold;

    2008-01-01

    Wound healing is a complex process involving multiple cellular events, including cell proliferation, migration, and tissue remodeling. A disintegrin and metalloprotease 12 (ADAM12) is a membrane-anchored metalloprotease, which has been implicated in activation-inactivation of growth factors that ...

  13. 75 FR 51519 - Regional Transportation District-Acquisition Exemption-Union Pacific Railroad Company in Adams...

    Science.gov (United States)

    2010-08-20

    ... Surface Transportation Board Regional Transportation District--Acquisition Exemption--Union Pacific Railroad Company in Adams, Denver, and Jefferson Counties, CO Regional Transportation District (RTD) \\1... an exchange of property to accommodate the relocation of UP's lead accessing its Burnham Shop in...

  14. ADAM-17: a novel therapeutic target for triple negative breast cancer.

    LENUS (Irish Health Repository)

    McGowan, P M

    2013-02-01

    Validated targeted therapy is currently unavailable for patients with invasive breast cancer negative for oestrogen receptors, progesterone receptors and HER2 [i.e., those with triple-negative (TN) disease]. ADAM-17 is a protease involved in the activations of several ligands that bind to and promotes intracellular signalling from the EGFR\\/HER family of receptors.

  15. The role of metalloproteinase ADAM17 in regulating ICOS ligand-mediated humoral immune responses

    DEFF Research Database (Denmark)

    Marczynska, Joanna; Ozga, Aleksandra; Wlodarczyk, Agnieszka;

    2014-01-01

    Immune cells regulate cell surface receptor expression during their maturation, activation, and motility. Although many of these receptors are regulated largely at the level of expression, protease-mediated ectodomain shedding represents an alternative means of refashioning the surface of immune ...... suggest a functional link between ADAM17 and ICOSL in controlling adaptive immune responses....

  16. Book review: think tank: the story of the Adam Smith Institute, by Madsen Pirie

    OpenAIRE

    Abelson, Donald

    2012-01-01

    In Think Tank: The Story of the Adam Smith Institute, Madsen Pirie documents the fascinating history of one of the world’s biggest think tanks, and the many projects in which it has been engaged over the past three decades. Donald Abelson values the wealth of information with which scholars can develop and refine their observations about how think tanks exercise influence.

  17. Music for Elementary Teachers; Self-Help Guide (MUS 370). Adams State College.

    Science.gov (United States)

    Stokes, Cloyce

    This self-help guide for the music teacher is one of a series of eight Teacher Education Modules developed by Adams State College Teacher Corps Program. The guide itself consists of 11 modules, the first five of which focus on the mathematical and scientific aspects of music--pitch, tempo, furation, time, and key. These five modules are…

  18. Implementation of Distributed ADAMS Over Legion Using a Component DBMS Design. Final Report

    Energy Technology Data Exchange (ETDEWEB)

    Pfaltz, John L. [Univ. of Virginia, Charlottesville, VA (United States). Dept. of Computer Science; Orlandic, Ratko [Illinois Inst. of Tech., Chicago, IL (United States). Dept. of Computer Science

    2002-11-26

    There were four primary research areas reported in the final report for the original funding period They are: implementation of high dimensional data spaces; knowledge discovery in scientific databases; and mismatch between implementing components; demonstrate the utility of ADAMS in a specific domain science.

  19. An Austrian (mis)reads Adam Smith: a critique of Rothbard as intellectual historian

    Czech Academy of Sciences Publication Activity Database

    Matthews, P. H.; Ortmann, Andreas

    2002-01-01

    Roč. 14, č. 3 (2002), s. 379-392. ISSN 0953-8259 Institutional research plan: CEZ:AV0Z7085904 Keywords : Adam Smith * Rothbard Subject RIV: AH - Economics http://search.ebscohost.com/login.aspx?direct=true&db=bth&AN=6998203&site=ehost-live

  20. Back to Beginnings: Credentialism, Productivity, and Adam Smith's Division of Labour.

    Science.gov (United States)

    Davis, Denis J.

    1981-01-01

    The foundation of factional pressures for upgrading educational credentials in the labor market is examined through a review of human capital and screening theories. The writings of Adam Smith are referenced to show that the claims of the beneficial effects of educational upgrading have been questioned for 200 years. (Author/MLW)

  1. Rhetorical Studies: A Reassessment of Adam Smith's Lectures on Rhetoric and Belles Lettres.

    Science.gov (United States)

    Purcell, William M.

    1986-01-01

    Offers a dissenting interpretation of Adam Smith's Lectures on Rhetoric and Belles Lettres and a more conservative perspective on Smith's significance to the history of rhetorical theory. Views the lectures as an historical commentary on literature and rhetoric from the perspective of an eighteenth-century lecturer. (JD)

  2. Adam Smith and the Educative Critique: A Response to My Commentators

    Science.gov (United States)

    Weinstein, Jack Russell

    2015-01-01

    This paper is both a response to the four reviewers in a special symposium on my book Adam Smith's Pluralism and a substantive discussion of philosophy of education. In it, I introduce what I call "the educative critique," a mode of analysis similar to Marxist, feminist, or postcolonial critiques, but focusing on the educative role of a…

  3. How To Survive in Postindustrial Environments: Adam Smith's Advice for Today's Colleges and Universities.

    Science.gov (United States)

    Ortmann, Andreas

    1997-01-01

    Adam Smith's discussion of the payment modes of teachers and resulting consequences for the quality of teaching and process of curricular innovation are reviewed through the conceptual lens of modern agency theory. Smith's analysis of higher education in his day (eighteenth century) sheds light on faculty incentive and assessment problems that…

  4. Comparing Adam Smith's Wealth of Nations to James Madison's Federalist #10.

    Science.gov (United States)

    Mundell, Jean

    1987-01-01

    Presents a lesson which calls upon students to compare Adam Smith's WEALTH OF NATIONS to James Madison's FEDERALIST #10 to see how the ancient concept of individual rights and liberties was used to describe both economic and governmental systems. Presents questions to provide the basis for comparison. (GEA)

  5. Two Rival Conceptions of Vocational Education: Adam Smith and Friedrich List.

    Science.gov (United States)

    Winch, Christopher

    1998-01-01

    Examines and discusses two views of political economy: (1) the classical model of Adam Smith; and (2) the social capitalist model associated with Friedrich List. Explores two varieties of vocational education and training that emerge from a comparison of Smith's and List's ideas. (CMK)

  6. A chain morphism for Adams operations on rational algebraic K-theory

    DEFF Research Database (Denmark)

    Feliu, Elisenda

    2010-01-01

    For any regular noetherian scheme X and every k>0, we define a chain morphism between two chain complexes whose homology with rational coefficients is isomorphic to the algebraic K-groups of X tensored by Q. These morphisms induce in homology the Adams operations defined by Gillet and Soulé or th...

  7. ADAM: A computer program to simulate selective-breeding schemes for animals

    DEFF Research Database (Denmark)

    Pedersen, L D; Sørensen, A C; Henryon, M;

    2009-01-01

    ADAM is a computer program that models selective breeding schemes for animals using stochastic simulation. The program simulates a population of animals and traces the genetic changes in the population under different selective breeding scenarios. It caters to different population structures...

  8. Highlighting High Performance Buildings: Adam Joseph Lewis Center for Environmental Studies

    Energy Technology Data Exchange (ETDEWEB)

    None

    2002-11-01

    Oberlin College's Adam Joseph Lewis Center for Environmental Studies is a high-performance building featuring an expansive photovoltaic system and a closed-loop groundwater heat pump system. Designers incorporated energy-efficient components and materials that are local, non-toxic, and durable.

  9. Fractional Adams-Bashforth/Moulton methods: An application to the fractional Keller-Segel chemotaxis system

    Science.gov (United States)

    Zayernouri, Mohsen; Matzavinos, Anastasios

    2016-07-01

    We first formulate a fractional class of explicit Adams-Bashforth (A-B) and implicit Adams-Moulton (A-M) methods of first- and second-order accuracy for the time-integration of t τ 0 CD u (x,t) = g (t ; u), τ ∈ (0 , 1 ], where t τ 0 CD denotes the fractional derivative in the Caputo sense. In this fractional setting and in contrast to the standard Adams methods, an extra history load term emerges and the associated weight coefficients are τ-dependent. However when τ = 1, the developed schemes reduce to the well-known A-B and A-M methods with standard coefficients. Hence, in terms of scientific computing, our approach constitutes a minimal modification of the existing Adams libraries. Next, we develop an implicit-explicit (IMEX) splitting scheme for linear and nonlinear fractional PDEs of a general advection-reaction-diffusion type, and we apply our scheme to the time-space fractional Keller-Segel chemotaxis system. In this context, we evaluate the nonlinear advection term explicitly, employing the fractional A-B method in the prediction step, and we treat the corresponding diffusion term implicitly in the correction step using the fractional A-M scheme. Moreover, we perform the corresponding spatial discretization by employing an efficient and spectrally-accurate fractional spectral collocation method. Our numerical experiments exhibit the efficiency of the proposed IMEX scheme in solving nonlinear fractional PDEs.

  10. Surface expression and limited proteolysis of ADAM10 are increased by a dominant negative inhibitor of dynamin

    Directory of Open Access Journals (Sweden)

    Slack Barbara E

    2011-05-01

    Full Text Available Abstract Background The amyloid precursor protein (APP is cleaved by β- and γ-secretases to generate toxic amyloid β (Aβ peptides. Alternatively, α-secretases cleave APP within the Aβ domain, precluding Aβ formation and releasing the soluble ectodomain, sAPPα. We previously showed that inhibition of the GTPase dynamin reduced APP internalization and increased release of sAPPα, apparently by prolonging the interaction between APP and α-secretases at the plasma membrane. This was accompanied by a reduction in Aβ generation. In the present study, we investigated whether surface expression of the α-secretase ADAM (a disintegrin and metalloprotease10 is also regulated by dynamin-dependent endocytosis. Results Transfection of human embryonic kidney (HEK cells stably expressing M3 muscarinic receptors with a dominant negative dynamin I mutant (dyn I K44A, increased surface expression of both immature, and mature, catalytically active forms of co-expressed ADAM10. Surface levels of ADAM10 were unaffected by activation of protein kinase C (PKC or M3 receptors, indicating that receptor-coupled shedding of the ADAM substrate APP is unlikely to be mediated by inhibition of ADAM10 endocytosis in this cell line. Dyn I K44A strongly increased the formation of a C-terminal fragment of ADAM10, consistent with earlier reports that the ADAM10 ectodomain is itself a target for sheddases. The abundance of this fragment was increased in the presence of a γ-secretase inhibitor, but was not affected by M3 receptor activation. The dynamin mutant did not affect the distribution of ADAM10 and its C-terminal fragment between raft and non-raft membrane compartments. Conclusions Surface expression and limited proteolysis of ADAM10 are regulated by dynamin-dependent endocytosis, but are unaffected by activation of signaling pathways that upregulate shedding of ADAM substrates such as APP. Modulation of ADAM10 internalization could affect cellular behavior in two

  11. ADAM17-mediated CD44 cleavage promotes orasphere formation or stemness and tumorigenesis in HNSCC

    International Nuclear Information System (INIS)

    CD44, an extracellular matrix (ECM) receptor, has been described as a cancer stem cell marker in multiple cancers, including head and neck squamous cell carcinoma (HNSCC). HNSCC orasphere formation or stemness was characterized by cleavage of CD44, and thus we hypothesized that this proteolytic processing may be critical to stemness and tumorigenesis. We tested this hypothesis by examining the mechanisms that regulate this process in vitro and in vivo, and by exploring its clinical relevance in human specimens. Sphere assays have been used to evaluate stemness in vitro. Spheres comprised of HNSCC cells or oraspheres and an oral cancer mouse model were used to examine the significance of CD44 cleavage using stable suppression and inhibition approaches. These mechanisms were also examined in HNSCC specimens. Oraspheres exhibited increased levels of CD44 cleavage compared to their adherent counterparts. Given that disintegrin and metalloproteinase domain-containing protein 17 (ADAM17) is a major matrix metalloproteinase known to cleave CD44, we chemically inhibited and stably suppressed ADAM17 expression in HNSCC cells and found that these treatments blocked CD44 cleavage and abrogated orasphere formation. Furthermore, stable suppression of ADAM17 in HNSCC cells also diminished tumorigenesis in an oral cancer mouse model. Consistently, stable suppression of CD44 in HNSCC cells abrogated orasphere formation and inhibited tumorigenesis in vivo. The clinical relevance of these findings was confirmed in matched primary and metastatic human HNSCC specimens, which exhibited increased levels of ADAM17 expression and concomitant CD44 cleavage compared to controls. CD44 cleavage by ADAM17 is critical to orasphere formation or stemness and HNSCC tumorigenesis

  12. MiR-153 inhibits migration and invasion of human non-small-cell lung cancer by targeting ADAM19

    International Nuclear Information System (INIS)

    Highlights: • Decreased miR-153 and up-regulated ADAM19 are correlated with NSCLC pathology. • MiR-153 inhibits the proliferation and migration and invasion of NSCLC cells in vitro. • ADAM19 is a direct target of miR-153. • ADAM19 is involved in miR-153-suppressed migration and invasion of NSCLC cells. - Abstract: MiR-153 was reported to be dysregulated in some human cancers. However, the function and mechanism of miR-153 in lung cancer cells remains unknown. In this study, we investigated the role of miR-153 in human non-small-cell lung cancer (NSCLC). Using qRT-PCR, we demonstrated that miR-153 was significantly decreased in clinical NSCLC tissues and cell lines, and downregulation of miR-153 was significantly correlated with lymph node status. We further found that ectopic expression of miR-153 significantly inhibited the proliferation and migration and invasion of NSCLC cells in vitro, suggesting that miR-153 may be a novel tumor suppressor in NSCLC. Further integrated analysis revealed that ADAM19 is as a direct and functional target of miR-153. Luciferase reporter assay demonstrated that miR-153 directly targeted 3′UTR of ADAM19, and correlation analysis revealed an inverse correlation between miR-153 and ADAM19 mRNA levels in clinical NSCLC tissues. Knockdown of ADAM19 inhibited migration and invasion of NSCLC cells which was similar with effects of overexpression of miR-153, while overexpression of ADAM19 attenuated the function of miR-153 in NSCLC cells. Taken together, our results highlight the significance of miR-153 and ADAM19 in the development and progression of NSCLC

  13. MiR-153 inhibits migration and invasion of human non-small-cell lung cancer by targeting ADAM19

    Energy Technology Data Exchange (ETDEWEB)

    Shan, Nianxi [Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008 (China); Institute of Medical Sciences, Xiangya Hospital, Central South University, Changsha, Hunan 410008 (China); Shen, Liangfang [Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008 (China); Wang, Jun; He, Dan [Institute of Medical Sciences, Xiangya Hospital, Central South University, Changsha, Hunan 410008 (China); Duan, Chaojun, E-mail: duancjxy@163.com [Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008 (China); Institute of Medical Sciences, Xiangya Hospital, Central South University, Changsha, Hunan 410008 (China)

    2015-01-02

    Highlights: • Decreased miR-153 and up-regulated ADAM19 are correlated with NSCLC pathology. • MiR-153 inhibits the proliferation and migration and invasion of NSCLC cells in vitro. • ADAM19 is a direct target of miR-153. • ADAM19 is involved in miR-153-suppressed migration and invasion of NSCLC cells. - Abstract: MiR-153 was reported to be dysregulated in some human cancers. However, the function and mechanism of miR-153 in lung cancer cells remains unknown. In this study, we investigated the role of miR-153 in human non-small-cell lung cancer (NSCLC). Using qRT-PCR, we demonstrated that miR-153 was significantly decreased in clinical NSCLC tissues and cell lines, and downregulation of miR-153 was significantly correlated with lymph node status. We further found that ectopic expression of miR-153 significantly inhibited the proliferation and migration and invasion of NSCLC cells in vitro, suggesting that miR-153 may be a novel tumor suppressor in NSCLC. Further integrated analysis revealed that ADAM19 is as a direct and functional target of miR-153. Luciferase reporter assay demonstrated that miR-153 directly targeted 3′UTR of ADAM19, and correlation analysis revealed an inverse correlation between miR-153 and ADAM19 mRNA levels in clinical NSCLC tissues. Knockdown of ADAM19 inhibited migration and invasion of NSCLC cells which was similar with effects of overexpression of miR-153, while overexpression of ADAM19 attenuated the function of miR-153 in NSCLC cells. Taken together, our results highlight the significance of miR-153 and ADAM19 in the development and progression of NSCLC.

  14. Extraction and Separation Modeling of Orion Test Vehicles with ADAMS Simulation

    Science.gov (United States)

    Fraire, Usbaldo, Jr.; Anderson, Keith; Cuthbert, Peter A.

    2013-01-01

    The Capsule Parachute Assembly System (CPAS) project has increased efforts to demonstrate the performance of fully integrated parachute systems at both higher dynamic pressures and in the presence of wake fields using a Parachute Compartment Drop Test Vehicle (PCDTV) and a Parachute Test Vehicle (PTV), respectively. Modeling the extraction and separation events has proven challenging and an understanding of the physics is required to reduce the risk of separation malfunctions. The need for extraction and separation modeling is critical to a successful CPAS test campaign. Current PTV-alone simulations, such as Decelerator System Simulation (DSS), require accurate initial conditions (ICs) drawn from a separation model. Automatic Dynamic Analysis of Mechanical Systems (ADAMS), a Commercial off the Shelf (COTS) tool, was employed to provide insight into the multi-body six degree of freedom (DOF) interaction between parachute test hardware and external and internal forces. Components of the model include a composite extraction parachute, primary vehicle (PTV or PCDTV), platform cradle, a release mechanism, aircraft ramp, and a programmer parachute with attach points. Independent aerodynamic forces were applied to the mated test vehicle/platform cradle and the separated test vehicle and platform cradle. The aero coefficients were determined from real time lookup tables which were functions of both angle of attack ( ) and sideslip ( ). The atmospheric properties were also determined from a real time lookup table characteristic of the Yuma Proving Grounds (YPG) atmosphere relative to the planned test month. Representative geometries were constructed in ADAMS with measured mass properties generated for each independent vehicle. Derived smart separation parameters were included in ADAMS as sensors with defined pitch and pitch rate criteria used to refine inputs to analogous avionics systems for optimal separation conditions. Key design variables were dispersed in a Monte

  15. 利用分化的SH-SY5Y细胞观察加兰他敏对ADAM10和ADAM17表达的影响%Effects of galantamine on ADAM10 and ADAM17 expression in differentiated human neuroblastoma SH-SY5Y cells

    Institute of Scientific and Technical Information of China (English)

    张慧芳; 李倩倩; 赵兴鹃; 董妍; 张艳

    2012-01-01

    Objective To investigate the effect of galantamine (acetylcholinesterase inhibitor) on a disintegrin and metalloproteinase 10 (ADAM10) and ADAM17 expression and soluble amyloid precursor protein a (sAPPct) release; and to explore the possible mechanism of amyloid precursor protein (APP) metabolic pathway intervened by galantamine. Methods Differentiated human neuroblastoma cell line (SH-SY5Y) was induced by 10 μmol/L all trans-retinoic acid. The SH-SY5Y cells were maintained in serum-free medium for 2 h, and then treated with galantamine (0. 3 μmol/L, 0. 9 μmol/L, or 10 μmol/L) for 18 h. The expression of APP, ADAM10, ADAM17 and sAPPa was determined by Western blot. Results The 80-kDa band expression level of ADAM17 in the galantamine-treated group (10 μmol/L) was 2. 0670 + 0. 0903, which was higher than that in the control group (1. 0000 + 0. 0864, P0. 05). Conclusions Galantamine could significantly increase ADAM17 expression, and could promote the generation of sAPPa in the APP metabolism.%目的 观察经胆碱酯酶抑制剂加兰他敏处理的人神经母细胞瘤细胞(SH-SY5Y细胞)中解整合素样金属蛋白酶(ADAM) 10和ADAM17以及可溶性淀粉样前体蛋白α(sAPPα)表达,探讨加兰他敏干预淀粉样前体蛋白( APP)代谢途径的可能机制.方法 SH-SY5Y细胞经全反式维甲酸诱导分化后,分别在含0.3、0.9或10 μmol/L加兰他敏的无血清培养基中培养18 h.以Western blot方法检测细胞内APP、ADAM10、ADAM17和sAPPα水平.结果 10 μmol/L加兰他敏组ADAM17蛋白相对分子质量(Mr) 80 000条带表达量(2.0670±0.0903)高于对照组(1.0000±0.0864,P<0.01),亦高于0.3、0.9 μmol/L加兰他敏组(分别为1.4422±0.0374、1.8592±0.1018,均P<0.05);ADAM17蛋白Mr 130 000条带表达量(1.5938±0.0476)高于对照组、0.3和0.9 μmol/L加兰他敏组(分别为1.0000±0.0523、1.2533±0.0658、1.4724±0.0576,均P<0.05).与对照组(1.0000±0.0603)比较,0.3、0.9和10 μmol/L加兰他敏组s

  16. A disintegrin and metalloproteinase 12 (ADAM12) localizes to invasive trophoblast, promotes cell invasion and directs column outgrowth in early placental development.

    Science.gov (United States)

    Aghababaei, M; Perdu, S; Irvine, K; Beristain, A G

    2014-03-01

    During pregnancy, stromal- and vascular-remodeling trophoblasts serve critical roles in directing placental development acquiring pro-invasive characteristics. The A Disintegrin and Metalloproteinase (ADAM) family of multifunctional proteins direct cellular processes across multiple organ systems via their intrinsic catalytic, cell adhesive and intracellular signaling properties. ADAM12, existing as two distinct splice variants (ADAM12L and ADAM12S), is highly expressed in the human placenta and promotes cell migration and invasion in several tumor cell lines; however, its role in trophoblast biology is unknown. In this study, ADAM12 was localized to anchoring trophoblast columns in first trimester placentas and to highly invasive extracellular matrix-degrading trophoblasts in placental villous explants. The importance of ADAM12 in directing trophoblast invasion was tested using loss-of and gain-of-function strategies, where siRNA-directed knockdown of ADAM12 inhibited trophoblast cell invasion while over-expression promoted migration and invasion in two trophoblastic cell models. In placental villous explant cultures, siRNA-directed loss of ADAM12 significantly dampened trophoblast column outgrowth. Additionally, we provide functional evidence for the ADAM12S variant in promoting trophoblast invasion and column outgrowth through a mechanism requiring its catalytic activity. This is the first study to assign a function for ADAM12 in trophoblast biology, where ADAM12 may play a central role regulating the behavior of invasive trophoblast subsets in early pregnancy. This study also underlines the importance of ADAM12L and ADAM12S in directing cell motility in normal developmental processes outside of cancer, specifically highlighting a potentially important function of ADAM12S in directing early placental development. PMID:24243624

  17. O mercado como ordem social em Adam Smith, Walras e Hayek The market as a social order in Adam Smith , Walras and Hayek

    Directory of Open Access Journals (Sweden)

    Angela Ganem

    2012-04-01

    Full Text Available O objetivo do artigo é apresentar criticamente as teorias do mercado de Adam Smith, Leon Walras e F. A. Hayek, sublinhando o que se considera terem em comum, ou seja, a ideia de mercado como expressão da ordem social capitalista. Entende-se que esta concepção do mercado como ordem social aparece originariamente na história do pensamento econômico e na história das ideias através da solução de Adam Smith frente aos filósofos do contrato e avança, analiticamente, um século após, na tentativa de demonstração lógico-matemática da Teoria do Equilíbrio Geral em Walras para adquirir a souplesse teórica necessária a sua sobrevivência, no século XX, na teoria de Hayek, em que a história realizaria o autodesenvolvimento da ordem do mercado. O texto percorre as filiações filosóficas e as implicações metodológicas das teorias do mercado desses grandes autores, mostrando as formas diferenciadas que elas assumem: ordem natural para Smith, ordem racional para Walras e ordem espontânea para Hayek.The objective of the article is to critically present the liberal theories of Adam Smith, Leon Walras and F. A. Hayek, underlining what they have in common, that is, the idea of market as a general theory of society and the construction of scientific attributes that make possible the understanding of the supremacy of market order against other forms of social organization. It is assumed that this conception of market as social order appears originally in the history of economical thought and in the history of ideas through Adam Smith's solution against contract philosophers and that it advances analytically, a century later, in the attempt of logic-mathematic demonstration in Walras, to acquire the necessary theoretical souplesse for its survival, in the XX century, in the Darwinian adventures of the Austrian school libertarians, specially Hayek, for whom history would realize the self-development of the market. The text will traverse the

  18. Record of Decision for the Rocky Mountain Arsenal On-Post Operable Unit in southern Adams County, Commerce City, Colorado.

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — This Record of Decision (ROD) presents the selected remedial action for the Rocky Mountain Arsenal (RMA) On-Post Operable Unit in southern Adams County (east of...

  19. Adam Smith ja tema "nähtamatu käsi" / Arno Köörna

    Index Scriptorium Estoniae

    Köörna, Arno

    2004-01-01

    Majandusliku ja sotsiaalse efektiivsuse optimaalsest vahekorrast. Inglise majandusteoreetiku, liberaalse turumajandusteooria klassikalise esindaja Adam Smithi (1723-1790) põhiteosest "Uurimus rahvaste rikkuse olemusest ja põhjustest". "Inimnäolise" kapitalismi võimalikkusest Eestis

  20. Cardboard Boxes and Invisible Fences: Homelessness and Public Space in City of Victoria v. Adams

    Directory of Open Access Journals (Sweden)

    Sarah Buhler

    2016-01-01

    Full Text Available This paper analyzes the recent decision of the British Columbia Supreme Court in City of Victoria v. Adams. Specifically, the paper considers three interlocking themes that emerge from the decision: (1 the nature of “public space” in the context of homelessness; (2 the autonomy of homeless individuals; and (3 the meaning and value of the “homeless body.” With reference to each theme, the paper explores how the judgment in Adams grapples with the purportedly normative “Law and Economics”- type arguments put forth by the City of Victoria. By drawing on insights from Critical Legal Studies theory and feminist jurisprudence, the paper shows that Adams subverts and destabilizes certain “normative” perspectives about public space and homelessness. However, the paper goes on to argue that in its conflation of “cardboard box” shelters with the “invisible fences” envisioned by Justice Wilson in Morgentaler, Adams presents an ambiguous victory for anti-poverty advocates. The paper argues that the decision may serve to increase barriers for a broader and more progressive understanding of section 7 in the future. Dans cet article, on analyse le jugement récent de la Cour Suprême de la Colombie Britannique dans City of Victoria v. Adams. Plus précisément, on considère trois thèmes qui ressortent du jugement et qui s’entrecroisent : (1 la nature d’«espace public» dans le contexte de l’itinérance; (2 l’autonomie des sans-abri; et (3 la signification et la valeur du «corps sans abri». En rapport avec chaque thème, on explore comment l’arrêt Adams compose avec les arguments supposément normatifs du genre «La Loi et l’Économie» avancés par la ville de Victoria. En s’inspirant de perceptions tirées de la théorie des Critical Legal Studies et de la jurisprudence féministe, l’auteure démontre que l’arrêt Adams subvertit et déséquilibre certaines perspectives «normatives» au sujet de l

  1. Stabilized Adams type method with a block extension for the valuation of options

    Directory of Open Access Journals (Sweden)

    Samuel N. Jator

    2013-10-01

    Full Text Available We construct a continuous stabilized Adams type method (CSAM that is defined for all values of the independent variable on the range of interest. This continuous scheme has the ability to provide a continuous solution between all the grid points with a uniform accuracy comparable to that obtained at the grid points. Hence, discrete schemes which are recovered from the CSAM as by-products are combined to form a stabilized block Adams type method (SBAM. The SBAM is then extended on the entire interval and applied as a single block matrix equation for the valuation of options on a non-dividend-paying stock by solving a system resulting from the semi-discretization of the Black-Scholes model. The stability of the SBAM is discussed and the convergence of the block extension of the SBAM is given. A numerical example is given to show the accuracy of the method.

  2. Simulation Analysis Module of High-speed Rail Bearings Based on Secondary Development in ADAMS

    Institute of Scientific and Technical Information of China (English)

    ZHANG Li; YE Jun; XU Juan; LUO Yi-chao

    2013-01-01

    This paper develops a strong secondary development based on ADAMS feature which creates high-speed rail bearings for simulation analysis module. This thesis is in the case of non-circular pattern instructions of how to achieve rapid roller modeling, with analysis of functions and parameters required for the design of the simulation module of the high-speed rail bearing , as well as the design of dialog boxes, the environment and file structure. The specific modules is based on the secondary development language provided by ADAMS/View. Through the menus, dialog boxes which input parameters, it can achieve high iron bearing automatic modeling, dynamic analysis and post-processing to simplify the analysis of high-speed rail bearing operations, as well as improving the high-speed rail bearing development efficiency.

  3. XOPÓS = Chorós : the dance of Adam

    DEFF Research Database (Denmark)

    Isar, Nicoletta

    space. Byzantine chorography is the inscription of sacred space ¿¿¿a by the mystical dance,¿¿¿¿¿. Chorography is intimately associated with Hierotopy in spirit and vocation, for both aim to contribute to uncovering the apparatus and the process, by which sacred space was created in Byzantium. The...... is contained in the very title of the book: “the Dance of Adam.” This dance alone gives ontological meaning to the Byzantine subject, to the whole Byzantine ¿¿¿¿¿¿¿a. In this choral equation, Adam stands for the humanity all-embracing. The book reads ¿¿¿¿¿ from an interdisciplinary perspective...

  4. Association of ADAM33 gene polymorphisms with adult allergic asthma and rhinitis in a Chinese Han population

    OpenAIRE

    Jin Lianhong; Lü Fuzhen; Sui Hong; Zhang Ximei; Su Dongju; Zhang Jing

    2008-01-01

    Abstract Background Rhinitis and asthma are very common diseases involving genetic and environmental factors. Most patients with asthma also have rhinitis, which suggests the concept of 'one airway, one disease.' A disintegrin and metalloproteinase 33 (ADAM33) is the first asthma-susceptible gene to be discovered by positional cloning. To evaluate the potential influence of ADAM33 gene polymorphisms on allergic rhinitis (AR) and allergic asthma (AS), a case-control study was conducted on the ...

  5. Mass spectrometry reveals thioredoxin-1 as a new partner of ADAM17 that can modulate its sheddase activity

    Energy Technology Data Exchange (ETDEWEB)

    Aragao, A.Z.B.; Simabuco, F.M.; Smetana, J.H.C. [Laboratorio Nacional de Biociencias - LNBIO, Campinas, SP (Brazil); Yokoo, S.; Paes Leme, A.F. [Laboratorio Nacional de Luz Sincrotron (LNLS), Campinas, SP (Brazil); Rodrigues, E.; Mercadante, A.Z. [Universidade Estadual de Campinas (UNICAMP), SP (Brazil)

    2012-07-01

    Full text: ADAMs are a family of membrane-associated metalloproteinases with a complex multi-domain structure: a metalloproteinase domain, a disintegrin domain, a cysteine-rich region, an epidermal growth factor-like repeat, a transmembrane domain and a cytoplasmic tail. These proteases are responsible for shedding the ectodomains of cell surface proteins, modulating regulatory mechanisms. Many ADAMs are highly associated with tumorigenesis and tumor progression. The aim of this study is identify novel binding partners that can modulate ADAM17 activation via cytoplasmatic domain. We performed the cloning and overexpression of the ADAM17 cytoplasmic tail in HEK-293 cell line and the ligands were determined by LC-MS/MS after proteins immunoprecipitation (IP) with anti-FLAG M2 Affinity Gel (Sigma). Thioredoxin-1 (Trx-1) and others ligands were identified at least in two independent experiments, and this binding is independent of phosphorylation. The IP of Trx-1 was confirmed by Western blot, furthermore Trx-1 immunolocalized with full length ADAM17-HA and cytoplasmic tail-FLAG recombinant proteins in HEK293 and HeLa cells. Trx-1 is part of the system peroxiredoxin/thioredoxin/thioredoxin reductase, one of the mechanisms by which cells maintain the reduced cellular environment, inactivating the reactive oxygen species (ROS). We investigate whether ADAM17 activity is modulate by Trx-1 on AP reporter assay that was performed using HEK293 and SCC-9 cells transfected stably with HB-EGF-AP in co-transfection with transient recombinant Trx-1-HA. The results indicate that Trx-1 can modulate negatively the activity or maturation of ADAM17 in presence of PMA, which is known to increase ROS. In summary, this study identifies Trx-1 and suggest that this protein can modulate ADAM17 activity in normal and tumorigenic cells lines. (author)

  6. Mass spectrometry reveals thioredoxin-1 as a new partner of ADAM17 that can modulate its sheddase activity

    International Nuclear Information System (INIS)

    Full text: ADAMs are a family of membrane-associated metalloproteinases with a complex multi-domain structure: a metalloproteinase domain, a disintegrin domain, a cysteine-rich region, an epidermal growth factor-like repeat, a transmembrane domain and a cytoplasmic tail. These proteases are responsible for shedding the ectodomains of cell surface proteins, modulating regulatory mechanisms. Many ADAMs are highly associated with tumorigenesis and tumor progression. The aim of this study is identify novel binding partners that can modulate ADAM17 activation via cytoplasmatic domain. We performed the cloning and overexpression of the ADAM17 cytoplasmic tail in HEK-293 cell line and the ligands were determined by LC-MS/MS after proteins immunoprecipitation (IP) with anti-FLAG M2 Affinity Gel (Sigma). Thioredoxin-1 (Trx-1) and others ligands were identified at least in two independent experiments, and this binding is independent of phosphorylation. The IP of Trx-1 was confirmed by Western blot, furthermore Trx-1 immunolocalized with full length ADAM17-HA and cytoplasmic tail-FLAG recombinant proteins in HEK293 and HeLa cells. Trx-1 is part of the system peroxiredoxin/thioredoxin/thioredoxin reductase, one of the mechanisms by which cells maintain the reduced cellular environment, inactivating the reactive oxygen species (ROS). We investigate whether ADAM17 activity is modulate by Trx-1 on AP reporter assay that was performed using HEK293 and SCC-9 cells transfected stably with HB-EGF-AP in co-transfection with transient recombinant Trx-1-HA. The results indicate that Trx-1 can modulate negatively the activity or maturation of ADAM17 in presence of PMA, which is known to increase ROS. In summary, this study identifies Trx-1 and suggest that this protein can modulate ADAM17 activity in normal and tumorigenic cells lines. (author)

  7. 基于 ADAMS 的曲柄滑块机构运动仿真研究%Motion Simulation of Slider Crank Based on ADAMS

    Institute of Scientific and Technical Information of China (English)

    何毅斌; 胡荣博; 刘慧; 杨兵宽; 张雨

    2014-01-01

    应用 ADAMS 软件建立曲柄滑块机构的虚拟样机,对曲柄滑块中做往复运动的滑块进行运动学分析。运动仿真表明,曲柄转速一定,曲柄大小的改变对滑块的速度和加速度有较显著影响,对连杆影响较小;此外,滑块加速度在近半个运动周期时间内基本保持稳定。这些结果对以曲柄滑块机构为原型的设备设计开发具有参考价值。%The ADAMS software was applied to establish the virtual prototype of crank slider mechanism, and the slider of crank slider to do reciprocating motion kinematics analysis was carried out.The motion simulation shows that,under the rotational speed of the crank,the change of the lider crank size had a sig-nificant effect on its velocity and acceleration and the linkage effects is small;in addition,the slider accel-eration in half a cycle time maintained the basic stability.These results are helpful f for the design and de-velopment of the devices using the crank slider mechanism as the prototype.

  8. Karakteristik Retinopati Hipertensi Di RSUP Haji Adam Malik Medan Periode Januari-Desember 2012

    OpenAIRE

    Yumardika, Deza

    2016-01-01

    Hypertension is a disease that has a relatively high morbidity worldwide, including Indonesia.Hipertensi influence retinal vascularization changes, which can result in hypertension retinopathy. The purpose of this study to investigate the characteristics of hypertensive retinopathy in Adam Malik Medan hospital period January to December 2012. This study is a retrospective descriptive study nature. Data obtained from the medical records of patients with hypertensive retinopathy who went to ...

  9. Nonadiabatic squeezed-photon generation by a Fourier-modified Janszky–Adam scheme

    Energy Technology Data Exchange (ETDEWEB)

    Matsuo, Shigemasa [Graduate School of Integrated Arts and Sciences, Hiroshima University, Higashi-Hiroshima 739-8521 (Japan); Fujii, Toshiyuki [Department of Physics, Asahikawa Medical University, Midorigaoka-higashi, Asahikawa 078-8510 (Japan); Research Institute for Science and Engineering, Waseda University, Shinjuku-ku, Tokyo 169-8555 (Japan); Hatakenaka, Noriyuki, E-mail: noriyuki@hiroshima-u.ac.jp [Graduate School of Integrated Arts and Sciences, Hiroshima University, Higashi-Hiroshima 739-8521 (Japan)

    2015-07-15

    We propose a Fourier-modified Janszky–Adam scheme for the efficient nonadiabatic generation of squeezed photons in a harmonic oscillator with a time-dependent frequency. The higher-order Fourier components of frequency modulations introduce steep frequency changes in the time required for nonadiabatic quantum processes. The proposed Fourier scheme significantly improves the degree of squeezing compared with conventional sinusoidal frequency modulations.

  10. Faktor Risiko Kanker Rongga Mulut di Divisi Bedah Onkologi RSUP Haji Adam Malik Medan

    OpenAIRE

    Fahrunnisa’, Mutia Fri

    2015-01-01

    There is increasing trend in oral cancer incidence each year. This cancer is caused by many factors. One main factor is the habit of chewing betel in Batak society which is still exists today. The purpose of this study was to determine the risk factors, such as smoking, chewing tobacco, chewing betel, and alcohol consumption in patients with oral cancer in RSUP H. Adam Malik Medan. This study was descriptive with cross-sectional approach. The samples were taken by total sampling met...

  11. orignal paper: Beyond natural selection and divine intervention: The Lamarckian implication of Adam Smith's invisible hand

    OpenAIRE

    Khalil, Elias L.

    2000-01-01

    Adam Smith's invisible hand metaphor (IH) is examined in light of two different accounts of the origin of traits: Charles Darwin's theory of evolutionary optimization and William Paley's theory of divine intervention. Smith's stand supersedes both accounts. For Smith, intermediating drives, such as the sexual one, neither arise accidentally and favored according to their fitness , la Darwin nor planted by the Deity , la Paley. For Smith, such drives are adopted in light of their ultimate end....

  12. Pola Resistensi Primer Pada Penderita Tb Paru Kategori I Di RSUP H. Adam Malik, Medan

    OpenAIRE

    Sihombing, Hendra

    2012-01-01

    Backgrounds : The resistance case is a problem for TB prevention and eradication program of the world. Primary resistance cases that was founded in TB patients are often used to evaluate new transmission or infection resistant strains of bacteria. Therefore, it is important to investigate how much the rate and the pattern of primary resistance. Objective : To evaluation the proportion of primary resistance incidence in category I of pulmonary TB patients in H. Adam Malik Hosp...

  13. Pengetahuan Orangtua Pasien Poliklinik Anak RSU H. Adam Malik, Medan, Tentang Helioterapi.

    OpenAIRE

    Pathmanathan, Hemalatha

    2012-01-01

    For centuries, sunlight has been used for therapeutic purposes. Parents still sun their infants to treat neonatal jaundice, nappy rash or mostly to supply vitamin D for bone development as a consequence of health beliefs. This study was aimed to assess knowledge of parents attending to the Peadiatric Clinic of RSU H. Adam Malik, Medan, for their children's health care, about heliotherapy. This is a descriptive study using cross sectional method. The data was obtained by usin...

  14. Program for the evaluation of TL-brick dating: 'ADAM-1-EVA'

    International Nuclear Information System (INIS)

    Although the evaluation of the TL-mean date has presented very little diversity since first published, the error evaluation has prompted a lot of discussion. Particularly the physical, chemical, statistical and mathematical differences as reflected in the specifics of the evaluation of the individual random and systematic errors in ceramic and brick dating are undervalued in literature. The construction of an automated TL-Reader (ADAM-1) at the Czech Technical University in Prague was taken as an opportunity to create a whole new software package for the evaluation ('EVA') of TL-dates. ADAM-1 is designed primarily for brick dating, using the fine-grain technique. The philosophy of data processing is similar to that applied by the Berlin group in their research of Venetian Villas. The program was developed using Delphi, as it is user-friendlier than pure Pascal, offers a strong graphic platform and allows flexibility in data management. This was important, as the program was conceived to either interact directly with ADAM-1, or to be operated independently for data evaluation and management. The software package consists of two discrete yet combinable components: one for the calculation of the TL mean date, using all raw data obtained from ADAM-1 and peripheral measurements; the other for the evaluation of systematic, random and context errors of individual samples and sample groups. All steps in the calculations are also graphically available, e.g. glow curves, plateau test, TL vs. dose dependence and charts summarising the results of all calculations for an individual sample and a given context. (author)

  15. Differences in the Diunral and Nocturnal Defense Mechanisms of Octopus Bocki (Adams, 1941)

    OpenAIRE

    Valencia, Natalie

    2006-01-01

    Octopuses are known for the advanced behaviors and elaborate displays used in predator avoidance. Although studies have provided anecdotal evidence on the defense mechanisms of these animals, whether these behaviors vary under light and dark conditions is unknown. This study investigated the diurnal and nocturnal predator defense mechanism s of Octopus bocki (Adams, 1941) in Moorea, French Polynesia. Seven behaviors were identified as primary defense mechanisms for protection from fish predat...

  16. Adams Oliver syndrome: Description of a new phenotype with cerebellar abnormalities in a family

    International Nuclear Information System (INIS)

    To describe cerebellar abnormalities in a family composed by a father and two affected sibs with Adams Oliver syndrome (AOS) (OMIM 100300). Brain MRI and MR angiography were performed at 1.5T. The siblings presented cerebellar cortex dysplasia characterized by the presence of cysts. Abnormalities of CNS are an unusual manifestation of AOS. To our knowledge, this is the first report of cerebellar cortical dysplasia in a family with AOS

  17. Comparison of manual and automated quantification methods of {sup 123}I-ADAM

    Energy Technology Data Exchange (ETDEWEB)

    Kauppinen, T. [Helsinki Univ. Central Hospital (Finland). HUS Helsinki Medical Imaging Center; Helsinki Univ. Central Hospital (Finland). Division of Nuclear Medicine; Koskela, A.; Ahonen, A. [Helsinki Univ. Central Hospital (Finland). Division of Nuclear Medicine; Diemling, M. [Hermes Medical Solutions, Stockholm (Sweden); Keski-Rahkonen, A.; Sihvola, E. [Helsinki Univ. (Finland). Dept. of Public Health; Helsinki Univ. Central Hospital (Finland). Dept. of Psychiatry

    2005-07-01

    {sup 123}I-ADAM is a novel radioligand for imaging of the brain serotonin transporters (SERTs). Traditionally, the analysis of brain receptor studies has been based on observer-dependent manual region of interest definitions and visual interpretation. Our aim was to create a template for automated image registrations and volume of interest (VOI) quantification and to show that an automated quantification method of {sup 123}I-ADAM is more repeatable than the manual method. Patients, methods: A template and a predefined VOI map was created from {sup 123}I-ADAM scans done for healthy volunteers (n=15). Scans of another group of healthy persons (HS, n=12) and patients with bulimia nervosa (BN, n=10) were automatically fitted to the template and specific binding ratios (SBRs) were calculated by using the VOI map. Manual VOI definitions were done for the HS and BN groups by both one and two observers. The repeatability of the automated method was evaluated by using the BN group. Results: For the manual method, the interobserver coefficient of repeatability was 0.61 for the HS group and 1.00 for the BN group. The intra-observer coefficient of repeatability for the BN group was 0.70. For the automated method, the coefficient of repeatability was 0.13 for SBRs in midbrain. Conclusion: An automated quantification gives valuable information in addition to visual interpretation decreasing also the total image handling time and giving clear advantages for research work. An automated method for analysing {sup 123}I-ADAM binding to the brain SERT gives repeatable results for fitting the studies to the template and for calculating SBRs, and could therefore replace manual methods. (orig.)

  18. Evaluasi Determinan Kematian Maternal Di RSUP.H. Adam Malik Medan Tahun 2010-2012

    OpenAIRE

    Sembiring, Morel

    2016-01-01

    Background: Number of maternal death is one of the indicator to evaluate the degree of female health. According to data from WHO 99% of maternal death due to problems in labor or birth happens in developing countries. Objective: To determine causes of maternal death that happened in Adam Malik General Hospital according to factors that cover far determinant, inter determinants, result determinants as risk factors causing maternal death. Method: This is a retrospective analytical resea...

  19. El sujeto económico y la racionalidad en Adam Smith

    OpenAIRE

    Vanesa Valeria D’Elia

    2009-01-01

    The assumption of rationality is central in current economic theory. This hypothesis is the pillar for the creation of the homo economicus of conventional theory. Starting with Adam Smith’s approach to rationality, the aim of this paper is to contribute to the discussion of the main characteristics of the individual underlying the rational man of economics and their implications for economic analysis. The meaning of rationality in several authors is reexamined and it is argued that the basis ...

  20. Parallel Journeys: Adam Smith and Milton Friedman on the Regulation of Banking

    OpenAIRE

    Rockoff, Hugh

    2010-01-01

    Adam Smith and Milton Friedman are famous for championing Laissez Faire, yet both supported government regulation of the banking system. In both cases their deviation from free market orthodoxy was based on a careful reading of financial history: especially Smith's reading of the Crisis of 1772 and Friedman's reading of the Crisis of 1929-33. In both cases they based their reading on a complex and nuanced account of human nature. This paper describes their parallel journeys to the conclusion ...

  1. For a Sustainable Agriculture, We Need More Adam Smith, Not Less

    OpenAIRE

    James, Harvey S., Jr.

    2005-01-01

    There are two competing approaches sustainability in agriculture. One stresses a strict economic approach in which market forces should be allowed to guide the activities of agricultural producers. The other advocates the need to balance economic with environmental and social objectives, even to the point of reducing profitability. This paper shows how the writings of the 18th century moral philosopher Adam Smith could bridge the debate. First, he is recognized by those advocating the economi...

  2. ADAM10/17-Dependent Release of Soluble c-Met Correlates with Hepatocellular Damage

    Czech Academy of Sciences Publication Activity Database

    Chalupský, Karel; Kanchev, Ivan; Žbodáková, Olga; Buryová, Halka; Jiroušková, Markéta; Kořínek, Vladimír; Gregor, Martin; Sedláček, Radislav

    2013-01-01

    Roč. 59, č. 2 (2013), s. 76-78. ISSN 0015-5500 R&D Projects: GA ČR GAP305/10/2143; GA ČR GAP303/10/2044; GA AV ČR IAA500520812 Institutional support: RVO:68378050 Keywords : c-Met * HGF * shedding * ADAM metalloproteinase * liver Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 0.778, year: 2013

  3. Liver protective effect of ursodeoxycholic acid includes regulation of ADAM17 activity

    Czech Academy of Sciences Publication Activity Database

    Buryová, Halka; Chalupský, Karel; Žbodáková, Olga; Kanchev, Ivan; Jiroušková, Markéta; Gregor, Martin; Sedláček, Radislav

    2013-01-01

    Roč. 13, 30.10.2013 (2013), s. 155-155. ISSN 1471-230X R&D Projects: GA ČR GAP305/10/2143; GA ČR GAP303/10/2044; GA AV ČR IAA500520812; GA MŠk ED1.1.00/02.0109 Institutional support: RVO:68378050 Keywords : ursodeoxycholic acid * ADAM17 * shedding * cholestasis * liver Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.113, year: 2013

  4. Hubungan Derajat Hipertensi Dengan Kolesterol Pada Pasien Hipertensi di RSUP Adam Malik Pada Tahun 2010

    OpenAIRE

    Shakir Ariff Bin Zulkifli

    2012-01-01

    BACKGROUND: Hypertension is a disorder of the arteries that causes lack of supply oxygen and nutrients carried by blood to the body tissues. One risk factor for the occurrence of hypertension is high blood cholesterol levels. This study was conducted to see the relationship between cholesterol and the degree of hypertension, in patients from Rumah Sakit Umum Pusat Haji Adam Malik during the year of 2010. METHODOLOGY: This study is a type of analytical study to analyze the relationship betw...

  5. Hubungan Penderita Diabetes Melitus Tipe-2 Dengan Terjadinya Gangguan Pendengaran Di RSUP. H. Adam Malik Medan

    OpenAIRE

    Yarisman, Lilia

    2014-01-01

    Introduction: Microangiopathy and neuropathy is either a complication of diabetes mellitus that can occur in the inner ear and result in hearing impairment. Microangiopathy in organ of Cortiis able to cause atrophy and loss of hair cells in the cochlea, neuropathy is caused by microangiopathy that eventually result in hearing impairment. Objective: To determine whether there is a relationship between Type-2 Diabetes Mellitus andthe incidence of hearing impairment in Haji Adam Malik General...

  6. Comparison of manual and automated quantification methods of 123I-ADAM

    International Nuclear Information System (INIS)

    123I-ADAM is a novel radioligand for imaging of the brain serotonin transporters (SERTs). Traditionally, the analysis of brain receptor studies has been based on observer-dependent manual region of interest definitions and visual interpretation. Our aim was to create a template for automated image registrations and volume of interest (VOI) quantification and to show that an automated quantification method of 123I-ADAM is more repeatable than the manual method. Patients, methods: A template and a predefined VOI map was created from 123I-ADAM scans done for healthy volunteers (n=15). Scans of another group of healthy persons (HS, n=12) and patients with bulimia nervosa (BN, n=10) were automatically fitted to the template and specific binding ratios (SBRs) were calculated by using the VOI map. Manual VOI definitions were done for the HS and BN groups by both one and two observers. The repeatability of the automated method was evaluated by using the BN group. Results: For the manual method, the interobserver coefficient of repeatability was 0.61 for the HS group and 1.00 for the BN group. The intra-observer coefficient of repeatability for the BN group was 0.70. For the automated method, the coefficient of repeatability was 0.13 for SBRs in midbrain. Conclusion: An automated quantification gives valuable information in addition to visual interpretation decreasing also the total image handling time and giving clear advantages for research work. An automated method for analysing 123I-ADAM binding to the brain SERT gives repeatable results for fitting the studies to the template and for calculating SBRs, and could therefore replace manual methods. (orig.)

  7. Justice as a Virtue – Justice as a Principle in Adam Smith's Thought

    OpenAIRE

    Vivenza, G. (Gloria)

    2010-01-01

    The paper deals with the character of justice in Adam Smith's thought. Justice is considered both as a virtue, different from all other virtues for its enforceability; and as a principle on which all the systems of law should be grounded. Smith could not achieve his project of writing a theory of jurisprudence, but some parts of his thought have been analyzed under different points of view: the political "paradigms" of civic humanism and natural law; the dilemma about property, whether it exi...

  8. Hubungan Beratnya Pekerjaan dengan Kejadian Hernia Nukleus Pulposus di RSUP. H. Adam Malik pada Tahun 2014

    OpenAIRE

    Ciatawi, Thamrin

    2016-01-01

    Hernia nucleus pulposus (HNP) or herniation of intervertebral disc is a state which the protrusion of intervertebral discs suppress the spinal cord and resulting the symptoms of pain and limitation of daily activities. One of the risk factor of herniated disc is the occupation. Therefore, this study was designed to examine the relationship of occupation with the incidence of herniated invertebral disc in RSUP H. Adam Malik Medan in 2014. The method used in this study is descriptive based s...

  9. The Risk of Decubitus on Hospitalized Patients in General Hospital of Haji Adam Malik Medan

    OpenAIRE

    Samsinar

    2014-01-01

    The risk of decubitus on hospitalized patients Decubitus risk in patients varies. Elderly patients with total care and partial care in hospitals a chance to suffer from decubitus. This research aims to know the risks in patients treated decubitus in General Hospital of Haji Adam Malik Medan. This research uses descriptive design with the total sample obtained 48 respondents. Samples were taken using the technique of total sampling. Data collection is done using the research instrument consist...

  10. Profil Penderita Karsinoma Kolorektal Di RSUP H. Adam Malik Medan Pada Tahun 2009-2012

    OpenAIRE

    Lubis, Nelfi Disya Amalia

    2014-01-01

    Colorectal carcinoma ranks as the third most common cancer worldwide after lung cancer and breast cancer. Colorectal carcinoma is closely related to sociocultural factors and poor lifestyle, such as obesity, lack of physical activity, and habits of eating processed foods. The aim of this research was to determine the characteristics of patients with colorectal carcinoma based on age, gender, family history, stage, treatment, and mortality in H. Adam Malik General Hospital Medan from 2009 –...

  11. Penilaian Pasien terhadap Profesionalisme Dokter di Unit Rawat Jalan RSUP Haji Adam Malik Medan

    OpenAIRE

    Burhan, Fatmadina

    2015-01-01

    Medical Professionalism is one of the competencies required for physician in Indonesia.Various kinds of methods are used to assess the professionalism of physicians, one of them from patient’s view for instance. This study aims to determine the patient's assessment of the physician’s professionalism and to identify the effect of patients’ characteristic to the given assessment . The method used in this study was cross-sectional study with patient in outpatient installation at Adam Malik...

  12. Solving Directly Two Point Non Linear Boundary Value Problems Using Direct Adams Moulton Method

    OpenAIRE

    Zanariah A. Majid; Phang P. See; Mohamed Suleiman

    2011-01-01

    Problem statement: In this study, a direct method of Adams Moulton type was developed for solving non linear two point Boundary Value Problems (BVPs) directly. Most of the existence researches involving BVPs will reduced the problem to a system of first order Ordinary Differential Equations (ODEs). This approach is very well established but it obviously will enlarge the systems of first order equations. However, the direct method in this research will solved the second ord...

  13. The eroticism of artificial flesh in Villiers de L'Isle Adam's L'Eve Future

    OpenAIRE

    Pulham, Patricia

    2008-01-01

    Villiers de L'Isle Adam's L'Eve Future published in 1886 features a fictional version of the inventor Thomas Edison who constructs a complex, custom-made android for Englishman Lord Ewald as a substitute for his unsatisfactory lover. Hadaly, the android, has a number of literary and cultural precursors and successors. Her most commonly accepted ancestor is Olympia in E. T. A. Hoffmann's 'The Sandman' (1816) and among her fascinating descendants are Oskar Kokoschka's 'Silent Woman'; Model Borg...

  14. Simulation and analysis of vehicle stability based on ADAMS/CAR differential brake

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    To improve the braking safety of automobiles, the author studied the effect of differential brake on the stabilities. To analyze the mechanical characteristics of differential brake, automotive subsystem models were built by applying ADAMS/CAR, and automotive mechanics simulation model was built by setting the main subsystems such as body, engine and brake. The simulation model studied the distribution mode of three kinds of differential brake, and beeline braking stability and turning braking stability wer...

  15. Investigating topics and style in Vuta N`Kuvute by Shafi Adam Shafi

    OpenAIRE

    Traoré, Flavia Aiello

    2012-01-01

    In the last decades many literary critics have appraised the works of Zanzibarian writers; referring to the prose of Mohamed Suleiman Mohamed, Said Ahmed Mohamed and Shafi Adam Shafi, M M. Mulokozi wrote in 1985: \\"The most significant, and certainly most spectacular, development in the Swahili fiction of the Seventies and Eighties has been the emergence of Zanzibar as the producer of the best Swahili fiction to date, and the apparent torch bearer for the Kiswahili novel of the near future\\" ...

  16. Laporan Praktek Kerja Profesi Farmasi Rumah Sakit Di RSUP Adam Malik

    OpenAIRE

    Yuvi

    2011-01-01

    Telah selesai dilakukan Praktek Kerja Profesi (PKP) Farmasi rumah sakit di RSUP H. Adam Malik. PKP ini bertujuan untuk memberikan pembekalan, keterampilan dan keahlian kepada calon apoteker dalam mengelola perbekalan Farmasi di rumah sakit dan melihat secara langsung peran apoteker dalam pelayanan kefarmasian di rumah sakit. Praktek Kerja Profesi ini dilaksanakan pada tanggal 22 Mei sampai 22 Juni 2010 dengan jumlah jam efektif 7 jam per hari dimulai pukul 08.00- 15.00 WIB. Kegiatan PKP di r...

  17. Perbedaan Stres Kerja Ditinjau Dari Sistem Kerja Shift Pada Perawat RSUPH Adam Malik Medan

    OpenAIRE

    Mandasari, Etika

    2015-01-01

    This research aims to maintan the differences job stress of nurses based shift work system. Job stress is people’s reaction towards excessive pressure or demand of the workplace that are harmful. There are three factors which cause job stress: environment factor, organization, and person. One of organization factors is shift work. H Adam Malik Hospital uses a shift work system. Because the hospital operates for 24 hours in prividing health services to the public. The nurses ...

  18. Adam Smith’s Green Thumb and Malthus’ Three Horsemen: Cautionary tales from classical political economy

    OpenAIRE

    Dale, G

    2012-01-01

    This essay identifies a contradiction between the flourishing interest in the environmental economics of the classical period and a lack of critical parsing of the works of its leading representatives. Its focus is the work of Adam Smith and Thomas Malthus. It offers a critical analysis of their contribution to environmental thought and surveys the work of their contemporary devotees. It scrutinizes Smith's contribution to what Karl Polanyi termed the "economistic fallacy," as well as his def...

  19. Reading Adam Smith after Darwin: On the Evolution of Propensities, Institutions, and Sentiments

    OpenAIRE

    Schliesser, Eric

    2010-01-01

    This paper calls attention to Smith's "Considerations Concerning the First Formation of Languages" in order to facilitate understanding Adam Smith from an evolutionary perspective. In particular, such an evolutionary view can be discerned in how Smith saw that generic "natural sentiments" are applied and articulated, in light of local circumstances, into "moral sentiments." In doing so, the paper calls attention to the developmental interplay between the propensities of human nature in Smith'...

  20. The Profit Theory is False Since Adam Smith. What About the True Distribution Theory?

    OpenAIRE

    Kakarot-Handtke, Egmont

    2014-01-01

    All popular schools lack a consistent profit theory. Economists have no true conception of the most important phenomenon in their universe. This methodological defect persists since Adam Smith. Therefore, the theories of income and wealth distribution are wrong by logical implication. If the conclusions of a theory do not find any counterpart in reality the fault lies in the premises. In order to rectify distribution theory it is necessary to substitute the conventional subjective-behavioral ...

  1. The test facility EVA II/ADAM II - Description and operational results

    International Nuclear Information System (INIS)

    The Nuclear research Center Juelich (KFA) and the Rheinische Braunkohlewerke AG, Cologne, signed a contract for the research and development project 'Nukleare Fernenergie' (NFE) in 1975. Among others, one task of this project was to construct and operate a test facility EVA-II/ADAM-II. The general aim of the project was tp elaborate the data necessary for the design and construction of a heat transport system using thermo-chemical cycle steam reforming/methanation

  2. Gambaran Pewarnaan Imunohistokimia S100 Pada Meningioma Di RSUP. H. Adam Malik Medan

    OpenAIRE

    Prihartomo, Gatot Aji

    2015-01-01

    Objective: This study explores and describe the S100 immunohistochemical staining in meningioma. Methods: From February 2010 to February 2013 obtained 31 sample specimens from 31 patients who had meningioma undergo tumor removal surgery in the Adam Malik General Hospital Medan. This specimen has previously been carried out basic hematoxylin eosin staining and was confirmed as meningioma by Epithelial Membrane Antigene (EMA) imunohystochemistry staining. Representative slides are made of pa...

  3. Gambaran Kasus Perdarahan Postpartum Di RSUP Haji Adam Malik Medan Tahun 2009 – 2011

    OpenAIRE

    Perdana, Abduh Halim

    2013-01-01

    Background: The incidence of postpartum hemorrhage in developed countries about 5% of births, while in developing countries could reach 28% of the labor and became a major problem in maternal mortality. The cause of uterine atony 90%, 7% rips intertwine born, the rest due to retained placenta and blood clotting disorders. To reveal the characteristic form of postpartum hemorrhage cases, risk factors, causes, and treatment of postpartum hemorrhage cases in RSUP Haji. Adam Malik. Methods: Th...

  4. ADAM: a general method for using various data types in asteroid reconstruction

    Science.gov (United States)

    Viikinkoski, Matti; Kaasalainen, Mikko; Durech, Josef

    2015-04-01

    We introduce ADAM, the All-Data Asteroid Modelling algorithm. ADAM is simple and universal since it handles all disk-resolved data types (adaptive optics or other images, interferometry, and range-Doppler radar data) in a uniform manner via the 2D Fourier transform, enabling fast convergence in model optimization. The resolved data can be combined with disk-integrated data (photometry). In the reconstruction process, the difference between each data type is only a few code lines defining the particular generalized projection from 3D onto a 2D image plane. Occultation timings can be included as sparse silhouettes, and thermal infrared data are efficiently handled with an approximate algorithm that is sufficient in practice because of the dominance of the high-contrast (boundary) pixels over the low-contrast (interior) pixels. This is of particular importance to the raw ALMA data that can be directly handled by ADAM without having to construct the standard image. We study the reliability of the inversion, using the independent shape supports of function series and control-point surfaces. When other data are lacking, one can carry out fast non-convex lightcurve-only inversions, but any shape models resulting from it should only be taken as illustrative large-scale models. The code is only available at the CDS via anonymous ftp to http://cdsarc.u-strasbg.fr (ftp://130.79.128.5) or via http://cdsarc.u-strasbg.fr/viz-bin/qcat?J/A+A/576/A8

  5. ADAM: a general method for using various data types in asteroid reconstruction

    CERN Document Server

    Viikinkoski, Matti; Durech, Josef

    2015-01-01

    We introduce ADAM, the All-Data Asteroid Modelling algorithm. ADAM is simple and universal since it handles all disk-resolved data types (adaptive optics or other images, interferometry, and range-Doppler radar data) in a uniform manner via the 2D Fourier transform, enabling fast convergence in model optimization. The resolved data can be combined with disk-integrated data (photometry). In the reconstruction process, the difference between each data type is only a few code lines defining the particular generalized projection from 3D onto a 2D image plane. Occultation timings can be included as sparse silhouettes, and thermal infrared data are efficiently handled with an approximate algorithm that is sufficient in practice due to the dominance of the high-contrast (boundary) pixels over the low-contrast (interior) ones. This is of particular importance to the raw ALMA data that can be directly handled by ADAM without having to construct the standard image. We study the reliability of the inversion by using the...

  6. Endostatin and irradiation modifies the activity of ADAM10 and neprilysin in breast cancer cells.

    Science.gov (United States)

    Aydemir, Esra Arslan; Şimşek, Ece; Korcum, Aylin Fidan; Fişkin, Kayahan

    2016-09-01

    Angiogenesis, the formation of new blood vessels, is regarded as a key cancer cell property. Endostatin (ES) is a potential antiangiogenic agent and it may be useful when implemented in combination with other cancer therapeutic strategies. The present study investigated the in vitro effects of ES, radiotherapy (RT) or combination therapy (ES + RT) on two important proteases, a disintegrin and metalloproteinase domain‑containing protein 10 (ADAM10) and neprilysin (NEP) in 4T1 mouse breast cancer cells and the more metastatic phenotype of 4THMpc breast cancer cells. 4T1 and 4THMpc cells were treated with recombinant murine ES (4 µg/ml) alone, RT (45 Gy) alone or with ES + RT. ADAM10 enzyme activity was determined using a tumor necrosis factor‑α converting enzyme (α‑secretase) activity assay kit, and NEP enzyme activity was measured with a fluorometric assay based on the generation of free dansyl‑D‑Ala‑Gly from N-dansyl-Ala-Gly-D-nitro-Phe-Gly, the substrate of NEP. Western blotting analysis was performed to determine whether the altered enzyme activity levels of the two cell lines occurred due to changes in expression level. These data indicate that ES independently potentiates the activity of ADAM10 and NEP enzymes in 4T1 and 4THMpc breast cancer cells. PMID:27430992

  7. Sir John Adams: His Legacy to the World of Particle Accelerators

    CERN Document Server

    CERN. Geneva

    2009-01-01

    John Adams acquired an unrivalled reputation for his leading part in designing and constructing the PS in CERN’s early days. In 1968, and after several years heading a fusion laboratory in the UK, he came back to Geneva to pilot the SPS project to approval and then to direct its construction. At the time of his untimely death in 1984 he had built Europe’s two largest proton accelerators at CERN. He went on, during the second of his terms as DG, to lay the groundwork for the proton-antiproton collider which led to the discovery of the intermediate vector boson. How did someone without any formal academic qualification achieve this? What was the magic behind his leadership? How did he achieve political success with the Member States of CERN in turning the almost hopeless quest for approval of the SPS to CERN’s advantage? How did he view his US counterpart, R. R. Wilson? The speaker, who worked many years alongside Adams, will discuss these questions and speculate on how Sir John Adams might have viewed to...

  8. Sir John Adams - His Legacy to the World of Particle Accelerators

    CERN Document Server

    CERN. Geneva

    2009-01-01

    John Adams acquired an unrivalled reputation for his leading part in designing and constructing the PS in CERN’s early days. In 1968, and after several years heading a fusion laboratory in the UK, he came back to Geneva to pilot the SPS project to approval and then to direct its construction. At the time of his untimely death in 1984 he had built Europe’s two largest proton accelerators at CERN. He went on, during the second of his terms as DG, to lay the groundwork for the proton-antiproton collider which led to the discovery of the intermediate vector boson. How did someone without any formal academic qualification achieve this? What was the magic behind his leadership? How did he achieve political success with the Member States of CERN in turning the almost hopeless quest for approval of the SPS to CERN’s advantage? How did he view his US counterpart, R. R. Wilson? The speaker, who worked many years alongside Adams, will discuss these questions and speculate on how Sir John Adams might have viewed t...

  9. Co-simulation of Six DOF Wire Driven Parallel Mechanism Based on ADAMS and Matlab

    Directory of Open Access Journals (Sweden)

    Tang Aofei

    2015-01-01

    Full Text Available The dynamic model of the 6 DOF Wire Driven Parallel Mechanism (WDPM system is introduced. Based on MATLAB system, the simulation of the inverse dynamic model is achieved. According to the simulation result, the mechanical model for the WDPM system is reasonable. Using ADAMS system, the dynamic model of the virtual prototype is verified by the simulation analysis. The combined control model based on ADAMS/Simulink is derived. The WDPM control system is designed with MATLAB/Simulink. The torque control method is selected for the outer ring and the PD control method for the inner ring. Combined with the ADAMS control model and control law design, the interactive simulation analysis of the WDPM system is completed. According to the simulation results of the spatial circle tracking and line tracking at the end of the moving platform, the tracking error can be reduced by the designed control algorithm. The minimum tracking error is 0.2 mm to 0.3 mm. Therefore, the theoretical foundation for designing hardware systems of the WDPM control system is established.

  10. An evolutionary recent neuroepithelial cell adhesion function of huntingtin implicates ADAM10-Ncadherin.

    Science.gov (United States)

    Lo Sardo, Valentina; Zuccato, Chiara; Gaudenzi, Germano; Vitali, Barbara; Ramos, Catarina; Tartari, Marzia; Myre, Michael A; Walker, James A; Pistocchi, Anna; Conti, Luciano; Valenza, Marta; Drung, Binia; Schmidt, Boris; Gusella, James; Zeitlin, Scott; Cotelli, Franco; Cattaneo, Elena

    2012-05-01

    The Huntington's disease gene product, huntingtin, is indispensable for neural tube formation, but its role is obscure. We studied neurulation in htt-null embryonic stem cells and htt-morpholino zebrafish embryos and found a previously unknown, evolutionarily recent function for this ancient protein. We found that htt was essential for homotypic interactions between neuroepithelial cells; it permitted neurulation and rosette formation by regulating metalloprotease ADAM10 activity and Ncadherin cleavage. This function was embedded in the N terminus of htt and was phenocopied by treatment of htt knockdown zebrafish with an ADAM10 inhibitor. Notably, in htt-null cells, reversion of the rosetteless phenotype occurred only with expression of evolutionarily recent htt heterologues from deuterostome organisms. Conversely, all of the heterologues that we tested, including htt from Drosophila melanogaster and Dictyostelium discoideum, exhibited anti-apoptotic activity. Thus, anti-apoptosis may have been one of htt’s ancestral function(s), but, in deuterostomes, htt evolved to acquire a unique regulatory activity for controlling neural adhesion via ADAM10-Ncadherin, with implications for brain evolution and development. PMID:22466506

  11. Reliability evaluation of I-123 ADAM SPECT imaging using SPM software and AAL ROI methods

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Bang-Hung [Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan (China); Department of Nuclear Medicine, Taipei Veterans General Hospital, Taiwan (China); Tsai, Sung-Yi [Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan (China); Department of Imaging Medical, St.Martin De Porres Hospital, Chia-Yi, Taiwan (China); Wang, Shyh-Jen [Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan (China); Department of Nuclear Medicine, Taipei Veterans General Hospital, Taiwan (China); Su, Tung-Ping; Chou, Yuan-Hwa [Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan (China); Chen, Chia-Chieh [Institute of Nuclear Energy Research, Longtan, Taiwan (China); Chen, Jyh-Cheng, E-mail: jcchen@ym.edu.tw [Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan (China)

    2011-08-21

    The level of serotonin was regulated by serotonin transporter (SERT), which is a decisive protein in regulation of serotonin neurotransmission system. Many psychiatric disorders and therapies were also related to concentration of cerebral serotonin. I-123 ADAM was the novel radiopharmaceutical to image SERT in brain. The aim of this study was to measure reliability of SERT densities of healthy volunteers by automated anatomical labeling (AAL) method. Furthermore, we also used statistic parametric mapping (SPM) on a voxel by voxel analysis to find difference of cortex between test and retest of I-123 ADAM single photon emission computed tomography (SPECT) images. Twenty-one healthy volunteers were scanned twice with SPECT at 4 h after intravenous administration of 185 MBq of {sup 123}I-ADAM. The image matrix size was 128x128 and pixel size was 3.9 mm. All images were obtained through filtered back-projection (FBP) reconstruction algorithm. Region of interest (ROI) definition was performed based on the AAL brain template in PMOD version 2.95 software package. ROI demarcations were placed on midbrain, pons, striatum, and cerebellum. All images were spatially normalized to the SPECT MNI (Montreal Neurological Institute) templates supplied with SPM2. And each image was transformed into standard stereotactic space, which was matched to the Talairach and Tournoux atlas. Then differences across scans were statistically estimated on a voxel by voxel analysis using paired t-test (population main effect: 2 cond's, 1 scan/cond.), which was applied to compare concentration of SERT between the test and retest cerebral scans. The average of specific uptake ratio (SUR: target/cerebellum-1) of {sup 123}I-ADAM binding to SERT in midbrain was 1.78{+-}0.27, pons was 1.21{+-}0.53, and striatum was 0.79{+-}0.13. The cronbach's {alpha} of intra-class correlation coefficient (ICC) was 0.92. Besides, there was also no significant statistical finding in cerebral area using SPM2

  12. Reliability evaluation of I-123 ADAM SPECT imaging using SPM software and AAL ROI methods

    Science.gov (United States)

    Yang, Bang-Hung; Tsai, Sung-Yi; Wang, Shyh-Jen; Su, Tung-Ping; Chou, Yuan-Hwa; Chen, Chia-Chieh; Chen, Jyh-Cheng

    2011-08-01

    The level of serotonin was regulated by serotonin transporter (SERT), which is a decisive protein in regulation of serotonin neurotransmission system. Many psychiatric disorders and therapies were also related to concentration of cerebral serotonin. I-123 ADAM was the novel radiopharmaceutical to image SERT in brain. The aim of this study was to measure reliability of SERT densities of healthy volunteers by automated anatomical labeling (AAL) method. Furthermore, we also used statistic parametric mapping (SPM) on a voxel by voxel analysis to find difference of cortex between test and retest of I-123 ADAM single photon emission computed tomography (SPECT) images.Twenty-one healthy volunteers were scanned twice with SPECT at 4 h after intravenous administration of 185 MBq of 123I-ADAM. The image matrix size was 128×128 and pixel size was 3.9 mm. All images were obtained through filtered back-projection (FBP) reconstruction algorithm. Region of interest (ROI) definition was performed based on the AAL brain template in PMOD version 2.95 software package. ROI demarcations were placed on midbrain, pons, striatum, and cerebellum. All images were spatially normalized to the SPECT MNI (Montreal Neurological Institute) templates supplied with SPM2. And each image was transformed into standard stereotactic space, which was matched to the Talairach and Tournoux atlas. Then differences across scans were statistically estimated on a voxel by voxel analysis using paired t-test (population main effect: 2 cond's, 1 scan/cond.), which was applied to compare concentration of SERT between the test and retest cerebral scans.The average of specific uptake ratio (SUR: target/cerebellum-1) of 123I-ADAM binding to SERT in midbrain was 1.78±0.27, pons was 1.21±0.53, and striatum was 0.79±0.13. The cronbach's α of intra-class correlation coefficient (ICC) was 0.92. Besides, there was also no significant statistical finding in cerebral area using SPM2 analysis. This finding might help us

  13. Reliability evaluation of I-123 ADAM SPECT imaging using SPM software and AAL ROI methods

    International Nuclear Information System (INIS)

    The level of serotonin was regulated by serotonin transporter (SERT), which is a decisive protein in regulation of serotonin neurotransmission system. Many psychiatric disorders and therapies were also related to concentration of cerebral serotonin. I-123 ADAM was the novel radiopharmaceutical to image SERT in brain. The aim of this study was to measure reliability of SERT densities of healthy volunteers by automated anatomical labeling (AAL) method. Furthermore, we also used statistic parametric mapping (SPM) on a voxel by voxel analysis to find difference of cortex between test and retest of I-123 ADAM single photon emission computed tomography (SPECT) images. Twenty-one healthy volunteers were scanned twice with SPECT at 4 h after intravenous administration of 185 MBq of 123I-ADAM. The image matrix size was 128x128 and pixel size was 3.9 mm. All images were obtained through filtered back-projection (FBP) reconstruction algorithm. Region of interest (ROI) definition was performed based on the AAL brain template in PMOD version 2.95 software package. ROI demarcations were placed on midbrain, pons, striatum, and cerebellum. All images were spatially normalized to the SPECT MNI (Montreal Neurological Institute) templates supplied with SPM2. And each image was transformed into standard stereotactic space, which was matched to the Talairach and Tournoux atlas. Then differences across scans were statistically estimated on a voxel by voxel analysis using paired t-test (population main effect: 2 cond's, 1 scan/cond.), which was applied to compare concentration of SERT between the test and retest cerebral scans. The average of specific uptake ratio (SUR: target/cerebellum-1) of 123I-ADAM binding to SERT in midbrain was 1.78±0.27, pons was 1.21±0.53, and striatum was 0.79±0.13. The cronbach's α of intra-class correlation coefficient (ICC) was 0.92. Besides, there was also no significant statistical finding in cerebral area using SPM2 analysis. This finding might help

  14. The expression pattern of Adam10 in the central nervous system of adult mice: Detection by in situ hybridization combined with immunohistochemistry staining.

    Science.gov (United States)

    Guo, Zhi-Bao; Su, Ying-Ying; Wang, Yi-Hui; Wang, Wei; Guo, Da-Zhi

    2016-09-01

    ADAM10 (a disintegrin and metalloprotease 10) is a member of the ADAMs family, which is key in the development of the nervous system, by regulating proliferation, migration, differentiation and survival of various cells, including axonal growth and myelination. Previous studies have investigated the embryonic or postnatal expression of ADAM10, however, detailed information regarding its cellular distribution in the adult stage, to the best of our knowledge, is not available. The present study investigated the expression pattern of the ADAM10 gene in the adult mouse central nervous system (CNS) using an ADAM10 complementary RNA probe for in situ hybridization (ISH). Immunohistochemical staining was used to identify the type of the ISH staining‑positive cells with neuron‑ or astrocyte‑specific antibodies. The results of the current study demonstrated that the ADAM10 gene was predominantly expressed in the neurons of the cerebral cortex, hippocampus, thalamus and cerebellar granular cells in adult mouse CNS. PMID:27431484

  15. Evaluation of ADAM-12 as a diagnostic biomarker of ectopic pregnancy in women with a pregnancy of unknown location.

    Directory of Open Access Journals (Sweden)

    Andrew W Horne

    Full Text Available BACKGROUND: Ectopic pregnancy (EP remains the most life-threatening acute condition in modern gynaecology. It remains difficult to diagnose early and accurately. Women often present at emergency departments in early pregnancy with a 'pregnancy of unknown location' (PUL and diagnosis/exclusion of EP is challenging due to a lack of reliable biomarkers. Recent studies suggest that serum levels of a disintegrin and metalloprotease protein-12 (ADAM-12 can be used differentiate EP from viable intrauterine pregnancy (VIUP. Here we describe a prospective study evaluating the performance of ADAM-12 in differentiating EP from the full spectrum of alternative PUL outcomes in an independent patient cohort. METHODOLOGY/PRINCIPAL FINDINGS: Sera were collected from 120 patients at their first clinical presentation with a PUL and assayed for ADAM-12 by ELISA. Patients were categorized according to final pregnancy outcomes. Serum ADAM-12 concentrations were increased in women with histologically-confirmed EP (median 442 pg/mL; 25%-75% percentile 232-783 pg/mL compared to women with VIUP (256 pg/mL; 168-442 pg/mL or miscarriage (192 pg/mL; 133-476 pg/mL. Serum ADAM-12 did not differentiate histologically-confirmed EP from spontaneously resolving PUL (srPUL (416 pg/mL; 154-608 pg/mL. The diagnostic potential of ADAM-12 was only significant when 'ambiguous' PUL outcomes were excluded from the analysis (AROC = 0.6633; P = 0.03901. CONCLUSIONS/SIGNIFICANCE: When measured in isolation, ADAM-12 levels had limited value as a diagnostic biomarker for EP in our patient cohort. The development of a reliable serum biomarker-based test for EP remains an ongoing challenge.

  16. Compensation for dystrophin-deficiency: ADAM12 overexpression in skeletal muscle results in increased alpha 7 integrin, utrophin and associated glycoproteins

    DEFF Research Database (Denmark)

    Moghadaszadeh, Behzad; Albrechtsen, Reidar; Guo, Ling T;

    2003-01-01

    humans. More specifically ADAM12 appeared to prevent muscle cell necrosis in the mdx mice as evidenced by morphological analysis and by the reduced levels of serum creatine kinase. In the present study we demonstrated that ADAM12 may compensate for the dystrophin deficiency in mdx mice by increasing the...... expression and redistribution of several components of the muscle cell-adhesion complexes. First, we analyzed transgenic mice that overexpress ADAM12 and found mild myopathic changes and accelerated regeneration following acute injury. We then analyzed changes in gene-expression profiles in mdx/ADAM12...

  17. High Percentage of ADAM-10 Positive Melanoma Cells Correlates with Paucity of Tumor-Infiltrating Lymphocytes but Does Not Predict Prognosis in Cutaneous Melanoma Patients

    Directory of Open Access Journals (Sweden)

    Piotr Donizy

    2015-01-01

    Full Text Available ADAM-10 (CDw156, CD156c, and kuzbanian is a protein belonging to a superfamily of metalloproteases, enzymes capable of degrading the extracellular matrix. ADAMs have also been shown to be primarily involved in ectodomain cleavage. The aim of the study was to assess the expression and intracellular location of ADAM-10 in 104 primary skin melanomas and 16 metastatic lesions from regional lymph nodes. Also, prognostic significance of ADAM-10 expression in primary tumor cells and metastatic lesion cells was evaluated during 5-year observation. It was revealed that high expression of ADAM-10 positive cells was strictly related with lower intensity of tumor-infiltrating lymphocytes (P=0.037, which suggests that ADAM-10 regulates immunoresponse in melanoma initiation and progression. No statistically significant correlations were found between ADAM-10 expression in primary tumor cells and nodal metastases and other histopathological parameters analyzed. Decreased immunoreactivity of ADAM-10 in cancer cells from regional lymph nodes was correlated with worse prognosis; however this correlation was statistically nonsignificant (P=0.065. Review of the literature shows that our study is the first one ever to describe the significance of ADAM-10 expression in correlation with detailed histopathological parameters of the primary tumor and data on long-term survival of cutaneous melanoma patients.

  18. IL-13-induced proliferation of airway epithelial cells: mediation by intracellular growth factor mobilization and ADAM17

    Directory of Open Access Journals (Sweden)

    Sandifer Tracy

    2007-07-01

    Full Text Available Abstract Background The pleiotrophic cytokine interleukin (IL-13 features prominently in allergic and inflammatory diseases. In allergic asthma, IL-13 is well established as an inducer of airway inflammation and tissue remodeling. We demonstrated previously that IL-13 induces release of transforming growth factor-α (TGFα from human bronchial epithelial cells, with proliferation of these cells mediated by the autocrine/paracrine action of this growth factor. TGFα exists as an integral membrane protein and requires proteolytic processing to its mature form, with a disintegrin and metalloproteinase (ADAM17 responsible for this processing in a variety of tissues. Methods In this study, normal human bronchial epithelial (NHBE cells grown in air/liquid interface (ALI culture were used to examine the mechanisms whereby IL-13 induces release of TGFα and cellular proliferation. Inhibitors and antisense RNA were used to examine the role of ADAM17 in these processes, while IL-13-induced changes in the intracellular expression of TGFα and ADAM17 were visualized by confocal microscopy. Results IL-13 was found to induce proliferation of NHBE cells, and release of TGFα, in an ADAM17-dependent manner; however, this IL-13-induced proliferation did not appear to result solely from ADAM17 activation. Rather, IL-13 induced a change in the location of TGFα expression from intracellular to apical regions of the NHBE cells. The apical region was also found to be a site of significant ADAM17 expression, even prior to IL-13 stimulation. Conclusion Results from this study indicate that ADAM17 mediates IL-13-induced proliferation and TGFα shedding in NHBE cells. Furthermore, they provide the first example wherein a cytokine (IL-13 induces a change in the intracellular expression pattern of a growth factor, apparently inducing redistribution of intracellular stores of TGFα to the apical region of NHBE cells where expression of ADAM17 is prominent. Thus, IL-13

  19. One case of Lance-Adams symptom%Lance-Adams综合征1例

    Institute of Scientific and Technical Information of China (English)

    游建友; 聂红兵; 黄瑛; 陈志颖

    2015-01-01

    Lance-Adams symptom also called secondary to hypoxic encephalopathy intentionality or action myoclonus syndrome.Domestic reports on treating Lance-Adams syndrome was relatively small.Our hospital treated one patients with Lance-Adams symptom by using antiepileptic drugs liked diazepam and valproic acid.The clinical feature and electroencephalogram situation was observed to explore the clinical feature of Lance-Adams symptom and treatment method.Then enhance the understanding about Lance-Adams symptom,in order to early diagnosis and timely treatment. After a series of treatment,clinical symptoms of patient under control,electroencephalogram results from the initially mainly with 3-5 Hz high-frequency theta and delta waves and with medium and high amplitude,spike wave and spine slow wave gradually transformed into mainly with 8-10 Hz rhythmic alpha pointed, spike wave and spine slow wave disappeared.The disease process and signs of this patient were consistent with the relevant literature.Throuhg treated with diazepam and valproic acid,this patient’s condition effectively alleviated,life quality improved obvious.Diazepam and valproic acid may be a good choice for Lance-Adams symptom.%Lance-Adams综合征,又称为继发于低氧性脑病的意向性或动作性肌阵挛综合征。国内关于治疗Lance-Adams综合征的报道相对较少,我院通过采用地西泮、丙戊酸等抗癫痫药物对1例Lance-Adams综合征患者进行治疗,并观察其临床表现及脑电图情况,以探究Lance-Adams综合征的临床发病特点及治疗方法,提高对Lance-Adams综合征的认识,便以早诊断、及时救治。经过一系列的治疗之后,患者的临床症状得到有效控制,脑电图结果由起初以3~5 Hz的高频兹波、啄波为主,伴有中、高幅尖、棘波以及棘慢综合波逐渐转变为以8~10 Hz有节律的α波为主,尖、棘波以及棘慢综合波消失。本病例的发病过程及体征情况与相关文献

  20. Poor interoperability of the Adams-Harbertson method for analysis of anthocyanins: comparison with AOAC pH differential method.

    Science.gov (United States)

    Brooks, Larry M; Kuhlman, Benjamin J; McKesson, Doug W; McCloskey, Leo

    2013-01-01

    The poor interoperability of anthocyanin glycosides measurements by two pH differential methods is documented. Adams-Harbertson, which was proposed for commercial winemaking, was compared to AOAC Official Method 2005.02 for wine. California bottled wines (Pinot Noir, Merlot, and Cabernet Sauvignon) were assayed in a collaborative study (n=105), which found mean precision of Adams-Harbertson winery versus reference measurements to be 77 +/- 20%. Maximum error is expected to be 48% for Pinot Noir, 42% for Merlot, and 34% for Cabernet Sauvignon from reproducibility RSD. Range of measurements was actually 30 to 91% for Pinot Noir. An interoperability study (n=30) found Adams-Harbertson produces measurements that are nominally 150% of the AOAC pH differential method. Large analytical chemistry differences are: AOAC method uses Beer-Lambert equation and measures absorbance at pH 1.0 and 4.5, proposed a priori by Flueki and Francis; whereas Adams-Harbertson uses "universal" standard curve and measures absorbance ad hoc at pH 1.8 and 4.9 to reduce the effects of so-called co-pigmentation. Errors relative to AOAC are produced by Adams-Harbertson standard curve over Beer-Lambert and pH 1.8 over pH 1.0. The study recommends using AOAC Official Method 2005.02 for analysis of wine anthocyanin glycosides. PMID:23513962

  1. ADAM12 and PAPP-A: Candidate regulators of trophoblast invasion and first trimester markers of healthy trophoblasts.

    Science.gov (United States)

    Christians, Julian K; Beristain, Alexander G

    2016-03-01

    Proper placental development and function is crucial for a healthy pregnancy, and there has been substantial research to identify markers of placental dysfunction for the early detection of pregnancy complications. Low first-trimester levels of a disintegrin and metalloproteinase 12 (ADAM12) and pregnancy-associated plasma protein-A (PAPP-A) have been consistently associated with the subsequent development of preeclampsia and fetal growth restriction. These molecules are both metalloproteinases secreted by the placenta that cleave insulin-like growth factor binding proteins (IGFBPs), although ADAM12 also has numerous other substrates. Recent work has identified ADAM12, and particularly its shorter variant, ADAM12S, as a regulator of the migration and invasion of trophoblasts into the lining of the uterus, a critical step in normal placental development. While the mechanisms underlying this regulation are not yet clear, they may involve the liberation of heparin-binding EGF-like growth factor (HB-EGF) and/or IGFs from IGFBPs. In contrast, there has been relatively little functional work examining PAPP-A or the IGFBP substrates of ADAM12 and PAPP-A. Understanding the functions of these markers and the mechanisms underlying their association with disease could improve screening strategies and enable the development of new therapeutic interventions. PMID:26417939

  2. Single lane traffic in Adams road (Prévessin Site)

    CERN Multimedia

    2003-01-01

    From 20th August, ST Division will be opening trenches in order to allow a number of power, control and optical fibre cables to be laid across Adams road (see plan). For the duration of the work, the road will be barred to all heavy loads/lorries and alternative arrangements will be put in place for normal traffic. Temporary lights will be installed. We kindly ask all users to respect these temporary arrangements. The work will take two weeks given favorable conditions. Thank you for your understanding in this matter. ST-EL Group Tel. 72978 - 164082

  3. Single lane traffic in Adams road (Prévessin Site)

    CERN Document Server

    2003-01-01

    From 20th August, ST Division will be opening trenches in order to allow a number of power, control and optical fibre cables to be laid across Adams road (see plan). For the duration of the work, the road will be barred to all heavy loads/lorries and alternative arrangements will be put in place for normal traffic. Temporary lights will be installed. We kindly ask all users to respect these temporary arrangements. The work will take two weeks given favorable conditions. Thank you for your understanding in this matter. ST-EL Group Tél. 72978 - 164082

  4. Self-interest, Sympathy and the Invisible Hand: From Adam Smith to Market Liberalism

    OpenAIRE

    Avner Offer

    2012-01-01

    Adam Smith rejected Mandeville's invisible-hand doctrine of ‘private vices, publick benefits'. In The Theory of Moral Sentiments his model of the ‘impartial spectator' is driven not by sympathy for other people, but by their approbation. The innate capacity for sympathy makes approbation credible. Approbation needs to be authenticated, and in Smith's model authentication relies on innate virtue, which is not realistic. An alternative model of ‘regard' makes use of signalling and is more...

  5. Adam Smith's answer to the Feldstein-Horioka paradox: The invisible hand revisited

    OpenAIRE

    Yasutomi, Ayumu; Horioka, Charles Yuji

    2010-01-01

    In this paper, we show that Adam Smith pointed out the existence of the Feldstein-Horioka Paradox or Puzzle and even gave an explanation for it more than 200 years before the publication of Feldstein and Horioka (1980). Smith argues that it is the pursuit of their own security that leads owners of capital to invest their capital in their own country to as great an extent as possible and that it is the pursuit of security rather than the pursuit of profit that leads individuals to promote the ...

  6. An Embedding for the E2-term of the Adams Spectral Sequence at Odd Primes

    Institute of Scientific and Technical Information of China (English)

    Maurizio BRUNETTI; Adriana CIAMPELLA; Luciano A. LOMONACO

    2006-01-01

    Let p be an odd prime. In this paper we introduce a quadratic linear Fp-algebra Q1 obtained by suitably changing the generators of Q, the homogeneous quadratic algebra of cohomology operations in the category of H∞-ring spectra, and study the map induced on cohomology by the quotient (π): Q1 → Ap.Like in the case p = 2, it turns out that (π)* is injective. Thus, its target contains the E2-term of the classical Adams spectral sequence as subalgebra. An explicit description of ExtQ1 (Fp, Fp) is given under the reasonable assumption on Q to be a Koszul algebra.

  7. Gambaran Karakteristik Ibu Yang Melahirkan Bayi Prematur di RSUP H Adam Malik Medan Tahun 2007.

    OpenAIRE

    Alvonso D. Paulus P

    2011-01-01

    Premature birth can increase the infant mortality rate that’s needed the preventive action, like; doing observation about determinant factors must such as the characteristic of delivery mother. This research was descriptive to know the secondary data from medical record to know the characteristics of mother in delivery their babies at RSU H. Adam Malik Medan, 2007 The research results obtained are the most premature baby to a baby boy (54.0%), the age group 20-35 years old (88.9%), pari...

  8. Examining â The Adam Smith Problemâ : Individuals, Society, and Value

    OpenAIRE

    Crowder, Rachel E

    2012-01-01

    In this paper I offer an analysis of the Adam Smith Problem. This Problem arises from perceived inconsistencies between Smithâ s economic work, The Wealth of Nations, and his moral theory, the Theory of Moral Sentiments. I argue that far from being inconsistent with Smithâ s economic theory, his moral theory serves as a necessary foundation. I suggest that, because he takes humans to be moral by nature, Smith defends social capitalism which requires moral economic agents rather than homo ec...

  9. Jean-Michel Adam, La linguistique textuelle. Introduction à l’analyse textuelle des discours

    OpenAIRE

    Viprey, Jean-Marie

    2013-01-01

    Jean-Michel Adam semble décidé à constituer de ses propres travaux un dossier complexe de génétique textuelle dont un point de départ serait Linguistique textuelle. Des genres de discours aux textes, publié en 1999 chez Nathan. En 2005, changeant d’éditeur (Colin), il en publiait une nouvelle mouture, complètement remaniée, sous le titre augmenté de l’article, La linguistique textuelle, et un nouveau sous-titre : Introduction à l’analyse textuelle des discours, afin principalement d’introduir...

  10. Calculation of nuclear reactivity using the generalised Adams-Bashforth-Moulton predictor corrector method

    Energy Technology Data Exchange (ETDEWEB)

    Suescun-Diaz, Daniel [Surcolombiana Univ., Neiva (Colombia). Groupo de Fisica Teorica; Narvaez-Paredes, Mauricio [Javeriana Univ., Cali (Colombia). Groupo de Matematica y Estadistica Aplicada Pontificia; Lozano-Parada, Jamie H. [Univ. del Valle, Cali (Colombia). Dept. de Ingenieria

    2016-03-15

    In this paper, the generalisation of the 4th-order Adams-Bashforth-Moulton predictor-corrector method is proposed to numerically solve the point kinetic equations of the nuclear reactivity calculations without using the nuclear power history. Due to the nature of the point kinetic equations, different predictor modifiers are used in order improve the precision of the approximations obtained. The results obtained with the prediction formulas and generalised corrections improve the precision when compared with previous methods and are valid for various forms of nuclear power and different time steps.

  11. The Co-simulation of Humanoid Robot Based on Solidworks, ADAMS and Simulink

    Science.gov (United States)

    Song, Dalei; Zheng, Lidan; Wang, Li; Qi, Weiwei; Li, Yanli

    A simulation method of adaptive controller is proposed for the humanoid robot system based on co-simulation of Solidworks, ADAMS and Simulink. A complex mathematical modeling process is avoided by this method, and the real time dynamic simulating function of Simulink would be exerted adequately. This method could be generalized to other complicated control system. This method is adopted to build and analyse the model of humanoid robot. The trajectory tracking and adaptive controller design also proceed based on it. The effect of trajectory tracking is evaluated by fitting-curve theory of least squares method. The anti-interference capability of the robot is improved a lot through comparative analysis.

  12. The Prevailing of the Human Nature in the Economics of Adam Smith

    Directory of Open Access Journals (Sweden)

    Mara Magda Maftei

    2006-09-01

    Full Text Available Adam Smith is thought to be the first economist, his economic considerations being even nowadays valid, no matter the everchanging connotations of capitalism throughtout the world. Unfortunately, only The Wealth of Nations was translated in Romanian, and that is why there is a tendency among us to analyze Smith only by means of his economic paradigma, leaving out his preoccupations of moral philosophy, of finding the connections between political, juridical and economic aspects. Above all, we should insist on his obsession with human nature, obsession to be embbeded within the increasing importance of economic sciences in his time, growing out of moral philosophy and jurisprudence.

  13. The Role of the Imagination in Adam Smith’s Refutation of the Homo Economicus Thesis

    Directory of Open Access Journals (Sweden)

    José de la Cruz Garrido

    2015-12-01

    Full Text Available Adam Smith’s moral philosophy is grounded in the role of the imagination in explaining the social order at a macro level and as a mechanism for affective identification at the micro level. In both cases, the role of the imagination in our moral psychology refutes the homo economicus thesis according to which human beings are motivated to enter into society due to personal interests. This premise serves to refute the Hobbesian position of a historical state of nature that underlies the moral judgments grounding civil society and the need for a magistrate.

  14. The Role of the Imagination in Adam Smith’s Refutation of the Homo Economicus Thesis

    OpenAIRE

    José de la Cruz Garrido

    2015-01-01

    Adam Smith’s moral philosophy is grounded in the role of the imagination in explaining the social order at a macro level and as a mechanism for affective identification at the micro level. In both cases, the role of the imagination in our moral psychology refutes the homo economicus thesis according to which human beings are motivated to enter into society due to personal interests. This premise serves to refute the Hobbesian position of a historical state of nature that underlies the moral j...

  15. Calculation of nuclear reactivity using the generalised Adams-Bashforth-Moulton predictor corrector method

    International Nuclear Information System (INIS)

    In this paper, the generalisation of the 4th-order Adams-Bashforth-Moulton predictor-corrector method is proposed to numerically solve the point kinetic equations of the nuclear reactivity calculations without using the nuclear power history. Due to the nature of the point kinetic equations, different predictor modifiers are used in order improve the precision of the approximations obtained. The results obtained with the prediction formulas and generalised corrections improve the precision when compared with previous methods and are valid for various forms of nuclear power and different time steps.

  16. ADAM: Analysis of Discrete Models of Biological Systems Using Computer Algebra

    Directory of Open Access Journals (Sweden)

    Blekherman Grigoriy

    2011-07-01

    Full Text Available Abstract Background Many biological systems are modeled qualitatively with discrete models, such as probabilistic Boolean networks, logical models, Petri nets, and agent-based models, to gain a better understanding of them. The computational complexity to analyze the complete dynamics of these models grows exponentially in the number of variables, which impedes working with complex models. There exist software tools to analyze discrete models, but they either lack the algorithmic functionality to analyze complex models deterministically or they are inaccessible to many users as they require understanding the underlying algorithm and implementation, do not have a graphical user interface, or are hard to install. Efficient analysis methods that are accessible to modelers and easy to use are needed. Results We propose a method for efficiently identifying attractors and introduce the web-based tool Analysis of Dynamic Algebraic Models (ADAM, which provides this and other analysis methods for discrete models. ADAM converts several discrete model types automatically into polynomial dynamical systems and analyzes their dynamics using tools from computer algebra. Specifically, we propose a method to identify attractors of a discrete model that is equivalent to solving a system of polynomial equations, a long-studied problem in computer algebra. Based on extensive experimentation with both discrete models arising in systems biology and randomly generated networks, we found that the algebraic algorithms presented in this manuscript are fast for systems with the structure maintained by most biological systems, namely sparseness and robustness. For a large set of published complex discrete models, ADAM identified the attractors in less than one second. Conclusions Discrete modeling techniques are a useful tool for analyzing complex biological systems and there is a need in the biological community for accessible efficient analysis tools. ADAM provides

  17. Pengaruh Terapi Sinema Terhadap Kecemasan Praoperatif pada Anak Usia Sekolah di RSUP. H. Adam Malik Medan

    OpenAIRE

    Roswati, Maristha

    2015-01-01

    Operation procedure can cause pre-operative anxiety in childrf!n because of anesthesia, hospital environment, strange people, physical deJecl, 1:md separation from their parents. The objective oj this research was to identifY the influence oj cinema therapy on pre-operative anxiety in school-aged children in RSUP H. Adam Malik, Medon. The research was quasi experiment with pre-post test design which consisted oj one intervention group. The samples were 8 respondents, taken b...

  18. Daniel Adam z Veleslavína a jeho nomenklátory

    Czech Academy of Sciences Publication Activity Database

    Černá, Alena M.

    Praha: Karolinum, 2012 - (Čmejrková, S.; Hoffmannová, J.; Klímová, J.), s. 201-206 ISBN 978-80-246-2121-0. [Čeština v pohledu synchronním a diachronním. Praha (CZ), 01.06.2011-03.06.2011] R&D Projects: GA ČR GAP406/10/1140 Institutional research plan: CEZ:AV0Z90610518 Keywords : Humanistic Czech * Daniel Adam of Veleslavin * vocabulary Subject RIV: AI - Linguistics

  19. Uji Diagnostik Genexpert MTB/RIF Di Rumah Sakit Umum Pusat Haji Adam Malik Medan

    OpenAIRE

    Susanty, Elva

    2015-01-01

    Cases of multidrug resistant tuberculosis (MDR TB) is increasing in number in the world and requires early detection to prevent further transmission. GeneXpert MTB/RIF is a tool that can be used for detection of rifampicin resistance, as a surrogate marker for multidrug-resistant tuberculosis. This study aims to assess the sensitivity and specificity of the GeneXpert MTB/RIF in the diagnosis of MDR TB. The study was conducted at a poly MDR TB General Hospital Haji Adam Malik Medan. The subje...

  20. 宫颈癌组织中ADAM-19、Ki-67的表达及临床意义%The expression and clinical significance of ADAM-19,Ki-67 in cervical cancer

    Institute of Scientific and Technical Information of China (English)

    逯仁波; 王小川; 马荣; 耿晓星

    2011-01-01

    目的 研究早期宫颈癌组织中去整合素基质金属蛋白酶-19(a disintegrin and metalloproteinase,ADAM-19)、癌细胞增殖指数(Ki-67)的表达及临床意义.方法 应用免疫组化SP法检测18例正常宫颈上皮(normal cervical epithelium,NCE)、22例宫颈上皮内瘤变(cervical intraepithelial neoplasm,CIN)和82例宫颈早期浸润癌(invasive cervix carsinoma,ICC)组织中ADAM-19和Ki-67的表达情况.结果 在宫颈癌中ADAM-19表达于癌细胞浆和或细胞膜;Ki-67表达于细胞核.从正常宫颈上皮(normal cervical epithelium,NCE)到宫颈上皮内瘤变(cervical intraepithelial neoplasm,CIN)再到宫颈浸润癌(invasive carsinoma cervix,ICC),ADAM-19、Ki-67的阳性表达率逐步升高(P<0.05).ADAM-19在宫颈浸润癌中的表达与盆腔淋巴结转移、脉管浸润、间质浸润、国际妇产科联盟(FIGO)分期、组织学分级和Ki-67表达有关(P<0.05);但与年龄和组织学类型无明显相关性(P>0.05).有盆腔淋巴结转移、脉管浸润、突破深层间质浸润、FIGO分期为Ⅱ期、组织学分级为Ⅲ级及Ki-67高度表达者,其ADAM-19阳性表达率显著高于无盆腔淋巴结转移、无脉管浸润、浸润深度在浅层间质以内、FIGO分期为Ⅰ期、组织学分级未超过Ⅱ级及Ki-67表达在中度以内者(P<0.05).结论 ADAM-19阳性表达可能在癌细胞增殖和侵袭转移中起重要作用.ADAM-19过度表达者,癌细胞增殖活跃,更易发生侵袭转移,但并非唯一决定因素.检测宫颈癌中ADAM-19表达对进一步了解宫颈癌生物学行为和判断其预后有一定价值.%Objective To evaluate the expression and clinical significance of A disintegrin and metalloproteinase( ADAM - 19 ),Ki - 67 in early invasive cervical cancer. Methods Expression of ADAM - 19 and Ki - 67 in 18 cases of normal cervical epithelium( NCE ),22 cases of cervical intraepithelial neoplasm( CIN ) and 82 cases of invasive carcinoma cervix( ICC )were detected by

  1. Neutralization of ADAM8 ameliorates liver injury and accelerates liver repair in carbon tetrachloride-induced acute liver injury.

    Science.gov (United States)

    Li, San-Qiang; Zhu, Sha; Wan, Xue-Dong; Xu, Zheng-Shun; Ma, Zhao

    2014-04-01

    Although some studies have described the function of ADAM8 (a disintegrin and metalloprotease 8) related with rheumatoid arthritis, cancer and asthma, etc., the concrete role of ADAM8 in acute liver injury is still unknown. So mice respectively received anti-ADAM8 monoclonal antibody (mAb) of 100 μg/100 μl, 200 μg/100 μl or 300 μg/100 μl in PBS or PBS pre-injection. Then acute liver injury was induced in the mice by intraperitoneal (i.p.) injection of carbon tetrachloride (CCl₄). Serum AST and ALT level, Haematoxylin-eosin (H&E) staining, the expression level of vascular endothelial growth factor (VEGF), cytochrome P450 1A2 (CYP1A2) and proliferating cell nuclear antigen (PCNA) were detected in the mice after CCl4 administration. Our results showed that anti-ADAM8 mAb pre-injection could effectively lower AST and ALT levels (P < 0.05 or P < 0.01) and reduce liver injury (P < 0.05 or P <0.01), induce the expression of VEGF, CYP1A2 and PCNA (P <0.05 or P < 0.01) in dose-dependent manner compared with the control mice which received PBS pre-injection. In summary, our study suggested that ADAM8 might promote liver injury by inhibiting the proliferation of hepatocytes, angiogenesis and affecting the metabolism function of liver during acute liver injury induced by CCl₄. Anti-ADAM8 mAb injection might be suitable as a potential method for acute liver injury therapy. PMID:24646716

  2. Adam Smith

    OpenAIRE

    Peil, J.J.M.

    2004-01-01

    The Handbook of Economics and Ethics portrays an understanding of economic methodology in which facts and values, though distinct, are closely interconnected in a variety of ways. From theory building to data collection, and from modelling to policy evaluation, this encyclopaedic Handbook is at the intersection of economics and ethics.

  3. John G.C. Adams: father of Dental Public Health in Canada.

    Science.gov (United States)

    Kenny, David J; Dale, Anne C; Wencer, David G

    2014-01-01

    John Gennings Curtis Adams (1839-1922), Canada's first resident dental missionary, was the father of Dental Public Health in Canada. He established, personally funded and operated the first free dental hospital in North America for poor children and their mothers in Toronto from 1872, three years before the founding of The Hospital for Sick Children; he later became their first dentist of record. He was a visionary zealot for prevention of decay, dental education, and treatment over extraction. Dr. Adams understood that neither parents (rich or poor) nor physicians were aware of the extent of pathosis present in children's mouths. He petitioned individuals, lobbied politicians and unions and pressured dental organizations on the importance of twice-annual school inspections to demonstrate disease so that parents would seek care for their children. He wanted government-funded dental hospitals like his own to treat those who could not afford care. He realized his objectives and his reforms to prevent suffering, as Toronto school inspections began in 1911 and Toronto's first publicly-funded free dental clinic opened in 1913. He was Canada's first dental philanthropist and a visionary for preventive dentistry. PMID:25549402

  4. Introduction: REVIEW SYMPOSIUM ON GIOVANNI ARRIGHI’S ADAM SMITH IN BEIJING

    Directory of Open Access Journals (Sweden)

    Thomas D. Hall

    2015-08-01

    Full Text Available About sixteen months ago we began discussing commissioning a series of review essays on Arrighi’s Adam Smith in Beijing. The original idea was to publish a collection of essays from various world-systems scholars, and have Arrighi respond. As we all know, Giovanni became ill and sadly passed in summer of 2009. In commissioning the essays as book review editor I faced a special challenge. Some likely writers had already committed to essays for other venues (e.g., Janet Abo-Lughod 2008; Chris Chase-Dunn forthcoming. I also wanted to get a variety of approaches so that the entire collection would represent a diverse set of views. The following essays do that. We are especially fortunate to have an essay from Robert Denemark, who I asked to comment on Andre Gunder Frank’s probable take(s on Adam Smith in Beijing. The remaining essays offer various insights into this important work.

  5. Sharp Adams type inequalities in Sobolev spaces W(Rn) for arbitrary integer m

    Science.gov (United States)

    Lam, Nguyen; Lu, Guozhen

    The main purpose of our paper is to prove sharp Adams type inequalities in unbounded domains of Rn for the Sobolev space W(Rn) for any positive integer m less than n. Our results complement those of Ruf and Sani (in press) [35] where such inequalities have been established for even integer m. We extend the main techniques of Ruf and Sani (in press) [35], which are the combinations of the comparison principle of Talenti (1976) [36] and Trombetti and Vázquez (1985) [38] for polyharmonic operators and a symmetrization argument together with constructions of radial auxiliary functions, to the case when m is odd. Moreover, we offer a completely different but much simpler approach to prove the comparison principle using the power of Bessel potentials and the Riesz rearrangement (see Remarks 3.2 and 3.3). This approach is of independent interest and works for any differential operators with appropriate radial kernels. As corollaries of our main theorems, we will derive the Adams type inequalities in the case when n=2m for all positive integer m by using different Sobolev norms.

  6. Dalla teoria delle passioni al nuovo ordine: mercato e capitalismo in Adam Smith

    Directory of Open Access Journals (Sweden)

    T. RAFFAELLI

    2013-10-01

    Full Text Available It is the paradigm of political economy as an autonomous science, distinguished from ethics and politics, that Adam Smith is considered to be the "founding father" of. However, this confinement has at time resulted in a distorted of his views with regards to the central themes of later times, making him at times to be the supporter of methodological individualism, of unconditional liaise faire and the minimal state, and of the full coherence between private and public interest. Indeed, he has been pushed out of his historical context to take on almost absurd traits. Stereotypical and anti-historical aspects of these images of Smith were often detected in the past, but only recently have they become the subject of a critique that also involves the paradigmatic character of the Smith’s work. Taking into account this extraordinary wealth of new studies, the author proposes some reasons in favour of the interpretation of Smith as the theorist of capitalism and the father of political economy.  JEL Codes: B12Keywords: Adam Smith, political economy, capitalism

  7. Adams-Oliver syndrome, a successful conservative approach for a large scalp defect

    Directory of Open Access Journals (Sweden)

    Vera Baptista

    2015-12-01

    Full Text Available Adams-Oliver syndrome was first described in 1945 as a multiple congenital malformations association including aplasia cutis congenita and terminal transverse limb defects, along with cardiovascular and central nervous system anomalies. We report the case of a boy, prenatally diagnosed with a malformation of feet and right hand. At birth, a malformation of the skull was observed, at midline and right frontal, parietal and occipital region, with meningeal exposition. He presented with abnormal feet and right hand with hypoplastic fingers and also exhibiting cutis marmorata telangiectatica. Cardiac, abdominal and central nervous system malformations were excluded. He started a conservative approach based on daily dressings. The scalp defect closed at 4 months with this management strategy. At this age, a skull defect about 5 cm long was still perceptible by palpation of the area. The boy showed normal growth and neurologic development. No complications were reported. This report reinforces the effectiveness of conservative management strategies for extensive bone and epithelization defects in syndromes of aplasia cutis congenita like Adams-Oliver syndrome.

  8. Targeting CD13 (aminopeptidase-N) in turn downregulates ADAM17 by internalization in acute myeloid leukaemia cells

    OpenAIRE

    Bouchet, Sandrine; TANG, RUOPING; Fava, Fanny; Legrand, Ollivier; Bauvois, Brigitte

    2014-01-01

    Secreted matrix metalloproteinases (MMP)-2 and MMP-9 and membrane-anchored aminopeptidase-N/CD13 are abnormally expressed in human acute myeloid leukaemia (AML). We previously showed that CD13 ligation by anti-CD13 monoclonal antibodies can induce apoptosis in AML cells. Here, we assessed ADAM17 expression in primary blood blasts CD13+CD33+ from patients with AML. Primary AML cells expressed ADAM17 transcript and its surface expression was higher in subtype M4 (myelomonocytic) and M5 (monocyt...

  9. Lokalisation und Aktivierung von ADAM-Proteasen im Kontext der Fas-Ligand-Proteolyse in T-Zellen

    OpenAIRE

    Ebsen, Henriette

    2014-01-01

    Die Expression des Fas-Liganden wird u.a. durch posttranslationale Modifikationen reguliert, z.B. durch proteolytische Prozessierung. Die Aktivierung von T-Zellen durch TPA/Ionomycin bzw. T-Zellrezeptor/CD3/CD28-Stimulation führt zum gesteigerten Shedding durch die Metalloproteasen ADAM10 und/oder ADAM17. TZR/CD3/CD28-Aktivierung führt weiterhin zu einer partiellen Translokation der Proteasen und des FasL zu Detergenz-resistenten Membranen (DRMs). The expression of the death factor Fas Lig...

  10. Gambaran Penderita Demam Berdarah Dengue Pada Anak Di RSUP. H. Adam Malik Medan Tahun 2008-2010

    OpenAIRE

    Maurieza, Keishya

    2011-01-01

    Dengue Hemmoraghic Fever is still a major problem of infectious disease in a various parts of the world. The incidence rate of DHF in the city of medan is also high. The aims of this study to know the descriptions of patients with DHFamong children in RSUP. H. Adam Malik Medan in the year 2008-2010. These type of the researchis a descriptive study. The study was conducted in RSUP. H. Adam Malik Medan between the months of May to November 2010. The source data of this research were secondary d...

  11. Dynamic change of Adamalysin 19 (ADAM19) in human placentas and its effects on cell invasion and adhesion in human trophoblastic cells

    Institute of Scientific and Technical Information of China (English)

    SANG; QingXiang; Amy

    2009-01-01

    Human ADAM19 is a recently identified member of the ADAM family.It is highly expressed in human placentas,but its dynamic change and function at the human feto-maternal interface during placentation remain to be elucidated.In this present study,the spatial and temporal expression and cellular localization of ADAM19 in normal human placentas were first demonstrated,and the effects of ADAM19 on trophoblast cell adhesion and invasion were further investigated by using a human choriocarcinoma cell line(JEG-3) as an in vitro model.The data demonstrated that ADAM19 was widely distributed in villous cytotrophoblast cells,syncytiotrophoblast cells,column trophoblasts,and villous capillary endothelial cells during early pregnancy.The mRNA and protein level of ADAM19 in placentas was high at gestational weeks 8-9,but diminished significantly at mid-and term pregnancy.In JEG-3 cells,the overexpression of ADAM19 led to diminished cell invasion,as well as increases in cell adhesiveness and the expression of E-cadherin,with no changes in β-catenin expression observed.These data indicate that ADAM19 may participate in the coordinated regulation of human trophoblast cell behaviors during the process of placentation.

  12. Skin Barrier Defects Caused by Keratinocyte-Specific Deletion of ADAM17 or EGFR Are Based on Highly Similar Proteome and Degradome Alterations.

    Science.gov (United States)

    Tholen, Stefan; Wolf, Cristina; Mayer, Bettina; Knopf, Julia D; Löffek, Stefanie; Qian, Yawen; Kizhakkedathu, Jayachandran N; Biniossek, Martin L; Franzke, Claus-Werner; Schilling, Oliver

    2016-05-01

    Keratinocyte-specific deletion of ADAM17 in mice impairs terminal differentiation of keratinocytes leading to severe epidermal barrier defects. Mice deficient for ADAM17 in keratinocytes phenocopy mice with a keratinocyte-specific deletion of epidermal growth factor receptor (EGFR), which highlights the role of ADAM17 as a "ligand sheddase" of EGFR ligands. In this study, we aim for the first proteomic/degradomic approach to characterize the disruption of the ADAM17-EGFR signaling axis and its consequences for epidermal barrier formation. Proteomic profiling of the epidermal proteome of mice deficient for either ADAM17 or EGFR in keratinocytes at postnatal days 3 and 10 revealed highly similar protein alterations for ADAM17 and EGFR deficiency. These include massive proteome alterations of structural and regulatory components important for barrier formation such as transglutaminases, involucrin, filaggrin, and filaggrin-2. Cleavage site analysis using terminal amine isotopic labeling of substrates revealed increased proteolytic processing of S100 fused-type proteins including filaggrin-2. Alterations in proteolytic processing are supported by altered abundance of numerous proteases upon keratinocyte-specific Adam17 or Egfr deletion, among them kallikreins, cathepsins, and their inhibitors. This study highlights the essential role of proteolytic processing for maintenance of a functional epidermal barrier. Furthermore, it suggests that most defects in formation of the postnatal epidermal barrier upon keratinocyte-specific ADAM17 deletion are mediated via EGFR. PMID:27089454

  13. Analysis of the sediments of the Julian Adame Alatorre dam by the INAA; Analisis de sedimentos de la presa Julian Adame Alatorre por la tecnica de AANI

    Energy Technology Data Exchange (ETDEWEB)

    Oliva, J.E.; Lugo, J.F.; Mireles, F.; Quirino, L.L.; Davila, J.I.; Pinedo, J.L.; Rios, C. [UAZ, Cipres 10, Fracc. La Penuela, 98068 Zacatecas (Mexico); Miller, W.H. [Nuclear Science and Engineering Institute, E2433 Engineering Building East, University of Missouri-Columbia, MO 65211 (United States)]. e-mail: jeolivag@yahoo.com.mx

    2003-07-01

    Its were taken eight samples of sediment of the Julian Adame Alatorre dam located in the Villanueva municipality, in the State of Zacatecas, Mexico; with the end of determining the presence of elements of anthropogenic origin, as well as the concentration of the same ones. It was used the Instrumental neutron activation analysis (AANI) with a flow of thermal neutrons of 8 x 10{sup 13} and 5 x 10{sup 13} n cm{sup -2} s{sup -1}. With the purpose of determining the concentration of these elements at level of traces; finding presence of 32 elements among which its were find elements in greater concentrations and others at level of traces. Of these 32 elements, five of anthropogenic origin were identified which its were: Cr, Co, Zn, As and Mn; but that whose concentration is very low, in comparison with the one reported in other places of the world. In this work there are presented the obtained results of the elementary analysis of this samples. (Author)

  14. 78 FR 37791 - In the Matter of: Jose Guadalupe Reyes-Martinez, Inmate Number #85993-279, CI Adams County...

    Science.gov (United States)

    2013-06-24

    ... by successive Presidential Notices, the most recent being that of August 15, 2012 (77 FR 49699..., CI Adams County, Correctional Institution, P.O. Box 1600, Washington, MS 39190; Order Denying Export... November 21, 2021, Jose Guadalupe Reyes-Martinez, with a last known address at: Inmate Number 85993-279,...

  15. The disintegrin and metalloproteinase ADAM12 contributes to TGF-beta signaling through interaction with the type II receptor

    DEFF Research Database (Denmark)

    Atfi, Azeddine; Dumont, Emmanuelle; Colland, Frédéric;

    2007-01-01

    independent of its protease activity to facilitate the activation of TGF-beta signaling, including the phosphorylation of Smad2, association of Smad2 with Smad4, and transcriptional activation. Furthermore, ADAM12 induces the accumulation of TbetaRII in early endosomal vesicles and stabilizes the Tbeta...

  16. ADAM12 induces actin cytoskeleton and extracellular matrix reorganization during early adipocyte differentiation by regulating beta1 integrin function

    DEFF Research Database (Denmark)

    Kawaguchi, Nobuko; Sundberg, Christina; Kveiborg, Marie;

    2003-01-01

    Changes in cell shape are a morphological hallmark of differentiation. In this study we report that the expression of ADAM12, a disintegrin and metalloprotease, dramatically affects cell morphology in preadipocytes, changing them from a flattened, fibroblastic appearance to a more rounded shape. We...... early adipocyte differentiation....

  17. Kuidas meeldib välismaalastele Eestis [õppida]? / Shazia Javed, Charina de Asis, Adam Luke Vern-Barnett, Predrag Tasevski

    Index Scriptorium Estoniae

    2011-01-01

    Küsimusele vastasid välisüliõpilased: rahvusvahelisi suhteid õppiv Charina de Asis Filipiinidelt, magistriõppes rahvusvahelist õigust õppiv Adam Luke Vern-Barnett Austraaliast, küberkaitset õppiv Predrag Tasevski Makedooniast ja tarkvara arendust õppiv Shazia Javed Pakistanist

  18. 77 FR 25229 - Adams-Warnock Railway, Inc.-Lease and Operation Exemption-Norfolk Southern Railway Company

    Science.gov (United States)

    2012-04-27

    ... Surface Transportation Board Adams-Warnock Railway, Inc.--Lease and Operation Exemption-- Norfolk Southern... exemption under ] 49 CFR 1150.31 to lease from Norfolk Southern Railway Company (NSR), and to operate, a... the lease agreement that is expected to be completed prior to the effective date of the...

  19. Lightweight robotic mobility: template-based modeling for dynamics and controls using ADAMS/car and MATLAB

    Science.gov (United States)

    Adamczyk, Peter G.; Gorsich, David J.; Hudas, Greg R.; Overholt, James

    2003-09-01

    The U.S. Army is seeking to develop autonomous off-road mobile robots to perform tasks in the field such as supply delivery and reconnaissance in dangerous territory. A key problem to be solved with these robots is off-road mobility, to ensure that the robots can accomplish their tasks without loss or damage. We have developed a computer model of one such concept robot, the small-scale "T-1" omnidirectional vehicle (ODV), to study the effects of different control strategies on the robot's mobility in off-road settings. We built the dynamic model in ADAMS/Car and the control system in Matlab/Simulink. This paper presents the template-based method used to construct the ADAMS model of the T-1 ODV. It discusses the strengths and weaknesses of ADAMS/Car software in such an application, and describes the benefits and challenges of the approach as a whole. The paper also addresses effective linking of ADAMS/Car and Matlab for complete control system development. Finally, this paper includes a section describing the extension of the T-1 templates to other similar ODV concepts for rapid development.

  20. The Fire of Life. Adam Zagajewski’s poem “About My Mother”

    Directory of Open Access Journals (Sweden)

    Anna Czabanowska-Wróbel

    2012-01-01

    Full Text Available Any interpretation of one of the most personal poems written by Adam Zagajewski provides a good opportunity to reassess in the new light the elegiac, deeply personal body of his poetry, as well as the role of recollections and memory in the poet’s poetical and essayist writing. The work is interpreted not only within the parental context of the literary output of the author of the essay Lekka przesada [A slight exaggeration] (2011, but also against the background of the important theme in Polish poetry, including modern poetry, i.e. the motif of the mother. The title for the present sketch has been drawn from the essay The Fire of Life, the apology of poetry authored by Richard Rorty, and stresses its unique role in expressing human experience, indicated by the American philosopher.

  1. ADAM: Analysis of Discrete Models of Biological Systems Using Computer Algebra

    CERN Document Server

    Hinkelmann, Franziska; Guang, Bonny; McNeill, Rustin; Blekherman, Grigoriy; Veliz-Cuba, Alan; Laubenbacher, Reinhard

    2010-01-01

    Motivation: Many biological systems are modeled qualitatively with discrete models, such as probabilistic Boolean networks, logical models, bounded Petri nets, and agent-based models. Simulation is a common practice for analyzing discrete models, but many systems are far too large to capture all the relevant dynamical features through simulation alone. Results: We convert discrete models into algebraic models and apply tools from computational algebra to analyze their dynamics. The key feature of biological systems that is exploited by our algorithms is their sparsity: while the number of nodes in a biological network may be quite large, each node is affected only by a small number of other nodes. In our experience with models arising in systems biology and random models, this structure leads to fast computations when using algebraic models, and thus efficient analysis. Availability: All algorithms and methods are available in our package Analysis of Dynamic Algebraic Models (ADAM), a user friendly web-interf...

  2. Simulation Study of AC Contactor Dynamic Contacts Contact Pressure Based on ADAMS

    Directory of Open Access Journals (Sweden)

    Gu Yungao

    2015-01-01

    Full Text Available A multi-body dynamics simulation model of CJ20-25 AC contactor was established with Pro/E(Pro/Engineerin this paper. A coupling simulation with machine, electric, magnetic on the contactor has been achieved in this model. Dynamic parameters which were called use the secondary development technology of ADAMS. The dynamic contact pressure signal of an AC contactor was obtained with ADAMS’s own simultaneous solution such as electromagnetic suction, kinematics and dynamics equations. The simulation results and actual measurement of contactor contact pressure signals are very similar. However, the complexity of the measured contacts vibration is greater than the simulation results because the actual working condition is more complex. This result provides a theoretical foundation to the dynamic contacts contact pressure test.

  3. Adam Smith's invisible hand is unstable: physics and dynamics reasoning applied to economic theorizing

    Science.gov (United States)

    McCauley, Joseph L.

    2002-11-01

    Neo-classical economic theory is based on the postulated, nonempiric notion of utility. Neo-classical economists assume that prices, dynamics, and market equilibria are supposed to be derived from utility. The results are supposed to represent mathematically the stabilizing action of Adam Smith's invisible hand. In deterministic excess demand dynamics, however, a utility function generally does not exist mathematically due to nonintegrability. Price as a function of demand does not exist and all equilibria are unstable. Qualitatively, and empirically, the neo-classical prediction of price as a function of demand describes neither consumer nor trader demand. We also discuss five inconsistent definitions of equilibrium used in economics and finance, only one of which is correct, and then explain the fallacy in the economists’ notion of ‘temporary price equilibria’.

  4. The dynamic nature of the Adams ring arcs—Fraternite, Egalite (2,1), Liberte, Courage

    Science.gov (United States)

    Tsui, K. H.

    2007-11-01

    By considering the finite mass of Fraternite, the dynamic nature of the Adams ring arcs is regarded as caused by the reaction of a test body (a minor arc) through the Lindblad resonance (LR). Assuming the eccentricity of the test body is larger than that of Galatea, this generates several locations along the ring in the neighborhood of Fraternite where the time averaged force on a test body vanishes. These locations appear to correspond to the time dependent configuration of Egalite (2,1), Liberte, and Courage, and seem to be able to account for the dynamics of the arcs. Such a configuration is a dynamic one because the minor arcs are not bounded by the corotation eccentricity resonance (CER) externally imposed by Galatea, but are self-generated by LR reacting to the external fields.

  5. 2-dimensional modelling of the steam refomer of the ADAM/EVA II facility

    International Nuclear Information System (INIS)

    For the steam reformer of the ADAM/EVA II facility a 2-dimensional computer code is made, which includes local radiation quantities and by-pass circuits. Not only integral sizes (reaction, fission and temperature) and curve states as well as individual tube states are computable by this programme. It is shown that the experimental results are to understand very good with this model. For a steam reformer with NTIW-geometry in the 20 MW range the model was changed. Finally an anchor cooling is proposed to release the thermal-mechanical heavily loaded supporting structure. It is possible to describe quantitatively the cooling effect with the plotted computer code. It shows that the anchor wall temperature falls round about 50 K in a 5% cooling circuit. This could prevent the extension of anchors, as well as prolong the lifetime of the bundle and make possible the competence of license. (orig.)

  6. Simulation and analysis of vehicle stability based on ADAMS/CAR differential brake

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    To improve the braking safety of automobiles, the author studied the effect of differential brake on the stabilities. To analyze the mechanical characteristics of differential brake, automotive subsystem models were built by applying ADAMS/CAR, and automotive mechanics simulation model was built by setting the main subsystems such as body, engine and brake. The simulation model studied the distribution mode of three kinds of differential brake, and beeline braking stability and turning braking stability were simulated. It shows that differential brake can amend turning shortage of automobile brake and improve its braking stability, but the effect of automobile mass on its braking stability is great. So the distribution mode of braking force and the effect of mass change should be considered while differential brake is applied.

  7. Analysis of the sediments of the Julian Adame Alatorre dam by the INAA

    International Nuclear Information System (INIS)

    Its were taken eight samples of sediment of the Julian Adame Alatorre dam located in the Villanueva municipality, in the State of Zacatecas, Mexico; with the end of determining the presence of elements of anthropogenic origin, as well as the concentration of the same ones. It was used the Instrumental neutron activation analysis (AANI) with a flow of thermal neutrons of 8 x 1013 and 5 x 1013 n cm-2 s-1. With the purpose of determining the concentration of these elements at level of traces; finding presence of 32 elements among which its were find elements in greater concentrations and others at level of traces. Of these 32 elements, five of anthropogenic origin were identified which its were: Cr, Co, Zn, As and Mn; but that whose concentration is very low, in comparison with the one reported in other places of the world. In this work there are presented the obtained results of the elementary analysis of this samples. (Author)

  8. ADAM Project – A generic web interface for retrieval and display of ATLAS TDAQ information.

    CERN Document Server

    Harwood, A; The ATLAS collaboration; Lehmann Miotto, G

    2011-01-01

    This paper describes a new approach to the visualization of stored information about the operation of the ATLAS Trigger and Data Acquisition system. ATLAS is one of the two general purpose detectors positioned along the Large Hadron Collider at CERN. Its data acquisition system consists of several thousand computers interconnected via multiple gigabit Ethernet networks, that are constantly monitored via different tools. Operational parameters ranging from the temperature of the computers, to the network utilization are stored in several databases for a posterior analysis. Although the ability to view these data-sets individually is already in place, there currently is no way to view this data together, in a uniform format, from one location. The ADAM project has been launched in order to overcome this limitation. It defines a uniform web interface to collect data from multiple diversely structured providers. It is capable of aggregating and correlating the data according to user defined criteria. Finally it v...

  9. The ADAM project: a generic web interface for retrieval and display of ATLAS TDAQ information.

    CERN Document Server

    Harwood, A; The ATLAS collaboration; Magnoni, L; Vandelli, W; Savu, D

    2011-01-01

    This paper describes a new approach to the visualization of stored information about the operation of the ATLAS Trigger and Data Acquisition system. ATLAS is one of the two general purpose detectors positioned along the Large Hadron Collider at CERN. Its data acquisition system consists of several thousand computers interconnected via multiple gigabit Ethernet networks, that are constantly monitored via different tools. Operational parameters ranging from the temperature of the computers to the network utilization are stored in several databases for later analysis. Although the ability to view these data-sets individually is already in place, currently there is no way to view this data together, in a uniform format, from one location. The ADAM project has been launched in order to overcome this limitation. It defines a uniform web interface to collect data from multiple providers that have different structures. It is capable of aggregating and correlating the data according to user defined criteria. Finally, ...

  10. ADAM17 promotes proliferation of collecting duct kidney epithelial cells through ERK activation and increased glycolysis in polycystic kidney disease.

    Science.gov (United States)

    Beck Gooz, Monika; Maldonado, Eduardo N; Dang, Yujing; Amria, May Y; Higashiyama, Shigeki; Abboud, Hanna E; Lemasters, John J; Bell, P Darwin

    2014-09-01

    Polycystic kidney disease (PKD) is a common genetic disorder leading to cyst formation in the kidneys and other organs that ultimately results in kidney failure and death. Currently, there is no therapy for slowing down or stopping the progression of PKD. In this study, we identified the disintegrin metalloenzyme 17 (ADAM17) as a key regulator of cell proliferation in kidney tissues of conditional knockout Ift88(-/-) mice and collecting duct epithelial cells from Ift88°(rpk) mice, animal models of autosomal recessive polycystic kidney disease (ARPKD). Using Western blotting, an enzyme activity assay, and a growth factor-shedding assay in the presence or absence of the specific ADAM17 inhibitor TMI-005, we show that increased expression and activation of ADAM17 in the cystic kidney and in collecting duct epithelial cells originating from the Ift88°(rpk) mice (designated as PKD cells) lead to constitutive shedding of several growth factors, including heparin-binding EGF-like growth factor (HB-EGF), amphiregulin, and transforming growth factor-α (TGF-α). Increased growth factor shedding induces activation of the EGFR/MAPK/ERK pathway and maintains higher cell proliferation rate in PKD cells compared with control cells. PKD cells also displayed increased lactate formation and extracellular acidification indicative of aerobic glycolysis (Warburg effect), which was blocked by ADAM17 inhibition. We propose that ADAM17 is a key promoter of cellular proliferation in PKD cells by activating the EGFR/ERK axis and a proproliferative glycolytic phenotype. PMID:24899059

  11. The SPECT tracer [123I]ADAM binds selectively to serotonin transporters: a double-blind, placebo-controlled study in healthy young men

    International Nuclear Information System (INIS)

    The tracer 123I-2-([2-({dimethylamino}methyl)phenyl]thio)-5-iodophenylamine ([123I]ADAM) has been developed to image serotonin transporters (SERTs) with SPECT. Preclinical studies have shown that [123I]ADAM binds selectively to SERTs. Moreover, initial human studies have shown that [123I]ADAM binding could be blocked by selective serotonin reuptake inhibitors (SSRIs). However, in humans it has not been proven that [123I]ADAM binds selectively to SERTs. We examined the in vivo availability of SERTs in 12 healthy young volunteers 5 h after bolus injection of [123I]ADAM. To evaluate the selectivity of binding, four participants were pretreated (double-blinded design) with placebo, four with paroxetine (20 mg) and four with the dopamine/norepinephrine blocker methylphenidate (20 mg). SPECT studies were performed on a brain-dedicated system (Neurofocus), and the SPECT images were coregistered with individual MR scans of the brain. ADAM binding in SERT-rich brain areas and cerebellar cortex (representing non-specific binding) was assessed by drawing regions of interest (ROIs) on the individual MR images. Specific to non-specific ratios were used as the outcome measure. We found that specific to non-specific ratios were statistically significantly lower in paroxetine-pretreated participants than in placebo- or methylphenidate-pretreated participants. No such difference was found between groups pretreated with placebo or methylphenidate. Our preliminary findings suggest that [123I]ADAM binds selectively to SERTs in human brain. (orig.)

  12. A new approach to sharp Moser-Trudinger and Adams type inequalities: A rearrangement-free argument

    Science.gov (United States)

    Lam, Nguyen; Lu, Guozhen

    The main purpose of this paper is two-fold. On the one hand, we will develop a new approach to establish sharp singular Moser-Trudinger and Adams type inequalities in unbounded domains of Euclidean spaces without using the standard symmetrization. On the other hand, we will prove the sharp singular Adams type inequality on high order Sobolev spaces W(Rn) of arbitrary integer order m (Theorem 1.1) which improves the results of Ruf and Sani (2013) [48] where sharp Adams inequalities were established for even m and those of the authors (Lam and Lu, 2012 [28,29]) for odd m but with different and more restricted norms. We first establish the sharp local singular Adams inequality on domains Ω in Rn of finite measure (Theorem 1.4). We take a perspective that any function in the high order Sobolev spaces W(Rn) can be represented as a Bessel potential. Thus, we can fully use the tools from harmonic analysis and the kernel properties of the polyharmonic operators (. Once we have established this sharp local Adams inequality, then we can adapt the rearrangement-free method we will develop in this paper to derive a global sharp Adams inequality from a local one. Our argument substantially simplifies those in Ruf and Sani (2013) [48] and Lam and Lu (2012) [28,29] and avoids the use of rather deep and complicated comparison principle of solutions to polyharmonic operators used in Ruf and Sani (2013) [48], Lam and Lu (2012) [28,29]. Moreover, our theorem holds on Sobolev spaces W(Rn) of any positive fractional order αinequalities with less restrictions on the Sobolev norms (see Theorems 1.2, 1.3 and 1.5). Our approach is surprisingly simple and general and can be easily applied to scenarios such as Riemannian and sub-Riemannian manifolds where symmetrization argument does not work (see, e.g., on the Heisenberg group Lam and Lu (2012) [30]).

  13. N-terminal cleavage and release of the ectodomain of Flt1 is mediated via ADAM10 and ADAM 17 and regulated by VEGFR2 and the Flt1 intracellular domain.

    Directory of Open Access Journals (Sweden)

    Nandita S Raikwar

    Full Text Available Flt is one of the cell surface VEGF receptors which can be cleaved to release an N-terminal extracellular fragment which, like alternately transcribed soluble Flt1 (sFlt1, can antagonize the effects of VEGF. In HUVEC and in HEK293 cells where Flt1 was expressed, metalloprotease inhibitors reduced Flt1 N-terminal cleavage. Overexpression of ADAM10 and ADAM17 increased cleavage while knockdown of ADAM10 and ADAM17 reduced N-terminal cleavage suggesting that these metalloproteases were responsible for Flt1 cleavage. Protein kinase C (PKC activation increased the abundance and the cleavage of Flt1 but this did not require any residues within the intracellular portion of Flt1. ALLN, a proteasomal inhibitor, increased the abundance of Flt1 which was additive to the effect of PKC. Removal of the entire cytosolic region of Flt1 appeared to stimulate cleavage of Flt1 and Flt1 was no longer sensitive to ALLN suggesting that the cytosolic region contained a degradation domain. Knock down of c-CBL, a ring finger ubiquitin ligase, in HEK293 cells increased the expression of Flt1 although it did not appear to require a previously published tyrosine residue (1333Y in the C-terminus of Flt1. Increasing VEGFR2 expression increased VEGF-stimulated sFlt1 expression and progressively reduced the cleavage of Flt1 with Flt1 staying bound to VEGFR2 as a heterodimer. Our results imply that secreted sFlt1 and cleaved Flt1 will tend to have local effects as a VEGF antagonist when released from cells expressing VEGFR2 and more distant effects when released from cells lacking VEGFR2.

  14. The cysteine-rich domain of human ADAM 12 supports cell adhesion through syndecans and triggers signaling events that lead to beta1 integrin-dependent cell spreading

    DEFF Research Database (Denmark)

    Iba, K; Albrechtsen, R; Gilpin, B;

    2000-01-01

    spread on ADAM 12. However, spreading could be efficiently induced by the addition of either 1 mM Mn(2+) or the beta1 integrin-activating monoclonal antibody 12G10, suggesting that in these carcinoma cells, the ADAM 12-syndecan complex fails to modulate the function of beta1 integrin.......-dependent manner attach to ADAM 12 via members of the syndecan family. After binding to syndecans, mesenchymal cells spread and form focal adhesions and actin stress fibers. Integrin beta1 was responsible for cell spreading because function-blocking monoclonal antibodies completely inhibited cell spreading, and...... chondroblasts lacking beta1 integrin attached but did not spread. These data suggest that mesenchymal cells use syndecans as the initial receptor for the ADAM 12 cysteine-rich domain-mediated cell adhesion, and then the beta1 integrin to induce cell spreading. Interestingly, carcinoma cells attached but did not...

  15. Record of Decision for the Final Remedial Action for the Rocky Mountain Arsenal Offpost Unit in southern Adams County, Commerce City, Colorado

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — This decision document presents the selected remedial action for the Rocky Mountain Arsenal (RMA) Offpost Operable Unit (OU) in southern Adams County, east of...

  16. Polyaza crown ether as non-nucleosidic building blocks in DNA-conjugates

    DEFF Research Database (Denmark)

    Jakobsen, Ulla; Rohr, Katja; Madsen, Rasmus K;

    2007-01-01

    The synthesis of amphiphilic polyaza crown ether monomers X (palmityl-substituted), Y (cholesteryl-substituted) and Z (dipalmityl-subtituted) and their incorporation into oligonucleotides are described. Their effects on thermal duplex stability were investigated by UV melting curve analysis. Ther...

  17. Exploring isoxazole and carboxamide derivatives as potential non-nucleoside reverse transcriptase inhibitors.

    Science.gov (United States)

    Kurup, Sudheer S; Joshi, Kaustubh A

    2016-04-01

    Nonnucleoside reverse transciptase inhibitors (NNRTI) are a class of drug molecules with a specific target of HIV-1 reverse transcriptase (RT). In the present work, we evaluated a set of selected oxazole and carboxamide derivatives to identify potential pharmacophoric features using molecular docking approach. The docking approach employed has been validated by enrichment factor calculation at top 1% (EF1%). It shows a considerable improvement in EF1%value compared to earlier reported study carried out on specific dataset of ligands and decoys for RT, in the directory of useful decoys (DUD). The carboxamide derivatives show better activity as NNRT inhibitors than oxazole derivatives. From this study, four pharmacophoric groups including a triazine ring, an aniline substituent, a benzyl amide moiety and a trimethylphenoxy substituent have been recognized and used for designing new NNRT inhibitors. Newly designed molecules show significant enhancement in docking scores over the native ligand, parent and other training set molecules. In addition, some functional groups have also been identified to assist in improving the activity of these pharmacophores. Thus a nitrile group, an amide and fluoro substitution turn out to be an important requisite for NNRT potential inhibitors. PMID:26973048

  18. Synthesis of Novel Uracil Non-Nucleoside Derivatives as Potential Reverse Transcriptase Inhibitors of HIV-1

    DEFF Research Database (Denmark)

    El-Brollosy, Nasser R.; Al-Deeb, Omar. A.; El-Emam, Ali A.;

    2009-01-01

    with cyclopropylmethyloxymethyl 9a-d, 2-phenylethyloxymethyl 9e-h, and 3-phenylprop-1-yloxymethyl 9i-l were prepared on treatment of the corresponding uracils with the appropriate acetals 8a-c. Some of the tested compounds showed good activity against HIV-1 wild type. Among them, 1-cyclopropylmethyloxymethyl-5-ethyl-6...

  19. Discovery of potent HIV-1 non-nucleoside reverse transcriptase inhibitors from arylthioacetanilide structural motif.

    Science.gov (United States)

    Li, Wenxin; Li, Xiao; De Clercq, Erik; Zhan, Peng; Liu, Xinyong

    2015-09-18

    The poor pharmacokinetics, side effects and particularly the rapid emergence of drug resistance compromise the efficiency of the clinically used anti-HIV drugs. Therefore, the discovery of novel and effective NNRTIs is still an extremely primary mission. Arylthioacetanilide family is one of the highly active HIV-1 NNRTIs against wide-type (WT) HIV-1 and a wide range of drug-resistant mutant strains. Especially, VRX-480773 and RDEA806 have been chosen as candidates for further clinical studies. In this article, we review the discovery and development of the arylthioacetanilides, and, especially, pay much attention to the structural modifications, SARs conclusions and molecular modeling. Moreover, several medicinal chemistry strategies to overcome drug resistance involved in the optimization process of arylthioacetanilides are highlighted, providing valuable clues for further investigations. PMID:26276432

  20. Optimization of 2,4-Diarylanilines as Non-nucleoside HIV-1 Reverse Transcriptase Inhibitors

    OpenAIRE

    Sun, Lian-Qi; Qin, Bingjie; Huang, Li; Qian, Keduo; Chen, Chin-Ho; Lee, Kuo-Hsiung; Xie, Lan

    2012-01-01

    The current optimization of 2,4-diarylaniline analogs (DAANs) on the central phenyl ring provided a series of new active DAAN derivatives 9a–9e, indicating an accessible modification approach that could improve anti-HIV potency against wild-type and resistant strains, aqueous solubility, and metabolic stability. A new compound 9e not only exhibited extremely high potency against wild-type virus (EC50 0.53 nM) and several resistant viral strains (EC50 0.36 – 3.9 nM), but also showed desirable ...

  1. Discovery of diarylpyridine derivatives as novel non-nucleoside HIV-1 reverse transcriptase inhibitors

    OpenAIRE

    Tian, Xingtao; Qin, Bingjie; LU, Hong; Lai, Weihong; Jiang, Shibo; Lee, Kuo-Hsiung; Ho Chen, Chin; Xie, Lan

    2009-01-01

    Two series (4 and 5) of diarylpyridine derivatives were designed, synthesized, and evaluated for anti-HIV-1 activity. The most promising compound, 5e, inhibited HIV-1 IIIB, NL4-3, and RTMDR1 with low nanomolar EC50 values and selectivity indexes of >10,000. The results of this study indicate that diarylpyridine can be used as a novel scaffold to derive a new class of potent NNRTIs, active against both wild-type and drug resistant HIV-1 strains.

  2. Characterization of 4-[18F]-ADAM as an imaging agent for SERT in non-human primate brain using PET: a dynamic study

    International Nuclear Information System (INIS)

    Introduction: Serotonin transporter (SERT) has been associated with many psychiatric diseases. This study investigated the biodistribution of a serotonin transporter imaging agent, N,N-dimethyl-2-(2-amino-4-18F-fluorophenylthio)benzylamine (4-[18F]-ADAM), in nonhuman primate brain using positron emission tomography (PET). Methods: Six and four Macaca cyclopis monkeys were used to determine the transit time (i.e., time necessary to reach biodistribution equilibrium) and the reproducibility of 4-[18F]-ADAM biodistribution in the brain, respectively. The sensitivity and specificity of 4-[18F]-ADAM binding to SERT were evaluated in one monkey challenged with different doses of fluoxetine and one monkey treated with 3,4-methylendioxymethamphetamine (MDMA). Dynamic PET imaging was performed for 3 h after 4-[18F]-ADAM intravenous bolus injection. The specific uptake ratios (SURs) in the midbrain (MB), thalamus (TH), striatum (ST) and frontal cortex (FC) were calculated. Results: The distribution of 4-[18F]-ADAM reached equilibrium 120–150 min after injection. The mean SURs were 2.49±0.13 in MB, 1.59±0.17 in TH, 1.35±0.06 in ST and 0.34±0.03 in FC, and the minimum variability was shown 120–150 min after 4-[18F]-ADAM injection. Using SURs and intraclass coefficient of correlation, the test/retest variability was under 8% and above 0.8, respectively, in SERT-rich areas. Challenge with fluoxetin (0.75–2 mg) dose-dependently inhibited the SURs in various brain regions. 4-[18F]-ADAM binding was markedly reduced in the brain of an MDMA-treated monkey compared to that in brains of normal controls. Conclusion: 4-[18F]-ADAM appears to be a highly selective radioligand for imaging SERT in monkey brain.

  3. Kejadian Infeksi Luka Episiotomi Dan Pola Bakteri Pada Persalinan Normal Di RSUP.H.Adam Malik Dan RSUD. Dr. Pirngadi Medan

    OpenAIRE

    Sim Romi

    2009-01-01

    Tujuan : untuk memberikan informasi mengenai kejadian infeksi luka episiotomi dan pola bakteri pada persalinan normal di RSUP. H. Adam Malik dan RSUD. Dr. Pirngadi Medan, serta hasil uji kepekaan terhadap berbagai jenis antibiotika dari bakteri yang ditemukan. Rancangan Penelitian : Penelitian dilakukan dengan menggunakan rancangan observasional dengan pendekatan potong lintang (cross sectional) yang dilakukan pada semua ibu yang melahirkan normal di kamar bersalin RSUP. H. Adam Malik da...

  4. Analisis Pengaruh Lingkungan Kerja Dan Karakteristik Pekerjaan Terhadap Motivasi Kerja Karyawan Bagian Akuntansi Dan Verifikasi Di RSUP H.Adam Malik Medan

    OpenAIRE

    Sitohang, Ivory M. M

    2013-01-01

    This research aimed to find factors that affect employee motivation of Accounting and Verification Department of H. Adam Malik Public Hospital Medan. Those factors were work environment and job characteristics. Employees who have a high motivation to work will have a positive effect for the organization, therefore organization purpose reached. Hypothesis examination carries out by spreads the questionnaire about 34 employees of Accounting and Verification Department of H. Adam Malik Medan ...

  5. Book Review: Happiness and place: why life is better outside of the city by Adam Okulicz-Kozaryn

    OpenAIRE

    Meyer, William B.

    2015-01-01

    In Happiness and Place: Why Life is Better Outside of the City, Adam Okulicz-Kozaryn challenges the assumption that urban life is most conducive to happiness and wellbeing, arguing that cities are stressful, dissatisfying and inhibit connection with other humans and nature. While William B. Meyer praises this book as a useful and lively challenge to social science orthodoxy that tends to vaunts the urban, he suggests that its thesis, largely centred on the US case, requires further evidence t...

  6. Association of ADAM33 gene polymorphisms with adult-onset asthma and its severity in an Indian adult population

    Indian Academy of Sciences (India)

    Priya Tripathi; Shally Awasthi; Rajendra Prasad; Nuzhat Husain; Subramaniam Ganesh

    2011-08-01

    ADAM33, a member of the ADAM (a disintegrin and metalloprotease) gene family, is an asthma susceptibility gene originally identified by positional cloning. In the present study, we investigated the possible association of five single-nucleotide polymorphisms (SNPs) in the ADAM33 (rs511898, rs528557, rs44707, rs597980 and rs2787094) with adult-onset asthma in an Indian population. The study included 175 patients with mild intermittent ($n = 44$), mild persistent ($n = 108$) or moderate persistent ($n = 23$) subgroups of asthma, and 253 nonasthmatic control individuals. SNPs were genotyped with the help of restriction fragment length polymorphism polymerase chain reaction (RFLP-PCR) method, and data were analysed using chi-square test and logistic regression model. Bonferroni’s correction for multiple comparisons was applied for each hypothesis. Genotypes and allele frequencies of SNPs rs511898 and rs528557 were significantly associated with adult-onset asthma ($P = 0.010-\\lt 0.001$). A significant association of the homozygous mutant genotype and mutant alleles of SNPs rs2787094, rs44707 and rs597980 with the asthma was also observed ($P = 0.020-\\lt 0.001$). A positive association between asthma and haplotypes AGCCT, GGCCT, AGACT, GCAGT, GGACT, ACCCC and AGACC were also found ($P = 0.036-\\lt 0.001$, OR $= 2.07-8.49$). Haplotypes AGCGT, GCAGC, ACAGC, ACAGT, GGAGC and GGCGT appear to protect against asthma ($P = 0.013-\\lt 0.0001$, OR $= 0.34-0.10$). Our data suggest that ADAM33 gene polymorphisms serve as genetic risk factors for asthma in Indian adult population.

  7. The Inner Man and his Deed: Jerzy Grotowski and the legacy of Adam Mickiewicz and polish romanticism

    Directory of Open Access Journals (Sweden)

    Kris Salata

    2013-03-01

    Full Text Available This article locates Grotowski in a concrete cultural milieu of Polish Romanticism and of the lifework of the Romantic poet Adam Mickiewicz. The bulk of my focus goes towards the notion of the deed and the act of doing that dematerialises the work of art turning it into an inner process – all features of Mickiewicz’s and Grotowski’s projects.

  8. Type II Diabetic Control and Prevalence in Tegucigalpa, Honduras: Patients of the James Moody Adams Clinic at the Baxter Institute

    OpenAIRE

    Magalhaes, Edward Pereira

    2011-01-01

    The purpose of this study was to determine the prevalence of known risk factors associated with diabetes among James Moody Adams (JMA) clinic patients in order to develop and test educational material and clinical interventions to reduce the incidence of pre-diabetes and uncontrolled Type II Diabetes. The research objectives for this study focused on: 1. prevalence of Type II Diabetic patients at the Clinic; 2. pre- and post-test knowledge level of patients regarding their Type II Diabetes; ...

  9. Hubungan Dukungan Keluarga Dengan Harga Diri Pasien Kanker Payudara Yang Menjalani Kemoterapi Di RSUP H. Adam Malik Medan

    OpenAIRE

    Siburian, Christine Handayani

    2013-01-01

    Family support is a valuable support for individuals from his family. Self-esteem is result of acceptance or rejection of the individual against himself. The purpose of this research is to identify family support and self-esteem correlation of patient with chemotherapy breast cancer in RSUP H. Adam Malik Medan during February to March 2012. The research design applied descriptive correlation. Sampling technique in research was Purposive Sampling with 30 respondens. The research instruments us...

  10. Karakteristik Penderita Asma Bronkial Dewasa Rawat Inap di RSUP H. Adam Malik Medan Tahun 1999-2001

    OpenAIRE

    Tobing, Martha D.L.

    2013-01-01

    Asma tercatat sebagai penyebab kematian nomor tiga pada penyakit saluran pernafasan. Prevalensinya di Indonesia diperkirakan 3-8% dari jumlah penduduk. Tahun 2002 penderita asma di Medan telah mencapai 4,4% dari jumlah penduduk Medan. Untuk mengetahui karakteristik penderita asma di RSUP H. Adam Malik Medan telah dilakukan penelitian yang bersifat cross sectional. Sebagai sampel adalah seluruh populasi asma bronkial dewasa rawat inap tahun 1999-2001 yang bejumlah 95 orang. Sumber dat...

  11. Angka Kejadian Mukositis Oral pada Anak Menderita Leukemia Limfoblastik Akut yang Menjalani Kemoterapi di RSUP Haji Adam Malik Medan

    OpenAIRE

    Azmi, Rommanah binti

    2015-01-01

    Acute Lymphoblastic Leukemia (ALL) accounts for 70-80% of childhood leukemias. One of the main treatments for ALL is chemotherapy. One of the most common side effects of chemotherapy is oral mucositis. Oral mucositis is an inflammation of the oral mucosa which leads to erythematous and ulcerative lesions. This study describes the incidence of oral mucositis in children with ALL undergoing chemotherapy in Haji Adam Malik Hospital during 2008-2012. This is a descriptive study with cross- sec...

  12. Prevalensi Nyeri Kepala Setelah Punksi Dura Pasca Anestesi Spinal Pada Operasi Elektif Di Rsup Haji Adam Malik Medan Tahun 2013

    OpenAIRE

    Ongko, Eric Gradiyanto

    2016-01-01

    PDPH (post-dural puncture headache) is one of the most common complication from spinal anesthesia. PDPH is a complication that should not be treated lightly. There is the potential for considerable morbidity. The purpose of this research is to know the prevalence of the post-dural puncture headache after spinal anesthesia on elective surgery at RSUP Haji Adam Malik in Medan 2013. There are sixty-four samples were taken with consecutive sampling as the sampling technique. Data were collect...

  13. Laporan Praktik Kerja Profesi Apoteker Farmasi Rumah Sakit di Rumah Sakit Umum Pusat Haji Adam Malik Medan

    OpenAIRE

    Ramadhani, Nurul Laili

    2015-01-01

    Praktik Kerja Profesi Apoteker (PKPA) farmasi rumah sakit di RSUP H. Adam Malik telah selesai dilakukan. Praktik Kerja Profesi Apoteker (PKPA) ini bertujuan agar apoteker dapat mempelajari pengelolaan farmasi rumah sakit sesuai dengan ketentuan yang berlaku didalam sistem pelayanan kefarmasian di Rumah Sakit. Praktik kerja profesi apoteker (PKPA) dilaksanakan pada tanggal pada 15 April 2014 s/d 14 Juni 2014. Kegiatan PKPA di rumah sakit meliputi melihat peran Instalasi Farmasi Rumah Sakit (IF...

  14. Gottes-Bilder und ökonomische Theorie: Naturtheologie und Moralität bei Adam Smith

    OpenAIRE

    Ötsch, Walter O.

    2006-01-01

    Viele neoliberale Kommentaren (zum Begriff vgl. Walpen 2004, S. 62ff.) und die meisten Lehrbücher der Mikroökonomie preisen Adam Smith als den theoretischen Begründer der Marktwirtschaft bzw. des Kapitalismus und stellen ihr eigenes Denken in eine kontinuierliche Tradition mit ihm. Im Gegensatz dazu muss Smith, das ist mein Ausgangspunkt, im Kontext seiner Zeit und ihrer philosophischen und moraltheoretischen Hintergründe betrachtet werden, - sie widersprechen gängigen neoliberalen und neokla...

  15. Ludological research traditions in the Institute of Applied Linguistics at Adam Mickiewicz University in Poznań

    OpenAIRE

    Surdyk, Augustyn

    2011-01-01

    This paper aims to introduce briefly the basic assumptions of ludology as an academic discipline dealing with games research (including educational linguistic and communicational games in teaching foreign languages) and to present the achievements of the Games Research Association of Poland being the first ludological association in Poland, and closely cooperating with the Institute of Applied Linguistics at Adam Mickiewicz University in Poznań. The paper also summarises that cooperation a...

  16. Detrital zircon geochronology of the Adams Argillite and Nation River Formation, east-central Alaska, U.S.A

    Science.gov (United States)

    Gehrels, G.E.; Johnsson, M.J.; Howell, D.G.

    1999-01-01

    The Cambrian Adams Argillite and the Devonian Nation River Formation are two sandstone-bearing units within a remarkably complete Paleozoic stratigraphic section in east-central Alaska. These strata, now foreshortened and fault-bounded, were originally contiguous with miogeoclinal strata to the east that formed as a passive-margin sequence along the northwestern margin of the North American continent. Seventy-five detrital zircon grains from the Adams Argillite and the Nation River Formation were analyzed in an effort to provide constraints on the original sources of the grains, and to generate a detrital zircon reference for miogeoclinal strata in the northern Cordillera. Thirty-five single zircon grains from a quartzite in the Adams Argillite yield dominant age clusters of 1047-1094 (n = 6), 1801-1868 (n = 10), and 2564-2687 (n = 5) Ma. Forty zircons extracted from a sandstone in the Nation River Formation yield clusters primarily of 424-434 (n = 6), 1815-1838 (n = 6), 1874-1921 (n = 7), and 2653-2771 (n = 4) Ma. The Early Proterozoic and Archean grains in both units probably originated in basement rocks in a broad region of the Canadian Shield. In contrast, the original igneous sources for mid-Protcrozoic grains in the Adams Argillite and ??? 430 Ma grains in the Nation River Formation are more difficult to identify. Possible original sources for the mid-Proterozoic grains include: (1) the Grenville Province of eastern Laurentia, (2) the Pearya terrane along the Arctic margin, and (3) mid-Proterozoic igneous rocks that may have been widespread along or outboard of the Cordilleran margin. The ??? 430 Ma grains may have originated in: (1) arc-type sources along the Cordilleran margin, (2) the Caledonian orogen, or (3) a landmass, such as Pearya, Siberia, or crustal fragments now in northern Asia, that resided outboard of the Innuitian orogen during mid-Paleozoic time. Copyright ?? 1999, SEPM (Society for Sedimentary Geology).

  17. Biodistribution and radioimmunoimage of iodine-125 labeled anti-human ADAM15 polyclonal antibody in nude mice bearing human gastric carcinoma xenografts

    International Nuclear Information System (INIS)

    Objective: To investigate the biodistribution of Iodine-125 labeled anti-human ADAM15 polyclonal antibody in nude mice bearing human gastric carcinoma xenografts. Methods: The anti-human ADAM15 polyclonal antibody was labeled with I-125 using Chloramine-T method. The labeling efficiency and radiochemical purity of 125I-anti-ADAM15 antibody were measured. The SPECT planar imaging of nude mice bearing gastric carcinoma xenografts were performed at 1, 4, 8, 24, and 48 h post-injection and the biodistribution of 125I-anti-ADAM15 antibody was measured at 48 h after injection. Results: The labeling efficiency of 125I-anti-ADAM15 antibody was (75.16±9.43)% and its radiochemical purity was (99.44±0.21)% . Tumors could be cleanly visualized in SPECT planar images, and the radioactivity ratio of tumor to non-tumor tissue was 3.84±0.43 at 48 h post-injection. Conclusion: 125I-anti-ADAM15 antibody can target the gastric carcinoma in vivo, and provide good radioimmunoimages. (authors)

  18. Posttranslational proteolytic processing of Leda-1/Pianp involves cleavage by MMPs, ADAM10/17 and gamma-secretase.

    Science.gov (United States)

    Biswas, Siladitta; Adrian, Monica; Weber, Jochen; Evdokimov, Konstantin; Winkler, Manuel; Géraud, Cyrill

    2016-09-01

    Leda-1/Pianp is a type I transmembrane protein expressed by CNS cells, murine melanoma cell line B16F10 and rat liver sinusoidal endothelial cells. The early steps of posttranslational modifications of Leda-1/Pianp have been described to include glycosylation and processing by proprotein convertases. Here, we comprehensively characterized the subsequent steps of proteolytic processing of Leda-1/Pianp. For this purpose specific protease inhibitors and cell lines deficient in PS1, PS2, PS1/PS2 and ADAM10/17 were deployed. Leda-1/Pianp was cleaved at numerous cleavage sites within the N-terminal extracellular domain. The sheddases involved included MMPs and ADAM10/17. Ectodomain shedding yielded C-terminal fragments (CTF) of ∼15 kDa. The CTF was further processed by the γ (gamma)-secretase complex to generate the intracellular domain (ICD) of ∼10 kDa. Although PS1 was the dominant intramembrane protease, PS2 was also able to cleave Leda-1/Pianp in the absence of PS1. Thus, Leda-1/Pianp is constitutively processed by proprotein convertases, sheddases including MMPs and ADAM10/17 and intramembrane protease γ-secretase. PMID:27349870

  19. Solving Directly Two Point Non Linear Boundary Value Problems Using Direct Adams Moulton Method

    Directory of Open Access Journals (Sweden)

    Zanariah A. Majid

    2011-01-01

    Full Text Available Problem statement: In this study, a direct method of Adams Moulton type was developed for solving non linear two point Boundary Value Problems (BVPs directly. Most of the existence researches involving BVPs will reduced the problem to a system of first order Ordinary Differential Equations (ODEs. This approach is very well established but it obviously will enlarge the systems of first order equations. However, the direct method in this research will solved the second order BVPs directly without reducing it to first order ODEs. Approach: Lagrange interpolation polynomial was applied in the derivation of the proposed method. The method was implemented using constant step size via shooting technique in order to determine the approximated solutions. The shooting technique will employ the Newton’s method for checking the convergent of the guessing values for the next iteration. Results: Numerical results confirmed that the direct method gave better accuracy and converged faster compared to the existing method. Conclusion: The proposed direct method is suitable for solving two point non linear boundary value problems.

  20. Kinematic characterization and optimization of vehicle front-suspension design based on ADAMS

    Institute of Scientific and Technical Information of China (English)

    YU Hai-bo; LI You-de; MEN Yu-zhuo

    2008-01-01

    To improve the suspension performance and steering stability of light vehicles, we built a kinematic simulation model of a whole independent double-wishbone suspension system by using ADAMS software, created random excitations of the test platforms of respectively the left and the right wheels according to actual running conditions of a vehicle, and explored the changing patterns of the kinematic characteristic parameters in the process of suspension motion. The irrationality of the suspension guiding mechanism design was pointed out through simulation and analysis, and the existent problems of the guiding mechanism were optimized and calculated. The results show that all the front-wheel alignment parameters, including the camber, the toe, the caster and the inclination, only slightly change within corresponding allowable ranges in design before and after optimization. The optimization reduces the variation of the wheel-center distance from 47.01 mm to a change of 8.28 mm within the allowable range of -10 mm to 10 mm, promising an improvement of the vehicle steering stability. The optimization also confines the front-wheel sideways slippage to a much smaller change of 2.23 mm; this helps to greatly reduce the wear of tires and assure the straight running stability of the vehicle.

  1. No Child Left Behind: The Adam Walsh Act and Pennsylvania Juvenile Sex Offenders

    Directory of Open Access Journals (Sweden)

    Neal F. Wilson

    2008-04-01

    Full Text Available At a White House ceremony on July 27, 2006, President Bush signed into law the Adam Walsh Child Protection and Safety Act of 2006. At the ceremony, the President hailed the Walsh Act as being comprehensive and an important part of the “solemn responsibility” of lawmakers to protect children. Indeed, the Walsh Act is the latest in a series of federal legislation, dating back to the 1980s, which aims to protect the public, and children in particular, from becoming victims of sexual crimes. The public’s fear of the rapist and the child molester led to a great increase in the criminal penalties for sexual crimes throughout the 1980s and 1990s, as well as the imposition of federal laws focusing on these crimes. And at a time when television shows such as “To Catch a Predator” receive millions of viewers, it is clear that the nation’s fear of those who would commit sexual crimes against children, and the desire that they be brought to justice, remains at a fever pitch. By passing the Walsh Act, Congress and the President responded to a national outcry that children were not safe from sex offenders.

  2. A turning point in the concept of justice: from Adam Smith to John Stuart Mill

    Directory of Open Access Journals (Sweden)

    Estrella Trincado Aznar

    2015-07-01

    Full Text Available Classical economists, John Stuart Mill included, based their theories on Adam Smith’s system. At some point, they labelled it as a "utilitarian" theory. However, Smith was non-utilitarian, perhaps even anti-utilitarian. One of the most amazing differences between classical economics versus Smithian theory consists of their concept of justice. Classical economics were based on a utilitarian concept; Smith criticizes the concept of utilitarian justice. Utility being a subjective picture, classical economists find it more difficult to draw limits to state intervention than Smith does. This paper compares Smith’s and John Stuart Mill’s concept of justice when they make the case for land tenure. Mill admits that society cannot properly be said to owe anything to the poor. However, not arguing from 'abstract rights,' but from 'utility' understood in its largest sense, Mill defended the nationalization of land. Mill was unable to draw any limits to state intervention. Conversely, Smith defended that justice is not a utilitarian concept. In this case, limits to state intervention are more easily drawn.

  3. The Eroticism of Artificial Flesh in Villiers de L'Isle Adam's L'Eve Future

    Directory of Open Access Journals (Sweden)

    Patricia Pulham

    2008-10-01

    Full Text Available Villiers de L'Isle Adam's 'L'Eve Future' published in 1886 features a fictional version of the inventor Thomas Edison who constructs a complex, custom-made android for Englishman Lord Ewald as a substitute for his unsatisfactory lover. Hadaly, the android, has a number of literary and cultural precursors and successors. Her most commonly accepted ancestor is Olympia in E. T. A. Hoffmann's 'The Sandman' (1816 and among her fascinating descendants are Oskar Kokoschka's 'Silent Woman'; Model Borghild, a sex doll designed by German technicians during World War II;‘Caracas' in Tommaso Landolfi's short story ‘Gogol's Wife' (1954; a variety of gynoids and golems from the realms of science fiction, including Ira Levin's 'Stepford Wives' (1972; and, most recently, that silicon masterpiece - the Real Doll. All, arguably, have their genesis in the classical myth of Pygmalion. This essay considers the tension between animation and stasis in relation to this myth, and explores the necrophiliac aesthetic implicit in Villiers's novel.

  4. Adam Smith's conceptual contributions to international economics: Based on the Wealth of Nations

    Directory of Open Access Journals (Sweden)

    Ismail Kucukaksoy

    2011-01-01

    Full Text Available The 1776 dated "Wealth of Nations" work of Adam Smith has formed economic dimension of the Industrial Revolution and also transformed economics into the identity of a social science. As if the wealth of nations, namely the welfare increase became the top goal two and a half centuries ago, it is the top goal today and in the future as well. So understanding Smith's works well carries importance in fighting against poverty in the world. According to Smith, in the basis of the welfare increases (wealth of nations are labor and cooperation. Tendency underlying cooperation is the tendency of swap. In the light of this identification of Smith, who is a moralist, and his "Wealth of Nations" work, the aim and importance of the study can be stated in these sentences: Poverty is the most important problem of global world. It is considered that understanding Smith's works well will provide solution for poor countries and therefore contribute to poor population in the world to decrease. For solving poverty and problems concerning welfare (destitution, hunger, etc., Smith's works need historic examination more. In this study it was aimed to contribute to the given examination.

  5. The role of polymorphisms in ADAM33, a disintegrin and metalloprotease 33, in childhood asthma and lung function in two German populations

    Directory of Open Access Journals (Sweden)

    Klopp Norman

    2006-06-01

    Full Text Available Abstract Background ADAM33, the first asthma candidate gene identified by positional cloning, may be associated with childhood asthma, lung function decline and bronchial hyperresponsiveness. However, replication results have been inconclusive in smaller previous study populations probably due to inconsistencies in asthma phenotypes or yet unknown environmental influences. Thus, we tried to further elucidate the role of ADAM33 polymorphisms (SNPs in a genetic analysis of German case control and longitudinal populations. Methods Using MALDI-TOF, ten ADAM33 SNPs were genotyped in 1,872 children from the International Study of Asthma and Allergy in Childhood (ISAAC II in a case control setting and further 824 children from the longitudinal cohort Multicentre Study of Allergy (MAS. In both populations the effects of single SNPs and haplotypes were studied and a gene environment analysis with passive smoke exposure was performed using SAS/Genetics. Results No single SNP showed a significant association with doctor's diagnosis of asthma. A trend for somewhat more profound effects of ADAM33 SNPs was observed in individuals with asthma and BHR. Haplotype analyses suggested a minor effect of the ADAM33 haplotype H4 on asthma (p = 0.033 but not on BHR. Associations with non atopic asthma and baseline lung function were identified but no interaction with passive smoke exposure could be detected. Conclusion The originally reported association between ADAM33 polymorphisms and asthma and BHR could not be confirmed. However, our data may suggest a complex role of ADAM33 polymorphisms in asthma ethiology, especially in non atopic asthma.

  6. The SPECT tracer [{sup 123}I]ADAM binds selectively to serotonin transporters: a double-blind, placebo-controlled study in healthy young men

    Energy Technology Data Exchange (ETDEWEB)

    Giessen, Elsmarieke van de [University of Amsterdam, Academic Medical Center, Graduate School Neurosciences Amsterdam, Department of Nuclear Medicine, Amsterdam (Netherlands); Booij, Jan [University of Amsterdam, Academic Medical Center, Graduate School Neurosciences Amsterdam, Department of Nuclear Medicine, Amsterdam (Netherlands); University of Amsterdam, Academic Medical Center, Department of Nuclear Medicine, F2-236, Amsterdam (Netherlands)

    2010-08-15

    The tracer {sup 123}I-2-([2-({l_brace}dimethylamino{r_brace}methyl)phenyl]thio)-5-iodophenylamine ([{sup 123}I]ADAM) has been developed to image serotonin transporters (SERTs) with SPECT. Preclinical studies have shown that [{sup 123}I]ADAM binds selectively to SERTs. Moreover, initial human studies have shown that [{sup 123}I]ADAM binding could be blocked by selective serotonin reuptake inhibitors (SSRIs). However, in humans it has not been proven that [{sup 123}I]ADAM binds selectively to SERTs. We examined the in vivo availability of SERTs in 12 healthy young volunteers 5 h after bolus injection of [{sup 123}I]ADAM. To evaluate the selectivity of binding, four participants were pretreated (double-blinded design) with placebo, four with paroxetine (20 mg) and four with the dopamine/norepinephrine blocker methylphenidate (20 mg). SPECT studies were performed on a brain-dedicated system (Neurofocus), and the SPECT images were coregistered with individual MR scans of the brain. ADAM binding in SERT-rich brain areas and cerebellar cortex (representing non-specific binding) was assessed by drawing regions of interest (ROIs) on the individual MR images. Specific to non-specific ratios were used as the outcome measure. We found that specific to non-specific ratios were statistically significantly lower in paroxetine-pretreated participants than in placebo- or methylphenidate-pretreated participants. No such difference was found between groups pretreated with placebo or methylphenidate. Our preliminary findings suggest that [{sup 123}I]ADAM binds selectively to SERTs in human brain. (orig.)

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

    Science.gov (United States)

    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

  8. Metode dan Pendekatan dalam Studi Islam: Pembacaan atas Pemikiran Charles J. Adams

    Directory of Open Access Journals (Sweden)

    Luluk Fikri Zuhriyah

    2014-01-01

    Full Text Available Islam has been an interesting object of study for both Muslims and non-Muslims over a long period of time. A number of methods and approaches have also been introduced. In due time, Islam is now no longer understood solely as a doctrine or a set of belief system. Nor is it interpreted merely as an historical process. Islam is a social system comprising of a complex web of human experience. Islam does not only consist of formal codes that individuals should look at and obey. It also contains some cultural, political and economic values. Islam is a civilization. Given the complex nature of Islam it is no longer possible to deal with it from a single point of view. An inter-disciplinary perspective is required. In the West, social and humanities sciences have long been introduced in the study of religion; studies that put a stronger emphasis on what we currently know as the history of religion, psychology of religion, sociology of religion and so on. This kind of approach in turn, is also applied in the Western studies of the Eastern religions and communities. Islam as a religion is also dealt with in this way in the West. It is treated as part of the oriental culture to the extent that—as Muhammad Abdul Raouf has correctly argued—Islamic studies became identical to the oriental studies. By all means, the West preceded the Muslims in studying Islam from modern perspectives; perspective that puts more emphasis on social, cultural, behavioral, political and economic aspects. Among the Western scholars that approach Islam from this angle is Charles Joseph Adams whose thought this research is interested to explore.

  9. Encefalopatia mioclonica pós-anoxica (sindrome de Lance-Adams: registro de seis casos

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    Pedro F. Moreira Filho

    1981-06-01

    Full Text Available São estudados seis pacientes, cinco do sexo feminino e um dos masculino, os quais, após terem sofrido períodos variáveis de hipóxia cerebral provocada ou por parada cardio-respiratória (cinco casos ou por comprometimento pulmonar agudo, apresentaram alterações dos níveis de consciência, que variaram de obnubilação ao coma. Horas após, tiveram crises convulsivas generalizadas do tipo tônico clônica. À medida que vieram recuperando a consciência, desenvolveram abalos mioclônicos generalizados, de grande intensidade. Assim ficou caracterizada a encefalopatia mioclônica pós-anóxica que em homenagem aos autores que a descreveram, em 1963, é denominada também de síndrome de Lance-Adams. Cinco enfermos foram submetidos a exame eletrencefalográfico, cujos traçados, em alguns, mostraram potenciais típicos de mioclonias e, em outros, características de comprometimento ceberal difuso por anóxia. Em um dos pacientes foi feito exame eletromiográfico e em outros dois, tomografia cerebral por computador que revelou, em um deles, pronunciado alargamento das cisuras silvianas na base, especialmente à direita que justifica o quadro demencial apresentado por tal paciente. A análise bioquímica do líquido cefalorraquidiano feito em cinco casos, não apresentou alterações.

  10. ADAM2 interactions with mouse eggs and cell lines expressing α4/α9 (ITGA4/ITGA9 integrins: implications for integrin-based adhesion and fertilization.

    Directory of Open Access Journals (Sweden)

    Ulyana V Desiderio

    Full Text Available BACKGROUND: Integrins are heterodimeric cell adhesion molecules, with 18 α (ITGA and eight β (ITGB subunits forming 24 heterodimers classified into five families. Certain integrins, especially the α(4/α(9 (ITGA4/ITGA9 family, interact with members of the ADAM (a disintegrin and metalloprotease family. ADAM2 is among the better characterized and also of interest because of its role in sperm function. Having shown that ITGA9 on mouse eggs participates in mouse sperm-egg interactions, we sought to characterize ITGA4/ITGA9-ADAM2 interactions. METHODOLOGY/PRINCIPAL FINDINGS: An anti-β(1/ITGB1 function-blocking antibody that reduces sperm-egg binding significantly inhibited ADAM2 binding to mouse eggs. Analysis of integrin subunit expression indicates that mouse eggs could express at least ten different integrins, five in the RGD-binding family, two in the laminin-binding family, two in the collagen-binding family, and ITGA9-ITGB1. Adhesion assays to characterize ADAM2 interactions with ITGA4/ITGA9 family members produced the surprising result that RPMI 8866 cell adhesion to ADAM2 was inhibited by an anti-ITGA9 antibody, noteworthy because ITGA9 has only been reported to dimerize with ITGB1, and RPMI 8866 cells lack detectable ITGB1. Antibody and siRNA studies demonstrate that ITGB7 is the β subunit contributing to RPMI 8866 adhesion to ADAM2. CONCLUSIONS/SIGNIFICANCE: These data indicate that a novel integrin α-β combination, ITGA9-ITGB7 (α(9β(7, in RPMI 8866 cells functions as a binding partner for ADAM2. ITGA9 had previously only been reported to dimerize with ITGB1. Although ITGA9-ITGB7 is unlikely to be a widely expressed integrin and appears to be the result of "compensatory dimerization" occurring in the context of little/no ITGB1 expression, the data indicate that ITGA9-ITGB7 functions as an ADAM binding partner in certain cellular contexts, with implications for mammalian fertilization and integrin function.

  11. [{sup 11}C]SMe-ADAM, an imaging agent for the brain serotonin transporter: synthesis, pharmacological characterization and microPET studies in rats

    Energy Technology Data Exchange (ETDEWEB)

    Zessin, Joerg [Institut fuer Bioanorganische und Radiopharmazeutische Chemie, Forschungszentrum Rossendorf, 01314 Dresden (Germany)]. E-mail: j.zessin@fz-rossendorf.de; Deuther-Conrad, Winnie [Institut fuer Interdisziplinaere Isotopenforschung, 04318 Leipzig (Germany); Kretzschmar, Marion [Institut fuer Bioanorganische und Radiopharmazeutische Chemie, Forschungszentrum Rossendorf, 01314 Dresden (Germany); Wuest, Frank [Institut fuer Bioanorganische und Radiopharmazeutische Chemie, Forschungszentrum Rossendorf, 01314 Dresden (Germany); Pawelke, Beate [Institut fuer Bioanorganische und Radiopharmazeutische Chemie, Forschungszentrum Rossendorf, 01314 Dresden (Germany); Brust, Peter [Institut fuer Interdisziplinaere Isotopenforschung, 04318 Leipzig (Germany); Steinbach, Joerg [Institut fuer Interdisziplinaere Isotopenforschung, 04318 Leipzig (Germany); Bergmann, Ralf [Institut fuer Bioanorganische und Radiopharmazeutische Chemie, Forschungszentrum Rossendorf, 01314 Dresden (Germany)

    2006-01-15

    N,N-Dimethyl-2-(2-amino-4-methylthiophenylthio)benzylamine (S Me-Adam, 1) is a highly potent and selective inhibitor of the serotonin transporter (SPERT). This compound was labeled with carbon-11 by methylation of the S-desmethyl precursor 10 with [{sup 11}C]methyl iodide to obtain the potential positron emission tomography (PET) radioligand [{sup 11}C]S Me-Adam. The radiochemical yield was 27{+-}5%, and the specific radioactivity was 26-40 GBq/{mu}mol at the end of synthesis. Ex vivo and in vivo biodistribution experiments in rats demonstrated a rapid accumulation of the radiotracer in brain regions known to be rich in SPERT, such as the thalamus/hypothalamus region (3.59{+-}0.41%ID/g at 5 min after injection). The specific uptake reached a thalamus to cerebellum ratio of 6.74{+-}0.95 at 60 min postinjection. The [{sup 11}C]SMe-ADAM uptake in the thalamus was significantly decreased by pretreatment with fluoxetine to 38{+-}11% of the control value. Furthermore, no metabolites of [{sup 11}C]SMe-ADAM could be detected in the SERT-rich regions of the rat brain. It is concluded that [{sup 11}C]SMe-ADAM may be a suitable PET ligand for SERT imaging in the living brain.

  12. [11C]SMe-ADAM, an imaging agent for the brain serotonin transporter: synthesis, pharmacological characterization and microPET studies in rats

    International Nuclear Information System (INIS)

    N,N-Dimethyl-2-(2-amino-4-methylthiophenylthio)benzylamine (S Me-Adam, 1) is a highly potent and selective inhibitor of the serotonin transporter (SPERT). This compound was labeled with carbon-11 by methylation of the S-desmethyl precursor 10 with [11C]methyl iodide to obtain the potential positron emission tomography (PET) radioligand [11C]S Me-Adam. The radiochemical yield was 27±5%, and the specific radioactivity was 26-40 GBq/μmol at the end of synthesis. Ex vivo and in vivo biodistribution experiments in rats demonstrated a rapid accumulation of the radiotracer in brain regions known to be rich in SPERT, such as the thalamus/hypothalamus region (3.59±0.41%ID/g at 5 min after injection). The specific uptake reached a thalamus to cerebellum ratio of 6.74±0.95 at 60 min postinjection. The [11C]SMe-ADAM uptake in the thalamus was significantly decreased by pretreatment with fluoxetine to 38±11% of the control value. Furthermore, no metabolites of [11C]SMe-ADAM could be detected in the SERT-rich regions of the rat brain. It is concluded that [11C]SMe-ADAM may be a suitable PET ligand for SERT imaging in the living brain

  13. Microarray identifies ADAM family members as key responders to TGF-β1 in alveolar epithelial cells

    Directory of Open Access Journals (Sweden)

    Walls Dermot

    2006-09-01

    Full Text Available Abstract The molecular mechanisms of Idiopathic Pulmonary Fibrosis (IPF remain elusive. Transforming Growth Factor beta 1(TGF-β1 is a key effector cytokine in the development of lung fibrosis. We used microarray and computational biology strategies to identify genes whose expression is significantly altered in alveolar epithelial cells (A549 in response to TGF-β1, IL-4 and IL-13 and Epstein Barr virus. A549 cells were exposed to 10 ng/ml TGF-β1, IL-4 and IL-13 at serial time points. Total RNA was used for hybridisation to Affymetrix Human Genome U133A microarrays. Each in vitro time-point was studied in duplicate and an average RMA value computed. Expression data for each time point was compared to control and a signal log ratio of 0.6 or greater taken to identify significant differential regulation. Using normalised RMA values and unsupervised Average Linkage Hierarchical Cluster Analysis, a list of 312 extracellular matrix (ECM proteins or modulators of matrix turnover was curated via Onto-Compare and Gene-Ontology (GO databases for baited cluster analysis of ECM associated genes. Interrogation of the dataset using ontological classification focused cluster analysis revealed coordinate differential expression of a large cohort of extracellular matrix associated genes. Of this grouping members of the ADAM (A disintegrin and Metalloproteinase domain containing family of genes were differentially expressed. ADAM gene expression was also identified in EBV infected A549 cells as well as IL-13 and IL-4 stimulated cells. We probed pathologenomic activities (activation and functional activity of ADAM19 and ADAMTS9 using siRNA and collagen assays. Knockdown of these genes resulted in diminished production of collagen in A549 cells exposed to TGF-β1, suggesting a potential role for these molecules in ECM accumulation in IPF.

  14. 14th July 2009-UK-John Adams Institute for Accelerator Science delegation visiting ATLAS and CCC with E. Tsesmelis

    CERN Multimedia

    Maximilien Brice

    2009-01-01

    Tirage 1; 11-16: the delegation visiting the tunnel with Beams Department Head, P. Collier Tirage 2;7-8: Signature of the Collaboration Agreement with R. Heuer and K. Peach Tirage 3-6:S. Iversen, B. Foster and R. Heuer Tirage 9: S. Iversen signing the Guest book with R. Heuer Tirage 10: A. Tickell signing the Guest book with R. Heuer Tirage 11-16: The delegation visiting the LHC tunnel with P. Collier Tirage 17: Commemorative photo at John Adams Road with P. Collier, E. Tsesmelis, A. Tickell, S. Iversen, K. Peach, G. Blair, J. Schinzel, B. Foster

  15. “The West Wing with Wigs” ? Politics and History in HBO’s John Adams

    OpenAIRE

    Godet, Aurélie

    2016-01-01

    In 2008, HBO released a $ 100 million, seven-part mini-series based on David McCullough’s Pulitzer Prize-winning biography of John Adams. The reviews were enthusiastic, with most people praising the cinematography, the storytelling, and Paul Giamatti and Laura Linney’s acting. Soon, however, historians started to complain about various historical inaccuracies in the show. Jeremy Stern, for example, wrote on the History News Network that “the first episode especially is fundamentally marred by...

  16. Self-denial and self-assertion in some plays of Thomas kilroy: The Madame MacAdam Travelling Theatre

    OpenAIRE

    Hayley, Barbara

    2012-01-01

    Thomas Kilroy has always been preoccupied with the notion of self-denial as the only way in which certain personalities can assert themselves. His latest play, The Madame MacAdam Travelling Theatre , is the most subtle and disturbing of his expressions of this phenomenon, calling upon the resources, illusions and dislocations of Jacobean drama to examine it. Earlier works prepare the ground for it. Talbot’s Box, first performed at the Peacock Theatre, Dublin, on 13 October 1977, holds such a ...

  17. Hubungan Pengetahuan, Komunikasi Interpersonal, dan Keterampilan Teknik dengan Penerapan Proses Keperawatan di Ruang Rawat Inap RSUP Haji Adam Malik Medan

    OpenAIRE

    Panjaitan, Misrah

    2015-01-01

    Nursing process is a cycle whose purpose, in general, is to prepare the conceptual framework based on the condition of individual (client), family and community in order to meet their needs. Nursing process is a stage of action design intended to meet the objective of nursing including the maintenance of the health condition of the client as optimal as possible. The purpose of this explanatory study with cross-sectional design conducted in the in-patient wards of H. Adam Malik General Hosp...

  18. Profil Ibu-Ibu yang Melahirkan Bayi BBLR (Berat Badan Lahir Rendah) di RSUP Haji Adam Malik tahun 2010

    OpenAIRE

    Pramono, Gesit

    2012-01-01

    According to the WHO definition (1980), low birth weight babies who are born less than 2500 grams. Babies born with low weight is one of the risk factors that have contributed to infant mortality, especially in the perinatal period. The purpose of this study was to determine the profiles of mothers who gave birth to low birth weight babies. The research method used is descriptive research to determine the profiles mothers who gave birth to low birth weight babies in RSUP H. Adam Malik. The...

  19. Association between ADAM33 genetic polymorphsim and susceptibility of asthma: A Meta-analysis%ADAM33基因遗传多态性与支气管哮喘易感性关系的Meta分析

    Institute of Scientific and Technical Information of China (English)

    李宏彬; 张国富; 赵兵; 席景砖

    2013-01-01

    Objective:To explore whether the polymorphisms of Met764Thr and Pro774Ser in ADAM33 (A Disintegrin and Metalloproteinase 33) gene contribute to the susceptibility to asthma.Methods:According to the same criteria,all the clinical studies related to the polymorphisms of ADAM33 gene and asthma were searched through PubMed,Ovid-Medline,CNKI,Weipu database.All retrieved articles were screened and evaluated followed by Meta-analysis using RevMan 5 software.Results:Fourteen studies were included based on the selection criteria.In these studies,twelve of them investigated the codon 764 of ADAM33 (3 520 controls and 3 418 asthmatic patients) and eight studied the codon 774 (3 207 controls and 2 793 asthmatic patients).The results of Meta-analys is showed the genotype of 764Met/Thr and 764Thr/Thr have higher susceptibility(1.56 fold)to be asthmatics than the one with the genotype of 764 Met/Met (OR =1.56,95% CI =1.09-2.22).The mutant genotype of ADAM33 codon 774 was also associated with increased asthma risk(OR =1.39,95% CI =1.00-1.93).Furthermore,subgroup analysis indicated that the association between these two loci and asthma could only be found in Chinese population (codon 764:OR =2.73,95% CI =1.79-4.17 ; codon 774:OR =2.32,95% CI =1.30-4.15).Conclusion:Polymorphisms of ADAM33 codons 764 and 774 seem to be involved in elevated risk of asthma.%目的:综合评价解整合素金属蛋白酶33 (ADAM33)基因Met764Thr和Pro774Ser位点多态性与哮喘易感性的关系.方法:按照统一的检索策略,检索Pubmed、Ovid-Medline、CNKI及维普数据库中有关ADAM33基因多态性与哮喘易感性关系的病例-对照研究,按照纳入和排除标准选择文献提取相关信息,应用Review Manager 5.0软件进行Meta分析.结果:本研究纳入国内外14篇合格文献,其中Met764Thr位点12篇,共3 418例哮喘病例和3 520例对照;Pro774Ser位点8篇,共2 793例哮喘病例和3 207例对照.Meta分析结果显示,携带764位点Met/Thr或Thr/Thr

  20. Digitization Procedures of Analogue Seismograms from the Adam Dziewonski Observatory (HRV) at Harvard, MA

    Science.gov (United States)

    Torpey, M.; Ishii, M.

    2010-12-01

    This project explores methods of digitization of analogue seismic recordings for better preservation and to facilitate data distribution to the community. Different techniques are investigated using seismograms from one particular station, the Adam Dziewonski Observatory (HRV) at Harvard, Massachusetts. This seismological station, still in operation as a part of the Global Seismographic Network today, is one of the oldest stations in the United States. The station was built in 1933, and since its installation, the station has produced approximately 16,000 analogue seismograms. The majority of these recordings were taken between 1933 and 1953, with some intermittent recordings between 1962 and 1998 after digital seismometers had become a standard. These analogue seismograms have the potential of expanding the database for seismological research such as identification of events previously not catalogued. Due to poor storage environment at the station, some of the records, especially those on regular type of paper, are damaged beyond repair. Nevertheless, many of the records on photographic paper are in better condition, and we have focused on a subset of these recordings that are least damaged. Even these seismograms require cleaning and, in consultation with the Weissman Preservation Center of Harvard Library, preparation techniques for the photographic records are examined. After the seismograms are cleaned and flattened, three different equipments are investigated for digitization, i.e., a copy machine, scanner, and camera. These instruments allow different imaging resolutions, ranging from 200 dots per inch (dpi) to 800 dpi. The image resolution and the bit depth have a wide range of implications that are closely linked to the digitization program one chooses to convert the image to time series. We explore three different software for this conversion, SeisDig (Bromirski and Chuang, 2003), Teseo2 (Pintore and Quintiliani, 2008), and NeuraLog (www

  1. The ADAM project: a generic web interface for retrieval and display of ATLAS TDAQ information

    International Nuclear Information System (INIS)

    This paper describes a new approach to the visualization of information about the operation of the ATLAS Trigger and Data Acquisition system. ATLAS is one of the two general purpose detectors positioned along the Large Hadron Collider at CERN. Its data acquisition system consists of several thousand computers interconnected via multiple gigabit Ethernet networks, that are constantly monitored via different tools. Operational parameters ranging from the temperature of the computers to the network utilization are stored in several databases for later analysis. Although the ability to view these data-sets individually is already in place, currently there is no way to view this data together, in a uniform format, from one location. The ADAM project has been launched in order to overcome this limitation. It defines a uniform web interface to collect data from multiple providers that have different structures. It is capable of aggregating and correlating the data according to user defined criteria. Finally, it visualizes the collected data using a flexible and interactive front-end web system. Structurally, the project comprises of 3 main levels of the data collection cycle: The Level 0 represents the information sources within ATLAS. These providers do not store information in a uniform fashion. The first step of the project was to define a common interface with which to expose stored data. The interface designed for the project originates from the Google Data Protocol API. The idea is to allow read-only access to data providers, through HTTP requests similar in format to the SQL query structure. This provides a standardized way to access this different information sources within ATLAS. The Level 1 can be considered the engine of the system. The primary task of the Level 1 is to gather data from multiple data sources via the common interface, to correlate this data together, or over a defined time series, and expose the combined data as a whole to the Level 2 web

  2. Upper mantle structures beneath central Europe. From first Antal Adam's results to recent ones

    International Nuclear Information System (INIS)

    Complete text of publication follows. The first detection of the mantle conductive asthenosphere in the Europe was made by professor Antal Adam as early as 1966 by the magnetotelluric sounding method. The result awakened interest in investigations of the geoelectrical properties of the upper mantle. The local results obtained later by the induction soundings of the mantle in Europe had high scatter of inversion results. This brings up the question: is asthenosphere a regional or global phenomenon? Perhaps the exact answer cannot be obtained in the frame of the ground induction soundings only. However, recent regional studies including the northern (BEAR) and central (CEMES) Europe projects have established that the lithosphere is more resistive beneath the East European Plate than beneath the western Paleozoic one and has essentially different thickness. So, if we are using term of asthenosphere, its depth is changing from less than 100 km beneath the Pannonian Basin up to ∼ 300 km beneath East European craton. The boundary between those plates coincides with the Trans European Suture Zone (TESZ), which is crossed now by many profiles with electromagnetic field observations. These profiles are situated from the Sweden - Germany profile in the north-west TESZ to the Ukraine - Hungary one in the south-east TESZ. The majority of the profiles were concentrated and carried out in Poland. Comparison of the geoelectrical structures between these profiles is presented in this work, as well as the regional distribution of the upper mantle conductance according the induction soundings made in the frame of the CEMES project. Besides, the estimation of the mid-mantle conductance (700-900 km) using the response functions obtained independently by J. Roberts, A. Schultz, V. Semenov and N. Olsen based on the geomagnetic observatory data from the European region has pointed out that the structure cannot be considered as homogeneous. The obtained regional results of the mantle

  3. ADAM17调控Hippo信号转导通路对人脑胶质瘤细胞增殖和迁移的影响%Effects of ADAM17 on Proliferation and Migration of Human Glioma Cells through Hippo Signaling Pathway

    Institute of Scientific and Technical Information of China (English)

    张春利; 韩秀; 熊二梦; 彭琬昕; 杜凤仪; 周海浪; 龚爱华

    2016-01-01

    为探讨去整合素-金属蛋白酶17(disintegrin and metalloproteinase 17,ADAM17)对人胶质瘤细胞增殖和迁移的影响及其调控机制,该研究用ADAM17 shRNA质粒转染ADAM17高表达的胶质瘤细胞U87MG、 U251MG,用过表达ADAM17载体转染ADAM17低表达细胞SW1783,q-PCR和Western blot检测ADAM17表达水平的变化,同时检测ADAM17和Hippo信号通路中相关蛋白质表达水平,CCK-8法分析细胞增殖能力并绘制生长曲线,划痕实验检测细胞迁移率.结果表明,下调ADAM17后,U87MG、U251MG细胞增殖和迁移能力减弱,而Hippo信号通路中MST2、p-MOBl、p-YAP蛋白表达水平升高;上调ADAM17后,SW1783细胞增殖和迁移能力增强,而MST2、p-MOB1、p-YAP蛋白表达水平降低.结果说明,ADAM17在脑胶质瘤细胞的增殖和迁移中发挥了重要作用,这可能是通过抑制Hippo信号通路来实现的,MST2被抑制,p-MOB1水平降低,从而YAP的磷酸化水平也降低,促进了胶质瘤细胞的增殖和迁移.

  4. HIV-Nef and ADAM17-Containing Plasma Extracellular Vesicles Induce and Correlate with Immune Pathogenesis in Chronic HIV Infection

    Science.gov (United States)

    Lee, Jung-Hyun; Schierer, Stephan; Blume, Katja; Dindorf, Jochen; Wittki, Sebastian; Xiang, Wei; Ostalecki, Christian; Koliha, Nina; Wild, Stefan; Schuler, Gerold; Fackler, Oliver T.; Saksela, Kalle; Harrer, Thomas; Baur, Andreas S.

    2016-01-01

    Antiretroviral therapy (ART) efficiently suppresses HIV replication but immune activation and low CD4 T cell counts often persist. The underlying mechanism of this ART-resistant pathogenesis is not clear. We observed that levels of plasma extracellular vesicles (pEV) are strongly elevated in HIV infection and do not decline during ART. Surprisingly, these vesicles contained the viral accessory proteins Nef and Vpu, which are assumed to be not expressed under efficient ART, as well as pro-inflammatory effectors, including activated ADAM17. HIV pEV were characterized by the presence of activated αvβ3 and absence of CD81 and Tsg101. Correlating with immune activation, peripheral monocytes ingested large amounts of pEV, giving rise to an increased population of CD1c+ CD14+ cells that secreted inflammatory cytokines. Importantly, the pro-inflammatory content, particularly ADAM17 activity, correlated with low T cell counts. Preliminary evidence suggested that HIV pEV derived from peripheral mononuclear cells and from an unknown myeloid cell population. In summary we propose an important role of pro-inflammatory pEV in chronic HIV infection due to ongoing viral Nef activity.

  5. Simulation reseach on vehicle ride based on ASAMS/Car Ride%基于ADAMS/Car Ride车辆平顺性仿真研究

    Institute of Scientific and Technical Information of China (English)

    宋宇; 郑泉; 陈黎卿

    2007-01-01

    以虚拟样机技术进行车辆平顺性仿真研究,建立了基于ADAMS/Car Ride的多体动理学模型,通过虚拟四柱试验台对模型进行仿真试验.仿真结果表明,ADAMS/Car Ride可方便地进行路面功率谱密度响应仿真试验,所建立的包含虚拟四柱试验台的整车模型可深入进行车辆平顺性研究.

  6. INTERNATIONAL UNION OF OPERATING ENGINEERS NATIONAL HAZMAT PROGRAM - ADAMANT CIRCULAR SAW OENHP NUMBER: 2001-05, VERSION A

    International Nuclear Information System (INIS)

    Florida International University's (FIU) Hemispheric Center for Environmental Technology (HCET) evaluated five saws for their effectiveness in cutting up specially prepared fiberglass-reinforced plywood crates. These crates were built as surrogates for crates that presently hold radioactive contaminated glove boxes at the Department of Energy's (DOE) Los Alamos facility. The Adamant circular saw was assessed on August 14, 2001. During the FIU test of efficacy, a team from the Operating Engineers National Hazmat Program (OENHP) evaluated the occupational safety and health issues associated with this technology. The Adamant was only used during a limited ''test'' on a regular plywood crate due to safety considerations of the tool for this application. The Adamant circular saw, a counter-rotating twin-cutter, constructed with blades that work differently than conventional cutting wheels with twin blades, each rotating in opposite directions. It is used to cut wood and metals. Each blade is approximately 8 3/4 inches in diameter with a maximum cutting depth of 2 1/2 inches. The machine has two rotation speeds: 1,900 and 2,900 rotations per minute (rpm). The saw is operated with an interlocked, guarded trigger switch located at the end of the saw opposite the cutting blades. To operate the saw, the safety interlock must be depressed prior to powering the saw with the trigger control. The saw is supported by a handle at the front of the saw near the cutting blades. The top part of the blades is guarded near the handle, with approximately three-fourths of the face of the blades exposed. The Adamant circular saw is an innovative technology used to cut metals and wood. Its safety features include: interlocking switch for powering the saw, overload indicator and shutoff, and an electronic brake that stops the engine immediately when the start button is released. The top part of the blades is guarded near the motor. With approximately three-fourths of the face of the blades

  7. INTERNATIONAL UNION OF OPERATING ENGINEERS NATIONAL HAZMAT PROGRAM - ADAMANT CIRCULAR SAW OENHP{number_sign}: 2001-05, VERSION A

    Energy Technology Data Exchange (ETDEWEB)

    Unknown

    2002-01-01

    Florida International University's (FIU) Hemispheric Center for Environmental Technology (HCET) evaluated five saws for their effectiveness in cutting up specially prepared fiberglass-reinforced plywood crates. These crates were built as surrogates for crates that presently hold radioactive contaminated glove boxes at the Department of Energy's (DOE) Los Alamos facility. The Adamant circular saw was assessed on August 14, 2001. During the FIU test of efficacy, a team from the Operating Engineers National Hazmat Program (OENHP) evaluated the occupational safety and health issues associated with this technology. The Adamant was only used during a limited ''test'' on a regular plywood crate due to safety considerations of the tool for this application. The Adamant circular saw, a counter-rotating twin-cutter, constructed with blades that work differently than conventional cutting wheels with twin blades, each rotating in opposite directions. It is used to cut wood and metals. Each blade is approximately 8 3/4 inches in diameter with a maximum cutting depth of 2 1/2 inches. The machine has two rotation speeds: 1,900 and 2,900 rotations per minute (rpm). The saw is operated with an interlocked, guarded trigger switch located at the end of the saw opposite the cutting blades. To operate the saw, the safety interlock must be depressed prior to powering the saw with the trigger control. The saw is supported by a handle at the front of the saw near the cutting blades. The top part of the blades is guarded near the handle, with approximately three-fourths of the face of the blades exposed. The Adamant circular saw is an innovative technology used to cut metals and wood. Its safety features include: interlocking switch for powering the saw, overload indicator and shutoff, and an electronic brake that stops the engine immediately when the start button is released. The top part of the blades is guarded near the motor. With approximately three

  8. Événement et trauma dans Doctor Atomic de John Adams

    Directory of Open Access Journals (Sweden)

    Mathieu Duplay

    2011-04-01

    , opéra de John Adams sur un livret de Peter Sellars, s’avère particulièrement instructif, non seulement parce qu’il y est question de l’un des plus violents traumatismes du xxe siècle — l’essai nucléaire de Los Alamos, prélude au bombardement atomique d’Hiroshima et de Nagasaki — mais encore parce que, non contente de mettre en scène l’impensable, cette œuvre met en évidence ce qui, de l’événement (qu’il soit historique ou esthétique, en appelle à une pensée encore informulée ; or c’est ce qui révèle sa nature traumatique, comme le discours de la psychanalyse le laisse entendre, parfois à son corps défendant.

  9. Measuring SSRI occupancy of SERT using the novel tracer [{sup 123}I]ADAM: a SPECT validation study

    Energy Technology Data Exchange (ETDEWEB)

    Erlandsson, Kjell; Lui, Dominic; Townsend, Caroline E.; Ell, Peter J. [Middlesex Hospital, Institute of Nuclear Medicine, University College London, London (United Kingdom); Sivananthan, Tharani; Mu, Song; Lucas, Richard [Lilly Research Centre, Eli Lilly and Company, Windlesham, Surrey (United Kingdom); Spezzi, Andrea; Warrington, Steven [Central Middlesex Hospital, Hammersmith Medicines Research, London (United Kingdom)

    2005-11-01

    Serotonergic brain regions play a crucial role in the modulation of emotion, and serotonergic dysfunction may contribute to several neurological disorders. [{sup 123}I]ADAM is a novel SPECT tracer which binds with high affinity to serotonin transporters (SERT). The objective of this study was to compare different methods for the quantification of tracer binding and to develop a simplified single-scan protocol for this tracer, as well as to investigate its potential for characterisation of the transporter occupancy versus plasma concentration curve of a selective serotonin re-uptake inhibitor (SSRI). Dynamic SPECT scans were performed on 16 healthy volunteers after administration of {proportional_to}150 MBq [{sup 123}I]ADAM. Data were acquired from the time of injection until {proportional_to}5.5 h after injection in 30- or 45-min sessions. Each subject was scanned twice: with and without pre-treatment with the SSRI citalopram in various dosage regimens. The plasma concentration of citalopram (C{sub p}) was determined from venous samples. Images were reconstructed by filtered back-projection with scatter and attenuation correction. Tracer binding was quantified for midbrain, striatum and thalamus using cerebellum as a reference region. Quantification was done by kinetic modelling, graphical analysis and multi-linear regression, as well as by the ratio method, with binding potential (BP{sub 2}) as the outcome measure. The SERT occupancy by citalopram was determined relative to the baseline scan for each subject, and the occupancy versus C{sub p} curve was fitted with the E{sub max} model. The highest binding of [{sup 123}I]ADAM was in midbrain (mean baseline BP{sub 2}{+-}SD=1.31{+-}0.29), with lower binding in thalamus (0.79{+-}0.16) and striatum (0.66{+-}0.13). There was good agreement between BP{sub 2} values obtained by different quantification methods. Using the ratio method, the best agreement with kinetic modelling was obtained with data from the time interval

  10. Les derniers écrits d’Adam Scot. Analyse linguistique et stylistique du «De quadripertito exercitio cellae». [Reseña

    OpenAIRE

    Cantera-Montenegro, S. (S.)

    2005-01-01

    Reseña de: Francesco PALLESCHI, Les derniers écrits d’Adam Scot. Analyse linguistique et stylistique du «De quadripertito exercitio cellae», Universität Salzburg («Analecta Cartusiana», 168), Salzburgo 2002, 199 pp.

  11. Co je nového v archeogenetice. Stárnoucí Adam a jeho (ne)zdatní synové

    Czech Academy of Sciences Publication Activity Database

    Černý, Viktor

    2015-01-01

    Roč. 63, č. 4 (2015), s. 153-154. ISSN 0044-4812 Institutional support: RVO:67985912 Keywords : archaeogenetics * phylogeography Subject RIV: AC - Archeology, Anthropology, Ethnology http://ziva.avcr.cz/files/ziva/pdf/co-je-noveho-v-archeogenetice-starnouci-adam-a-jeh.pdf

  12. Binding of ADAM12, a marker of skeletal muscle regeneration, to the muscle-specific actin-binding protein, alpha -actinin-2, is required for myoblast fusion

    DEFF Research Database (Denmark)

    Galliano, M F; Huet, C; Frygelius, J;

    2000-01-01

    differentiation. Using the yeast two-hybrid screen, we found that the muscle-specific alpha-actinin-2 strongly binds to the cytoplasmic tail of ADAM12. In vitro binding assays with GST fusion proteins confirmed the specific interaction. The major binding site for alpha-actinin-2 was mapped to a short sequence in...

  13. Comercio y lenguaje: la retórica de la persuasión de Adam Smith

    OpenAIRE

    Alonso-Cortés Manteca, Ángel

    2008-01-01

    La especie humana dispone de tres rasgos universales, que concurren en ella únicamente: la división del trabajo, el intercambio de bienes, y el lenguaje simbólico. Tales rasgos fueron enunciados por Adam Smith a lo largo de su obra.En particlar, en Smith, la retórica, un uso comunicativo del lenguaje, tiene un papel destacado en su filosofía moral y en su economía política. La propiedad y la persuasión son los dos constituyentes básicos de la comunicación lingüística en que S. sustenta su fil...

  14. Production of uranous nitrate with hydrazine nitrate as reducing agent in presence of Adams catalyst for uranium reconversion purposes

    International Nuclear Information System (INIS)

    The reconversion of 233U to its oxide was done through ADU route in Uranium Thorium Separation Facility (UTSF). As this process has some drawbacks an alternative route for uranium reconversion was envisaged. In this method uranium is first reduced to its tetra-valency and the tetra-valent uranium is precipitated as oxalate. Of the existing methods available for uranyl reduction, the reduction with uranium with hydrazine nitrate in presence of Adams catalyst was chosen and accordingly new equipment has been designed, fabricated and extensively tested for its performance. It was found that near 100 % conversion could be achieved even at the concentration normally encountered in PRTRF. As this method is simple and is amenable to remote operation, this method of reduction can be adopted in Power Reactor Thoria Reprocessing Facility. (author)

  15. Lack of ADAM2, CALR3 and SAGE1 Cancer/Testis Antigen Expression in Lung and Breast Cancer

    DEFF Research Database (Denmark)

    Maheswaran, Emeaga; Pedersen, Christina B; Ditzel, Henrik J; Gjerstorff, Morten F

    2015-01-01

    Immunotherapy is emerging as a supplement to conventional cancer treatment, and identifying antigen targets for specific types of cancer is critical to optimizing therapeutic efficacy. Cancer/testis antigens are highly promising targets for immunotherapy due to their cancer-specific expression and...... other CT antigens, such as MAGE-A proteins. Surprisingly, we detected no ADAM2, CALR3 and SAGE1 in the 67 lung cancers (mainly non-small lung cancer) and 189 breast cancers, while MAGE-A proteins were present in 15% and 7-16% of these tumor types, respectively. Treatment with DNA methyltransferase...... and SAGE1 cancer/testis antigens are not promising targets for immunotherapy of breast and lung cancer....

  16. A NEW PARADIGMA OF THE ECONOMICAL AGENT. FROM ADAM SMITHS HOMO ECONOMICUS TO HOMO GENEROSUS BASED ON SOCIAL RESPONSIBILITY

    Directory of Open Access Journals (Sweden)

    PUP ANCA

    2010-12-01

    Full Text Available Analyzed form outside, many actions of the economical agent seem to be impulse by the self interest. As a prototype of this kind of person we have the Homo economicus as Adam Smith described it. In a blitz portrait we identify some characteristics: he is perfect rational, perfect egoist, perfect free, perfect competitive and perfect social. The aim of this research is to permute the barycentre from Homo economicus based on self interest, to Homo generosus, based on social responsibility. As a support we have used the prison dilemma to illustrate the roll of cooperation instead self interest. This new coordination will be analyzed to the level of ethical system. Homo economicus is identified in ethics of consequences and the homo generosus in ethics of duty. In my vision, the prototype of homo generosus, is delineated under Kant's categorical imperative: respectful, based on principles as subject and sovereign.

  17. Sentimiento moral y razón: la noción de justicia en Adam Smith y Amartya Sen

    Directory of Open Access Journals (Sweden)

    Augusto Aleán Pico

    2014-12-01

    Full Text Available Amartya Sen plantea que su noción de justicia tiene como antecedente el pensamiento de Adam Smith. Sen usa de una manera particular los conceptos de la simpatía y del espectador imparcial para elaborar su noción de justicia. Más allá de la afirmación de Sen, estamos interesados en indagar si la noción de justicia de Smith es compatible con la que propone Sen. El principal hallazgo es que hay diferencias significativas entre las teorías y, por tanto, no son compatibles. Smith enfatizó la importancia del juicio moral basado en el sentimiento. Por el contrario, Amartya Sen enfatiza la necesidad de utilizar la razón y el debate público como elementos claves de una teoría de la justicia.

  18. Visit of H.E. Mr. Attila Chikan, Minister of Economic Affairs, Prof. Adam Török, President, National Committee for Technological Development, Mr. Pal Koncz, Deputy Director General, National Committee for Technological Development, Hungary

    CERN Multimedia

    Laurent Guiraud

    1999-01-01

    Visit of H.E. Mr. Attila Chikan, Minister of Economic Affairs, Prof. Adam Török, President, National Committee for Technological Development, Mr. Pal Koncz, Deputy Director General, National Committee for Technological Development, Hungary

  19. 基于ADAMS的麦弗逊悬架的运动学仿真与结构优化%The Dynamic Simulation and Structural Optimization of Mcpherson Suspension Based on ADAMS

    Institute of Scientific and Technical Information of China (English)

    廖力成; 熊禾根

    2009-01-01

    利用ADAMS/Car建立某车前麦弗逊悬架的模型,选取"两侧车轮同向跳动"工况进行运动学仿真,通过分析悬架性能参数的变化特性,找出引起轮胎过度磨损的主要原因,并在ADAMS/Insight中对悬架的结构进行优化.

  20. Relasi Laki-Laki dengan Perempuan Menurut Pandangan Islam dalam Novel Maha Cinta Adam-Hawa Karya Muhammad El-Natsir: Sosiologi Sastra

    OpenAIRE

    Mulyati, Sri

    2015-01-01

    Karya sastra diciptakan untuk menyampaikan ide, pesan yang terkandung di dalamnya kepada pembaca. Salah satu bentuk karya sastra adalah novel. Novel pada umumnya berbicara tentang berbagai masalah kehidupan yang dihadapi oleh manusia. Salah satunya adalah menyinggung masalah relasi antara laki-laki dengan perempuan. Penelitian ini bertujuan mendeskripsikan tentang relasi laki-laki dengan perempuan menurut pandangan Islam secara objektif. Sumber data penelitian ini adalah novel Maha Cinta Adam...

  1. Gambaran Skrining Depresi Postpartum Pada Wanita Postpartum Dengan Menggunakan Edinburgh Postnatal Depression Scale (EPDS) Di RSUP.H.Adam Malik Dan RSU DR.Pirngadi Medan

    OpenAIRE

    Sinaga, Rahmanita

    2014-01-01

    BACKGROUND : More than 80 % of women after childbirth experience some form of postpartum depression symptoms , commonly known as the " baby blues " or sadness because of the presence of children . Women with levels increasing depressive symptoms may be a state of postpartum depression . Unlike minor depression , postpartum depression usually can not be cured without clinical intervention OBJECTIVE : To determine the postpartum depression screening at postpartum women in Adam Malik and Pir...

  2. Analisis Perilaku Pemeliharaan Kesehatan Gigi Dan Mulut Terhadap Status Oral Higiene Dan Periodontal Pasien Kompromis Medis Rawat Inap Di RSUP H. Adam Malik Medan

    OpenAIRE

    Yusdani, Herniza

    2016-01-01

    Medically compromised condition, especially in hospitalized patients, has long been known as a potential risk factor to the incidence of periodontal disease. Many studies reported about the correlation between medically compromised patients with periodontal disease. The purpose of this study was to analyze oral hygiene and periodontal status of medically compromised and non-compromised patients at Rumah Sakit H. Adam Malik, a general hospital in Medan, based on oral healthcare behavior such a...

  3. Pengaruh Edukasi terhadap Kemampuan Keluarga dalam Perawatan Stoma pada Anggota Keluarga yang Mengalami Kolostomi di Rindu B Ruang 2A RSUP. H. Adam Malik Medan

    OpenAIRE

    Nainggolan, Santy Ercelina

    2015-01-01

    Stoma merupakan lubang usus yang muncul dipermukaan abdomen yang berupa mukosa kemerahan. Edukasi merupakan suatu intervensi yang dapat membantu pasien dan keluarga untuk menjaga kesehatan stoma dengan perawatan yang tepat. Tujuan dari penelitian ini adalah untuk mengetahui pengaruh edukasi terhadap kemampuan keluarga dalam perawatan stoma pada anggota keluarga yang mengalami kolostomi di Rindu B Ruang 2A RSUP. H. Adam Malik Medan yang dilaksanakan pada tanggal 14 Maret sampai 21 Mei 2012. De...

  4. A NEW PARADIGMA OF THE ECONOMICAL AGENT. FROM ADAM SMITH’S HOMO ECONOMICUS TO HOMO GENEROSUS BASED ON SOCIAL RESPONSIBILITY

    OpenAIRE

    PUP ANCA

    2010-01-01

    Analyzed form outside, many actions of the economical agent seem to be impulse by the self interest. As a prototype of this kind of person we have the Homo economicus as Adam Smith described it. In a blitz portrait we identify some characteristics: he is perfect rational, perfect egoist, perfect free, perfect competitive and perfect social. The aim of this research is to permute the barycentre from Homo economicus based on self interest, to Homo generosus, based on social responsibility. As a...

  5. Gambaran Kejadian Abortus Spontan dengan Usia Ibu di Rumah Sakit Umum Pusat (RSUP) Haji Adam Malik dari Tahun 2005 hingga Tahun 2010

    OpenAIRE

    Muhammad Khir Zikri Bin Abdul Mutalib

    2011-01-01

    Background : Spontaneous Abortion is the health problem that occurred to the pregnancy women where the gestational ages are below than 20 weeks and the fetus is under 1000 gram in weight. There are many factor contributing to the high prevalens cases, and one of them is maternal age. Objectif : This study objectif is to observed the incidences of Spontaneous Abortion within Maternal Age at RSUP H. Adam Malik, Medan between 2005 and 2010. Method : This research is a descriptif researc...

  6. Perbedaan Laju Aliran Saliva Sebelum Dan Sesudah Berkumur Dengan Larutan Baking Soda Pada Pasien Hipertensi Dengan Xerostomia Di RSUP H. Adam Malik Medan

    OpenAIRE

    Wahyuni, Diny

    2014-01-01

    Perbedaan Laju Aliran Saliva Sebelum dan Sesudah Berkumur Dengan Larutan Baking Soda pada Pasien Hipertensi Dengan Xerostomia di RSUP H. Adam Malik Medan.xi + 35 halaman Hipertensi adalah meningkatnya tekanan darah sistolik lebih tinggi atau sama dengan 140 mm Hg serta tekanan darah diastoliknya lebih tinggi atau sama dengan 90 mm Hg atau ketika seseorang sedang mengonsumsi antihipertensi untuk mengontrol tekanan darah. Beberapa golongan dari obat antihipertensi mempunyai efek samping xero...

  7. Pengaruh Pengetahuan, Sikap Dan Keterampilan Perawat Terhadap Pelaksanaan Promosi Kesehatan Di Ruang Rawat Inap Terpadu B2 Bedah RSUP H.Adam Malik Tahun 2013

    OpenAIRE

    Bangun, Ita

    2016-01-01

    Health Promotion in Hospital (PKRS) constitutes an attempt to provide the understanding about disease and its prevention to patients, families, and hospital visitors. Health promotion in the Integrated Inpatient Wards (Rindu) B2 Surgery at RSUP H. Adam Malik conducted by nurses is not sufficiently implemented, due to the lack of knowledge, attitude, and skill. The aim of the research was to analyze the influence of nurses’ knowledge, attitude, and skill on the implementation of health pro...

  8. Pengaruh Edukasi Dan Latihan Senam Kaki Pasien Dm Tipe Ii Terhadap Pengetahuan Dan Kemampuan Pasien Dalam Melakukan Latihan Senam Kaki Di Rsup H. Adam Malik Medan

    OpenAIRE

    Siahaan, Ifan Pratama

    2014-01-01

    Health education is a process of dynamic change in behavior. Foot gymnastics can help improve blood circulation and strengthens the small muscles of the foot and prevent the occurrence of deformities of the feet. This research aims to know the influence of education and gymnastics exercises feet against the level of knowledge and practice gymnastics walk in patients in performing gymnastics in DM at H. Adam Malik Public Hospital Medan during the month of October until November 2013 by using Q...

  9. The Elsevier Trophoblast Research Award Lecture: Importance of metzincin proteases in trophoblast biology and placental development: a focus on ADAM12.

    Science.gov (United States)

    Aghababaei, Mahroo; Beristain, Alexander G

    2015-04-01

    Placental development is a highly regulated process requiring signals from both fetal and maternal uterine compartments. Within this complex system, trophoblasts, placental cells of epithelial lineage, form the maternal-fetal interface controlling nutrient, gas and waste exchange. The commitment of progenitor villous cytotrophoblasts to differentiate into diverse trophoblast subsets is a fundamental process in placental development. Differentiation of trophoblasts into invasive stromal- and vascular-remodeling subtypes is essential for uterine arterial remodeling and placental function. Inadequate placentation, characterized by defects in trophoblast differentiation, may underlie the earliest cellular events driving pregnancy disorders such as preeclampsia and fetal growth restriction. Molecularly, invasive trophoblasts acquire characteristics defined by profound alterations in cell-cell and cell-matrix adhesion, cytoskeletal reorganization and production of proteolytic factors. To date, most studies have investigated the importance of the matrix metalloproteinases (MMPs) and their ability to efficiently remodel components of the extracellular matrix (ECM). However, it is now becoming clear that besides MMPs, other related proteases regulate trophoblast invasion via mechanisms other than ECM turnover. In this review, we will summarize the current knowledge on the regulation of trophoblast invasion by members of the metzincin family of metalloproteinases. Specifically, we will discuss the emerging roles that A Disintegrin and Metalloproteinases (ADAMs) play in placental development, with a particular focus on the ADAM subtype, ADAM12. PMID:25589360

  10. “Do the next thing”: an interview with Elizabeth Adams St. Pierre on post-qualitative methodology

    Directory of Open Access Journals (Sweden)

    Hanna Guttorm

    2015-06-01

    Full Text Available Professor Elizabeth Adams St. Pierre’s work focuses on critical and poststructural theories of language and the subject and what she has called post qualitative inquiry or post inquiry. She asks what might come after conventional humanist qualitative research methodology. She’s especially interested in the new empiricisms/new materialisms as well as new research practices enabled by the ontological turn. During St. Pierre's visit to the Finnish Educational Research Association (FERA Conference in Oulu in November 2014, we had the opportunity to talk with her about post qualitative research around some questions we had sent her beforehand. We then transcribed, edited, and translated the interview, and published it in the Finnish journal Kasvatus (Education in spring 2015. In this interview St. Pierre talks in the US context, where qualitative methodology is turning—or being pushed to turn—back to positivism with normalized and formalized practices, St. Pierre encourages researchers to constantly question the prevailing truths and the traditions they have learnt too well.

  11. Il Carroccio di Cortenuova: Nord e Sud Italia tra Papato e Impero nella Cronaca di Salimbene de Adam

    Directory of Open Access Journals (Sweden)

    Marina Nardone

    2013-12-01

    Full Text Available The Caroccio of Cortenuova Northern and Southern Italy between Papacy and Empire in the Cronaca of Salimbene de Adam Starting from a quote in recent literature on the Italian unification, this article attempts to explain the role played by the Italian Middle Ages in the construction of national memory and in the archeology of a prejudice. It admonishes that only a full recognition of the deep alterity of the Middle Ages can prevent misuses of medieval references. Next, it proceeds to discuss the quote in question, namely a reference to Salimbene de Adam’s well-known chronicle, and it examines what drove this Franciscan chronicler to change the final episode of the Battle of Cortenuova (1237. In his Cronaca Salimbene relates that, after Frederick II had beaten the Lombard League’s army and seized possession of the Carroccio, the symbol of communal autonomy and liberty, he offered it to the city of Rome, which, in turn, burned it. However, a still existing inscription testifies that the Carroccio was not an unwelcome gift for Rome at all. Despite this historical reality, the Franciscan chronicler preferred, as Ludovico Gatto has suggested, to present posterity with the image of a defiant Rome towards Frederick II, who was identified after all, in the Joachimite literature, as the Antichrist, the enemy of Christianity.

  12. The Moral Dignity of Inductive Method and the Reconciliation of Science and Faith in Adam Sedgwick's Discourse

    Science.gov (United States)

    Bellon, Richard

    2012-07-01

    Science's inductive method required patient, humble and self-controlled behavior; Christian revelation demanded the same virtues. The discoveries of science and the truths of scripture would always harmonize as long as both men of science and men of faith conducted themselves in scrupulous accordance with their duty. So ran a central argument in A Discourse on the studies of the university (1833; 5th ed, 1850) by Adam Sedgwick (1785-1873), the longtime professor of geology at the University of Cambridge. This sanctification of the inductive method provided the foundation for a theistic science which (in theory) did not subordinate scientific theory to religious doctrine. This vision provided the foundation for Sedgwick's lifelong crusade against all forms of evolutionary theory. Evolution's impiety, he insisted, resulted from (and exacerbated) a failure to behave inductively. The fact that Sedgwick (in principle if not always in practice) elevated norms of behavior above systems of belief had an important and paradoxical consequence. Even though his personal hatred of evolution never cooled, his Discourse nonetheless provided a dominant model for younger theists to reconcile faith with Charles Darwin's evolutionary theory.

  13. OpenADAM: an open source genome-wide association data management system for Affymetrix SNP arrays

    Directory of Open Access Journals (Sweden)

    Sham P C

    2008-12-01

    Full Text Available Abstract Background Large scale genome-wide association studies have become popular since the introduction of high throughput genotyping platforms. Efficient management of the vast array of data generated poses many challenges. Description We have developed an open source web-based data management system for the large amount of genotype data generated from the Affymetrix GeneChip® Mapping Array and Affymetrix Genome-Wide Human SNP Array platforms. The database supports genotype calling using DM, BRLMM, BRLMM-P or Birdseed algorithms provided by the Affymetrix Power Tools. The genotype and corresponding pedigree data are stored in a relational database for efficient downstream data manipulation and analysis, such as calculation of allele and genotype frequencies, sample identity checking, and export of genotype data in various file formats for analysis using commonly-available software. A novel method for genotyping error estimation is implemented using linkage disequilibrium information from the HapMap project. All functionalities are accessible via a web-based user interface. Conclusion OpenADAM provides an open source database system for management of Affymetrix genome-wide association SNP data.

  14. ADAM17-Dependent c-MET-STAT3 Signaling Mediates Resistance to MEK Inhibitors in KRAS Mutant Colorectal Cancer

    Directory of Open Access Journals (Sweden)

    Sandra Van Schaeybroeck

    2014-06-01

    Full Text Available There are currently no approved targeted therapies for advanced KRAS mutant (KRASMT colorectal cancer (CRC. Using a unique systems biology approach, we identified JAK1/2-dependent activation of STAT3 as the key mediator of resistance to MEK inhibitors in KRASMT CRC in vitro and in vivo. Further analyses identified acute increases in c-MET activity following treatment with MEK inhibitors in KRASMT CRC models, which was demonstrated to promote JAK1/2-STAT3-mediated resistance. Furthermore, activation of c-MET following MEK inhibition was found to be due to inhibition of the ERK-dependent metalloprotease ADAM17, which normally inhibits c-MET signaling by promoting shedding of its endogenous antagonist, soluble “decoy” MET. Most importantly, pharmacological blockade of this resistance pathway with either c-MET or JAK1/2 inhibitors synergistically increased MEK-inhibitor-induced apoptosis and growth inhibition in vitro and in vivo in KRASMT models, providing clear rationales for the clinical assessment of these combinations in KRASMT CRC patients.

  15. John Adams Lecture | Accelerator-Based Neutrino Physics: Past, Present and Future by Kenneth Long | 8 December

    CERN Multimedia

    2014-01-01

    John Adams Lecture: Accelerator-Based Neutrino Physics: Past, Present and Future by Dr. Kenneth Long (Imperial College London & STFC).   Monday, 8 December 2014 from 2 p.m. to 4 p.m. at CERN ( 503-1-001 - Council Chamber ) Abstract: The study of the neutrino is the study of physics beyond the Standard Model. We now know that the neutrinos have mass and that neutrino mixing occurs causing neutrino flavour to oscillate as neutrinos propagate through space and time. Further, some measurements can be interpreted as hints for new particles known as sterile neutrinos. The measured values of the mixing parameters make it possible that the matter-antimatter (CP) symmetry may be violated through the mixing process. The consequences of observing CP-invariance violation in neutrinos would be profound. To discover CP-invariance violation will require measurements of exquisite precision. Accelerator-based neutrino sources are central to the future programme and advances in technique are required ...

  16. Major, trace and rate earth elements in sediments of the Julian Adame-Alatorre dam by instrumental neutron activation analysis

    International Nuclear Information System (INIS)

    The rapid industrial development in regions of Mexico during recent years has had the side effect of introducing toxic metals, fertilizers, and pesticides into the ecosystem. Sediment cores were collected from eight locations around the Julian Adame-Alatorre dam located in Municipality of Villanueva in the Zacatecas State, Mexico. The cores were analyzed for 32 major, trace, and rare earth elements (As, La, Lu, Nd, Sm, U, Yb, Ce, Co, Cr, Cs, Eu, Fe, Hf, Rb, Sb, Sc, Sr, Ta, Tb, Th, Zn, Zr, Al, Ba, Ca, Dy, K, Mn, Na, Ti, V) in order to estimate the health risk. The samples were analyzed by instrument neutron activation analysis using thermal neutron fluxes of 8 x 1013 and 5 x 1013 n cm-2 s-1 for short and long irradiations, respectively. The results of the contamination levels for elements such as As, Ba, Cr, Fe, Mn, Ta, V, and Zn were compared with the Mexican regulations and the guidelines of US EPA. (Author)

  17. Three-dimensional viscoelastic time-domain finite-difference seismic modelling using the staggered Adams-Bashforth time integrator

    Science.gov (United States)

    Bohlen, Thomas; Wittkamp, Florian

    2016-03-01

    We analyse the performance of a higher order accurate staggered viscoelastic time-domain finite-difference method, in which the staggered Adams-Bashforth (ABS) third-order and fourth-order accurate time integrators are used for temporal discretization. ABS is a multistep method that uses previously calculated wavefields to increase the order of accuracy in time. The analysis shows that the numerical dispersion is much lower than that of the widely used second-order leapfrog method. Numerical dissipation is introduced by the ABS method which is significantly smaller for fourth-order than third-order accuracy. In 1-D and 3-D simulation experiments, we verify the convincing improvements of simulation accuracy of the fourth-order ABS method. In a realistic elastic 3-D scenario, the computing time reduces by a factor of approximately 2.4, whereas the memory requirements increase by approximately a factor of 2.2. The ABS method thus provides an alternative strategy to increase the simulation accuracy in time by investing computer memory instead of computing time.

  18. Application of Adams to powerplant mount system%Adams软件在发动机悬置上的应用

    Institute of Scientific and Technical Information of China (English)

    刘桂春; 黄文兵

    2009-01-01

    The virtual prototype models for two different design schemes of truck power train mount system are set up by means of software ADAMS. With the basic parameters obtained from the test, the natural frequencies and vibration isolation performance of the truck powertrain mount are simulated, and the two different schemes of mount system are analyzed and compared in terms of the rationality of parameter matching for improving the vibration isolation performance of power train mount system.%文章针对某中型载货车动力总成悬置系统的不同设计方案,利用Adams软件建立虚拟样机模型,通过实测其基本参数,对动力总成悬置系统的固有特性进行仿真计算,分析比较2种方案的悬置系统参数匹配的合理性,以求达到提高悬置系统隔振性能的目的.

  19. Characterization of bottom sediment of Adam bridge for its mineral content by spectrochemical and ICP-OES techniques

    International Nuclear Information System (INIS)

    Adam's Bridge also known as Rama's Bridge or Rama Setu is a chain of limestone shoals, between Rameswaram Island, off the southeastern coast of Tamil Nadu, India, and Mannar Island, off the northwestern coast of Sri Lanka. Geological evidence suggests that this bridge is a former land connection between India and Sri Lanka. During this work mineral content in the sand sample collected from four different locations were evaluated by using spectrochemical techniques such as FAAS (Flame atomic absorption spectroscopy), FES(Florescence Emission Spectroscopy), ICP-OES (Inductive coupled plasma optical emission spectroscopy) and UV - Visible Spectrophotometry. Various major elements like SiO2 , Al2O3, Fe2O3, MgO, CaO , Na2O , K2O, minor elements like MnO, TiO2, P2O5 and trace elements like ZrO2; V2O5, PbO and U etc. Validation of analytical methodology and reliability of analytical results were carried out by the analysis of the standard reference material. Trace elements were estimated after the selective removal of silica using AAS and ICP-OES technique. (author)

  20. ADAM 33基因多态性与支气管哮喘易感性关系的Meta 分析%Correlation of ADAM33 Gene F+1 and T1 polymorphisms and susceptibility to Asthma:A Meta-analysis

    Institute of Scientific and Technical Information of China (English)

    图尔荪阿依·艾尔肯; 阿不都吉力力·居来提; 胡昕; 黄毅; 齐曼古力·吾守尔

    2016-01-01

    Objective To explore the correlation of ADAM33 (a disintegrin and metalloproteinase domain 33)gene polymorphisms with asthma.Methods An electronic search of the PubMed,Web of science, Ovid,Embase,Medline,WanFang,ChaoXing,VIP database,CNKI and other electronic databases was performed from their foundation to October 2015.Retrieved case-control studies related to association of ADAM33 polymorphisms with asthma,and screened the included studies up to standard,collected and ex-tracted data.A meta-analysis was conducted on correlation between the ADAM33 F+1 and T1 polymor-phisms with asthma.Results A total of eight case-control studies were included,which were including 1718 asthma patients and 1622 healthy controls.Meta-analysis revealed that ADAM33 gene F+1 C allele decreased the risk of susceptibility to asthma in Chinese Han population (OR =0.855,95% CI =0.743 -0.984,P =0.029).ADAM33 gene T1 A allele also decreased asthma risk in Chinese Han population (OR=0.408,95% CI = 0.254 - 0.658,P =0.000).ADAM33 gene T1 AA genotype significantly decreased asthma risk in Chinese Han population in additive model,dominant model and recessive model [(OR =0.226,95% CI =0.100 -0.511,P =0.000),(OR =0.385,95% CI =0.162 -0.918,P =0.031),(OR =0.278,95% CI =0.186 - 0.415,P =0.000)].However,in codominant model,there was no correlation found between bronchial asthma and ADAM33 T1 polymorphism.Conclusion ADAM33 gene F+ 1 and T1 polymorphisms may decrease asthma risk in Chinese Han population.%目的:探讨整合素和金属蛋白酶域33(ADAM33)基因位点多态性与支气管哮喘易感性的关系。方法检索 Pubmed、Web of Sience、Ovid、Embase、Medline、万方数据知识服务平台、超星读秀、维普网、中国知网(CNKI)等电子数据库,检索时间均从建库至2015年10月,检索有关 ADAM33基因多态性与支气管哮喘易感性关系的病例对照研究,筛选符合纳入标准的文献,进行数据采集、提取,进行 ADAM33基因 F