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Sample records for adam non-nucleoside reverse

  1. Novel indazole non-nucleoside reverse transcriptase inhibitors using molecular hybridization based on crystallographic overlays.

    Jones, Lyn H; Allan, Gill; Barba, Oscar; Burt, Catherine; Corbau, Romuald; Dupont, Thomas; Knöchel, Thorsten; Irving, Steve; Middleton, Donald S; Mowbray, Charles E; Perros, Manos; Ringrose, Heather; Swain, Nigel A; Webster, Robert; Westby, Mike; Phillips, Chris

    2009-02-26

    A major problem associated with non-nucleoside reverse transcriptase inhibitors (NNRTIs) for the treatment of HIV is their lack of resilience to mutations in the reverse transcriptase (RT) enzyme. Using structural overlays of the known inhibitors efavirenz and capravirine complexed in RT as a starting point, and structure-based drug design techniques, we have created a novel series of indazole NNRTIs that possess excellent metabolic stability and mutant resilience.

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

    Spallarossa, Andrea; Cesarini, Sara; Ranise, Angelo; Ponassi, Marco; Unge, Torsten; Bolognesi, Martino

    2008-01-25

    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 2.8-3.0A resolution by X-ray crystallography. The conformations adopted by the enzyme-bound TCs were analyzed and compared with those of bioisosterically related NNRTIs.

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

    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.

  4. Novel non-nucleoside inhibitors of HIV-1 reverse transcriptase. 1. Tricyclic pyridobenzo- and dipyridodiazepinones.

    Hargrave, K D; Proudfoot, J R; Grozinger, K G; Cullen, E; Kapadia, S R; Patel, U R; Fuchs, V U; Mauldin, S C; Vitous, J; Behnke, M L

    1991-07-01

    Novel pyrido[2,3-b][1,4]benzodiazepinones (I), pyrido[2,3-b][1,5]benzodiazepinones (II), and dipyrido[3,2-b:2',3'-e][1,4]diazepinones (III) were found to inhibit human immunodeficiency virus type 1 (HIV-1) reverse transcriptase in vitro at concentrations as low as 35 nM. In all three series, small substituents (e.g., methyl, ethyl, acetyl) are preferred at the lactam nitrogen, whereas slightly larger alkyl moieties (e.g., ethyl, cyclopropyl) are favored at the other (N-11) diazepinone nitrogen. In general, lipophilic substituents are preferred on the A ring, whereas substitution on the C ring generally reduces potency relative to the corresponding compounds with no substituents on the aromatic rings. Maximum potency is achieved with methyl substitution at the position ortho to the lactam nitrogen atom; however, in this case an unsubstituted lactam nitrogen is preferred. Additional substituents on the A ring can be readily tolerated. The dipyridodiazepinone derivative 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e] [1,4]diazepin-6-one (96, nevirapine) is a potent (IC50 = 84 nM) and and selective non-nucleoside inhibitor of HIV-1 reverse transcriptase, and has been chosen for clinical evaluation.

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

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

    2016-01-01

    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.

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

    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.

  7. Synthesis of Novel Uracil Non-Nucleoside Derivatives as Potential Reverse Transcriptase Inhibitors of HIV-1

    El-Brollosy, Nasser R.; Al-Deeb, Omar. A.; El-Emam, Ali A.

    2009-01-01

    Novel emivirine and TNK-651 analogues 5a-d were synthesized by reaction of chloromethyl ethyl ether and / or benzyl chloromethyl ether, respectively, with uracils having 5-ethyl and 6-(4-methylbenzyl) or 6-(3,4-dimethoxybenzyl) substituents. A series of new uracil non-nucleosides substituted at N-1...... 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......-(3,5-dimethylbenzyl)uracil 9c and 5-ethyl-6-(3,5-dimethylbenzyl)-1-(2-phenylethyloxymethyl)uracil 9g showed inhibitory potency equally to emivirine against HIV-1 wild type. Furthermore, compounds 9c and 9g showed marginal better activity against NNRTI resistant mutants than emivirine....

  8. Virological and immunological impact of non-nucleoside reverse transcriptase inhibitor withdrawal in HIV-infected patients with multiple treatment failures.

    Piketty, Christophe; Gérard, Laurence; Chazallon, Corine; Calvez, Vincent; Clavel, François; Taburet, Anne-Marie; Girard, Pierre-Marie; Aboulker, Jean-Pierre

    2004-07-02

    No significant changes in viral load and CD4 cell count were observed 2-4 weeks after the withdrawal of non-nucleoside reverse transcriptase inhibitors (NNRTI) from the current therapy of patients exhibiting resistance mutations to this class of drugs. The data suggest that in the presence of specific resistance mutations NNRTIexert no residual antiretroviral activity and could be withdrawn without viral rebound.

  9. Structural and Preclinical Studies of Computationally Designed Non-Nucleoside Reverse Transcriptase Inhibitors for Treating HIV infection

    Kudalkar, Shalley N.; Beloor, Jagadish; Chan, Albert H.; Lee, Won-Gil; Jorgensen, William L.; Kumar, Priti; Anderson, Karen S.

    2017-02-06

    The clinical benefits of HIV-1 non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) are hindered by their unsatisfactory pharmacokinetic (PK) properties along with the rapid development of drug-resistant variants. However, the clinical efficacy of these inhibitors can be improved by developing compounds with enhanced pharmacological profiles and heightened antiviral activity. We used computational and structure-guided design to develop two next-generation NNRTI drug candidates, compounds I and II, which are members of a class of catechol diethers. We evaluated the preclinical potential of these compounds in BALB/c mice because of their high solubility (510 µg/ml for compound I and 82.9 µg/ml for compound II), low cytotoxicity, and enhanced antiviral activity against wild-type (WT) HIV-1 RT and resistant variants. Additionally, crystal structures of compounds I and II with WT RT suggested an optimal binding to the NNRTI binding pocket favoring the high anti-viral potency. A single intraperitoneal dose of compounds I and II exhibited a prolonged serum residence time of 48 hours and concentration maximum (Cmax) of 4000- to 15,000-fold higher than their therapeutic/effective concentrations. These Cmax values were 4- to 15-fold lower than their cytotoxic concentrations observed in MT-2 cells. Compound II showed an enhanced area under the curve (0–last) and decreased plasma clearance over compound I and efavirenz, the standard of care NNRTI. Hence, the overall (PK) profile of compound II was excellent compared with that of compound I and efavirenz. Furthermore, both compounds were very well tolerated in BALB/c mice without any detectable acute toxicity. Taken together, these data suggest that compounds I and II possess improved anti-HIV-1 potency, remarkable in vivo safety, and prolonged in vivo circulation time, suggesting strong potential for further development as new NNRTIs for the potential treatment of HIV infection.

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

    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

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

    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.

  12. Molecular design, synthesis and biological evaluation of BP-O-DAPY and O-DAPY derivatives as non-nucleoside HIV-1 reverse transcriptase inhibitors.

    Yang, Shiqiong; Pannecouque, Christophe; Daelemans, Dirk; Ma, Xiao-Dong; Liu, Yang; Chen, Fen-Er; De Clercq, Erik

    2013-07-01

    This paper reports the synthesis and antiviral evaluation of a series of non-nucleoside reverse transcriptase inhibitors (NNRTIs) that combine the peculiar structural features of diarylpyrimidine derivatives (DAPYs) and benzophenone derivatives (BPs). The DAPY derivatives bearing benzoyl or alkoxyl substitutes on the A-ring showed the inhibitory activity against wild-type HIV-1 at the cellular level within the range of EC50 values from micromolar to nanomolar. Among these compounds, 1u exhibited the most potent anti-HIV-1 activity (EC50 = 0.06 ± 0.01 μM, SI > 6260), which were about 1.8-fold more active than nevirapine (NVP) and delavirdine (DLV). In addition, the binding modes with HIV-1 RT and the preliminary SAR studies of these derivatives were also considered for further investigation.

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

    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.

  14. Progress of bis(heteroaryl)piperazines (BHAPs) as non-nucleoside reverse transcriptase inhibitors (NNRTIs) against human immunodeficiency virus type 1 (HIV-1).

    Xu, Hui

    2010-01-01

    Since the first case of acquired immunodeficiency syndrome (AIDS) was reported in 1981, AIDS, as the global disease affecting 33.2 million people in 2007, has always been an unsolved problem worldwide. Reverse transcriptase (RT) is a crucial enzyme in the life cycle of human immunodeficiency virus type 1 (HIV-1), and thereby has been the prime drugs target for antiretroviral (ARV) therapy against AIDS. To date, two classes of RT inhibitors (RTIs), e.g., nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs), and a lot of compounds tested as RTIs have been described. To our knowledge, bis(heteroaryl)piperazines (BHAPs) have been considered as one class of promising NNRTIs, such as structurally and chemically related NNRTI delavirdine, which was approved by the U. S. Food and Drug Administration (FDA) for the treatment of HIV-1 infection in 1997. In this mini-review, we make attempts to report the progress of synthesis and structure-activity relationship (SAR) of BHAPs, in the meantime, the synergistic inhibition of HIV-1 replication by combining delavirdine with other HIV-1 inhibitors is also discussed. It will pave the way for the design and development of BHAPs as anti-HIV-1 agents in AIDS chemotherapy in the future.

  15. Hydrophobic-core PEGylated graft copolymer-stabilized nanoparticles composed of insoluble non-nucleoside reverse transcriptase inhibitors exhibit strong anti-HIV activity.

    Leporati, Anita; Novikov, Mikhail S; Valuev-Elliston, Vladimir T; Korolev, Sergey P; Khandazhinskaya, Anastasia L; Kochetkov, Sergey N; Gupta, Suresh; Goding, Julian; Bolotin, Elijah; Gottikh, Marina B; Bogdanov, Alexei A

    2016-11-01

    Benzophenone-uracil (BPU) scaffold-derived candidate compounds are efficient non-nucleoside reverse transcriptase inhibitors (NNRTI) with extremely low solubility in water. We proposed to use hydrophobic core (methoxypolyethylene glycol-polylysine) graft copolymer (HC-PGC) technology for stabilizing nanoparticle-based formulations of BPU NNRTI in water. Co-lyophilization of NNRTI/HC-PGC mixtures resulted in dry powders that could be easily reconstituted with the formation of 150-250 nm stable nanoparticles (NP). The NP and HC-PGC were non-toxic in experiments with TZM-bl reporter cells. Nanoparticles containing selected efficient candidate Z107 NNRTI preserved the ability to inhibit HIV-1 reverse transcriptase polymerase activities with no appreciable change of EC50. The formulation with HC-PGC bearing residues of oleic acid resulted in nanoparticles that were nearly identical in anti-HIV-1 potency when compared to Z107 solutions in DMSO (EC50=7.5±3.8 vs. 8.2±5.1 nM). Therefore, hydrophobic core macromolecular stabilizers form nanoparticles with insoluble NNRTI while preserving the antiviral activity of the drug cargo.

  16. Synthesis, biological evaluation and molecular modeling of 4,6-diarylpyrimidines and diarylbenzenes as novel non-nucleosides HIV-1 reverse transcriptase inhibitors.

    Ribone, Sergio R; Leen, Volker; Madrid, Marcela; Dehaen, Wim; Daelemans, Dirk; Pannecouque, Christophe; Briñón, Margarita C

    2012-12-01

    A series of novel 4,6-diarylpyrimidines (4,6-DAPY) and diarylbenzenes (DABE) compounds were synthesized and evaluated as inhibitors of human immunodeficiency virus type-1 (HIV-1). Among them, the most potent HIV-1 inhibitors were 8b, 8d, 14b and 18 (EC(50) = 0.049, 0.381, 0.599 and 0.398 μM, respectively), with HIV-1 inhibitory activity improved or similar to nevirapine (NVP, EC(50) = 0.097 μM) and delavirdine (DEV, EC(50) = 0.55 μM). The other compounds displayed moderate activity (8c, EC(50) = 5.25 μM) or were inactive (8a and 14a) against HIV-1 replication. Molecular modeling studies were performed with the synthesized compounds in complex with the wild-type reverse transcriptase (RT). A correlation was found between the anti-HIV activity and the electrostatic energy of interaction with Lys101 residue. These findings enrich the SAR of these Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) families.

  17. 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

    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.

  18. Synthesis and biological evaluation of piperidine-substituted triazine derivatives as HIV-1 non-nucleoside reverse transcriptase inhibitors.

    Chen, Xuwang; Zhan, Peng; Pannecouque, Christophe; Balzarini, Jan; De Clercq, Erik; Liu, Xinyong

    2012-05-01

    A novel series of piperidine-substituted triazine derivatives have been synthesized and evaluated for anti-HIV activities in MT-4 cells. Most compounds displayed extremely promising activity against wild-type HIV-1 with EC(50) values in low nanomolar concentration, better than that of Nevirapine, Delavirdine, Zidovudine and Dideoxycitidine, and higher potency towards the resistant mutant strain K103N/Y181C than that of Nevirapine and Delavirdine. Selected compounds were also assayed against reverse transcriptase with lower IC(50) values than that of Nevirapine. The structure-activity relationship (SAR) of these novel structural congeners was also discussed.

  19. A randomized trial of Raltegravir replacement for protease inhibitor or non-nucleoside reverse transcriptase inhibitor in HIV-infected women with lipohypertrophy.

    Lake, Jordan E; McComsey, Grace A; Hulgan, Todd M; Wanke, Christine A; Mangili, Alexandra; Walmsley, Sharon L; Boger, M Sean; Turner, Ralph R; McCreath, Heather E; Currier, Judith S

    2012-09-01

    Lipohypertrophy in HIV-infected patients is associated with metabolic abnormalities. Raltegravir (RAL) is not known to induce fat changes or severe metabolic perturbations. HIV-infected women with central adiposity and HIV-1 RNA less than 50 copies per milliliter on non-nucleoside reverse transcriptase inhibitor (NNRTI)- or protease inhibitor (PI)-based antiretroviral therapy (ART) continued their nucleoside reverse transcriptase inhibitor (NRTI) backbone and were randomized to switch to open label RAL immediately or after 24 weeks. The primary end point was 24-week between-group change in computed tomography (CT)-quantified visceral adipose tissue (AT) volume. Fasting lipids, glucose, C-reactive protein (CRP), anthropometric measurements, and patient-reported quality of life assessments were also measured. Thirty-six subjects provided 80% power to detect a 10% between-group difference in visceral AT over 24 weeks. Thirty-seven of 39 enrolled subjects completed week 24. At entry, subjects were 75% black or Hispanic, and on 62% PI-based and 38% NNRTI-based regimens. The median age was 43 years, CD4 count 558 cells per microliter, and body mass index (BMI) 32 kg/m(2). After 24 weeks, no statistically significant changes in visceral or subcutaneous AT, anthropometrics, BMI, glucose, or CRP were observed. In subjects receiving RAL, significant improvements in total and LDL cholesterol (p=0.04), self-reported belly size (p=0.02) and composite body size (p=0.02) were observed. Body size changes correlated well with percent visceral AT change. No RAL-related adverse events occurred. Compared to continued PI or NNRTI, switch to RAL was associated with statistically significant 24-week improvements in total and LDL cholesterol but not AT volumes. Additional insights into AT and metabolic changes in women on RAL will be provided by 48-week follow-up of the immediate-switch arm.

  20. Amino acid substitutions in HIV-1 reverse transcriptase with corresponding residues from HIV-2. Effect on kinetic constants and inhibition by non-nucleoside analogs.

    Bacolla, A; Shih, C K; Rose, J M; Piras, G; Warren, T C; Grygon, C A; Ingraham, R H; Cousins, R C; Greenwood, D J; Richman, D

    1993-08-05

    Nevirapine is a highly potent and specific inhibitor of human immunodeficiency virus type 1 (HIV-1) polymerase, but is inactive against HIV-2 and other polymerase. Previous studies demonstrated that residues 176-190 of HIV-1 reverse transcriptase (RT) can confer nevirapine sensitivity to HIV-2 RT. To better characterize the role of this sequence in HIV-1 RT, we have progressively substituted residues 176-190 of HIV-2 RT for those of HIV-1 RT and monitored the impact on the kinetic properties; inhibitory activity of nevirapine (11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[2,3-b:2',3'-e] [1,4]diazepin-6-one), E-BPU (5-ethyl-1-benzyloxymethyl-6-(phenylthio)-uracil), and TIBO-R82150 ((+)-S-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5,1-j k] [1,4]benzodiazepin-2(1H)-thione); and inhibitor-induced fluorescence changes of the mutant enzymes. The study revealed that in addition to Try-181 and Tyr-188, a new amino acid residue (Gly-190) plays an important role in determining susceptibility to nevirapine and E-BPU, but not to TIBO-R82150. These data argue that these non-nucleoside inhibitors fit differently, even though they share a common binding pocket. Nevirapine was seen to exert inhibitory activity by altering the interaction of the enzyme with the template-primer. Kinetic parameters were modulated by the template (DNA versus RNA) as well as by some of the mutations.

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

    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

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

    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

  3. Structure-based virtual screening efforts against HIV-1 reverse transcriptase to introduce the new potent non-nucleoside reverse transcriptase inhibitor

    Hosseini, Yaser; Mollica, Adriano; Mirzaie, Sako

    2016-12-01

    The human immunodeficiency virus (HIV) which is strictly related to the development of AIDS, is treated by a cocktail of drugs, but due its high propensity gain drug resistance, the rational development of new medicine is highly desired. Among the different mechanism of action we selected the reverse transcriptase (RT) inhibition, for our studies. With the aim to identify new chemical entities to be used for further rational drug design, a set of 3000 molecules from the Zinc Database have been screened by docking experiments using AutoDock Vina software. The best ranked compounds with respect of the crystallographic inhibitor MK-4965 resulted to be five compounds, and the best among them was further tested by molecular dynamics (MD) simulation. Our results indicate that comp1 has a stronger interaction with the subsite p66 of RT than MK-4965 and that both are able to stabilize specific conformational changes of the RT 3D structure, which may explain their activity as inhibitors. Therefore comp1 could be a good candidate for biological tests and further development.

  4. Central nervous system disposition and metabolism of Fosdevirine (GSK2248761), a non-nucleoside reverse transcriptase inhibitor: an LC-MS and Matrix-assisted laser desorption/ionization imaging MS investigation into central nervous system toxicity.

    Castellino, Stephen; Groseclose, M Reid; Sigafoos, James; Wagner, David; de Serres, Mark; Polli, Joseph W; Romach, Elizabeth; Myer, James; Hamilton, Brad

    2013-02-18

    The CNS disposition and metabolism of Fosdevirine (FDV), an HIV non-nucleoside reverse transcriptase inhibitor, was investigated in four patients who unexpectedly experienced seizures after at least 4 weeks of treatment in a Phase IIb, HIV-1 treatment experienced study. In addition, the CNS disposition and metabolism of FDV was examined in samples from rabbit, minipig, and monkey studies. LC-MS was used to characterize and estimate the concentrations of FDV and its metabolites in cerebral spinal fluid (seizure patients, rabbit, and monkey) and brain homogenate (rabbit, minipig, and monkey). The application of matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) provided the spatial distribution of FDV and its metabolites in brain tissue (rabbit, minipig, and monkey). A cysteine conjugate metabolite resulting from an initial glutathione (GSH) Michael addition to the trans-phenyl acrylonitrile moiety of FDV was the predominant drug-related component in the samples from seizure patients, rabbits, and minipigs. This metabolite persisted in the CNS for an extended period of time after the last dose in both seizure patients and minipigs. Furthermore, the localization of this metabolite was found to be highly associated with the white matter in rabbit and minipig brain sections by MALDI IMS. In contrast, the predominant component in monkey CNS was FDV, which was shown to be highly associated with the gray matter. On the basis of these data, several hypothesizes are considered, which might provide insights into species differences in CNS toxicity/seizures observed after FDV dosing.

  5. Malaria in HIV-Infected Children Receiving HIV Protease-Inhibitor- Compared with Non-Nucleoside Reverse Transcriptase Inhibitor-Based Antiretroviral Therapy, IMPAACT P1068s, Substudy to P1060

    Hobbs, Charlotte V.; Gabriel, Erin E.; Kamthunzi, Portia; Tegha, Gerald; Tauzie, Jean; Petzold, Elizabeth; Barlow-Mosha, Linda; Chi, Benjamin H.; Li, Yonghua; Ilmet, Tiina; Kirmse, Brian; Neal, Jillian; Parikh, Sunil; Deygoo, Nagamah; Jean Philippe, Patrick; Mofenson, Lynne; Prescott, William; Chen, Jingyang; Musoke, Philippa; Palumbo, Paul; Duffy, Patrick E.; Borkowsky, William

    2016-01-01

    Background HIV and malaria geographically overlap. HIV protease inhibitors kill malaria parasites in vitro and in vivo, but further evaluation in clinical studies is needed. Methods Thirty-one children from Malawi aged 4–62 months were followed every 3 months and at intercurrent illness visits for ≤47 months (September 2009-December 2011). We compared malaria parasite carriage by blood smear microscopy (BS) and confirmed clinical malaria incidence (CCM, or positive BS with malaria symptoms) in children initiated on HIV antiretroviral therapy (ART) with zidovudine, lamivudine, and either nevirapine (NVP), a non-nucleoside reverse transcriptase inhibitor, or lopinavir-ritonavir (LPV-rtv), a protease inhibitor. Results We found an association between increased time to recurrent positive BS, but not CCM, when anti-malarial treatment and LPV-rtv based ART were used concurrently and when accounting for a LPV-rtv and antimalarial treatment interaction (adjusted HR 0.39; 95% CI (0.17,0.89); p = 0.03). Conclusions LPV-rtv in combination with malaria treatment was associated with lower risk of recurrent positive BS, but not CCM, in HIV-infected children. Larger, randomized studies are needed to confirm these findings which may permit ART optimization for malaria-endemic settings. Trial Registration ClinicalTrials.gov NCT00719602 PMID:27936233

  6. 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

    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.

  7. Anti-HIV cytotoxicity enzyme inhibition and molecular docking studies of quinoline based chalcones as potential non-nucleoside reverse transcriptase inhibitors (NNRT).

    Hameed, Asima; Abdullah, Muhammad Imran; Ahmed, Ejaz; Sharif, Ahsan; Irfan, Ahmad; Masood, Sara

    2016-04-01

    A series of fourteen (A1 - A14) qunioline based chalcones were screened for reverse transcriptase inhibitors (RT) and found potentially active against RT. Bioassay, theoretical and dockings studies with RT (the enzyme required for reverse transcription of viral RNA) results showed that the type and positions of the substituents seemed to be critical for their inhibition against RT. The bromo and chloro substituted chalcone displayed high degree of inhibition against RT. The A4 andA6 showed high interaction with RT, contributing high free binding energy (ΔG -9.30 and -9.13kcal) and RT inhibition value (IC50 0.10μg/ml and 0.11μg/ml).

  8. Molecular docking and 3D-QSAR studies on triazolinone and pyridazinone, non-nucleoside inhibitor of HIV-1 reverse transcriptase.

    Sivan, Sree Kanth; Manga, Vijjulatha

    2010-06-01

    Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are allosteric inhibitors of the HIV-1 reverse transcriptase. Recently a series of Triazolinone and Pyridazinone were reported as potent inhibitors of HIV-1 wild type reverse transcriptase. In the present study, docking and 3D quantitative structure activity relationship (3D QSAR) studies involving comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on 31 molecules. Ligands were built and minimized using Tripos force field and applying Gasteiger-Hückel charges. These ligands were docked into protein active site using GLIDE 4.0. The docked poses were analyzed; the best docked poses were selected and aligned. CoMFA and CoMSIA fields were calculated using SYBYL6.9. The molecules were divided into training set and test set, a PLS analysis was performed and QSAR models were generated. The model showed good statistical reliability which is evident from the r2 nv, q2 loo and r2 pred values. The CoMFA model provides the most significant correlation of steric and electrostatic fields with biological activities. The CoMSIA model provides a correlation of steric, electrostatic, acceptor and hydrophobic fields with biological activities. The information rendered by 3D QSAR model initiated us to optimize the lead and design new potential inhibitors.

  9. Novel non-nucleoside inhibitors of HIV-1 reverse transcriptase. 3. Dipyrido[2,3-b:2',3'-e]diazepinones.

    Proudfoot, J R; Patel, U R; Kapadia, S R; Hargrave, K D

    1995-04-14

    We have explored the potential of derivatives of the dipyrido[2,3-b:2',3'-e][1,4]diazepinone ring system as inhibitors of HIV-1 reverse transcriptase (RT). These compounds are isomeric to the potent RT inhibitor nevirapine and are available via a novel Smiles rearrangement on intermediates used for the synthesis of nevirapine analogs. Derivatives of this isomeric series are weaker inhibitors of RT than corresponding nevirapine analogs, although with appropriate substitution of the A- and C-pyridine rings activity can be improved.

  10. From the traditional Chinese medicine plant Schisandra chinensis new scaffolds effective on HIV-1 reverse transcriptase resistant to non-nucleoside inhibitors.

    Xu, Lijia; Grandi, Nicole; Del Vecchio, Claudia; Mandas, Daniela; Corona, Angela; Piano, Dario; Esposito, Francesca; Parolin, Cristina; Tramontano, Enzo

    2015-04-01

    HIV-1 reverse transcriptase (RT) is still an extremely attractive pharmaceutical target for the identification of new inhibitors possibly active on drug resistant strains. Medicinal plants are a rich source of chemical diversity and can be used to identify novel scaffolds to be further developed by chemical modifications. We investigated the ability of the main lignans from Schisandra chinensis (Turcz.) Baill. fruits, commonly used in Traditional Chinese Medicine, to affect HIV-1 RT functions. We purified 6 lignans from Schisandra chinensis fruits and assayed their effects on HIV-1 RT and viral replication. Among the S. chinensis fruit lignans, Schisandrin B and Deoxyschizandrin selectively inhibited the HIV-1 RT-associated DNA polymerase activity. Structure activity relationship revealed the importance of cyclooctadiene ring substituents for efficacy. In addition, Schisandrin B was also able to impair HIV-1 RT drug resistant mutants and the early phases of viral replication. We identified Schisandrin B and Deoxyschizandrin as new scaffold for the further development of novel HIV-1 RT inhibitors.

  11. Introducing Catastrophe-QSAR. Application on Modeling Molecular Mechanisms of Pyridinone Derivative-Type HIV Non-Nucleoside Reverse Transcriptase Inhibitors

    Putz, Mihai V.; Lazea, Marius; Putz, Ana-Maria; Duda-Seiman, Corina

    2011-01-01

    The classical method of quantitative structure-activity relationships (QSAR) is enriched using non-linear models, as Thom’s polynomials allow either uni- or bi-variate structural parameters. In this context, catastrophe QSAR algorithms are applied to the anti-HIV-1 activity of pyridinone derivatives. This requires calculation of the so-called relative statistical power and of its minimum principle in various QSAR models. A new index, known as a statistical relative power, is constructed as an Euclidian measure for the combined ratio of the Pearson correlation to algebraic correlation, with normalized t-Student and the Fisher tests. First and second order inter-model paths are considered for mono-variate catastrophes, whereas for bi-variate catastrophes the direct minimum path is provided, allowing the QSAR models to be tested for predictive purposes. At this stage, the max-to-min hierarchies of the tested models allow the interaction mechanism to be identified using structural parameter succession and the typical catastrophes involved. Minimized differences between these catastrophe models in the common structurally influential domains that span both the trial and tested compounds identify the “optimal molecular structural domains” and the molecules with the best output with respect to the modeled activity, which in this case is human immunodeficiency virus type 1 HIV-1 inhibition. The best molecules are characterized by hydrophobic interactions with the HIV-1 p66 subunit protein, and they concur with those identified in other 3D-QSAR analyses. Moreover, the importance of aromatic ring stacking interactions for increasing the binding affinity of the inhibitor-reverse transcriptase ligand-substrate complex is highlighted. PMID:22272148

  12. Introducing Catastrophe-QSAR. Application on Modeling Molecular Mechanisms of Pyridinone Derivative-Type HIV Non-Nucleoside Reverse Transcriptase Inhibitors

    Marius Lazea

    2011-12-01

    Full Text Available The classical method of quantitative structure-activity relationships (QSAR is enriched using non-linear models, as Thom’s polynomials allow either uni- or bi-variate structural parameters. In this context, catastrophe QSAR algorithms are applied to the anti-HIV-1 activity of pyridinone derivatives. This requires calculation of the so-called relative statistical power and of its minimum principle in various QSAR models. A new index, known as a statistical relative power, is constructed as an Euclidian measure for the combined ratio of the Pearson correlation to algebraic correlation, with normalized t-Student and the Fisher tests. First and second order inter-model paths are considered for mono-variate catastrophes, whereas for bi-variate catastrophes the direct minimum path is provided, allowing the QSAR models to be tested for predictive purposes. At this stage, the max-to-min hierarchies of the tested models allow the interaction mechanism to be identified using structural parameter succession and the typical catastrophes involved. Minimized differences between these catastrophe models in the common structurally influential domains that span both the trial and tested compounds identify the “optimal molecular structural domains” and the molecules with the best output with respect to the modeled activity, which in this case is human immunodeficiency virus type 1 HIV-1 inhibition. The best molecules are characterized by hydrophobic interactions with the HIV-1 p66 subunit protein, and they concur with those identified in other 3D-QSAR analyses. Moreover, the importance of aromatic ring stacking interactions for increasing the binding affinity of the inhibitor-reverse transcriptase ligand-substrate complex is highlighted.

  13. 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.

    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.

  14. 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

    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.

  15. Multicenter study of skin rashes and hepatotoxicity in antiretroviral-naïve HIV-positive patients receiving non-nucleoside reverse-transcriptase inhibitor plus nucleoside reverse-transcriptase inhibitors in Taiwan

    Wu, Pei-Ying; Cheng, Chien-Yu; Liu, Chun-Eng; Lee, Yi-Chien; Yang, Chia-Jui; Tsai, Mao-Song; Cheng, Shu-Hsing; Lin, Shih-Ping; Lin, De-Yu; Wang, Ning-Chi; Lee, Yi-Chieh; Sun, Hsin-Yun; Tang, Hung-Jen; Hung, Chien-Ching

    2017-01-01

    Objectives Two nucleos(t)ide reverse-transcriptase inhibitors (NRTIs) plus 1 non-NRTI (nNRTI) remain the preferred or alternative combination antiretroviral therapy (cART) for antiretroviral-naive HIV-positive patients in Taiwan. The three most commonly used nNRTIs are nevirapine (NVP), efavirenz (EFV) and rilpivirine (RPV). This study aimed to determine the incidences of hepatotoxicity and skin rashes within 4 weeks of initiation of cART containing 1 nNRTI plus 2 NRTIs. Methods Between June, 2012 and November, 2015, all antiretroviral-naive HIV-positive adult patients initiating nNRTI-containing cART at 8 designated hospitals for HIV care were included in this retrospective observational study. According to the national HIV treatment guidelines, patients were assessed at baseline, 2 and 4 weeks of cART initiation, and subsequently every 8 to 12 weeks. Plasma HIV RNA load, CD4 cell count and aminotransferases were determined. The toxicity grading scale of the Division of AIDS (DAIDS) 2014 was used for reporting clinical and laboratory adverse events. Results During the 3.5-year study period, 2,341 patients initiated nNRTI-containing cART: NVP in 629 patients, EFV 1,363 patients, and RPV 349 patients. Rash of any grade occurred in 14.1% (n = 331) of the patients. In multiple logistic regression analysis, baseline CD4 cell counts (per 100-cell/μl increase, adjusted odds ratio [AOR], 1.125; 95% confidence interval [95% CI], 1.031–1.228) and use of NVP (AOR, 2.443; 95% CI, 1.816–3.286) (compared with efavirenz) were independently associated with the development of skin rashes. Among the 1,455 patients (62.2%) with aminotransferase data both at baseline and week 4, 72 (4.9%) developed grade 2 or greater hepatotoxicity. In multiple logistic regression analysis, presence of antibody for hepatitis C virus (HCV) (AOR, 2.865; 95% CI, 1.439–5.704) or hepatitis B surface antigen (AOR, 2.397; 95% CI, 1.150–4.997), and development of skin rashes (AOR, 2.811; 95% CI, 1

  16. Synthesis, evaluation and molecular modelling studies of some novel 3-(3,4-dihydroisoquinolin-2(1)-yl)--(substitutedphenyl) propanamides as HIV-1 non-nucleoside reverse transcriptase inhibitors

    S Murugesan; Swastika Ganguly; Giovanni Maga

    2010-03-01

    A novel series of fifteen 3-(3,4-dihydroisoquinolin-2(1)-yl)--(substituted phenyl) propanamides 3(a-o) were synthesized by reacting the corresponding 3-chloro--(aryl) propanamides 2(a-o) with 1,2,3,4-tetrahydroisoquinoline 1 in acetonitrile. The compounds have been characterized on the basis of elemental analysis and spectral data. All the compounds were evaluated for their HIV-1 RT inhibitory activity. Among the synthesized compounds, 3-(3,4-dihydroisoquinolin-2(1)-yl)---tolyl propanamide 3d and 3-(3,4-dihydroisoquinolin-2(1)-yl)--(2,4,6-tribromophenyl)propanamide 3f were identified as significant inhibitors of HIV-1 reverse transcriptase with 56% and 43% residual RT activity respectively at the final concentration of 40 M when compared with the standard drug Efavirenz. Docking studies with HIV-1 RT (PDB ID 1rt2) were also performed in order to investigate the binding pattern of these compounds.

  17. 接受抗病毒治疗的AIDS患者HIV-1非核苷类逆转录酶抑制剂类耐药基因突变的选择动力学研究%Selective kinetics of HIV-1 non-nucleoside reverse transcriptase inhibitor drug resistanace-associated mutations in AIDS patients receiving highly active anti-retrovirul therapy

    李珏; 王哲; 李敬云; 焦丽燕; 李韩平; 李林; 刘永健; 庄道民; 鲍作义; 刘思扬; 李宏

    2009-01-01

    目的 研究接受抗病毒治疗的AIDS患者非核苷类逆转录酶抑制剂(non-nucleosidereverse transcriptase inhibitor,NNRTI)类耐药基因突变分子进化特征.方法 从我国中部农村抗病毒治疗AIDS患者研究队列中选择4例服药依从性较好,治疗初期为野生型毒株,在治疗过程中逐渐产生NNRTI类耐药基因突变的患者为研究对象,对每位患者的4~5次随访血浆样本的逆转录酶(reverse transcriptase,RT)基因进行克隆测序分析,观察每个克隆的基因型耐药性特征.结果 共检测了855个克隆,得到4例患者历次克隆序列中带各种NNRTI类耐药基因突变的构成图谱:4例患者表现出不同的HIV-1 NNRTI类耐药突变途径,发现4条主要NNRTI类耐药基因突变演变途径:(1)G190A,常伴随F227L突变出现,在长期的治疗过程中还有继续累加P236V突变的趋势;(2)Y188C,多单独出现,有时与P236V等同时发生;(3)Y181C,多与V179D或K103N同时出现,不同的患者选择趋向不同;(4)K103N,多与Y181C或M230L突变联合出现.结论 总结出4例患者HIV-1 NNRTI类耐药基因突变的选择动力学特征.4例患者表现出不同的NNRTI类耐药基因突变演变途径,最先筛选出来的耐药突变往往能够成为最后的优势种.%Objective To elucidate the molecular evolutional characteristics of HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI) drug resistance-associated mutations in AIDS patients receiving highly active antiretroviral therapy (HAART).Methods Four AIDS patients receiving HAART with good adherence within a HlV-1 drug resistance cohort from a rural region in central China were selected,who possessed susceptible virus at the beginning of treatment and gradually came to produce resistance to NNRTIs during the process of antiretroviral therapy (ART),reverse transcriptase (RT) genes from each patient's peripheral blood samples (from 3 to 30 months after withdrawal) were cloned and sequenced in succession

  18. Design and synthesis of conformationally constrained inhibitors of non-nucleoside reverse transcriptase.

    Gomez, Robert; Jolly, Samson J; Williams, Theresa; Vacca, Joseph P; Torrent, Maricel; McGaughey, Georgia; Lai, Ming-Tain; Felock, Peter; Munshi, Vandna; Distefano, Daniel; Flynn, Jessica; Miller, Mike; Yan, Youwei; Reid, John; Sanchez, Rosa; Liang, Yuexia; Paton, Brenda; Wan, Bang-Lin; Anthony, Neville

    2011-11-24

    Highly active antiretroviral therapy (HAART) significantly reduces human immunodeficiency virus (HIV) viral load and has led to a dramatic decrease in acquired immunodeficiency syndrome (AIDS) related mortality. Despite this success, there remains a critical need for new HIV therapies to address the emergence of drug resistant viral strains. Next generation NNRTIs are sought that are effective against these mutant forms of the HIV virus. The bound conformations of our lead inhibitors, MK-1107 (1) and MK-4965 (2), were divergent about the oxymethylene linker, and each of these conformations was rigidified using two isomeric cyclic constraints. The constraint derived from the bioactive conformation of 2provided novel, highly potent NNRTIs that possess broad spectrum antiviral activity and good pharmacokinetic profiles. Systematic SAR led to the identification of indazole as the optimal conformational constraint to provide MK-6186 (3) and MK-7445 (6). Despite their reduced flexibility, these compounds had potency comparable to that of the corresponding acyclic ethers in both recombinant enzyme and cell based assays against both the wild-type and the clinically relevant mutant strains.

  19. Identification of ADAM10 and ADAM17 with potential roles in the spermatogenesis of the Chinese mitten crab, Eriocheir sinensis.

    Li, Qing; Xie, Jing; He, Lin; Wang, Yuanli; Duan, Zelin; Yang, Hongdan; Wang, Qun

    2015-05-10

    The ADAM (a disintegrin and metalloprotease) family plays an important role in sperm and egg fusion, development, inflammation, adhesion and migration. ADAM10 and ADAM17 are involved in the spermatogenesis. To better understand the role of ADAM10 and ADAM17 in the Chinese mitten crab, Eriocheir sinensis, the full-length cDNAs of ADAM10 and ADAM17 were cloned, and named Es-ADAM10 and Es-ADAM17, respectively. Sequence and structural analysis showed that Es-ADAM10 and Es-ADAM17 have the typical structure of the ADAM family. Quantitative real-time reverse transcription polymerase chain reaction analysis showed that Es-ADAM10 and Es-ADAM17 mRNAs were distributed in the heart, hepatopancreas, intestines, brain, muscle, thoracic ganglia, hemolymph, stomach, testis, ovary, gill and accessory gland. Both mRNAs were highly expressed in the muscles, and relatively high in the testis, ovary and accessory gland. In addition, the Es-ADAM17 mRNA level was detected in every stage of testis development, being relatively high from July to September, the lowest during October and November, increasing from December to January, and reached a peak in January. By contrast, the expression of Es-ADAM10 mRNA was constant during testis development. Immunofluorescence further showed that Es-ADAM10 and Es-ADAM17 proteins were present in the cytoplasm and cytomembrane of spermatocytes, and both detected in the sperm. Furthermore, etoposide induced upregulation of Es-ADAM17 and Es-ADAM10 at both the mRNA and protein levels. This study first showed that Es-ADAM10 and Es-ADAM17 were also involved in the spermatogenesis and mainly participated in the later germ cell apoptosis in E. sinensis.

  20. Increase in transmitted resistance to non-nucleoside reverse transcriptase inhibitors among newly diagnosed HIV-1 infections in Europe

    D. Frentz (Dineke); D.A.M.C. van de Vijver (David); A.B. Abecasis (Ana ); J. Albert (Jan); O. Hamouda (Osamah); L.B. Jørgensen (Louise); C. Ku¨cherer (Claudia); D. Struck (Daniel); J.-C. Schmit (Jean-Claude); J. Vercauteren (Jurgen); B. A˚sjo¨ (Birgitta); C. Balotta (Claudia); D. Beshkov (Danail); R.J. Camacho (Ricardo Jorge); B. Clotet (Bonaventura); S. Coughlan (Suzie); A. Griskevicius (Algis); Z. Grossman (Zehava); A. Horban (Andrzej); T. Kolupajeva (Tatjana); K. Korn (Klaus); L.G. Kostrikis (Leondios); K. Liitsola (Kirsi); M. Linka (Marek); C. Nielsen (Claus); D. Otelea (Dan); D. Paraskevis (Dimitrios); R. Paredes (Roger); M. Poljak (Mario); E. Puchhammer-Sto¨ckl (Elisabeth); A. So¨nnerborg (Anders); D. Stanekova (Danica); M. Stanojevic (Maja); E. van Wijngaerden (Eric); A.M.J. Wensing (Annemarie); C.A. Boucher (Charles); E. Puchhammer-Stöckl (Elisabeth); M. Sarcletti (M.); B. Schmied (B.); M. Geit (M.); G. Balluch (G.); A.M. Vandamme (Anne Mieke); J. Vercauteren (Jurgen); I. Derdelinck (Inge); A. Sasse (A.); M. Bogaert (M.); H. Ceunen (H.); A. de Roo (Annie); M. De Wit (Meike); F. Echahidi (F.); K. Fransen (K.); J.-C. Goffard (J.); P. Goubau; E. Goudeseune (E.); J.-C. Yombi (J.); P. Lacor (Patrick); C. Liesnard (C.); M. Moutschen; L.A. Pierard; R. Rens (R.); J. Schrooten; D. Vaira (D.); L.P.R. Vandekerckhove; A. van den Heuvel (A.); B. van der Gucht (B.); M. van Ranst (Marc); E. Van Wijngaerden; B. Vandercam; M. Vekemans (M.); C. Verhofstede; N. Clumeck (N.); K. van Laethem (Kristel); L.G. Kostrikis (Leondios); I. Demetriades (I.); I. Kousiappa (Ioanna); V.L. Demetriou (Victoria); J. Hezka (Johana); M. Bruckova (Marie); M. Linka; L. Machala (L.); C. Nielsen; L.B. Jørgensen; J. Gerstoft (J.); L. Mathiesen (L.); C. Pedersen (Court); H. Nielsen; A. Laursen (A.); B. Kvinesdal (B.); M. Salminen (Mika); M. Ristola (M.); K. Liitsola (Kirsi); J. Suni (J.); J. Sutinen (J.); K. Korn; C. Ku¨cherer; T. Berg (Trine); P. Braun (P.); G. Poggensee (G.); M. Da¨umer; D. Eberle (David); O. Hamouda (Osamah); H. Heiken; R. Kaiser (R.); H. Knechten (H.); H. Mu¨ller; S. Neifer; J.-C. Schmit (Jean-Claude); H. Walter (Hauke); B. Gunsenheimer-Bartmeyer (B.); T. Harrer (T.); D. Paraskevis (Dimitrios); A. Hatzakis (Angelos); G. Magiorkinis (Gkikas); E. Hatzitheodorou (E.); C. Haida; A. Zavitsanou (A.); G. Magiorkinis (Gkikas); M. Lazanas; L. Chini; N. Magafas (N.); N. Tsogas (N.); V. Paparizos (V.); S. Kourkounti (S.); A. Antoniadou (A.); A. Papadopoulos; P. Panagopoulos (P.); G. Poulakou; V. Sakka (V.); G. Chryssos (G.); S. Drimis (S.); P. Gargalianos; M. Lelekis (M.); G. Chilomenos; M. Psichogiou (M.); G.L. Daikos (G.); G. Panos (G.); G. Haratsis (G.); T. Kordossis (T.); A. Kontos (Angelos); G. Koratzanis (G.); M. Theodoridou; G. Mostrou (G.); V. Spoulou; S. Coughlan (Suzie); C. de Gascun (Cillian); C. Byrne; M. Duffy; P. Bergin; D. Reidy; G. Farrell; J. Lambert (Julien); E. O'Connor; A. Rochford; J. Low (J.); P. Coakely (P.); S. O'Dea; W. Hall (W.); Z. Grossman (Zehava); I. Levi (I.); D. Chemtob (D.); C. Balotta (Claudia); C. Riva (Chiara); C. Mussini (C.); I. Caramma (I.); A. Capetti (A.); M.C. Colombo (M.); C. Rossi; F. Prati (Francesco); F. Tramuto; F. Vitale (F.); M. Ciccozzi; G. Angarano (Guiseppe); G. Rezza (G.); J.C. Schmit; D. Struck (Daniel); R. Hemmer (R.); V. Arendt (V.); T. Staub (T.); F. Schneider (François); F. Roman; A.M.J. Wensing (Annemarie); C.A. Boucher (Charles); D.A.M.C. van de Vijver (David); A. van Kessel; P.H.M. Van Bentum; K. Brinkman; E.L.M. Op de Coul (Eline); M.E. van der Ende (Marchina); I. Hoepelman (M.); M.E.E. van Kasteren (Marjo); J. Juttmann (Job); M. Kuipers; N. Langebeek (Nienke); C. Richter (Clemens); R. Santegoets (M.W.J.); L. Schrijnders-Gudde (L.); R. Schuurman (Rob); B.J.M. van de Ven (B. J M); B. A˚sjo¨; V. Ormaasen (Vidar); P. Aavitsland (P.); A. Horban (Andrzej); J. Stanczak (J.); G.P. Stanczak (G.); E. Firlag-Burkacka (E.); A. Wiercinska-Drapalo; E. Jablonowska (E.); E. Malolepsza (E.); M. Leszczyszyn-Pynka (M.); W. Szata (W.); R. Camacho; A. de Palma (Andre); F. Borges (F.); T. Paixa&tild; o; V. Duque (V.); F. Araújo; D.J. Jevtovic (D.); D. Salemovic (D.); D. Stanekova; M. Habekova (M.); M. Mokras; P. Truska; M. Poljak (Mario); M.M. Lunar (Maja M.); D. Babic; J. Tomazic (J.); S. Vidmar (Suzanna); T. Vovko; P. Karner (P.); B. Clotet (Bonaventura); P. Domingo; M.J. Galindo; C. Miralles; M.A. del Pozo; E. Ribera; C. Iribarren (Carlos); L. Ruiz (Lidia); J. de la Torre; F. Vidal; F. Garcia; R. Paredes (Roger); J. Albert (Jan); A. Heidarian; K. Aperia-Peipke (K.); M. Axelsson; M. Mild; A. Karlsson; A. So¨nnerborg; A. Thalme; L. Nave´r; G. Bratt (G.); A. Karlsson; A. Blaxhult; M. Gissle´n; B. Svennerholm; I.-M. Bergbrant (I.); P. Bjo¨rkman; C. Sa¨ll; A. Mellgren; A. Lindholm; N. Kuylenstierna; R. Montelius; F. Azimi; B. Johansson; M. Carlsson; E. Johansson; B. Ljungberg; H. Ekvall; A. Strand; S. Ma¨kitalo; S. o¨berg; P. Holmblad; M. Ho¨fer; H. Holmberg; P. Josefson; U. Ryding

    2014-01-01

    textabstractBackground: One out of ten newly diagnosed patients in Europe was infected with a virus carrying a drug resistant mutation. We analysed the patterns over time for transmitted drug resistance mutations (TDRM) using data from the European Spread program.Methods: Clinical, epidemiological a

  1. Biaryl ethers as novel non-nucleoside reverse transcriptase inhibitors with improved potency against key mutant viruses.

    Su, Dai-Shi; Lim, John J; Tinney, Elizabeth; Wan, Bang-Lin; Young, Mary Beth; Anderson, Kenneth D; Rudd, Deanne; Munshi, Vandna; Bahnck, Carolyn; Felock, Peter J; Lu, Meiquing; Lai, Ming-Tain; Touch, Sinoeun; Moyer, Gregory; DiStefano, Daniel J; Flynn, Jessica A; Liang, Yuexia; Sanchez, Rosa; Perlow-Poehnelt, Rebecca; Miller, Mike; Vacca, Joe P; Williams, Theresa M; Anthony, Neville J

    2009-11-26

    Biaryl ethers were recently reported as potent NNRTIs. Herein we disclose a detailed SAR study that led to the biaryl ether 6. This compound possessed excellent potency against WT RT and key clinically observed RT mutants and had an excellent pharmacokinetic profile in rats, dogs, and rhesus macaques. The compound also exhibited a clean safety profile in preclinical safety studies.

  2. Synthesis and Anti-HIV-1 Evaluation of Some Novel MC-1220 Analogs as Non-Nucleoside Reverse Transcriptase Inhibitors

    Loksha, Yasser M; Pedersen, Erik B; Loddo, Roberta;

    2016-01-01

    Some novel MC-1220 analogs were synthesized by condensation of 4,6-dichloro-N-methylpyrimidin-2-amine derivatives (1a,b and 15) and/or 4-chloro-6-methoxy-N,N,5-trimethylpyrimidin-2-amine (2a) with the sodium salt of 2,6-difluorophenylacetonitrile followed by treatment with aqueous sodium hydroxide...

  3. Synthesis and biological evaluation of imidazole thioacetanilides as novel non-nucleoside HIV-1 reverse transcriptase inhibitors.

    Zhan, Peng; Liu, Xinyong; Zhu, Junjie; Fang, Zengjun; Li, Zhenyu; Pannecouque, Christophe; Clercq, Erik De

    2009-08-15

    A series of 2-(1-aryl-1H-imidazol-2-ylthio)acetamide [imidazole thioacetanilide (ITA)] derivatives were synthesized and evaluated as potent inhibitors of human immunodeficiency virus type-1 (HIV-1). Among them, the most potent HIV-1 inhibitors were 4a5 (EC(50)=0.18microM), and 4a2 (EC(50)=0.20microM), which were more effective than the lead compound L1 (EC(50)=2.053microM) and the reference drugs nevirapine and delavirdine. The preliminary structure-activity relationship (SAR) of the newly synthesized congeners is discussed.

  4. Molecular profiling of ADAM12 in human bladder cancer

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

    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 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...

  5. DARPA ADAMS Project

    2015-05-11

    To) - UU UU UU UU 11-05-2015 5-Jun-2011 4-Aug-2014 Approved for Public Release; Distribution Unlimited Final Report for the DARPA ADAMS Project The...Aug-2014 ABSTRACT Final Report for the DARPA ADAMS Project Report Title The principal goal of the Anomaly Detection Engine for Networks (ADEN) was to...DETECTION ENGINE FOR NETWORKS 2015 FINAL REPORT FOR THE DARPA ADAMS PROJECT SUBMITTED TO ARMY RESEARCH OFFICE CONTRACT NUMBER W911NF-11-C

  6. Det Syriske Adams Testamente

    Holst, Søren; Christensen, Peter; Kristensen, Stefan;

    2015-01-01

    Artiklen præsenterer en dansk oversættelse af det ældste bevarede manuskript af det syriske Adams Testamente, samt en introduktion og diskussion af centrale aspekter af skriftets sprog og teologi, såsom fortolkningen af begivenhederne i Edens have, den forbudne frugt, Adams fremtidige skæbne og de...

  7. Pyrimidine non-nucleoside analogs: A direct synthesis of a novel class of N-substituted amino and N-sulfonamide derivatives of pyrimidines.

    Elgemeie, Galal H; Salah, Ali M; Abbas, Nermeen S; Hussein, Hoda A; Mohamed, Reham A

    2017-03-04

    A convenient method for the regioselective synthesis of pyrimidine non-nucleoside analogs was developed. This study reports a novel and efficient method for the synthesis of a new type of N-substituted amino methylsulfanylpyrimidines and the corresponding pyrazolo[3,4-d]pyrimidines. This series of compounds was designed through the reaction of dimethyl N-cyanodithioiminocarbonate with 2-cyano-N'-(thiophen-2-yl-, furan-2-yl- and pyridin-4-ylmethylene)acetohydrazide and N'-(2-cyanoacetyl)arylsulfonohydrazides. The scope and limitation of the method are demonstrated. The antibacterial and antifungal activities of the synthesized compounds were also evaluated.

  8. Ansel Adams: early works

    Throckmorton, Jodi

    2010-02-01

    Ansel Adams (1902-1984), photographer, musician, naturalist, explorer, critic, and teacher, was a giant in the field of landscape photography. In his images of the unspoiled Western landscape, he strove to capture the sublime: the transcendentalist concept that nature can generate the experience of awe for the viewer. Many viewers are familiar with the heroic, high-contrast prints on high-gloss paper that Adams made to order beginning in the 1970s; much less well known are the intimate prints that the artist crafted earlier in his career. This exhibition focuses on these masterful small prints from the 1920s into the 1950s. During this time period, Adams's printing style changed dramatically. The painterly, soft-focus, warm-toned style of the Parmelian Prints of the High Sierras from the 1920s evolved into the sharp-focus style of the f/64 school of photography that Adams co-founded in the 1930s with Edward Weston and Imogen Cunningham. After World War II, Adams opted for a cooler, higher-contrast look for his prints. Throughout the various styles in which he chose to work, Adams explored the power of nature and succeeded in establishing landscape photography as a legitimate form of modern art.

  9. Hepatocyte-specific delivery of siRNAs conjugated to novel non-nucleosidic trivalent N-acetylgalactosamine elicits robust gene silencing in vivo.

    Rajeev, Kallanthottathil G; Nair, Jayaprakash K; Jayaraman, Muthusamy; Charisse, Klaus; Taneja, Nate; O'Shea, Jonathan; Willoughby, Jennifer L S; Yucius, Kristina; Nguyen, Tuyen; Shulga-Morskaya, Svetlana; Milstein, Stuart; Liebow, Abigail; Querbes, William; Borodovsky, Anna; Fitzgerald, Kevin; Maier, Martin A; Manoharan, Muthiah

    2015-04-13

    We recently demonstrated that siRNAs conjugated to triantennary N-acetylgalactosamine (GalNAc) induce robust RNAi-mediated gene silencing in the liver, owing to uptake mediated by the asialoglycoprotein receptor (ASGPR). Novel monovalent GalNAc units, based on a non-nucleosidic linker, were developed to yield simplified trivalent GalNAc-conjugated oligonucleotides under solid-phase synthesis conditions. Synthesis of oligonucleotide conjugates using monovalent GalNAc building blocks required fewer synthetic steps compared to the previously optimized triantennary GalNAc construct. The redesigned trivalent GalNAc ligand maintained optimal valency, spatial orientation, and distance between the sugar moieties for proper recognition by ASGPR. siRNA conjugates were synthesized by sequential covalent attachment of the trivalent GalNAc to the 3'-end of the sense strand and resulted in a conjugate with in vitro and in vivo potency similar to that of the parent trivalent GalNAc conjugate design.

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

    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.

  11. Molecular profiling of ADAM12 in human bladder cancer

    Frolich, Camilla; Albrechtsen, Reidar; Andersen, Lars Dyrskjøt

    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...... 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...

  12. Adams Operations on Matrix Factorizations

    Brown, Michael K.; Miller, Claudia; Thompson, Peder; Walker, Mark E.

    2016-01-01

    We define Adams operations on matrix factorizations, and we show these operations enjoy analogues of several key properties of the Adams operations on perfect complexes with support developed by Gillet-Soul\\'e in their paper "Intersection Theory Using Adams Operations". As an application, we give a proof of a conjecture of Dao-Kurano concerning the vanishing of Hochster's theta invariant.

  13. Was Adam a Real Person?

    Lamoureux, Denis O.

    2011-01-01

    Belief in the historicity of Adam has been held firmly throughout the history of the church. In the light of modern biblical criticism and the evolutionary sciences, some conservative Christians are now questioning whether or not Adam was a real person. This paper argues that the existence of Adam in the opening chapters of scripture reflects an…

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

    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.

  15. The Adams family

    Douven, Igor; Verbrugge, Sara

    2010-01-01

    According to Adams's Thesis, the acceptability of an indicative conditional sentence goes by the conditional probability of its consequent given its antecedent. We test, for the first time, whether this thesis is descriptively correct and show that it is not; in particular, we show that it yields th

  16. The Adams Family

    Douven, Igor; Verbrugge, Sara

    2010-01-01

    According to Adams's Thesis, the acceptability of an indicative conditional sentence goes by the conditional probability of its consequent given its antecedent. We test, for the first time, whether this thesis is descriptively correct and show that it is not; in particular, we show that it yields the wrong predictions for people's judgments of the…

  17. ADAM Proteases and Gastrointestinal Function

    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

  18. ADAM Proteases and Gastrointestinal Function.

    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.

  19. Synthesis of Novel Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors-1-(3-Phthalimido-2-oxobutyl)-4-Substituted-phenylpiperazines

    2000-01-01

    We have designed and synthesized a series of new phthalimidopiperazines, biological activity test show that the target compounds(Ic, Ie, Ii) can inhibit HIV-1 RT with IC50 20.0, 43.8, and 63.7δ M, respectively.

  20. Molecular modelling studies on 2-amino 6-aryl-sulphonylbenzonitriles as non-nucleoside reverse transcriptase inhibitors of HIV-1: A QSPR approach

    Nitin S Sapre; Nilanjana Pancholi; Swagata Gupta; Arun Sikrwar; Neelima Sapre

    2007-11-01

    Lipophilicity or hydrophobicity is a crucial physico-chemical property of an oral drug compound. In the present study, we have analysed the structural parameters responsible for enhancing the lipophilicity expressed in terms of Octanol-Water partition coefficient, log , of 2-amino-6-arylsulfonylbenzonitrile (AASBN) derivatives used as NNRTIs in AIDS therapy. Connectivity based Randic () and Balaban () and atomistic Kier-Hall electrotopological state (-state) indices have been used to develop Quantitative Structure-Property Relationship (QSPR) and to predict the effect of substitution on the log . Model has been developed using multiple linear regression analysis (MLR) for the training set (67 compounds) and the model was tested on a test set (7 compounds). Significant results were obtained for the training set (2 = 0.948, $R^2_{\\text{adj}} = 0.939$, = 0.177, -ratio = 101.22). The results of the test set too implicated a good fit (2 = 0.941, $R^2_{\\text{adj}} = 0.929$, = 0.157, -ratio = 80.05). Among the two connectivity based topological indices; Randic () index showed better predictive ability than the Balaban () index. Kier-Hall -state indices indicated that among the functional groups, methyl, bromo, chloro groups on ring A, with their positive coefficients enhanced the lipophilicity. Amino, cyano group on ring B and the bridging S, SO, SO2 with their negative coefficients showed an adverse effect on the lipophilicity parameter. Thus, Kier-Hall -state indices along with topological indices could be well applied for deriving QSPR models and analysing substitution effects of various functional groups. The training set, correlation matrix and observed and experimental log values are available as supplementary material for this article.

  1. Concordance between allele-specific PCR and ultra-deep pyrosequencing for the detection of HIV-1 non-nucleoside reverse transcriptase inhibitor resistance mutations

    Hunt, Gillian M; Morris, Lynn; Moorthy, Anitha; Coovadia, Ashraf; Abrams, Elaine J; Strehlau, Renate; Kuhn, Louise; Persaud, Deborah

    2014-01-01

    Recent advances in genotyping technologies have allowed for detection of HIV-1 drug resistance mutations present at low levels. The presence and percentage of Y181C and K103N drug-resistant variants in the blood of 105 subtype C HIV-infected infants who failed single-dose nevirapine prophylaxis for HIV transmission were compared using two highly sensitive genotyping methods, allele-specific PCR (AS-PCR) and ultra-deep pyrosequencing. Significant correlations in detection between both methods were found for both Y181C (correlation coefficients of 0.94 [95% CI 0.91-0.96]) and K103N (0.89 [95% CI 0.84 – 0.92]) mutations. The majority of discordant specimens (3/5 Y181C and 8/11 K103N) had wild-type variants when population sequencing was used, but mutant variants were detectable at very low levels (≤5%) with either assay. This difference is most likely due to stochastic variations in the appearance of mutant variants. Overall, both AS-PCR and ultra-deep pyrosequencing methods have proven to be sensitive and accurate, and may confidently be used where feasible. PMID:25034127

  2. Hybrid chemistry. Part 4: Discovery of etravirine-VRX-480773 hybrids as potent HIV-1 non-nucleoside reverse transcriptase inhibitors.

    Wan, Zheng-Yong; Tao, Yuan; Wang, Ya-Feng; Mao, Tian-Qi; Yin, Hong; Chen, Fen-Er; Piao, Hu-Ri; De Clercq, Erik; Daelemans, Dirk; Pannecouque, Christophe

    2015-08-01

    A novel series of etravirine-VRX-480773 hybrids were designed using structure-guided molecular hybridization strategy and fusing the pharmacophore templates of etravirine and VRX-480773. The anti-HIV-1 activity and cytotoxicity was evaluated in MT-4 cell cultures. The most active hybrid compound in this series, N-(2-chlorophenyl)-2-((4-(4-cyano-2,6-dimethylphenoxy)pyrimidin-2-yl)thio)acetamide 3d (EC50=0.24 , SI>1225), was more potent than delavirdine (EC50=0.66 μM, SI>67) in the anti-HIV-1 in vitro cellular assay. Studies of structure-activity relationships established a correlation between anti-HIV activity and the substitution pattern of the acetanilide group.

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

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

    2008-01-01

    . METHODS: Patients in the drug-conservation arm of the Strategies for Management of Antiretroviral Therapy (SMART) trial who interrupted a fully suppressive NNRTI-regimen were evaluated. From 2003, SMART recommended interruption of an NNRTI by a staggered interruption, in which the NNRTI was stopped before...... the NRTIs, or by replacing the NNRTI with another drug before interruption. Simultaneous interruption of all antiretrovirals was discouraged. Resuppression rates 4-8 months after reinitiating NNRTI-therapy were assessed, as was the detection of drug-resistance mutations within 2 months of the treatment...... regimen. NNRTI drug-resistance mutations were observed in a relatively high proportion of patients. These data provide additional support for a staggered or switched interruption strategy for NNRTI drugs....

  4. The role of ADAMs in disease pathophysiology.

    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.

  5. John Adams in 1959

    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.

  6. Changing Perceptions in "Adam Bede."

    Loges, Max L.

    From the very beginning of "Adam Bede," the idea of sight or perception is emphasized. Indeed by reference to a quotation from Wordsworth, George Eliot announces the purpose of the novel: to reveal clearly, to remove from the shade. While most of the characters in "Adam Bede" do not perceive events clearly and must have their erroneous opinions…

  7. New Mathematical Dimensions: Adam's Story

    Manizade, Agida

    2009-01-01

    Adam, an 11th grader, was identified as gifted and accepted into a two week summer enrichment program. He signed up for "Geometry with Flash Programming." He had no prior programming experience but had a strong and healthy self-image as mathematics student. Although Adam had a positive attitude toward mathematics and saw himself as a successful…

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

    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.

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

    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.

  10. Evolution of Vertebrate Adam Genes; Duplication of Testicular Adams from Ancient Adam9/9-like Loci.

    Bahudhanapati, Harinath; Bhattacharya, Shashwati; Wei, Shuo

    2015-01-01

    Members of the disintegrin metalloproteinase (ADAM) family have important functions in regulating cell-cell and cell-matrix interactions as well as cell signaling. There are two major types of ADAMs: the somatic ADAMs (sADAMs) that have a significant presence in somatic tissues, and the testicular ADAMs (tADAMs) that are expressed predominantly in the testis. Genes encoding tADAMs can be further divided into two groups: group I (intronless) and group II (intron-containing). To date, tAdams have only been reported in placental mammals, and their evolutionary origin and relationship to sAdams remain largely unknown. Using phylogenetic and syntenic tools, we analyzed the Adam genes in various vertebrates ranging from fishes to placental mammals. Our analyses reveal duplication and loss of some sAdams in certain vertebrate species. In particular, there exists an Adam9-like gene in non-mammalian vertebrates but not mammals. We also identified putative group I and group II tAdams in all amniote species that have been examined. These tAdam homologues are more closely related to Adams 9 and 9-like than to other sAdams. In all amniote species examined, group II tAdams lie in close vicinity to Adam9 and hence likely arose from tandem duplication, whereas group I tAdams likely originated through retroposition because of their lack of introns. Clusters of multiple group I tAdams are also common, suggesting tandem duplication after retroposition. Therefore, Adam9/9-like and some of the derived tAdam loci are likely preferred targets for tandem duplication and/or retroposition. Consistent with this hypothesis, we identified a young retroposed gene that duplicated recently from Adam9 in the opossum. As a result of gene duplication, some tAdams were pseudogenized in certain species, whereas others acquired new expression patterns and functions. The rapid duplication of Adam genes has a major contribution to the diversity of ADAMs in various vertebrate species.

  11. John Adams Lecture

    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...

  12. Adam Smith on population.

    Spengler, J J

    1970-11-01

    Abstract Adam Smith dealt with questions of population mainly in his Wealth of Nations. His discussion falls roughly under five heads and reflects in considerable measure his image of the English economy. (1) A country's population capacity, given the average level of consumption, was conditioned by the stock of land, the skill with which it was cultivated, and the degree to which division of labour could be increased and thereby augment output for domestic use and sale in external markets. (2) Growth of population was essentially in response to growth of the demand for labour and served to increase division of labour. (3) The social mechanisms underlying elevation of the scale of living are touched upon, and in an optimistic spirit. (4) The distribution of a country's population responded to its progress in opulence, with the rate of this progress conditioned by the degree to which inappropriate (e.g. mercantilist) policies were avoided. (5) Smith dealt briefly with such matters as colonies, education, size of economy, environmental influences, and public policy, all of which he recognized as significant for the quantity and quality of a country's numbers.

  13. Adam Smith and dependency.

    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.

  14. ADAM17 is associated with EMMPRIN and predicts poor prognosis in patients with uterine cervical carcinoma.

    Xu, Qin; Ying, Mingang; Chen, Guilin; Lin, Ang; Xie, Yunqing; Ohara, Noriyuki; Zhou, Dongmei

    2014-08-01

    Metalloproteinase activities of a disintegrin and metalloproteinase 17 (ADAM17), amphiregulin (AREG), extracellular matrix metalloproteinase inducer (EMMPRIN), and matrix metalloproteinases (MMPs) are involved in tumor biology. In patients with uterine cervical carcinoma, the expression and prognostic significance of ADAM17 remain to be fully elucidated. The expression of ADAM17, AREG, EMMPRIN, phospho-epidermal growth factor receptor (p-EGFR), phospho-extracellular signal-regulated kinase (p-ERK), MMP-2, and MMP-9 was assessed by immunohistochemistry and/or Western blotting from cervical carcinoma cell lines, SiHa and HeLa cells, and cervical carcinoma tissues. AREG activity was measured by ELISA assay. The correlation of ADAM17, AREG, EMMPRIN, and MMP-9 expression with patients' survival rates was assessed by Kaplan-Meier and Cox regression analyses. RNA interference (RNAi) experiment was performed using small interfering mRNA to ADAM17 and EMMPRIN. ADAM17, EMMPRIN, and MMP-9 protein content was overexpressed in cervical carcinoma tissues compared with normal cervical tissues (P cervical cancer. ADAM17 RNAi decreased EMMPRIN, p-EGFR, p-ERK, MMP-2, and MMP-9 proteins in SiHa and HeLa cells. ELISA assay revealed that AREG activity was stimulated by ADAM17 and was reversed by ADAM17 RNAi in SiHa and HeLa cells. Our data suggest that the increased expression of ADAM17 in cervical cancer is significantly associated with aggressive progression and poor prognosis. ADAM17 may be a molecular marker for predicting the progression and prognosis in cervical cancer.

  15. Smith, Adam (1723-90)

    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...

  16. A Conversation with Adam Heller

    Heller, A.; Cairns, EJ

    2015-01-01

    © 2015 by Annual Reviews. All rights reserved.Adam Heller, Ernest Cockrell Sr. Chair in Engineering Emeritus of the John J. McKetta Department of Chemical Engineering at The University of Texas at Austin, recalls his childhood in the Holocaust and his contributions to science and technology that earned him the US National Medal of Technology and Innovation in a conversation with Elton J. Cairns, Professor of Chemical and Biomolecular Engineering at the University of California, Berkeley. Dr. ...

  17. ADAMs family and relatives in cardiovascular physiology and pathology.

    Zhang, Pu; Shen, Mengcheng; Fernandez-Patron, Carlos; Kassiri, Zamaneh

    2016-04-01

    A disintegrin and metalloproteinases (ADAMs) are a family of membrane-bound proteases. ADAM-TSs (ADAMs with thrombospondin domains) are a close relative of ADAMs that are present in soluble form in the extracellular space. Dysregulated production or function of these enzymes has been associated with pathologies such as cancer, asthma, Alzheimer's and cardiovascular diseases. ADAMs contribute to angiogenesis, hypertrophy and apoptosis in a stimulus- and cell type-dependent manner. Among the ADAMs identified so far (34 in mouse, 21 in human), ADAMs 8, 9, 10, 12, 17 and 19 have been shown to be involved in cardiovascular development or cardiomyopathies; and among the 19 ADAM-TSs, ADAM-TS1, 5, 7 and 9 are important in development of the cardiovascular system, while ADAM-TS13 can contribute to vascular disorders. Meanwhile, there remain a number of ADAMs and ADAM-TSs whose function in the cardiovascular system has not been yet explored. The current knowledge about the role of ADAMs and ADAM-TSs in the cardiovascular pathologies is still quite limited. The most detailed studies have been performed in other cell types (e.g. cancer cells) and organs (nervous system) which can provide valuable insight into the potential functions of ADAMs and ADAM-TSs, their mechanism of action and therapeutic potentials in cardiomyopathies. Here, we review what is currently known about the structure and function of ADAMs and ADAM-TSs, and their roles in development, physiology and pathology of the cardiovascular system.

  18. ADAMS-MATLAB Co-Simulation of A Serial Manipulator

    Parthasarathy Tejaswin

    2017-01-01

    Full Text Available This paper presents the dynamic modelling and simulation of a now redundant robot, Mitsubishi RM-501, and proposes a general algorithm for experimental simulation in kinematics, dynamics and control analysis to any such robot. Through reverse engineering, a model as accurate as the real robot was developed in SolidWorks.The simulations of the same were performed in ADAMS (dynamicmodeling software offered by MSC Software Corpalong with MATLAB for motion studies and control dynamics. Finally, with a user-input path the accuracy and precision of the simulator was verified.

  19. Reverse transcription of the HIV-1 pandemic.

    Basavapathruni, Aravind; Anderson, Karen S

    2007-12-01

    The HIV/AIDS pandemic has existed for >25 years. Extensive work globally has provided avenues to combat viral infection, but the disease continues to rage on in the human population and infected approximately 4 million people in 2006 alone. In this review, we provide a brief history of HIV/AIDS, followed by analysis of one therapeutic target of HIV-1: its reverse transcriptase (RT). We discuss the biochemical characterization of RT in order to place emphasis on possible avenues of inhibition, which now includes both nucleoside and non-nucleoside modalities. Therapies against RT remain a cornerstone of anti-HIV treatment, but the virus eventually resists inhibition through the selection of drug-resistant RT mutations. Current inhibitors and associated resistance are discussed, with the hopes that new therapeutics can be developed against RT.

  20. ADAM: Analyzer for Dialectal Arabic Morphology

    Wael Salloum

    2014-12-01

    Full Text Available While Modern Standard Arabic (MSA has many resources, Arabic Dialects, the primarily spoken local varieties of Arabic, are quite impoverished in this regard. In this article, we present ADAM (Analyzer for Dialectal Arabic Morphology. ADAM is a poor man’s solution to quickly develop morphological analyzers for dialectal Arabic. ADAM has roughly half the out-of-vocabulary rate of a state-of-the-art MSA analyzer and is comparable in its recall performance to an Egyptian dialectal morphological analyzer that took years and expensive resources to build.

  1. Activation of ADAM 12 protease by copper

    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...

  2. Adam Smith’s contribution to secularisation

    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.

  3. ADAM9 Is a Novel Product of Polymorphonuclear Neutrophils

    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 ...

  4. Catalytic properties of ADAM12 and its domain deletion mutants

    Jacobsen, Jonas; Visse, Robert; Sørensen, Hans Peter;

    2008-01-01

    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) consistin...

  5. Leukocytes require ADAM10 but not ADAM17 for their migration and inflammatory recruitment into the alveolar space.

    Pruessmeyer, Jessica; Hess, Franz Martin; Alert, Henriette; Groth, Esther; Pasqualon, Tobias; Schwarz, Nicole; Nyamoya, Stella; Kollert, Jos; van der Vorst, Emiel; Donners, Marjo; Martin, Christian; Uhlig, Stefan; Saftig, Paul; Dreymueller, Daniela; Ludwig, Andreas

    2014-06-26

    Inflammation is a key process in various diseases, characterized by leukocyte recruitment to the inflammatory site. This study investigates the role of a disintegrin and a metalloproteinase (ADAM) 10 and ADAM17 for leukocyte migration in vitro and in a murine model of acute pulmonary inflammation. Inhibition experiments or RNA knockdown indicated that monocytic THP-1 cells and primary human neutrophils require ADAM10 but not ADAM17 for efficient chemokine-induced cell migration. Signaling and adhesion events that are linked to cell migration such as p38 and ρ GTPase-family activation, F-actin polymerization, adhesion to fibronectin, and up-regulation of α5 integrin were also dependent on ADAM10 but not ADAM17. This was confirmed with leukocytes isolated from mice lacking either ADAM10 or ADAM17 in all hematopoietic cells (vav 1 guanine nucleotide exchange factor [Vav]-Adam10(-/-) or Vav-Adam17(-/-) mice). In lipopolysaccharide-induced acute pulmonary inflammation, alveolar recruitment of neutrophils and monocytes was transiently increased in Vav-Adam17(-/-) but steadily reduced in Vav-Adam10(-/-) mice. This deficit in alveolar leukocyte recruitment was also observed in LysM-Adam10(-/-) mice lacking ADAM10 in myeloid cells and correlated with protection against edema formation. Thus, with regard to leukocyte migration, leukocyte-expressed ADAM10 but not ADAM17 displays proinflammatory activities and may therefore serve as a target to limit inflammatory cell recruitment.

  6. Kellwood Company Finalizes Acquisition of ADAM

    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

  7. Identification and Function of a Novel Candidate Gene for Asthma:ADAM 33

    John W. Holloway

    2005-01-01

    Full Text Available Asthma is a complex disorder of inflammation and remodelling largely restricted to the conducting airways. It is a disorder where there are major genetics and environmental factors that interact together to initiate and propagate the disease into a chronic relapsing disorder. Until recently the genetic factors involved in disease pathogenesis have been restricted to variants in known molecules involved in the inflammatory or remodelling pathways. In this review evidence is presented for a new susceptibility gene for asthma, ADAM 33, that was identified by positional cloning. It is suggested that ADAM 33 plays a key role in predisposing to reduced lung function and bronchial hyperresponsiveness characteristic of asthma. Through an understanding of the disease-related SNPs(in ADAM 33it may be possible, not only to identify a gene based diagnostic test, but also to focus attention on developing a new treatment that reverses remodelling changes.

  8. Discovery and crystallography of bicyclic arylaminoazines as potent inhibitors of HIV-1 reverse transcriptase.

    Lee, Won-Gil; Frey, Kathleen M; Gallardo-Macias, Ricardo; Spasov, Krasimir A; Chan, Albert H; Anderson, Karen S; Jorgensen, William L

    2015-11-01

    Non-nucleoside inhibitors of HIV-1 reverse transcriptase (HIV-RT) are reported that incorporate a 7-indolizinylamino or 2-naphthylamino substituent on a pyrimidine or 1,3,5-triazine core. The most potent compounds show below 10 nanomolar activity towards wild-type HIV-1 and variants bearing Tyr181Cys and Lys103Asn/Tyr181Cys resistance mutations. The compounds also feature good aqueous solubility. Crystal structures for two complexes enhance the analysis of the structure-activity data.

  9. Substituted tetrahydroquinolines as potent allosteric inhibitors of reverse transcriptase and its key mutants

    Su, Dai-Shi; Lim, John J.; Tinney, Elizabeth; Wan, Bang-Lin; Young, Mary Beth; Anderson, Kenneth D.; Rudd, Deanne; Munshi, Vandna; Bahnck, Carolyn; Felock, Peter J.; Lu, Meiqing; Lai, Ming-Tain; Touch, Sinoeun; Moyer, Gregory; DiStefano, Daniel J.; Flynn, Jessica A.; Liang, Yuexia; Sanchez, Rosa; Prasad, Sridhar; Yan, Youwei; Perlow-Poehnelt, Rebecca; Torrent, Maricel; Miller, Mike; Vacca, Joe P.; Williams, Theresa M.; Anthony, Neville J.; Merck

    2010-09-27

    Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are key elements of multidrug regimens, called HAART (Highly Active Antiretroviral Therapy), that are used to treat HIV-1 infections. Elucidation of the structure-activity relationships of the thiocarbamate moiety of the previous published lead compound 2 provided a series of novel tetrahydroquinoline derivatives as potent inhibitors of HIV-1 RT with nanomolar intrinsic activity on the WT and key mutant enzymes and potent antiviral activity in infected cells. The SAR optimization, mutation profiles, preparation of compounds, and pharmacokinetic profile of compounds are described.

  10. Emergent HIV-1 Drug Resistance Mutations Were Not Present at Low-Frequency at Baseline in Non-Nucleoside Reverse Transcriptase Inhibitor-Treated Subjects in the STaR Study

    Danielle P. Porter

    2015-12-01

    Full Text Available At Week 96 of the Single-Tablet Regimen (STaR study, more treatment-naïve subjects that received rilpivirine/emtricitabine/tenofovir DF (RPV/FTC/TDF developed resistance mutations compared to those treated with efavirenz (EFV/FTC/TDF by population sequencing. Furthermore, more RPV/FTC/TDF-treated subjects with baseline HIV-1 RNA >100,000 copies/mL developed resistance compared to subjects with baseline HIV-1 RNA ≤100,000 copies/mL. Here, deep sequencing was utilized to assess the presence of pre-existing low-frequency variants in subjects with and without resistance development in the STaR study. Deep sequencing (Illumina MiSeq was performed on baseline and virologic failure samples for all subjects analyzed for resistance by population sequencing during the clinical study (n = 33, as well as baseline samples from control subjects with virologic response (n = 118. Primary NRTI or NNRTI drug resistance mutations present at low frequency (≥2% to 20% were detected in 6.6% of baseline samples by deep sequencing, all of which occurred in control subjects. Deep sequencing results were generally consistent with population sequencing but detected additional primary NNRTI and NRTI resistance mutations at virologic failure in seven samples. HIV-1 drug resistance mutations emerging while on RPV/FTC/TDF or EFV/FTC/TDF treatment were not present at low frequency at baseline in the STaR study.

  11. 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

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

    2006-01-01

    BACKGROUND: Antiretroviral therapy has greatly reduced HIV mortality and morbidity. However, the best sequence of regimens and implications of initial regimen for long-term therapeutic success are not well defined. METHODS: In INITIO, a large international randomised trial, we compared antiretrov...

  12. Synthesis and biological evaluation of novel 5-alkyl-2-arylthio-6-((3,4-dihydroquinolin-1(2H)-yl)methyl)pyrimidin-4(3H)-ones as potent non-nucleoside HIV-1 reverse transcriptase inhibitors.

    Zhang, Jing; Zhan, Peng; Wu, Jingde; Li, Zhenyu; Jiang, Yan; Ge, Weiying; Pannecouque, Christophe; De Clercq, Erik; Liu, Xinyong

    2011-07-15

    A series of novel S-DABO analogues of 5-alkyl-2-arylthio-6-((3,4-dihydroquinolin-1(2H)-yl)methyl)pyrimidin-4(3H)-ones were synthesized and evaluated as inhibitors of human immunodeficiency virus type-1 (HIV-1). Among them, the most potent HIV-1 inhibitors were compounds 6c1,6c6, and 6b1 (EC(50)=0.24 ± 0.05, 0.38 ± 0.13, 0.39 ± 0.05 μM, respectively), which possess improved or similar HIV-1 inhibitory activity compared with nevirapine (NVP) (EC(50)=0.21 μM) and delavirdine (DLV) (EC(50)=0.32 μM). None of these compounds were active against HIV-2 replication. Furthermore, enzyme inhibitory assays were performed with selected derivatives against HIV-1 wtRT, confirming that the main target of these compounds is the HIV-1 RT and these new S-DABOs are acting as NNRTIs. The preliminary structure-activity relationship (SAR) of these new congeners is discussed briefly and rationalized by docking studies.

  13. A Conversation with Adam Heller.

    Heller, Adam; Cairns, Elton J

    2015-01-01

    Adam Heller, Ernest Cockrell Sr. Chair in Engineering Emeritus of the John J. McKetta Department of Chemical Engineering at The University of Texas at Austin, recalls his childhood in the Holocaust and his contributions to science and technology that earned him the US National Medal of Technology and Innovation in a conversation with Elton J. Cairns, Professor of Chemical and Biomolecular Engineering at the University of California, Berkeley. Dr. Heller, born in 1933, describes the enslavement of his father by Hungarians in 1942; the confiscation of his family's home, business, and all its belongings in 1944; and his incarceration in a brick factory with 18,000 Jews who were shipped by the Hungarians to be gassed by Germans in Auschwitz. Dr. Heller and his immediate family survived the Holocaust and arrived in Israel in 1945. He studied under Ernst David Bergmann at the Hebrew University, and then worked at Bell Laboratories and GTE Laboratories, where he headed Bell Lab's Electronic Materials Research Department. At GTE Laboratories, he built in 1966 the first neodymium liquid lasers and in 1973 with Jim Auborn conceived and engineered the lithium thionyl chloride battery, one of the first to be manufactured lithium batteries, which is still in use. After joining the faculty of engineering of The University of Texas at Austin, he cofounded with his son Ephraim Heller TheraSense, now a major part of Abbott Diabetes Care, which produced a microcoulometer that made the monitoring of glucose painless by accurately measuring the blood glucose concentration in 300 nL of blood. He also describes the electrical wiring of enzymes, the basis for Abbott's state-of-the-art continuous glucose monitoring system. He discusses his perspective of reducing the risk of catastrophic global warming in a wealth-accumulating, more-energy-consuming world and provides advice for students entering careers in science or engineering.

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

    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

  15. Epithelial cell ADAM17 activation by Helicobacter pylori: role of ADAM17 C-terminus and Threonine-735 phosphorylation.

    McClurg, Urszula L; Danjo, Kazuma; King, Harry O; Scott, Gina B; Robinson, Philip A; Crabtree, Jean E

    2015-03-01

    Helicobacter pylori transactivates the epidermal growth factor receptor (EGFR) on gastric epithelial cells via a signalling cascade involving a disintegrin and metalloprotease 17 (ADAM17) cleavage of membrane bound heparin binding-epidermal growth factor (HB-EGF). The effects of H. pylori on ADAM17 C-terminus in epithelial cells have been examined. Total cellular ADAM17 and surface expression of ADAM17 were significantly increased by H. pylori in AGS gastric epithelial cells. These changes were associated with ADAM17 C-terminal phosphorylation at T375 and S791. AGS cells lacking the ADAM17 C-terminal domain induced significantly attenuated cleavage of HB-EGF and were also unable to upregulate HB-EGF and EGFR transcripts to the same extent as cells expressing full length ADAM17. In mitotic unstimulated AGS and ADAM17 over-expressing AGS cells, ADAM17 was highly T735 phosphorylated indicating ADAM17 T735 phosphorylation is modified during the cell cycle. In conclusion, H. pylori induced ADAM17 C-terminal T735 and/or S791 phosphorylation in gastric epithelial cells are likely to be an important trigger inducing ADAM17 activation and shedding of HB-EGF leading to EGFR transactivation. ADAM17 over-expression in gastric cancer represents a potential target for therapeutic intervention.

  16. Role of ADAMs in cancer formation and progression.

    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. Heparan sulfate regulates ADAM12 through a molecular switch mechanism

    Sørensen, Hans P; Vives, Romain R; Manetopoulos, Christina;

    2008-01-01

    The disintegrin and metalloproteases (ADAMs) are emerging as therapeutic targets in human disease, but specific drug design is hampered by potential redundancy. Unlike other metzincins, ADAM pro domains remain bound to the mature enzyme to regulate activity. Here ADAM12, a protease that promotes ...

  18. Women in History--Abigail Adams: Life, Accomplishments, and Ideas

    Kenan, Sharon K.

    2008-01-01

    This article profiles the life, accomplishments, and ideas of Abigail Adams. Born in 1944, Adams lacked a formal education, but she more than made up for that shortcoming with her love of reading, especially literature, and her interests in politics and events surrounding the young colonies. Adams was supportive of the advancement of women. She…

  19. 应用ADAMS/car设计汽车悬架

    殷卫乔

    2009-01-01

    ADAMS/CAR中建立麦弗逊悬架的三维模型,分析悬架参数在汽车行驶中的变化.依据ADAMS/insight,对ADAMS/car建立的模型进行悬架系统的优化求解,得到悬架系统的优化解.

  20. J. B. Adams Acting Director-General

    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.

  1. Adam Smith and the Rhetoric of Style.

    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…

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

    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)

  3. Paraprofessional of the Year 2009: Tina Adams

    Berry, John N., III

    2009-01-01

    There is no doubt among the staff and managers at North Carolina State University (NCSU) Libraries, Raleigh, that advanced library technician Tina Adams deserves to be the winner of the "Library Journal's "Paraprofessional of the Year Award for 2009." "Certainly this library has never seen anyone like her before, not in my nine years on staff,"…

  4. Paraprofessional of the Year 2009: Tina Adams

    Berry, John N., III

    2009-01-01

    There is no doubt among the staff and managers at North Carolina State University (NCSU) Libraries, Raleigh, that advanced library technician Tina Adams deserves to be the winner of the "Library Journal's "Paraprofessional of the Year Award for 2009." "Certainly this library has never seen anyone like her before, not in my nine…

  5. Exosome release of ADAM15 and the functional implications of human macrophage-derived ADAM15 exosomes.

    Lee, Hee Doo; Koo, Bon-Hun; Kim, Yeon Hyang; Jeon, Ok-Hee; Kim, Doo-Sik

    2012-07-01

    A disintegrin and metalloproteinase 15 (ADAM15), the only ADAM protein containing an Arg-Gly-Asp (RGD) motif in its disintegrin-like domain, is a widely expressed membrane protein that is involved in tumor progression and suppression. However, the underlying mechanism of ADAM15-mediated tumor suppression is not clearly understood. This study demonstrates that ADAM15 is released as an exosomal component, and ADAM15 exosomes exert tumor suppressive activities. We found that exosomal ADAM15 release is stimulated by phorbol 12-myristate 13-acetate, a typical protein kinase C activator, in various tumor cell types, and this results in a corresponding decrease in plasma membrane-associated ADAM15. Exosomes rich in ADAM15 display enhanced binding affinity for integrin αvβ3 in an RGD-dependent manner and suppress vitronectin- and fibronectin-induced cell adhesion, growth, and migration, as well as in vivo tumor growth. Exosomal ADAM15 is released from human macrophages, and macrophage-derived ADAM15 exosomes have tumor inhibitory effects. This work suggests a primary role of ADAM15 for exosome-mediated tumor suppression, as well as functional significance of exosomal ADAM protein in antitumor immunity.

  6. Application of ADAMS/CAR in Macpherson suspension%ADAMS/CAR在麦弗逊悬架中的应用

    朱天军; 郑红艳; 王玉昆

    2005-01-01

    ADAMS/CAR中建立麦弗逊悬架的三维模型,分析悬架参数在汽车行驶中的变化.依据ADAMS/Insight,对ADAMS/CAR建立的模型进行悬架系统的优化求解,得到悬架系统的优化解.

  7. Illnesses of the brain in John Quincy Adams.

    Paulson, George

    2004-12-01

    John Quincy Adams, the sixth and perhaps most scholarly American president, served courageously despite familial essential tremor, depression, and cerebrovascular disease. His cousin Samuel Adams and his father John Adams also had essential tremor, which the later called "quiveration". Alcoholism and depression affected several members of J.Q. Adams's family. Following his own time as president, J.Q. Adams returned to duty as the congressman who most assiduously fought slavery, a fight he continued even after he had suffered a major left hemispheric stroke. His fatal collapse in Congress, protesting the Mexican War, is legendary among the final illnesses of American statesmen.

  8. Cellular roles of ADAM12 in health and disease

    Kveiborg, Marie; Albrechtsen, Reidar; Couchman, John R;

    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-binding proteins...... 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...

  9. Hierarchy of ADAM12 binding to integrins in tumor cells

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

    2005-01-01

    ADAMs (a disintegrin and metalloprotease) comprise a family of cell surface proteins with protease and cell-binding activities. Using different forms and fragments of ADAM12 as substrates in cell adhesion and spreading assays, we demonstrated that alpha9beta1 integrin is the main receptor for ADAM......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......, whereas full-length ADAM12 supported attachment via alpha9 integrin and other integrin receptors. Cells that attached to full-length ADAM12 in an alpha9 integrin-dependent manner also attached to ADAM12 in which the putative alpha9beta1 integrin-binding motif in the disintegrin domain had been mutated...

  10. ADAMS Q&A%ADAMS问答

    陈志宇; 杨晓晔; 邱娴婷

    2012-01-01

    ADAMS is an anti-doping operational network data management system, which was set up at the middle of 2005, aiming to simplify the daily activities of various concerned beneficial parts and athletes in anti-doping work. The four crucial functions of ADAMS in anti-doping work are as follows: athlete whereabouts information management, information processing hub, doping control panel and therapeutic use exemption management.%1什么是ADAMS? 《世界反兴奋剂条例》规定,世界反兴奋剂机构(以下简称WADA)有义务协调全球反兴奋剂工作,并提供利益相关方执行该条例的机制。

  11. MBS Analysis Of Kinetic Structures Using ADAMS

    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. changing external climate factors, in order to improve the indoor climate performance of the building. The derivation of equations of motion for such spatial mechanical systems is a challenging issue in scientific community. However, with new symbolic tools one can automatically derive equations in so......-called multibody system (MBS) formalism. The present paper considers MBS modeling of kinetic architectural structures using the software packages ADAMS. As a result, it is found that symbolic MBS simulation tools facilitate a useful evaluation environment for MBS users during a design phase of responsive kinetic...

  12. Adam Smith: Anthropology and Moral Philosophy

    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...

  13. Reduction of the disintegrin and metalloprotease ADAM12 in preeclampsia

    Laigaard, Jennie; Sørensen, Tina; Placing, Sophie;

    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...

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

    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…

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

    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

  16. Adam Smith on public expenditure and taxation

    Maurício C. Coutinho

    2001-01-01

    Full Text Available This paper presents Adam Smith’s view on taxation and public expenditure, by means of an almost literal reading of the Wealth of Nations famous passages on the "duties of the sovereign" and on the "maxims of taxation". Contrarily to the commonest usage of these passages, we will show that their core is the preoccupation with the public expenditure soaring and the defence of decentralisation. Furthermore and also contrarily to the existing interpretations we defend the non-existence of any contradiction between Smith’s income and price theory (and the incidence hypothesis, provided due attention is paid to the guiding role of the "maxims".

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

    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.

  18. Shedding of klotho by ADAMs in the kidney

    van Loon, Ellen P. M.; Pulskens, Wilco P.; van der Hagen, Eline A. E.; Lavrijsen, Marla; Vervloet, Marc G.; van Goor, Harry; Bindels, Rene J. M.; Hoenderop, Joost G. J.

    2015-01-01

    The anti-aging gene klotho plays an important role in Ca2+ and phosphate homeostasis. Membrane-bound klotho is an essential coreceptor for fibroblast growth factor-23 and can be cleaved by proteases, including a disintegrin and metalloproteinase (ADAM) 10 and ADAM17. Cleavage of klotho occurs at a s

  19. Shedding of klotho by ADAMs in the kidney.

    Loon, E.P.M. van; Pulskens, W.P.C.; Hagen, E.A.E. van der; Lavrijsen, M.; Vervloet, M.G.; Goor, H van; Bindels, R.J.M.; Hoenderop, J.G.J.

    2015-01-01

    The anti-aging gene klotho plays an important role in Ca(2+) and phosphate homeostasis. Membrane-bound klotho is an essential coreceptor for fibroblast growth factor-23 and can be cleaved by proteases, including a disintegrin and metalloproteinase (ADAM)10 and ADAM17. Cleavage of klotho occurs at a

  20. Adams Predictor-Corrector Systems for Solving Fuzzy Differential Equations

    Dequan Shang

    2013-01-01

    Full Text Available A predictor-corrector algorithm and an improved predictor-corrector (IPC algorithm based on Adams method are proposed to solve first-order differential equations with fuzzy initial condition. These algorithms are generated by updating the Adams predictor-corrector method and their convergence is also analyzed. Finally, the proposed methods are illustrated by solving an example.

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

    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)

  2. "Adam of the Road" by Elizabeth Janet Gray. Literature Unit.

    Robbins, Mari Lu

    Intended as an aid to classroom teachers, this 48-page handbook presents a literature unit based on the children's book, "Adam of the Road" by Elizabeth Janet Gray. It begins with sample lesson plans, pre-reading activities, author information, a book summary, and vocabulary lists and suggested vocabulary activities. Next, chapters of "Adam of the…

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

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

    2009-01-01

    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...

  4. Om strukturledighed og Phillips-kurver i SMEC og ADAM

    Harck, Søren H.

    2001-01-01

    indeholder dels (ny) dokumentation af, at ADAM og SMEC (som antydet af PS) vitterligt bliver fortolket som NAIRU-modeller af prominente og toneangivende modelbrugere, og dels rummer indlægget (nye) teoretiske argumenter for, at ADAM og SMEC ikke indeholder en teoretisk veldefineret strukturarbejdsløshed...

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

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

    2014-01-01

    cells. Shedding is largely attributed to a family of a disintegrin and metalloprotease domain (ADAM) metalloproteases, including ADAM17. Although ADAM17 is well known to contribute to the innate immune response, mainly by releasing TNF-α, much less is known about whether/how this metalloprotease...... regulates adaptive immunity. To determine whether ADAM17 contributes to regulating adaptive immune responses, we took advantage of ADAM17 hypomorphic (ADAM17(ex/ex)) mice, in which ADAM17 expression is reduced by 90-95% compared with wild-type littermates. In this study, we show that that ADAM17 deficiency...

  6. Expression, immunolocalization and processing of fertilins ADAM-1 and ADAM-2 in the boar (sus domesticus spermatozoa during epididymal maturation

    Bonet Sergi

    2011-06-01

    Full Text Available Abstract Fertilin alpha (ADAM-1 and beta (ADAM-2 are integral membrane proteins of the ADAM family that form a fertilin complex involved in key steps of the sperm-oocyte membrane interaction. In the present work, we analyzed the presence of ADAM-1 and ADAM-2 mRNAs, the spermatozoa proteins' processing and their sub-cellular localization in epididymal samples from adult boars. ADAM-1 and ADAM-2 mRNAs were highly produced in the testis, but also in the vas efferens and the epididymis. On immunoblots of sperm extracts, ADAM-1 subunit appeared as a main reactive band of ~50-55 kDa corresponding to occurrence of different isoforms throughout the epididymal duct, especially in the corpus region where isoforms ranged from acidic to basic pI. In contrast, ADAM-2 was detected as several bands of ~90 kDa, ~75 kDa, ~50-55 kDa and ~40 kDa. The intensity of high molecular mass bands decreased progressively in the distal corpus where lower bands were also transiently observed, and only the ~40 kDa was observed in the cauda. The presence of bands of different molecular weights likely results from a proteolytic processing occurring mainly in the testis for ADAM-1, and also throughout the caput epididymis for ADAM-2. Immunolocalization showed that fertilin migrates from the acrosomal region to the acrosomal ridge during the sperm transit from the distal corpus to the proximal cauda. This migration is accompanied by an important change in the extractability of a part of ADAM-1 from the sperm membrane. This suggests that the fertilin surface migration may be triggered by the biochemical changes induced by the epididymal post-translational processing of both ADAM1 and ADAM-2. Different patterns of fertilin immunolocalization then define several populations of spermatozoa in the cauda epididymis. Characterization of such fertilin complex maturation patterns is an important step to develop fertility markers based on epididymal maturation of surface membrane proteins

  7. A Disintegrin and Metalloproteinase10 (ADAM10 Regulates NOTCH Signaling during Early Retinal Development.

    Joseph A Toonen

    Full Text Available ADAM10 and ADAM17 are two closely related members of the ADAM (a disintegrin and metalloprotease family of membrane-bound sheddases, which proteolytically cleave surface membrane proteins. Both ADAM10 and ADAM17 have been implicated in the proteolytic cleavage of NOTCH receptors and as such regulators of NOTCH signaling. During retinal development, NOTCH signaling facilitates retinal neurogenesis by maintaining progenitor cells in a proliferative state and by mediating retinal cell fates. However, the roles of ADAM10 and ADAM17 in the retina are not well defined. In this study, we set out to clarify the roles of ADAM10 and ADAM17 during early retinal development. The retinal phenotype of conditionally abated Adam17 retinae (Adam17 CKO did not differ from the controls whereas conditionally ablated Adam10 retinae (Adam10 CKO exhibited abnormal morphogenesis characterized by the formation of rosettes and a loss of retinal laminae phenotypically similar to morphological abnormalities identified in mice with retinal NOTCH signaling deficiency. Additionally, Adam10 CKO retinae exhibited abnormal neurogenesis characterized by fewer proliferating progenitor cells and greater differentiation of early photoreceptors and retinal ganglion cells. Moreover, constitutive activation of the NOTCH1-intracellular domain (N1-ICD rescued Adam10 CKO abnormal neurogenesis, as well as abnormal retinal morphology by maintaining retinal cells in the progenitor state. Collectively these findings provide in vivo genetic evidence that ADAM10, and not ADAM17, is indispensable for proper retinal development as a regulator of NOTCH signaling.

  8. A Disintegrin and Metalloproteinase10 (ADAM10) Regulates NOTCH Signaling during Early Retinal Development.

    Toonen, Joseph A; Ronchetti, Adam; Sidjanin, D J

    2016-01-01

    ADAM10 and ADAM17 are two closely related members of the ADAM (a disintegrin and metalloprotease) family of membrane-bound sheddases, which proteolytically cleave surface membrane proteins. Both ADAM10 and ADAM17 have been implicated in the proteolytic cleavage of NOTCH receptors and as such regulators of NOTCH signaling. During retinal development, NOTCH signaling facilitates retinal neurogenesis by maintaining progenitor cells in a proliferative state and by mediating retinal cell fates. However, the roles of ADAM10 and ADAM17 in the retina are not well defined. In this study, we set out to clarify the roles of ADAM10 and ADAM17 during early retinal development. The retinal phenotype of conditionally abated Adam17 retinae (Adam17 CKO) did not differ from the controls whereas conditionally ablated Adam10 retinae (Adam10 CKO) exhibited abnormal morphogenesis characterized by the formation of rosettes and a loss of retinal laminae phenotypically similar to morphological abnormalities identified in mice with retinal NOTCH signaling deficiency. Additionally, Adam10 CKO retinae exhibited abnormal neurogenesis characterized by fewer proliferating progenitor cells and greater differentiation of early photoreceptors and retinal ganglion cells. Moreover, constitutive activation of the NOTCH1-intracellular domain (N1-ICD) rescued Adam10 CKO abnormal neurogenesis, as well as abnormal retinal morphology by maintaining retinal cells in the progenitor state. Collectively these findings provide in vivo genetic evidence that ADAM10, and not ADAM17, is indispensable for proper retinal development as a regulator of NOTCH signaling.

  9. John Adams and CERN: Personal Recollections

    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

    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. Adam Smith on public expenditure and taxation

    Maurício C. Coutinho

    2009-05-01

    Full Text Available This paper presents Adam Smith’s view on taxation and public expenditure, by means of an almost literal reading of the Wealth of Nations famous passages on the “duties of the sovereign” and on the “maxims of taxation”. Contrarily to the commonest usage of these passages, we will show that their core is the preoccupation with the public expenditure soaring and the defence of decentralisation. Furthermore – and also contrarily to the existing interpretations – we defend the non-existence of any contradiction between Smith’s income and price theory (and the incidence hypothesis, provided due attention is paid to the guiding role of the “maxims”.

  12. Research on Goods and the Ship Interaction Based on ADAMS

    Song Fangzhen

    2017-01-01

    Full Text Available The equivalent method of the relative movement goods on board is discussed in details. This method is to establish dynamic model based on moving trajectory of gravity-center for goods and to take rigid body geometric model with the trajectory as constraints in ADAMS. The difference of simulation methods for the different goods in carrier rolling is compared. The interact of relative moving objects with bulk carrier is discussed by using the ADAMS model. It is verified that the ballast water can maintain the ship’s stability by means of the ADAMS model.

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

    Loechel, F; Gilpin, B J; Engvall, E

    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...... 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...

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

    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.

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

    Kotzsch, Alexander; Skovgaard, Tine; Buus, Uwe

    2014-01-01

    ADAM12 belongs to the A disintegrin and metalloprotease (ADAM) family of secreted sheddases activating extracellular growth factors such as epidermal growth factor receptor (EGFR) ligands and tumor necrosis factor-alpha (TNF-α). ADAM proteases, most notably ADAM17 (TNF-α-converting enzyme), have...

  16. Interactive Study between Two Types of 1-[2-(Hydroxyethoxy)methyl]-6-naphthylmethylthymines and HIV-1 Reverse Transcriptase

    2003-01-01

    Two different types of 1-[2-(hydroxyethoxy)methyl]-6-naphthylmethylthymines have been designed, synthesized and evaluated for their anti-HIV-1 activities in different cells lines. The binding free energy ((G) including steric and electrostatic between the two different ligands and reverse transcriptase Non-Nucleoside Binding Pocket (NNBP) have been docked and calculated to evaluate their accommodation circumstance on a SGI work station. The (G and anti-HIV-1 activity has been correlated in order to guide further drug design, which showed that the steric binding effect dominated in the whole binding action between the compounds and reverse transcriptase (RT). The results showed that more negative (G led to higher activity of compounds.

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

    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

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

    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

  19. Association of ADAM33 gene polymorphisms with allergic asthma

    Mohammad Reza Zand Karimi

    2014-09-01

    Conclusion: Polymorphisms of ADAM33 gene might be associated with severe asthma and sensitivity to aeroallergens in northeast of Iran, but further studies are needed to determine the polymorphisms in this area and other regions of our country.

  20. ADAM-15 Disintegrin-Like Domain Structure and Function

    Dong Lu

    2010-10-01

    Full Text Available The ADAM (a disintegrin-like and metalloproteinase proteins are a family of transmembrane cell-surface proteins with important functions in adhesion and proteolytic processing in all animals. Human ADAM-15 is the only member of the ADAM family with the integrin binding motif Arg-Gly-Asp (RGD in its disintegrin-like domain. This motif is also found in most snake venom disintegrins and other disintegrin-like proteins. This unique RGD motif within ADAM-15 serves as an integrin ligand binding site, through which it plays a pivotal role in interacting with integrin receptors, a large family of heterodimeric transmembrane glycoproteins. This manuscript will present a review of the RGD-containing disintegrin-like domain structures and the structural features responsible for their activity as antagonists of integrin function in relation to the canonical RGD template.

  1. Sherali-Adams Relaxations of Graph Isomorphism Polytopes

    Malkin, Peter N

    2011-01-01

    We investigate the Sherali-Adams lift & project hierarchy applied to a graph isomorphism polytope whose integer points encode the isomorphisms between two graphs. In particular, the Sherali-Adams relaxations characterize a new vertex classification algorithm for graph isomorphism, which we call the generalized vertex classification algorithm. This algorithm generalizes the classic vertex classification algorithm and generalizes the work of Tinhofer on polyhedral methods for graph automorphism testing. We establish that the Sherali-Adams lift & project hierarchy when applied to a graph isomorphism polytope needs Omega(n) iterations in the worst case before converging to the convex hull of integer points. We also show that this generalized vertex classification algorithm is also strongly related to the well-known Weisfeiler-Lehman algorithm, which we show can also be characterized in terms of the Sherali-Adams relaxations of a semi-algebraic set whose integer points encode graph isomorphisms.

  2. ADAM 12 protease induces adipogenesis in transgenic mice

    Kawaguchi, Nobuko; Xu, Xiufeng; Tajima, Rie

    2002-01-01

    in the perivascular space in muscle tissue of 1- to 2-week-old transgenic mice whereas mature lipid-laden adipocytes were seen at 3 to 4 weeks. Moreover, female transgenics expressing ADAM 12-S exhibited increases in body weight, total body fat mass, abdominal fat mass, and herniation, but were normoglycemic and did......-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 muscle creatine kinase promoter. Cells expressing a marker of early adipogenesis were apparent...... not exhibit increased serum insulin, cholesterol, or triglycerides. Male transgenics were slightly overweight and also developed herniation but did not become obese. Transgenic mice expressing a truncated form of ADAM 12-S lacking the prodomain and the metalloprotease domain did not develop this adipogenic...

  3. John of Salisbury, Adam of Balsham and The Cornifician Problem

    Bloch, David

    2010-01-01

    En undersøgelse af den Cornificius, som John of Salisbury angriber i sit værk Metalogicon. Der argumenteres for, at Cornificius er åbenlyst inspireret af den berømte Adam of Balsham......En undersøgelse af den Cornificius, som John of Salisbury angriber i sit værk Metalogicon. Der argumenteres for, at Cornificius er åbenlyst inspireret af den berømte Adam of Balsham...

  4. Mazungumzo na Adam Shafi juu ya uandishi wake wa riwaya

    Diegner, Lutz; Shafi, Adam

    2012-01-01

    Adam Shafi aliyezaliwa mwaka 1940 kisiwani Unguja ni mmojawapo wa waandishi mashuhuri wa riwaya ya Kiswahili. Hivi sasa mwandishi yumo mbioni kukamilisha muswada wa riwaya yake ya sita iitwayo Mtoto wa Mama. Mbali na uandishi, Adam Shafi aliwahi kufanya kazi mbalimbali za uandishi wa habari na kazi za ushirika wa kimataifa. Ni furaha yetu kubwa kuwa hatimaye tunaweza kutoa mazungumzo hayo baada ya kuyapitia na kuyahariri kidogo tu, kwa vile tunaamini utamu wa lugha inavyozungumzwa katika hali...

  5. 研华ST接口产品介绍——ADAM-6541/ST和ADAM-6521/ST

    2006-01-01

    研华推出ST接口系列模块中的两款产品ADAM-6541/ST和ADAM-6521/ST。ADAM-6541/ST是一款以太网到多模式ST光纤转换器;ADAM-6521/ST是一款带有1个多模式光纤ST端口的5端口工业级10/100Mbps以太网交换机。这些模块带有“ST”新型光纤接口,含有一个插头和插槽。能够与一个半螺旋卡口锁定在一起,确保牢固的连接。

  6. Who taught Adam to speak?1

    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.

  7. ADAM SMITH: THE INVISIBLE HAND OR CONFIDENCE

    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.

  8. TACE (ADAM17) inhibits Schwann cell myelination.

    La Marca, Rosa; Cerri, Federica; Horiuchi, Keisuke; Bachi, Angela; Feltri, M Laura; Wrabetz, Lawrence; Blobel, Carl P; Quattrini, Angelo; Salzer, James L; Taveggia, Carla

    2011-06-12

    Tumor necrosis factor-α-converting enzyme (TACE; also known as ADAM17) is a proteolytic sheddase that is responsible for the cleavage of several membrane-bound molecules. We report that TACE cleaves neuregulin-1 (NRG1) type III in the epidermal growth factor domain, probably inactivating it (as assessed by deficient activation of the phosphatidylinositol-3-OH kinase pathway), and thereby negatively regulating peripheral nervous system (PNS) myelination. Lentivirus-mediated knockdown of TACE in vitro in dorsal root ganglia neurons accelerates the onset of myelination and results in hypermyelination. In agreement, motor neurons of conditional knockout mice lacking TACE specifically in these cells are significantly hypermyelinated, and small-caliber fibers are aberrantly myelinated. Further, reduced TACE activity rescues hypomyelination in NRG1 type III haploinsufficient mice in vivo. We also show that the inhibitory effect of TACE is neuron-autonomous, as Schwann cells lacking TACE elaborate myelin of normal thickness. Thus, TACE is a modulator of NRG1 type III activity and is a negative regulator of myelination in the PNS.

  9. ADAMS/Car软件中随机路面建立方法%Method on Building Random Road in ADAMS/Car

    赵治

    2012-01-01

    The author introduces four kinds of method to build random road in ADAMS/Car software, it is of reference value with using ADAMS/Car software to simulate velicle ride comfrot.%介绍在ADAMS/Car中四种随机路面的建立方法,对于应用ADAMS/Car进行整车平顺性仿真分析具有参考价值。

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

    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.

  11. Adam Smith et les passions musicales

    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

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

    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.

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

    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.

  14. Bifunctional Inhibition of Human Immunodeficiency Virus Type 1 Reverse Transcriptase: Mechanism and Proof-of-Concept as a Novel Therapeutic Design Strategy

    Bailey, Christopher M.; Sullivan, Todd J.; Iyidogan, Pinar; Tirado-Rives, Julian; Chung, Raymond; Ruiz-Caro, Juliana; Mohamed, Ebrahim; Jorgensen, William; Hunter, Roger; Anderson, Karen S.

    2013-01-01

    Human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) is a major target for currently approved anti-HIV drugs. These drugs are divided into two classes: nucleoside and non-nucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs). This study illustrates the synthesis and biochemical evaluation of a novel bifunctional RT inhibitor utilizing d4T (NRTI) and a TMC-derivative (a diarylpyrimidine NNRTI) linked via a poly(ethylene glycol) (PEG) linker. HIV-1 RT successfully incorporates the triphosphate of d4T-4PEG-TMC bifunctional inhibitor in a base-specific manner. Moreover, this inhibitor demonstrates low nanomolar potency that has 4.3-fold and 4300-fold enhancement of polymerization inhibition in vitro relative to the parent TMC-derivative and d4T, respectively. This study serves as a proof-of-concept for the development and optimization of bifunctional RT inhibitors as potent inhibitors of HIV-1 viral replication. PMID:23659183

  15. Antiretroviral drug resistance mutations in the reverse transcriptase gene of HIV-1 isolates from Northern Indian patients: a follow-up study.

    Dutta Choudhury, Shubhasree; Chaudhury, Alok K; Kalra, Rajesh; Andrabi, Raiees; Wig, Naveet; Biswas, Ashutosh; Bala, Manju; Luthra, Kalpana

    2010-04-01

    The viral reverse transcriptase gene was amplified from the plasma of 27 drug-naïve and five drug-experienced HIV patients in Northern India. Follow-up samples of naïve patients after antiretroviral therapy initiation were collected in six patients at 3 months and three patients at 6 months. Phylogenetic analysis revealed two new recombinant forms, CRF_CH and CRF_CK, and an accessory non-nucleoside reverse transcriptase inhibitor mutation E138A, not previously reported from India. The major DRMs found in two 6-month follow-up samples were absent in their baseline blood samples. This is the first follow-up study to determine anti-retroviral drug resistance mutations in Indian HIV patients.

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

    Jacobsen, J; Wewer, U M

    2009-01-01

    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......) and 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...

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

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

    2011-01-01

    hypothesized, however, that the tumor-associated stroma may stimulate ADAM12 expression in tumor cells, based on the fact that TGF-ß1 stimulates ADAM12 expression and is a well-known growth factor released from tumor-associated stroma. TGF-ß1 stimulation of ADAM12-negative Lewis lung tumor cells induced ADAM12...... synthesis, and growth of these cells in vivo induced a >200-fold increase in ADAM12 expression. Our observation that ADAM12 expression is significantly higher in the terminal duct lobular units (TDLUs) adjacent to human breast carcinoma compared with TDLUs found in normal breast tissue supports our......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...

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

    Lafuste, Peggy; Sonnet, Corinne; Chazaud, Bénédicte;

    2005-01-01

    Knowledge on molecular systems involved in myogenic precursor cell (mpc) fusion into myotubes is fragmentary. Previous studies have implicated the a disintegrin and metalloproteinase (ADAM) family in most mammalian cell fusion processes. ADAM12 is likely involved in fusion of murine mpc and human...... rhabdomyosarcoma cells, but it requires yet unknown molecular partners to launch myogenic cell fusion. ADAM12 was shown able to mediate cell-to-cell attachment through binding alpha9beta1 integrin. We report that normal human mpc express both ADAM12 and alpha9beta1 integrin during their differentiation. Expression...... 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 fusion...

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

    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.

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

    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

  1. ADAM12-S stimulates bone growth in transgenic mice by modulating chondrocyte proliferation and maturation

    Kveiborg, Marie; Albrechtsen, Reidar; Rudkjaer, Lise;

    2006-01-01

    -extracellular matrix interactions in the growth plate. INTRODUCTION: The disintegrin and metalloprotease ADAM12 is expressed in both osteoblasts and osteoclasts, suggesting a regulatory role of ADAM12 in bone. However, thus far, no in vivo function of ADAM12 in the skeleton has been reported. MATERIALS AND METHODS......: Transgenic mice expressing the secreted form of human ADAM12, ADAM12-S, or a truncated metalloprotease-deficient form of ADAM12-S in the circulation were used to study the effects of ADAM12 on the skeleton. In addition, murine chondrocyte cultures were used to study the effect of ADAM12-S on cell...... in mice expressing higher levels of the transgene than in a lower-expressing line. Histological analysis revealed no alterations in the growth plate organization, but mean growth plate width was increased. Both the cellular incorporation of bromodeoxyuridine and the width of the collagen type X...

  2. The Role of ADAM9 in Tumor-Stromal Interactions in Breast Cancer

    2009-04-01

    endogenously express ADAM9-L and –S (Fig 1 ). Year two research focused on using isoform specific antibodies for immunocytochemistry in preparation for...migration. As outlined in the task 2 update, we have shown that the different isoforms of ADAM9 have opposing effects on breast cancer cell migration...both isoforms of ADAM-9, and our future work in this area will further define the relevant signaling pathways which participate in ADAM9 mediated

  3. Compendious Introduction of Co-simulation and ADAMS/Controls%联合仿真技术及ADAMS/Controls

    孙秀军; 王效岳; 杨燕

    2007-01-01

    ADAMS是机械系统动力学分析软件,MATLAB/Simulink是控制系统建模及仿真软件,运用ADAMS/Controls模块作为两软件的接口,可以实现机械系统与控制系统的联合仿真.简单介绍了联合仿真、ADAMS/Controls和MATLAB/Simulink,最后给出了球-梁模型联合仿真设计实例.

  4. ADAM19 expression in human nephrogenesis and renal disease : Associations with clinical and structural deterioration

    Melenhorst, W. B. W. H.; van den Heuvel, M. C.; Timmer, A.; Huitema, S.; Bulthuis, M.; Timens, W.; van Goor, H.

    2006-01-01

    ADAM19, an enzyme from the ADAM (a disintegrin and metalloproteinase) family, is involved in various cell-cell and cell-matrix interactions. It can cleave epidermal growth factor (EGF)-like growth factors, such as heparin-binding (HB)-EGF and neuregulin (NRG), from the cell membrane. ADAM-mediated E

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

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

    2012-01-01

    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-surface ...

  6. A novel, secreted form of human ADAM 12 (meltrin alpha) provokes myogenesis in vivo

    Gilpin, B J; Loechel, F; Mattei, M G;

    1998-01-01

    The ADAM (A Disintegrin And Metalloprotease) family of cell-surface proteins may have an important role in cellular interactions and in modulating cellular responses. In this report we describe a novel, secreted form of human ADAM 12 (meltrin alpha), designated ADAM 12-S (S for short), and a larg...

  7. Expression, purification and insights into structure and folding of the ADAM22 pro domain

    Sørensen, Hans Peter; Jacobsen, Jonas; Nielbo, Steen;

    2008-01-01

    . To understand the functions of human ADAM pro domains and to determine three-dimensional structures, we have screened promising targets for expression and purification properties when using Escherichia coli as the host. The pro domain of ADAM22 (ADAM22-P) expressed in E. coli was folded, as determined by CD...

  8. Extracellular engagement of ADAM12 induces clusters of invadopodia with localized ectodomain shedding activity

    Albrechtsen, Reidar; Hansen, Dorte Stautz; Sanjay, Archana;

    2011-01-01

    -Src interaction site in the ADAM12 cytoplasmic domain, but was independent of the catalytic activity of ADAM12. Caveolin-1 and transmembrane protease MMP14/MT1-MMP were both present in the ADAM12-induced clusters of invadopodia, and cholesterol depletion prevented their formation, suggesting that lipid-raft...

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

    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...

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

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

    2004-01-01

    as a 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...

  11. HISTORIA ECONÓMICA: El padre de la economia:Adam Smith

    Accensi Martínez, Maria Cinta

    2016-01-01

    Peer-reviewed Artículo que describe una pequeña bibliografía del padre de la economía Adam Smith Article que descriu una petita bibliografia sobre el pare de l'economia Adam Smith. This article include a brief bibliography about Adam Smith.

  12. Reverse Logistics

    Kulikova, Olga

    2016-01-01

    This thesis was focused on the analysis of the concept of reverse logistics and actual reverse processes which are implemented in mining industry and finding solutions for the optimization of reverse logistics in this sphere. The objective of this paper was the assessment of the development of reverse logistics in mining industry on the example of potash production. The theoretical part was based on reverse logistics and mining waste related literature and provided foundations for further...

  13. Adam Smith and the Teaching of English Literature.

    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)

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

    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)

  15. ADAM: A Collaborative Effort To Prepare Future Administrators.

    Richardson, Michael D.; And Others

    ADAM (Administrative Development and Management), an administrator preparation partnership between Greenwood (South Carolina) School District 50 and Clemson University, is described in this paper. The program uses practicing administrators in collaboration with college faculty to train prospective school administrators. The purpose is to provide…

  16. Indian Policy of John Adams Administration: Treaties with the Indians

    Nelin Timur V.

    2016-09-01

    Full Text Available In this article the author examines the treaties that were concluded with the Native Americans in the period of John Adams presidency. Treaties with the Natives can be a good source for the study of the US Indian policy. They help to understand the character of Indian-white relations, the attitudes of Federal authorities towards certain Indian nation, the actual problems of the Frontier and so on. Unfortunately the policy of the second President of the USA toward the Native Americans is investigated not so good as the policy of other Presidents of Early American Republic. The study of the treaties helps to know more about John Adams Indian policy. In the years of his presidency only few agreements were signed with the Native American tribes. These were the Mohawk, the Seneca, the Oneida of the Iroquois Nation and the Cherokee. The procedure of Indian-white agreements was well developed until 1797 year. And John Adams administration did not explore something new in this question. The second President of the United States adopted the George Washington’s principals of dealing with the Natives. But in fact he had to consider the internal and external situation in the country. The treaties with the Indians, concluded by the administration of John Adams did not become a bright episode of American history. However they helped to reduce tensions in US-Indian relations.

  17. Adams operations on higher arithmetic K-theory

    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...

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

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

    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.

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

    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...... the 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...

  1. Secretion-Positive LGI1 Mutations Linked to Lateral Temporal Epilepsy Impair Binding to ADAM22 and ADAM23 Receptors

    Dazzo, Emanuela; Belluzzi, Elisa; Malacrida, Sandro; Vitiello, Libero; Greggio, Elisa; Tosatto, Silvio C. E.

    2016-01-01

    Autosomal dominant lateral temporal epilepsy (ADTLE) is a focal epilepsy syndrome caused by mutations in the LGI1 gene, which encodes a secreted protein. Most ADLTE-causing mutations inhibit LGI1 protein secretion, and only a few secretion-positive missense mutations have been reported. Here we describe the effects of four disease-causing nonsynonymous LGI1 mutations, T380A, R407C, S473L, and R474Q, on protein secretion and extracellular interactions. Expression of LGI1 mutant proteins in cultured cells shows that these mutations do not inhibit protein secretion. This finding likely results from the lack of effects of these mutations on LGI1 protein folding, as suggested by 3D protein modelling. In addition, immunofluorescence and co-immunoprecipitation experiments reveal that all four mutations significantly impair interaction of LGI1 with the ADAM22 and ADAM23 receptors on the cell surface. These results support the existence of a second mechanism, alternative to inhibition of protein secretion, by which ADLTE-causing LGI1 mutations exert their loss-of-function effect extracellularly, and suggest that interactions of LGI1 with both ADAM22 and ADAM23 play an important role in the molecular mechanisms leading to ADLTE. PMID:27760137

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

    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.

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

    Zielinski Valerie

    2012-02-01

    Full Text Available Abstract Background 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. Methods 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. Results 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. Conclusion In summary ADAM8 expression is a prognostic factor for survival of patients with head and neck squamous cell carcinoma.

  4. ADAM17 silencing in mouse colon carcinoma cells: the effect on tumoricidal cytokines and angiogenesis.

    Das, Sudipta; Czarnek, Maria; Bzowska, Monika; Mężyk-Kopeć, Renata; Stalińska, Krystyna; Wyroba, Barbara; Sroka, Jolanta; Jucha, Jarosław; Deneka, Dawid; Stokłosa, Paulina; Ogonek, Justyna; Swartz, Melody A; Madeja, Zbigniew; Bereta, Joanna

    2012-01-01

    ADAM17 (a disintegrin and metalloprotease 17) is a major sheddase for numerous growth factors, cytokines, receptors, and cell adhesion molecules and is often overexpressed in malignant cells. It is generally accepted that ADAM17 promotes tumor development via activating growth factors from the EGF family, thus facilitating autocrine stimulation of tumor cell proliferation and migration. Here we show, using MC38CEA murine colon carcinoma model, that ADAM17 also regulates tumor angiogenesis and cytokine profile. When ADAM17 was silenced in MC38CEA cells, in vivo tumor growth and in vitro cell motility were significantly diminished, but no effect was seen on in vitro cell proliferation. ADAM17-silencing was accompanied by decreased in vitro expression of vascular endothelial growth factor-A and matrix metalloprotease-9, which was consistent with the limited angiogenesis and slower growth seen in ADAM17-silenced tumors. Among the growth factors susceptible to shedding by ADAM17, neuregulin-1 was the only candidate to mediate the effects of ADAM17 on MC38CEA motility and tumor angiogenesis. Concentrations of TNF and IFNγ, cytokines that synergistically induced proapoptotic effects on MC38CEA cells, were significantly elevated in the lysates of ADAM17-silenced tumors compared to mock transfected controls, suggesting a possible role for ADAM17 in host immune suppression. These results introduce new, complex roles of ADAM17 in tumor progression, including its impact on the anti-tumor immune response.

  5. ADAM17 silencing in mouse colon carcinoma cells: the effect on tumoricidal cytokines and angiogenesis.

    Sudipta Das

    Full Text Available ADAM17 (a disintegrin and metalloprotease 17 is a major sheddase for numerous growth factors, cytokines, receptors, and cell adhesion molecules and is often overexpressed in malignant cells. It is generally accepted that ADAM17 promotes tumor development via activating growth factors from the EGF family, thus facilitating autocrine stimulation of tumor cell proliferation and migration. Here we show, using MC38CEA murine colon carcinoma model, that ADAM17 also regulates tumor angiogenesis and cytokine profile. When ADAM17 was silenced in MC38CEA cells, in vivo tumor growth and in vitro cell motility were significantly diminished, but no effect was seen on in vitro cell proliferation. ADAM17-silencing was accompanied by decreased in vitro expression of vascular endothelial growth factor-A and matrix metalloprotease-9, which was consistent with the limited angiogenesis and slower growth seen in ADAM17-silenced tumors. Among the growth factors susceptible to shedding by ADAM17, neuregulin-1 was the only candidate to mediate the effects of ADAM17 on MC38CEA motility and tumor angiogenesis. Concentrations of TNF and IFNγ, cytokines that synergistically induced proapoptotic effects on MC38CEA cells, were significantly elevated in the lysates of ADAM17-silenced tumors compared to mock transfected controls, suggesting a possible role for ADAM17 in host immune suppression. These results introduce new, complex roles of ADAM17 in tumor progression, including its impact on the anti-tumor immune response.

  6. The sheddase activity of ADAM17/TACE is regulated by the tetraspanin CD9.

    Gutiérrez-López, Maria Dolores; Gilsanz, Alvaro; Yáñez-Mó, María; Ovalle, Susana; Lafuente, Esther M; Domínguez, Carmen; Monk, Peter N; González-Alvaro, Isidoro; Sánchez-Madrid, Francisco; Cabañas, Carlos

    2011-10-01

    ADAM17/TACE is a metalloproteinase responsible for the shedding of the proinflammatory cytokine TNF-α and many other cell surface proteins involved in development, cell adhesion, migration, differentiation, and proliferation. Despite the important biological function of ADAM17, the mechanisms of regulation of its metalloproteinase activity remain largely unknown. We report here that the tetraspanin CD9 and ADAM17 partially co-localize on the surface of endothelial and monocytic cells. In situ proximity ligation, co-immunoprecipitation, crosslinking, and pull-down experiments collectively demonstrate a direct association between these molecules. Functional studies reveal that treatment with CD9-specific antibodies or neoexpression of CD9 exert negative regulatory effects on ADAM17 sheddase activity. Conversely, CD9 silencing increased the activity of ADAM17 against its substrates TNF-α and ICAM-1. Taken together, our results show that CD9 associates with ADAM17 and, through this interaction, negatively regulates the sheddase activity of ADAM17.

  7. Clinical significance of ADAM-9 in hepatocellular carcinoma%ADAM-9 在肝细胞肝癌中的表达及意义

    边振光; 汤雨; 千年松

    2012-01-01

    Objective:To investigate the clinical significance of ADAM -9 in hepatocellular carcinoma (HCC). Methods: One hundred and sixty - seven cases of HCC were tested for expression of ADAM — 9 by SP immunohisto-chemistry. Results: Among 167 HCC samples,49 (29%) were negative for ADAM -9,118 (71%) had positive ADAM - 9 immunoreactivity. The ADAM - 9 - positive cells in HCC tissues showed unequivocal cytoplasmic and membrane cellular staining pattern. Among 56 normal liver tissue samples,38% of them were positive for ADAM - 9. Significant difference was found between HCC group and normal liver tissue group. HCC tissues with positive ADAM - 9 expression were larger and less differentiated than those with negative expression (P < 0. 05 ). Portal venous invasion , hepatic venous invasion, bile duct invasion, intrahepatic metastasis and high AFP levels were detected significantly more frequently in ADAM — 9 positive group ( P < 0. 05 ). Moreover, ADAM — 9 positive group had significantly poorer outcomes than ADAM - 9 negative group (P < 0. 05 ) . COX analysis showel that AMAD - 9 was an independent prognostic factor for overall survival (P < 0. 05 ). Conclusion: ADAM - 9 may play an important role in the development and metastasis of HCC.%目的:研究ADAM-9在肝细胞肝癌(HCC)中的表达及其与临床病理参数、预后之间的关系.方法:利用免疫组化方法检测167例HCC组织中ADAM-9的表达情况.结果:167例HCC标本中,49例(29%)标本为ADAM-9阴性,118例(71%)标本为ADAM-9阳性;而在56例正常肝组织中间质ADAM-9的表达阳性率为38%,两者比较有显著差异(P<0.05).HCC组织ADAM-9阳性细胞表现出典型的细胞膜和细胞质型表达.单因素分析结果显示ADAM-9在HCC癌组织的表达与肿瘤的大小、分化程度、侵袭转移、高AFP水平和复发有关,差异均具有统计学意义(P<0.05);K-M生存曲线显示ADAM-9阴性表达组生存率高于ADAM-9阳性表达组,

  8. ADAM17 Promotes Motility, Invasion, and Sprouting of Lymphatic Endothelial Cells.

    Renata Mężyk-Kopeć

    Full Text Available Tumor-associated lymphatic vessels actively participate in tumor progression and dissemination. ADAM17, a sheddase for numerous growth factors, cytokines, receptors, and cell adhesion molecules, is believed to promote tumor development, facilitating both tumor cell proliferation and migration, as well as tumor angiogenesis. In this work we addressed the issue of whether ADAM17 may also promote tumor lymphangiogenesis. First, we found that ADAM17 is important for the migratory potential of immortalized human dermal lymphatic endothelial cells (LEC. When ADAM17 was stably silenced in LEC, their proliferation was not affected, but: (i single-cell motility, (ii cell migration through a 3D Matrigel/collagen type I matrix, and (iii their ability to form sprouts in a 3D matrix were significantly diminished. The differences in the cell motility between ADAM17-proficient and ADAM17-silenced cells were eliminated by inhibitors of EGFR and HER2, indicating that ADAM17-mediated shedding of growth factors accounts for LEC migratory potential. Interestingly, ADAM17 depletion affected the integrin surface expression/functionality in LEC. ADAM17-silenced cells adhered to plastic, type I collagen, and fibronectin faster than their ADAM17-proficient counterparts. The difference in adhesion to fibronectin was abolished by a cyclic RGD peptide, emphasizing the involvement of integrins in the process. Using a soluble receptor array, we identified BIG-H3 among several candidate proteins involved in the phenotypic and behavioral changes of LEC upon ADAM17 silencing. In additional assays, we confirmed the increased expression of BIG-H3, as well as TGFβ2 in ADAM17-silenced LEC. The antilymphangiogenic effects of ADAM17 silencing in lymphatic endothelial cells suggest further relevance of ADAM17 as a potential target in cancer therapy.

  9. ADAM17 Promotes Motility, Invasion, and Sprouting of Lymphatic Endothelial Cells.

    Mężyk-Kopeć, Renata; Wyroba, Barbara; Stalińska, Krystyna; Próchnicki, Tomasz; Wiatrowska, Karolina; Kilarski, Witold W; Swartz, Melody A; Bereta, Joanna

    2015-01-01

    Tumor-associated lymphatic vessels actively participate in tumor progression and dissemination. ADAM17, a sheddase for numerous growth factors, cytokines, receptors, and cell adhesion molecules, is believed to promote tumor development, facilitating both tumor cell proliferation and migration, as well as tumor angiogenesis. In this work we addressed the issue of whether ADAM17 may also promote tumor lymphangiogenesis. First, we found that ADAM17 is important for the migratory potential of immortalized human dermal lymphatic endothelial cells (LEC). When ADAM17 was stably silenced in LEC, their proliferation was not affected, but: (i) single-cell motility, (ii) cell migration through a 3D Matrigel/collagen type I matrix, and (iii) their ability to form sprouts in a 3D matrix were significantly diminished. The differences in the cell motility between ADAM17-proficient and ADAM17-silenced cells were eliminated by inhibitors of EGFR and HER2, indicating that ADAM17-mediated shedding of growth factors accounts for LEC migratory potential. Interestingly, ADAM17 depletion affected the integrin surface expression/functionality in LEC. ADAM17-silenced cells adhered to plastic, type I collagen, and fibronectin faster than their ADAM17-proficient counterparts. The difference in adhesion to fibronectin was abolished by a cyclic RGD peptide, emphasizing the involvement of integrins in the process. Using a soluble receptor array, we identified BIG-H3 among several candidate proteins involved in the phenotypic and behavioral changes of LEC upon ADAM17 silencing. In additional assays, we confirmed the increased expression of BIG-H3, as well as TGFβ2 in ADAM17-silenced LEC. The antilymphangiogenic effects of ADAM17 silencing in lymphatic endothelial cells suggest further relevance of ADAM17 as a potential target in cancer therapy.

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

    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

  11. Empathy's purity, sympathy's complexities; De Waal, Darwin and Adam Smith.

    van der Weele, Cor

    2011-07-01

    Frans de Waal's view that empathy is at the basis of morality directly seems to build on Darwin, who considered sympathy as the crucial instinct. Yet when we look closer, their understanding of the central social instinct differs considerably. De Waal sees our deeply ingrained tendency to sympathize (or rather: empathize) with others as the good side of our morally dualistic nature. For Darwin, sympathizing was not the whole story of the "workings of sympathy"; the (selfish) need to receive sympathy played just as central a role in the complex roads from sympathy to morality. Darwin's understanding of sympathy stems from Adam Smith, who argued that the presence of morally impure motives should not be a reason for cynicism about morality. I suggest that De Waal's approach could benefit from a more thorough alignment with the analysis of the workings of sympathy in the work of Darwin and Adam Smith.

  12. Application of the ADAMS program to deployable space truss structures

    Calleson, R. E.

    1985-01-01

    The need for a computer program to perform kinematic and dynamic analyses of large truss structures while deploying from a packaged configuration in space led to the evaluation of several existing programs. ADAMS (automatic dynamic analysis of mechanical systems), a generalized program from performing the dynamic simulation of mechanical systems undergoing large displacements, is applied to two concepts of deployable space antenna units. One concept is a one cube folding unit of Martin Marietta's Box Truss Antenna and the other is a tetrahedral truss unit of a Tetrahedral Truss Antenna. Adequate evaluation of dynamic forces during member latch-up into the deployed configuration is not yet available from the present version of ADAMS since it is limited to the assembly of rigid bodies. Included is a method for estimating the maximum bending stress in a surface member at latch-up. Results include member displacement and velocity responses during extension and an example of member bending stresses at latch-up.

  13. Synthesis of serotonin transporter imaging agent [125I]ADAM

    LU Chun-Xiong; WU Chun-Ying; JIANG Quan-Fu; CHEN Zheng-Ping; ZHANG Tong-Xing; LI Xiao-Ming; WANG Song-Pei

    2005-01-01

    The synthesis of serotonin transporter imaging agent [125I] -2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine([125I] ADAM) was reported. The chemical structure of the labeling precursor 5- (tributylstannyl) -2-((2-((dimethylamino)methyl)phenyl)thio)phenylamine and all its intermediates were verified by IR,1HNMR and MS. The .radioiodinated compound was prepared using iododestannylation reaction by hydrogen peroxide. Final radiochemical purity was above 95% determined by TLC.

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

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

    2015-01-01

    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. ADAM10 regulates transcription factor expression required for plasma cell function.

    Natalia S Chaimowitz

    Full Text Available A disintegrin and metalloprotease 10 (ADAM10 is a key regulator of cellular processes by shedding extracellular domains of transmembrane proteins. We have previously demonstrated that deletion of B cell expressed ADAM10 results in changes in lymphoid tissue architecture and impaired germinal center (GC formation. In this study, mice were generated in which ADAM10 is deleted in B cells following class switch recombination (ADAM10(Δ/ΔIgG1-cre(+/- mice. Despite normal GC formation, antibody responses were impaired in ADAM10(Δ/ΔIgG1-cre(+/- mice, implicating ADAM10 in post-GC and extrafollicular B cell terminal differentiation. Surprisingly, plasma cell (PC numbers were normal in ADAM10(Δ/ΔIgG1-cre(+/- mice when compared to controls. However, PCs isolated from ADAM10(Δ/ΔIgG1-cre(+/- mice exhibited decreased expression of transcription factors important for PC function: Prdm1, Xbp1 and Irf4. Bcl6 is a GC transcriptional repressor that inhibits the PC transcriptional program and thus must be downregulated for PC differentiation to occur. Bcl6 expression was increased in PCs isolated from ADAM10(Δ/ΔIgG1-cre(+/- mice at both the mRNA and protein level. These results demonstrate that ADAM10 is required for proper transcription factor expression in PCs and thus, for normal PC function.

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

    Roy, Roopali; Wewer, Ulla M; Zurakowski, David

    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......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 affinity chromatography followed by protein identification by matrix-assisted laser desorption/ionization-time of flight mass spectrometry. Four peptides were identified that spanned the amino acid sequence of ADAM 12. Immunoblot analysis using ADAM 12-specific antibodies detected an approximately 68-k......Da band identified as the mature form of ADAM 12. To characterize catalytic properties of ADAM 12, full-length ADAM 12-S was expressed in COS-7 cells and purified. Substrate specificity studies demonstrated that ADAM 12-S degrades gelatin, type IV collagen, and fibronectin but not type I collagen...

  17. ADAM33, a new candidate for psoriasis susceptibility.

    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. [The importance of ADAM family proteins in malignant tumors].

    Walkiewicz, Katarzyna; Gętek, Monika; Muc-Wierzgoń, Małgorzata; Kokot, Teresa; Nowakowska-Zajdel, Ewa

    2016-02-11

    Increasing numbers of reports about the role of adamalysins (ADAM) in malignant tumors are being published. To date, more than 30 representatives of this group, out of which about 20 occur in humans, have been described. The ADAM family is a homogeneous group of proteins which regulate, from the stage of embryogenesis, a series of processes such as cell migration, adhesion, and cell fusion. Half of them have proteolytic activity and are involved in the degradation of the extracellular matrix and the disintegration of certain protein complexes, thereby regulating the bioavailability of various growth factors. Many of these functions have a direct role in the processes of carcinogenesis and promoting the growth of tumor, which affect some signaling pathways, including those related to insulin-like growth factors (IGF1, IGF2), vascular growth factor (VEGF), tumor necrosis factor α (TNFα) and the EGFR/HER pathway. Another branch of studies is the evaluation of the possibility of using members of ADAM family proteins in the diagnosis, especially in breast, colon and non- small cell lung cancer. The detection of concentrations of adamalysin in serum, urine and pleural aspirates might contribute to the development of methods of early diagnosis of cancer and monitoring the therapy. However, both the role of adamalysins in the development and progression of tumors and their importance as a diagnostic and predictive further research still need to be checked on large groups of patients.

  19. ADAM8 enhances osteoclast precursor fusion and osteoclast formation in vitro and in vivo.

    Ishizuka, Hisako; García-Palacios, Verónica; Lu, Ganwei; Subler, Mark A; Zhang, Heju; Boykin, Christina S; Choi, Sun Jin; Zhao, Liena; Patrene, Kenneth; Galson, Deborah L; Blair, Harry C; Hadi, Tamer M; Windle, Jolene J; Kurihara, Noriyoshi; Roodman, G David

    2011-01-01

    ADAM8 expression is increased in the interface tissue around a loosened hip prosthesis and in the pannus and synovium of patients with rheumatoid arthritis, but its potential role in these processes is unclear. ADAM8 stimulates osteoclast (OCL) formation, but the effects of overexpression or loss of expression of ADAM8 in vivo and the mechanisms responsible for the effects of ADAM8 on osteoclastogenesis are unknown. Therefore, to determine the effects of modulating ADAM expression, we generated tartrate-resistant acid phosphatase (TRAP)-ADAM8 transgenic mice that overexpress ADAM8 in the OCL lineage and ADAM8 knockout (ADAM8 KO) mice. TRAP-ADAM8 mice developed osteopenia and had increased numbers of OCL precursors that formed hypermultinucleated OCLs with an increased bone-resorbing capacity per OCL. They also had an enhanced differentiation capacity, increased TRAF6 expression, and increased NF-κB, Erk, and Akt signaling compared with wild-type (WT) littermates. This increased bone-resorbing capacity per OCL was associated with increased levels of p-Pyk2 and p-Src activation. In contrast, ADAM8 KO mice did not display a bone phenotype in vivo, but unlike WT littermates, they did not increase RANKL production, OCL formation, or calvarial fibrosis in response to tumor necrosis factor α (TNF-α) in vivo. Since loss of ADAM8 does not inhibit basal bone remodeling but only blocks the enhanced OCL formation in response to TNF-α, these results suggest that ADAM8 may be an attractive therapeutic target for preventing bone destruction associated with inflammatory disease.

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

    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

  1. ADAM8 Enhances Osteoclast Precursor Fusion and Osteoclast Formation In Vitro and In Vivo

    Ishizuka, Hisako; García-Palacios, Verónica; Lu, Ganwei; Subler, Mark A; Zhang, Heju; Boykin, Christina S; Choi, Sun Jin; Zhao, Liena; Patrene, Kenneth; Galson, Deborah L; Blair, Harry C; Hadi, Tamer M; Windle, Jolene J; Kurihara, Noriyoshi; Roodman, G David

    2011-01-01

    ADAM8 expression is increased in the interface tissue around a loosened hip prosthesis and in the pannus and synovium of patients with rheumatoid arthritis, but its potential role in these processes is unclear. ADAM8 stimulates osteoclast (OCL) formation, but the effects of overexpression or loss of expression of ADAM8 in vivo and the mechanisms responsible for the effects of ADAM8 on osteoclastogenesis are unknown. Therefore, to determine the effects of modulating ADAM expression, we generated tartrate-resistant acid phosphatase (TRAP)–ADAM8 transgenic mice that overexpress ADAM8 in the OCL lineage and ADAM8 knockout (ADAM8 KO) mice. TRAP-ADAM8 mice developed osteopenia and had increased numbers of OCL precursors that formed hypermultinucleated OCLs with an increased bone-resorbing capacity per OCL. They also had an enhanced differentiation capacity, increased TRAF6 expression, and increased NF-κB, Erk, and Akt signaling compared with wild-type (WT) littermates. This increased bone-resorbing capacity per OCL was associated with increased levels of p-Pyk2 and p-Src activation. In contrast, ADAM8 KO mice did not display a bone phenotype in vivo, but unlike WT littermates, they did not increase RANKL production, OCL formation, or calvarial fibrosis in response to tumor necrosis factor α (TNF-α) in vivo. Since loss of ADAM8 does not inhibit basal bone remodeling but only blocks the enhanced OCL formation in response to TNF-α, these results suggest that ADAM8 may be an attractive therapeutic target for preventing bone destruction associated with inflammatory disease. © 2011 American Society for Bone and Mineral Research. PMID:20683884

  2. 研华精巧型以太网络通讯控制器——ADAM-4501&ADAM-4501D

    2006-01-01

    研华所提供通讯控制器特点是具备以太网络转串行的强大通讯功能,产品系列可依操作系统分成两大类:ROM—DOS的ADAM-4500控制器及Windows CE的ADAM-6501控制器。现在推出的ADAM-4501/4501D则是ADAM-4500控制器的下一代,除了内存容量增加之外,及提供更丰富的输出入接口,ADAM-4501D还提供一个5位数的使用者自订LED显示屏,能够在组件的表面显示自订功能状态。

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

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

    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, alpha7B integrin, and dystroglycans. Ectopic ADAM12 expression in normal mouse skeletal muscle also improved regeneration after freeze injury, presumably by the same mechanism. Hence, it was suggested...... overexpressing ADAM12 (ADAM12(+)/mdx mice), even though their utrophin levels were mildly elevated compared with age-matched controls. Thus, membrane stabilization was not sufficient to provide protection during prolonged disease. Consequently, we reinvestigated skeletal muscle regeneration in ADAM12 transgenic...

  4. Dissecting the role of ADAM10 as a mediator of Staphylococcus aureus α-toxin action.

    von Hoven, Gisela; Rivas, Amable J; Neukirch, Claudia; Klein, Stefan; Hamm, Christian; Qin, Qianqian; Meyenburg, Martina; Füser, Sabine; Saftig, Paul; Hellmann, Nadja; Postina, Rolf; Husmann, Matthias

    2016-07-01

    Staphylococcus aureus is a leading cause of bacterial infections in humans, including life-threatening diseases such as pneumonia and sepsis. Its small membrane-pore-forming α-toxin is considered an important virulence factor. By destroying cell-cell contacts through cleavage of cadherins, the metalloproteinase ADAM10 (a disintegrin and metalloproteinase 10) critically contributes to α-toxin-dependent pathology of experimental S. aureus infections in mice. Moreover, ADAM10 was proposed to be a receptor for α-toxin. However, it is unclear whether the catalytic activity or specific domains of ADAM10 are involved in mediating binding and/or subsequent cytotoxicity of α-toxin. Also, it is not known how α-toxin triggers ADAM10's enzymatic activity, and whether ADAM10 is invariably required for all α-toxin action on cells. In the present study, we show that efficient cleavage of the ADAM10 substrate epithelial cadherin (E-cadherin) requires supra-cytotoxic concentrations of α-toxin, leading to significant increases in intracellular [Ca(2+)]; the fall in cellular ATP levels, typically following membrane perforation, became observable at far lower concentrations. Surprisingly, ADAM10 was dispensable for α-toxin-dependent xenophagic targeting of S. aureus, whereas a role for α-toxin attack on the plasma membrane was confirmed. The catalytic site of ADAM10, furin cleavage site, cysteine switch and intracellular domain of ADAM10 were not required for α-toxin binding and subsequent cytotoxicity. In contrast, an essential role for the disintegrin domain and the prodomain emerged. Thus, co-expression of the prodomain with prodomain-deficient ADAM10 reconstituted binding of α-toxin and susceptibility of ADAM10-deficient cells. The results of the present study may help to inform structural analyses of α-toxin-ADAM10 interactions and to design novel strategies to counteract S. aureus α-toxin action.

  5. Reverse logistics

    M.P. de Brito (Marisa); S.D.P. Flapper; R. Dekker (Rommert)

    2002-01-01

    textabstractThis paper gives an overview of scientific literature that describes and discusses cases of reverse logistics activities in practice. Over sixty case studies are considered. Based on these studies we are able to indicate critical factors for the practice of reverse logistics. In addi

  6. Discovery and development of diarylpyrimidines (DAPYs) as next-generation HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs)%二芳基嘧啶类HIV-1非核苷类逆转录酶抑制剂研究进展

    田兴涛; 谢蓝

    2010-01-01

    2008年FDA批准上市的新一代非核苷类逆转录酶抑制剂Etravirine(TMCl25)和Ⅲ期临床候选药Rilpivirine(TMC278)都是二芳基嘧啶(DAPY)类化合物,均对HIV野生型和多种耐药性病毒株有相当强的抑制作用.DAPY类药物的发现和发展是多学科合作研发新药的成功范例.本文综述了新一代HIV 非核苷类逆转录酶抑制剂DAPY类化合物的发现、发展及最新研究进展.

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

    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......ADAMs are a family of multidomain proteins having proteolytic and cell adhesion activities. We have previously shown that ADAM 12-S, the secreted soluble form of human ADAM 12, is a catalytically active protease. We now describe the purification of full-length recombinant ADAM 12-S and demonstrate...... 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 inhibitor of ADAM 12...

  8. John Adams's Montesquieuean Moment: Enlightened Historicism in the Discourses on Davila.

    Green, Jonathan

    2016-01-01

    At the outset of the French Revolution John Adams penned a series of Discourses of Davila, philosophical ruminations on the sixteenth-century French Wars of Religion. Recent historians have read these Discourses in terms of Adams's Machiavellianism-his conviction that men's passions lead to violence, if unrestrained. But this reading overlooks the extent to which Adams intended his Discourses as a particular investigation into the French nation's character, and into whether the revolutionaries could lay claim to a native, French tradition of mixed constitutional government. Situating the Discourses vis-à-vis Adams's contemporaneous reading of Montesquieu, this article argues for an underappreciated historicist dimension to his thought.

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

    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

  10. ADAM10 Is Involved in Cell Junction Assembly in Early Porcine Embryo Development.

    Jeongwoo Kwon

    Full Text Available ADAM10 (A Disintegrin and Metalloprotease domain-containing protein 10 is a cell surface protein with a unique structure possessing both potential adhesion and protease domains. However, the role of ADAM10 in preimplantation stage embryos is not clear. In this study, we examined the expression patterns and functional roles of ADAM10 in porcine parthenotes during preimplantation development. The transcription level of ADAM10 dramatically increased from the morula stage onward. Immunostaining revealed that ADAM10 was present in both the nucleus and cytoplasm in early cleavage stage embryos, and localized to the apical region of the outer cells in morula and blastocyst embryos. Knockdown (KD of ADAM10 using double strand RNA did not alter preimplantation embryo development until morula stage, but resulted in significantly reduced development to blastocyst stage. Moreover, the KD blastocyst showed a decrease in gene expression of adherens and tight junction (AJ/TJ, and an increase in trophectoderm TJ permeability by disrupting TJ assembly. Treatment with an ADAM10 specific chemical inhibitor, GI254023X, at the morula stage also inhibited blastocyst development and led to disruption of TJ assembly. An in situ proximity ligation assay demonstrated direct interaction of ADAM10 with coxsackie virus and adenovirus receptor (CXADR, supporting the involvement of ADAM10 in TJ assembly. In conclusion, our findings strongly suggest that ADADM10 is important for blastocyst formation rather than compaction, particularly for TJ assembly and stabilization in preimplantation porcine parthenogenetic development.

  11. The identification of seven metalloproteinase-disintegrin (ADAM) genes from genomic libraries.

    Poindexter, K; Nelson, N; DuBose, R F; Black, R A; Cerretti, D P

    1999-09-03

    Metalloproteinase-disintegrins (ADAMs) are membrane-spanning multi-domain proteins containing a zinc metalloproteinase domain and a disintegrin domain which may serve as an integrin ligand. Based on a conserved sequence within the disintegrin domain, GE(E/Q)CDCG, seven genes were isolated from a human genomic library. Two of these genes lack introns and show testis-specific expression (ADAM20 and ADAM21), while the other two genes contain introns (ADAM22 and ADAM23) and are expressed predominantly in the brain. In addition, three pseudogenes were isolated; one of which evolved from ADAM21. Human chromosomal mapping indicated that ADAM22 and ADAM23 mapped to chromosome 7q21 and 2q33, respectively, while the three pseudogenes 1-2, 3-3, and 1-32 mapped to chromosome 14q24.1, 8p23, and 14q24.1, respectively. An ancestral analysis of all known ADAMs indicates that the zinc-binding motif in the catalytic domain arose once in a common ancestor and was lost by those members lacking this motif.

  12. Conservation and divergence of ADAM family proteins in the Xenopus genome

    Shah Anoop

    2010-07-01

    Full Text Available Abstract Background Members of the disintegrin metalloproteinase (ADAM family play important roles in cellular and developmental processes through their functions as proteases and/or binding partners for other proteins. The amphibian Xenopus has long been used as a model for early vertebrate development, but genome-wide analyses for large gene families were not possible until the recent completion of the X. tropicalis genome sequence and the availability of large scale expression sequence tag (EST databases. In this study we carried out a systematic analysis of the X. tropicalis genome and uncovered several interesting features of ADAM genes in this species. Results Based on the X. tropicalis genome sequence and EST databases, we identified Xenopus orthologues of mammalian ADAMs and obtained full-length cDNA clones for these genes. The deduced protein sequences, synteny and exon-intron boundaries are conserved between most human and X. tropicalis orthologues. The alternative splicing patterns of certain Xenopus ADAM genes, such as adams 22 and 28, are similar to those of their mammalian orthologues. However, we were unable to identify an orthologue for ADAM7 or 8. The Xenopus orthologue of ADAM15, an active metalloproteinase in mammals, does not contain the conserved zinc-binding motif and is hence considered proteolytically inactive. We also found evidence for gain of ADAM genes in Xenopus as compared to other species. There is a homologue of ADAM10 in Xenopus that is missing in most mammals. Furthermore, a single scaffold of X. tropicalis genome contains four genes encoding ADAM28 homologues, suggesting genome duplication in this region. Conclusions Our genome-wide analysis of ADAM genes in X. tropicalis revealed both conservation and evolutionary divergence of these genes in this amphibian species. On the one hand, all ADAMs implicated in normal development and health in other species are conserved in X. tropicalis. On the other hand, some

  13. Increase of α-Secretase ADAM10 in Platelets Along Cognitively Healthy Aging.

    Schuck, Florian; Wolf, Dominik; Fellgiebel, Andreas; Endres, Kristina

    2016-01-01

    ADAM10 is one of the key players in ectodomain-shedding of the amyloid-β protein precursor (AβPP). Previous research with postmortem tissue has shown reduced expression and activity of ADAM10 within the central nervous system (CNS) of Alzheimer's disease (AD) patients. Determination of cerebral ADAM10 in living humans is hampered by its transmembrane property; only the physiological AβPP cleavage product generated by ADAM10, sAβPPα, can be assessed in cerebrospinal fluid. Establishment of surrogate markers in easily accessible material therefore is crucial. It has been demonstrated that ADAM10 is expressed in platelets and that platelet amount is decreased in AD patients. Just recently it has been shown that platelet ADAM10 and cognitive performance of AD patients positively correlate. In contrast to AD patients, to our knowledge almost no information has been published regarding ADAM10 expression during normal aging. We investigated ADAM10 amount and activity in platelets of cognitively healthy individuals from three different age groups ranging from 22-85 years. Interestingly, we observed an age-dependent increase in ADAM10 levels and activity in platelets.

  14. ADAM33 gene polymorphisms in chronic obstructive pulmonary disease

    Pabst S

    2009-12-01

    Full Text Available Abstract Study objective The pathogenesis of chronic obstructive pulmonary disease (COPD is characterized by an interaction of environmental influences, particularly cigarette smoking, and genetic determinants. Given the global increase in COPD, research on the genomic variants that affect susceptibility to this complex disorder is reviving. In the present study, we investigated whether single nucleotide polymorphisms in 'a disinter-grin and metalloprotease' 33 (ADAM33 are associated with the development and course of COPD. Patients and design We genotyped 150 German COPD patients and 152 healthy controls for the presence of the F+1 and S_2 SNPs in ADAM 33 that lead to the base pair exchange G to A and C to G, respectively. To assess whether these genetic variants are influential in the course of COPD, we subdivided the cohort into two subgroups comprising 60 patients with a stable and 90 patients with an unstable course of disease. Results In ADAM33, the frequency of the F+1 A allele was 35.0% among stable and 43.9% among unstable COPD subjects, which was not significantly different from the 35.5% found in the controls (P = 0.92 and P = 0.07, respectively. The frequency of the S_2 mutant allele in subjects with a stable COPD was 23.3% (P = 0.32, in subjects with an unstable course 30.6% (P = 0.47. Conclusion The study shows that there is no significant difference in the distribution of the tested SNPs between subjects with and without COPD. Furthermore, these polymorphisms appear to have no consequences for the stability of the disease course.

  15. Adam Smith y Sistemas Dinámicos

    Acuña, Osvaldo; Ulate, Fernán

    2008-01-01

    Presentamos un sistema dinámico sencillo con dos ecuaciones diferenciales, una representa la trayectoria del precio y la otra la de la cantidad de un bien en una economía. Nuestro modelo se basa sobre todo en la teoría clásica de precios expuesta por Adam Smith en La Riqueza de las Naciones. Al final del trabajo, se presenta, a modo de ejemplo, un estudio para el caso del ganado vacuno en la economía mundial.

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

    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.

  17. Adam Smith et le “républicanisme”

    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...

  18. Simulation of Naval Guns' Breechblock System Dynamics Based on ADAMS

    Tan, Bo; Liu, Hui-Min; Liu, Kai

    In order to study the dynamical characteristics of the breechblock system during gun firing, a virtual prototype model was established based on ADAMS, in which motion and force transmission among mechanisms are realized by collision. By simulation, kinematics and dynamics properties of main components are obtained, and the relationships between the motion of breechblock and the position of breechblock opening plate are analyzed. According to the simulation results, the collision among the breechblock opening plate and the roller is discontinuous, which may make the breechblock system fail to hitch the breechblock reliably. And within allowable scope of the structure, the breechblock opening template should be installed near the upside as much as possible.

  19. Adapting the ADAM Manikin Technology for Injury Probability Assessment

    1992-02-19

    injuries of interest for ADAM testing and to assess the state of the art for injury probability assessment criteria. This literature review, in and of...formed by the ischial and pubic rami are frequently at risk as is diastasis of the pubic symphysis and/or sacro -iliac joints. Based upon the historic,’l...Proceedings No. P-45). New York, NY, Society of Automotive Engineers, 296-308 (1972). 33. Gennarelli, T.A. State-of-the- Art of Head Injury Biomechanics

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

    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

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

    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.

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

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

    1999-01-01

    The ADAMs (A disintegrin and metalloprotease) comprise a family of membrane-anchored cell surface proteins with a putative role in cell-cell and/or cell-matrix interactions. By immunostaining, ADAM 12 (meltrin alpha) was up-regulated in several human carcinomas and could be detected along the tum...

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

    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...

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

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

    2002-01-01

    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...

  5. Evaluation of the Serotonin Transporter Ligand 123I-ADAM for SPECT Studies on Humans

    Frokjaer, V.G.; Pinborg, Lars Hageman; Madsen, J.;

    2008-01-01

    transporters using (123)I-labeled 2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine (ADAM) in humans: an arterial plasma input model, simplified and Logan reference tissue models, and standardized uptake value ratios. METHODS: Nine subjects were scanned with dynamic (123)I-ADAM SPECT (mean age, 31 y...

  6. ADAM30 Downregulates APP-Linked Defects Through Cathepsin D Activation in Alzheimer's Disease

    Florent Letronne

    2016-07-01

    Full Text Available Although several ADAMs (A disintegrin-like and metalloproteases have been shown to contribute to the amyloid precursor protein (APP metabolism, the full spectrum of metalloproteases involved in this metabolism remains to be established. Transcriptomic analyses centred on metalloprotease genes unraveled a 50% decrease in ADAM30 expression that inversely correlates with amyloid load in Alzheimer's disease brains. Accordingly, in vitro down- or up-regulation of ADAM30 expression triggered an increase/decrease in Aβ peptides levels whereas expression of a biologically inactive ADAM30 (ADAM30mut did not affect Aβ secretion. Proteomics/cell-based experiments showed that ADAM30-dependent regulation of APP metabolism required both cathepsin D (CTSD activation and APP sorting to lysosomes. Accordingly, in Alzheimer-like transgenic mice, neuronal ADAM30 over-expression lowered Aβ42 secretion in neuron primary cultures, soluble Aβ42 and amyloid plaque load levels in the brain and concomitantly enhanced CTSD activity and finally rescued long term potentiation alterations. Our data thus indicate that lowering ADAM30 expression may favor Aβ production, thereby contributing to Alzheimer's disease development.

  7. Microautoradiography of [{sup 123}I]ADAM in mice treated with fluoxetine and serotonin reuptake inhibitors

    Ye, X.-X.; Chen, J.-C.; Liu, R.-S.; Wey, S.-P.; Lee, J.-S.; Chen, C.-C.; Fu, Y.-K.; Ting, Gann; Hwang, J.-J. E-mail: jjhwang@ym.edu.tw

    2004-07-01

    A radiopharmaceutical, {sup 123}I-labeled 2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine ([{sup 123}I]ADAM), has been developed recently for evaluation of how serotonin transporters (SERT) function in the brain. However, the detailed biodistribution and specific binding in certain brain areas are not well investigated. In this study, both phosphor plate imaging and microautoradiography were applied to explore the binding characteristics of [{sup 123}I]ADAM in SERT neurons. The effect of two psychotropics and one narcotic on the binding of [{sup 123}I]ADAM to SERT was also studied. Fluoxetine and desipramine, both are psychotropics and specific SERT ligands and decreased the affinity of [{sup 123}I]ADAM, while p-chloroamphetamine (PCA), a narcotic, destroyed most of serotonergic neurons, as well as reducing the concentration of serotonin and the number of SERT in the brain as shown by the biodistribution of [{sup 123}I]ADAM. Significant and selective accumulation of [{sup 123}I]ADAM in the areas from midbrain to brain stem in normal mice with maximum target-to-background ratio was found at 90 minutes postinjection. A rapid clearance of [{sup 131}I]ADAM at 120 minutes postinjection was found in the CA1, CA3 and ThN brain areas. In addition, the inhibition effect on binding ability of [{sup 123}I]ADAM to SERT by the psychotropics and the narcotic was found to have the order of: PCA > fluoxetine > desipramine.

  8. At læse Adam Smith er både befriende og irriterende

    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...

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

    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......, genetic models, selection strategies, and mating designs. ADAM can be used to evaluate breeding schemes and generate genetic data to test statistical tools...

  10. Expression of ADAMs ("a disintegrin and metalloprotease") in the human lung

    Dijkstra, Antoon; Postma, Dirkje S.; Noordhoek, Jacobien A.; Lodewijk, Monique E.; Kauffman, Henk F.; ten Hacken, Nick H. T.; Timens, Wim

    2009-01-01

    In view of the associations of "a disintegrin and metalloprotease" (ADAM) with respiratory diseases, we assessed the expression of various ADAMs in human lung tissue. Lung tissue was obtained from nine individuals who underwent surgery for lung cancer or underwent lung transplantation for emphysema.

  11. ADAM in Holland? : Plan van aanpak voor de pilot monitoring drugsgebruik onder arrestanten bij politie Haaglanden

    Broek, H. van den; Klerks, P.; Otter, P. den

    1999-01-01

    In de VS worden sinds 1987 systematisch gegevens verzameld over drugsgebruik onder aangehouden verdachten in het kader van het ADAM-programma. Als eerste stap naar een Nederlandse ADAM is vastgesteld in hoeverre er draagvlak bestaat voor een pilot in de politieregio Haaglanden. Eind 1998 heeft op he

  12. A role for ADAM12 in breast tumor progression and stromal cell apoptosis

    Kveiborg, Marie; Frohlich, Camilla; Albrechtsen, Reidar;

    2005-01-01

    of stromal fibroblasts in tumor initiation and progression has been elucidated. Here, we show that stromal cell apoptosis occurs in human breast carcinoma but is only rarely seen in nonmalignant breast lesions. Furthermore, we show that ADAM12, a disintegrin and metalloprotease up-regulated in human breast...... cancer, accelerates tumor progression in a mouse breast cancer model. ADAM12 does not influence tumor cell proliferation but rather confers both decreased tumor cell apoptosis and increased stromal cell apoptosis. This dual role of ADAM12 in governing cell survival is underscored by the finding that ADAM......12 increases the apoptotic sensitivity of nonneoplastic cells in vitro while rendering tumor cells more resistant to apoptosis. Together, these results show that the ability of ADAM12 to influence apoptosis may contribute to tumor progression....

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

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

    1999-01-01

    , with the 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 protease domain. In addition to its latency function, the prodomain is required for exit of ADAM 12 protease from the endoplasmic reticulum. Tissue inhibitor of metalloprotease-1, -2, and -3 were not found to block proteolytic activity of ADAM 12, hence a physiological inhibitor of ADAM 12 protease...

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

    Shi, Z; Xu, Wei; Loechel, F

    2000-01-01

    , as 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...... medium on a heparin-Sepharose column also proteolyzed IGFBP-3. The degradation pattern was similar to that seen with pregnancy serum, and the presence of ADAM 12-S in serum during pregnancy was confirmed. The data suggest that ADAM 12-S has IGFBP-3 protease activity, and it may contribute to the IGFBP-3...

  15. Unite simulation and analysis for vehicle suspension based on ADAMS/Matlab%ADAMS/Matlab 环境下车辆悬架联合仿真分析

    梁栋; 邓兆祥; 郝军; 王恒元

    2012-01-01

    Based on the one-fourth automotive dynamics model in ADAMS/View,the optimal co-simulation system is established in the environment of Matlab/Simulink through the data connection between ADAMS and Matlab, then, the comparison is represented in term of co-simulation and single simulation in Matlab. It shows both of these two approaches make acceleration value of suspension mass-loaded and consumptive energy reduce, however, the approach of co-simulation has more pronounced effect.%针对ADAMS/View环境下某车辆1/4整车动力学模型,通过ADAMS/Control模块建立了ADAMS与Matlab软件之间的通信连接,在Matlab/Simulink环境下建立最优联合控制系统,运用ADAMS和Matlab/Simulink软件(即ADAMS/Matlab)进行联合仿真,并与在Matlab单一环境下运行的仿真模型进行对比分析.结果发现:两种分析方法都能使车辆悬架簧上总质量质心加速度均方根值和控制能量降低,而ADAMS/Matlab软件联合仿真控制下的悬架簧上总质量质心加速度和控制能量下降幅度更大.

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

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

    2015-01-01

    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...

  17. Reversible Computing

    1980-02-01

    will have been introduced. 9. Reversible celular autemata We shall assume the reader to have some familiarity with the concept of cel- lular...10003 Mr. Kin B. Thcmpson 1 copy Technical Director Information Systems Divisia.i Naval Research Laboratory (OP-91T) Technical Information Division

  18. Defenses and morality: Adam Smith, Sigmund Freud, and contemporary psychoanalysis.

    Gabrinetti, Paul A; Özler, Sule

    2014-10-01

    In this paper we follow the development and transmission of moral learning from Adam Smith's impartial spectator to Sigmund Freud's superego and then to contemporary psychoanalysis. We argue that defenses are an integral component in the acquisition of any moral system. Elaborating on this argument, we assert that there is a progression from defensive systems that are "closed" to defensive systems that are "open," as defined in a recent work by Novick and Novick. The former system is "static, avoids reality, and is characterized by power dynamics, sadomasochism, and omnipotent defense." The latter, on the other hand, is a system that allows for "joy, creativity, spontaneity, love and it is attuned to reality." Furthermore, while Smith and Freud's systems are more one-person systems of defense, contemporary psychoanalysis has moved to more of a two-person system.

  19. Econophysical visualization of Adam Smith’s invisible hand

    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.

  20. Adam Smith and the new era of China

    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.

  1. Instrumentality in health care: a response to Adam Oliver.

    Tanenbaum, Sandra J

    2015-07-01

    In his paper, 'Incentivizing improvements in health care delivery', Adam Oliver discusses recent efforts to manage the performance of health care workers in the United States and United Kingdom. Overall, the results of performance management seem to be mixed, but Oliver's discussion hints at a more fundamental question about this approach, specifically: what are the limits of a focused instrumentality in a context as rich, fluid and collaborative as the delivery of health care? Might performance management schemes actually frustrate the efforts of conscientious health care workers? Indicators make few allowances for the heterogeneity of treatment effects or patient values or preferences. Health care workers may also face pressure to appear to satisfy indicators that are actually impossible to satisfy.

  2. William E. Adams: Thomas Mann and The Magic Mountain.

    Naef, A P

    1998-01-01

    The lobectomy for carcinoma of the lung performed by William E. Adams in 1946 on Thomas Mann, author of the tuberculosis saga The Magic Mountain, deserves to be added to Harold Ellis's series of "historically famous operations." This lobectomy, by which the surgeon cured his far more famous patient, was only one episode in his 40 eventful years as Chicago's leading pioneer in early thoracic surgery. The historic case is well documented by preoperative, operative, and pathology reports obtained through the courtesy of still-living witnesses and associates, friends of the author. Thomas Mann died 9 years later of an aortoiliac rupture at the University Hospital in Zurich. At autopsy no local recurrence or distal metastasis was found.

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

    Nives Giebeler

    2016-04-01

    Full Text Available 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.

  4. A Pull Back Theorem in the Adams Spectral Sequence

    Jin Kun LIN

    2008-01-01

    This paper proves that, for any generator x∈Exts,tq (Zp,Zp), if (1L∧i)*φ*(x)∈Exts+1,tq+2qA (H*L∧M,Zp) is a perm anent cycle in the Adams spectral sequence (ASS), then h0x∈Exts+1,tq+q (Zp,Zp) also is a permenent cycle in the ASS. As an application, the paper obtains that h0x∈h0hnhm∈Ext3,p n q+p m q+q(Zp,Zp) is a permanent cycle in the ASS and it converges to elements of order p in the stable homotopy groups of spheres πpnq+pmq+q -3S ,where p≥5 is a prime, s≤4, n≥m +2 ≥4 and M is the Moore spectrum.

  5. The ADAMs family of proteases as targets for the treatment of cancer.

    Mullooly, Maeve; McGowan, Patricia M; Crown, John; Duffy, Michael J

    2016-08-01

    The ADAMs (a disintegrin and metalloproteases) are transmembrane multidomain proteins implicated in multiple biological processes including proteolysis, cell adhesion, cell fusion, cell proliferation and cell migration. Of these varied activities, the best studied is their role in proteolysis. However, of the 22 ADAMs believed to be functional in humans, only approximately a half possess matrix metalloproteinase (MMP)-like protease activity. In contrast to MMPs which are mostly implicated in the degradation of extracellular matrix proteins, the main ADAM substrates are the ectodomains of type I and type II transmembrane proteins. These include growth factor/cytokine precursors, growth factor/cytokine receptors and adhesion proteins. Recently, several different ADAMs, especially ADAM17, have been shown to play a role in the development and progression of multiple cancer types. Consistent with this role in cancer, targeting ADAM17 with either low molecular weight inhibitors or monoclonal antibodies was shown to have anti-cancer activity in multiple preclinical systems. Although early phase clinical trials have shown no serious side effects with a dual ADAM10/17 low molecular weight inhibitor, the consequences of long-term treatment with these agents is unknown. Furthermore, efficacy in clinical trials remains to be shown.

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

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

    2010-01-01

    activity may be of great value therapeutically and as an investigative tool to elucidate its mechanisms of action. We have previously reported the inhibitory profile of TIMPs (tissue inhibitor of metalloproteinases) against ADAM12, demonstrating in addition to TIMP-3, a unique ADAM-inhibitory activity...... activity of TIMPs against the transmembrane ADAM12-L (full-length ADAM12), verifying the distinctive inhibitory abilities of N-TIMP-2 and engineered N-TIMP-2 mutants in a cellular environment. Taken together, our findings support the idea that a distinctive ADAM12 inhibitor with future therapeutic...

  7. Biochemical, inhibition and inhibitor resistance studies of xenotropic murine leukemia virus-related virus reverse transcriptase.

    Ndongwe, Tanyaradzwa P; Adedeji, Adeyemi O; Michailidis, Eleftherios; Ong, Yee Tsuey; Hachiya, Atsuko; Marchand, Bruno; Ryan, Emily M; Rai, Devendra K; Kirby, Karen A; Whatley, Angela S; Burke, Donald H; Johnson, Marc; Ding, Shilei; Zheng, Yi-Min; Liu, Shan-Lu; Kodama, Ei-Ichi; Delviks-Frankenberry, Krista A; Pathak, Vinay K; Mitsuya, Hiroaki; Parniak, Michael A; Singh, Kamalendra; Sarafianos, Stefan G

    2012-01-01

    We report key mechanistic differences between the reverse transcriptases (RT) of human immunodeficiency virus type-1 (HIV-1) and of xenotropic murine leukemia virus-related virus (XMRV), a gammaretrovirus that can infect human cells. Steady and pre-steady state kinetics demonstrated that XMRV RT is significantly less efficient in DNA synthesis and in unblocking chain-terminated primers. Surface plasmon resonance experiments showed that the gammaretroviral enzyme has a remarkably higher dissociation rate (k(off)) from DNA, which also results in lower processivity than HIV-1 RT. Transient kinetics of mismatch incorporation revealed that XMRV RT has higher fidelity than HIV-1 RT. We identified RNA aptamers that potently inhibit XMRV, but not HIV-1 RT. XMRV RT is highly susceptible to some nucleoside RT inhibitors, including Translocation Deficient RT inhibitors, but not to non-nucleoside RT inhibitors. We demonstrated that XMRV RT mutants K103R and Q190M, which are equivalent to HIV-1 mutants that are resistant to tenofovir (K65R) and AZT (Q151M), are also resistant to the respective drugs, suggesting that XMRV can acquire resistance to these compounds through the decreased incorporation mechanism reported in HIV-1.

  8. Recombinant disintegrin domain of ADAM15 inhibits the proliferation and migration of Bel-7402 cells

    Hou, Y. [Key Laboratory of Industrial Biotechnology, Ministry of Education, School of Pharmaceutical Sciences, Jiangnan University, 1800 Lihu Rd., Wuxi, Jiangsu 214122 (China); Chu, M. [Key Laboratory of Industrial Biotechnology, Ministry of Education, School of Medicine, Jiangnan University, 1800 Lihu Rd., Wuxi, Jiangsu 214122 (China); Du, F.F.; Lei, J.Y.; Chen, Y.; Zhu, R.Y.; Gong, X.H.; Ma, X. [Key Laboratory of Industrial Biotechnology, Ministry of Education, School of Pharmaceutical Sciences, Jiangnan University, 1800 Lihu Rd., Wuxi, Jiangsu 214122 (China); Jin, J., E-mail: jinjian31@126.com [Key Laboratory of Industrial Biotechnology, Ministry of Education, School of Pharmaceutical Sciences, Jiangnan University, 1800 Lihu Rd., Wuxi, Jiangsu 214122 (China)

    2013-06-14

    Highlights: •rhddADAM15 inhibited the proliferation and migration of Bel-7402 cells. •rhddADAM15 inhibited growth and metastasis of Bel-7402 cells in zebrafish xenograft. •rhddADAM15 induced apoptosis in Bel-7402 cells and somatic cells of zebrafish. •Cell-cycle in Bel-7402 cells showed a partial G{sub 2}/S arrest. •Activity of caspases 8, 9 and 3 was increased in rhddADAM15-treated Bel-7402 cells. -- Abstract: ADAM15 (A Disintegrin And Metalloproteinase 15), a transmembrane protein containing seven domains, interacts with some integrins via its disintegrin domain and overexpresses in many solid tumors. In this study, the effect of the recombinant human disintegrin domain (rhddADAM15) on the proliferation and migration of Bel-7402 cells was evaluated in vitro and in vivo in zebrafish xenografts. rhddADAM15 (4 μM) severely inhibited the proliferation and migration of Bel-7402 cells, inducing a partial G{sub 2}/S arrest and morphological nucleus changes of apoptosis. Moreover, the activity of caspases 8, 9 and 3 in Bel-7402 cells was increased. In addition, the zebrafish was used as a model for apoptosis-induction and tumor-xenograft. rhddADAM15 (1 pM) inhibited the growth and metastasis of Bel-7402 cell xenografts in zebrafish and a lower concentration (0.1 pM) induced severe apoptosis in the somatic cells of zebrafish. In conclusion, our data identified rhddADAM15 as a potent inhibitor of tumor growth and metastasis, making it a promising tool for use in anticancer treatment.

  9. Apparent reduction of ADAM10 in scrapie-infected cultured cells and in the brains of scrapie-infected rodents.

    Chen, Cao; Lv, Yan; Zhang, Bao-Yun; Zhang, Jin; Shi, Qi; Wang, Jing; Tian, Chan; Gao, Chen; Xiao, Kang; Ren, Ke; Zhou, Wei; Dong, Xiao-Ping

    2014-12-01

    It has been described that A disintegrin and metalloproteinase (ADAM10) may involve in the physiopathology of prion diseases, but the direct molecular basis still remains unsolved. In this study, we confirmed that ADAM10 was able to cleave recombinant human prion protein in vitro. Using immunoprecipitation tests (IP) and immunofluorescent assays (IFA), reliable molecular interaction between the native cellular form of PrP (PrP(C)) and ADAM10 was observed not only in various cultured neuronal cell lines but also in brain homogenates of healthy hamsters and mice. Only mature ADAM10 (after removal of its prodomain) molecules showed the binding activity with the native PrP(C). Remarkably more prion protein (PrP)-ADAM10 complexes were detected in the membrane fraction of cultured cells. In the scrapie-infected SMB cell model, the endogenous ADAM10 levels, especially the mature ADAM10, were significantly decreased in the fraction of cell membrane. IP and IFA tests of prion-infected SMB-S15 cells confirmed no detectable PrP-ADAM10 complex in the cellular lysates and PrP-ADAM10 co-localization on the cell surface. Furthermore, we demonstrated that the levels of ADAM10 in the brain homogenates of scrapie agent 263K-infected hamsters and agent ME7-infected mice were also almost diminished at the terminal stage, showing time-dependent decreases during the incubation period. Our data here provide the solid molecular basis for the endoproteolysis of ADAM10 on PrP molecules and interaction between ADAM10 and PrP(C). Obvious loss of ADAM10 during prion infection in vitro and in vivo highlights that ADAM10 may play essential pathophysiological roles in prion replication and accumulation.

  10. Studying On The Emulate of Servo in NC Based On ADAMS/MATLAB%数控伺服系统的ADAMS/MATLAB联合仿真研究

    邢伟; 周西军

    2007-01-01

    将机械系统仿真分析工具同控制系统设计仿真软件有机地连接起来,利用ADAMS/Controls模块对数控机床X-Y工作平台的进给机械系统进行了建模、通过ADAMS/View或ADAMS/Solver中的信息文件或启动文件,确定ADAMS的输入和输出,通过定义输入和输出,实现了ADAMS和MATLAB控制程序之间的闭环通信,最终实现了复杂机电系统联合仿真.

  11. ADAM 10 expression in primary uveal melanoma as prognostic factor for risk of metastasis.

    Caltabiano, Rosario; Puzzo, Lidia; Barresi, Valeria; Ieni, Antonio; Loreto, Carla; Musumeci, Giuseppe; Castrogiovanni, Paola; Ragusa, Marco; Foti, Pietro; Russo, Andrea; Longo, Antonio; Reibaldi, Michele

    2016-11-01

    Uveal melanoma is the most frequent primary intraocular neoplasm in adults. Although malignant melanoma may be located at any point in the uveal tract, the choroid and ciliary body are more frequent locations than the iris. In the present study, we examined ADAM10 expression levels in primary uveal melanoma both with and without metastasis, and we evaluated their association with other high risk characteristics for metastasis in order to assess if ADAM10 can be used to predict metastasis. This study included a total of 52 patients, 23 men and 29 women, with uveal melanoma. A significantly high expression of ADAM-10 was seen in patients with metastasis (11/13, 84.6%), but not in patients without metastasis (15/39, 38.5%). In conclusion we found that ADAM10 expression was associated with a more rapid metastatic progression confirming its role in uveal melanoma metastasis.

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

    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

  13. 76 FR 45600 - Columbia National Wildlife Refuge, Adams and Grant Counties, WA; Draft Comprehensive Conservation...

    2011-07-29

    ... Fish and Wildlife Service Columbia National Wildlife Refuge, Adams and Grant Counties, WA; Draft Comprehensive Conservation Plan and Environmental Assessment AGENCY: Fish and Wildlife Service, Interior. ACTION... wildlife management, conservation, legal mandates, and our policies. In addition to outlining...

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

    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.

  15. The reverse transcription inhibitor abacavir shows anticancer activity in prostate cancer cell lines.

    Francesca Carlini

    Full Text Available BACKGROUND: Transposable Elements (TEs comprise nearly 45% of the entire genome and are part of sophisticated regulatory network systems that control developmental processes in normal and pathological conditions. The retroviral/retrotransposon gene machinery consists mainly of Long Interspersed Nuclear Elements (LINEs-1 and Human Endogenous Retroviruses (HERVs that code for their own endogenous reverse transcriptase (RT. Interestingly, RT is typically expressed at high levels in cancer cells. Recent studies report that RT inhibition by non-nucleoside reverse transcriptase inhibitors (NNRTIs induces growth arrest and cell differentiation in vitro and antagonizes growth of human tumors in animal model. In the present study we analyze the anticancer activity of Abacavir (ABC, a nucleoside reverse transcription inhibitor (NRTI, on PC3 and LNCaP prostate cancer cell lines. PRINCIPAL FINDINGS: ABC significantly reduces cell growth, migration and invasion processes, considerably slows S phase progression, induces senescence and cell death in prostate cancer cells. Consistent with these observations, microarray analysis on PC3 cells shows that ABC induces specific and dose-dependent changes in gene expression, involving multiple cellular pathways. Notably, by quantitative Real-Time PCR we found that LINE-1 ORF1 and ORF2 mRNA levels were significantly up-regulated by ABC treatment. CONCLUSIONS: Our results demonstrate the potential of ABC as anticancer agent able to induce antiproliferative activity and trigger senescence in prostate cancer cells. Noteworthy, we show that ABC elicits up-regulation of LINE-1 expression, suggesting the involvement of these elements in the observed cellular modifications.

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

    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 ...

  17. Insiden Hiperbilirubimenia Pada Bayi Aterm Di RSUP Haji Adam Malik Medan Pada Tahun 2014

    Ramarow, Nithya

    2016-01-01

    Hyperbilirubinemia in neonates that increased levels of bilirubin in the blood of the baby's body. The medical records at RSUP Haji Adam Malik Medan shows 69 babies diagnosed from hyperbilirubinemia. Majority babies with low birth weight suffering from hyperbilirubinemia. The study is focused on the spectrum incidence of occurrence hyperbilirubinemia in newborn babies at RSUP Haji Adam Malik Medan 2014. The study design used is descriptive statistic. The sample has been taken b...

  18. Engineering of Specific Tissue Inhibitors to Block ADAM Type Metalloprotease-Mediated Mammary Neoplasia

    2001-07-01

    ADAM9 cleaves the HB- EGF when PKCd is activated, but neither the wildtype, nor the dominant-negative ADAM9, affects the EGFR transactivation (Izumi et...S. V. Subramanian, M. L. Fitzgerald, M. Bernfield, J. Bi- that accounts for these observations re- not other TIMPs, induce apoptosis (19). e!. Chem...12. D. Pan and G. M. Rubin, Cell90, 271 (1997). fy the cytoplasmic domains of the pro- and induces apoptosis by binding to the Fas 13. C. Cho et a

  19. Simulation of Air Suspension and Full-vehicle with MSC Adams/Car%基于MSC Adams/Car的空气悬架及整车仿真

    王登峰; 郎锡泽; 马天飞

    2006-01-01

    利用MSC Adams/Car软件建立载货汽车后空气悬架系统多体动力学模型,仿真计算了悬架垂直刚度特性,证明模型的正确性. 建立Adams/Car的整车模型,进行稳态回转试验的仿真分析. 将仿真结果与道路试验结果进行比较,验证虚拟样机模型的正确性.

  20. Flammable Gas Alarm System Based on ADAM-6017%基于ADAM-6017的可燃气体报警系统

    王卫华; 赵庆云; 靳建水; 赵继安; 韩国栋

    2012-01-01

    利用智能型以太网I/O ADAM-6017的特性,以分布式控制方式构建某化工厂碳酸酯类等可燃气体报警系统,给出了系统的硬件架构和软件流程及其组态方式.%Basing on Ethernet I/O ADAM-6017 and distributed control mode, the flammable gas alarm system for carbonates in a chemical plant was proposed, including its hardware and software configuration and programming process.

  1. All-trans-retinoic acid induces integrin-independent B-cell adhesion to ADAM disintegrin domains.

    Bridges, Lance C; Lingo, Joshuah D; Grandon, Rachel A; Kelley, Melissa D

    2008-04-15

    Cell adhesion is an integral aspect of immunity facilitating extravasation of immune cells during homing and activation. All -trans-Retinoic acid ( t-RA) regulates leukocyte differentiation, proliferation, and transmigration. However, the role of t-RA in immune cell adhesion is poorly defined. In this study, we evaluated the impact of t-RA and its metabolism on B and T cell adhesion. Specifically, we address the impact of t-RA on the adhesive properties of the human mature B and T cell lines RPMI 8866, Daudi and Jurkats. The effect of t-RA exposure on cell adhesion to vascular cell adhesion molecule-1 (VCAM-1), a well-established integrin counter receptor involved in immunity, and to nonconventional ADAM integrin ligands was assessed. We show for the first time that t-RA potently induces B cell adhesion in an integrin-independent manner to both VCAM-1 and select ADAM disintegrin domains. Using retinoid extraction and reverse-phase HPLC analysis, we identify the retinoid that is functionally responsible for this augmented adhesion. We also provide evidence that this novel t-RA adhesive response is not prototypical of lymphocytes since both Daudi and Jurkats do not alter their adhesive properties upon t-RA treatment. Further, the t-RA metabolic profiles between these lineages is distinct with 9- cis-retinoic acid being exclusively detected in Jurkat media. This study is the first to demonstrate that t-RA directly induces B cell adhesion in an integrin-independent manner and is not contingent upon t-RA metabolism.

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

    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.

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

    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.

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

    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.

  5. ADAM SMITH: LA MANO INVISIBLE O LA CONFIANZA

    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.

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

    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.

  7. Adam Smith om forholdet mellem moralske fornemmelser og naturen

    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...

  8. Reversible Statistics

    Tryggestad, Kjell

    2004-01-01

    The study aims is to describe how the inclusion and exclusion of materials and calculative devices construct the boundaries and distinctions between statistical facts and artifacts in economics. My methodological approach is inspired by John Graunt's (1667) Political arithmetic and more recent work...... within constructivism and the field of Science and Technology Studies (STS). The result of this approach is here termed reversible statistics, reconstructing the findings of a statistical study within economics in three different ways. It is argued that all three accounts are quite normal, albeit...... in different ways. The presence and absence of diverse materials, both natural and political, is what distinguishes them from each other. Arguments are presented for a more symmetric relation between the scientific statistical text and the reader. I will argue that a more symmetric relation can be achieved...

  9. In vitro and ex vivo inhibition of human telomerase by anti-HIV nucleoside reverse transcriptase inhibitors (NRTIs but not by non-NRTIs.

    Kyle R Hukezalie

    Full Text Available Telomerase is a specialized reverse transcriptase responsible for the de novo synthesis of telomeric DNA repeats. In addition to its established reverse transcriptase and terminal transferase activities, recent reports have revealed unexpected cellular activities of telomerase, including RNA-dependent RNA polymerization. This telomerase characteristic, distinct from other reverse transcriptases, indicates that clinically relevant reverse transcriptase inhibitors might have unexpected telomerase inhibition profiles. This is particularly important for the newer generation of RT inhibitors designed for anti-HIV therapy, which have reported higher safety margins than older agents. Using an in vitro primer extension assay, we tested the effects of clinically relevant HIV reverse transcriptase inhibitors on cellular telomerase activity. We observed that all commonly used nucleoside reverse transcriptase inhibitors (NRTIs, including zidovudine, stavudine, tenofovir, didanosine and abacavir, inhibit telomerase effectively in vitro. Truncated telomere synthesis was consistent with the expected mode of inhibition by all tested NRTIs. Through dose-response experiments, we established relative inhibitory potencies of NRTIs on in vitro telomerase activity as compared to the inhibitory potencies of the corresponding dideoxynucleotide triphosphates. In contrast to NRTIs, the non-nucleoside reverse transcriptase inhibitors (NNRTIs nevirapine and efavirenz did not inhibit the primer extension activity of telomerase, even at millimolar concentrations. Long-term, continuous treatment of human HT29 cells with select NRTIs resulted in an accelerated loss of telomere repeats. All tested NRTIs exhibited the same rank order of inhibitory potencies on telomerase and HIV RT, which, according to published data, were orders-of-magnitude more sensitive than other DNA polymerases, including the susceptible mitochondria-specific DNA polymerase gamma. We concluded that

  10. The disintegrin/metalloprotease ADAM 10 is essential for Notch signalling but not for alpha-secretase activity in fibroblasts.

    Hartmann, Dieter; de Strooper, Bart; Serneels, Lutgarde; Craessaerts, Katleen; Herreman, An; Annaert, Wim; Umans, Lieve; Lübke, Torben; Lena Illert, Anna; von Figura, Kurt; Saftig, Paul

    2002-10-01

    The metalloprotease ADAM 10 is an important APP alpha-secretase candidate, but in vivo proof of this is lacking. Furthermore, invertebrate models point towards a key role of the ADAM 10 orthologues Kuzbanian and sup-17 in Notch signalling. In the mouse, this function is, however, currently attributed to ADAM 17/TACE, while the role of ADAM 10 remains unknown. We have created ADAM 10-deficient mice. They die at day 9.5 of embryogenesis with multiple defects of the developing central nervous system, somites, and cardiovascular system. In situ hybridization revealed a reduced expression of the Notch target gene hes-5 in the neural tube and an increased expression of the Notch ligand dll-1, supporting an important role for ADAM 10 in Notch signalling in the vertebrates as well. Since the early lethality precluded the establishment of primary neuronal cultures, APPs alpha generation was analyzed in embryonic fibroblasts and found to be preserved in 15 out of 17 independently generated ADAM 10-deficient fibroblast cell lines, albeit at a quantitatively more variable level than in controls, whereas a severe reduction was found in only two cases. The variability was not due to differences in genetic background or to variable expression of the alternative alpha-secretase candidates ADAM 9 and ADAM 17. These results indicate, therefore, either a regulation between ADAMs on the post-translational level or that other, not yet known, proteases are able to compensate for ADAM 10 deficiency. Thus, the observed variability, together with recent reports on tissue-specific expression patterns of ADAMs 9, 10 and 17, points to the existence of tissue-specific 'teams' of different proteases exerting alpha-secretase activity.

  11. 2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine (ADAM): an improved serotonin transporter ligand

    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.

  12. Monocyte ADAM17 promotes diapedesis during transendothelial migration: identification of steps and substrates targeted by metalloproteinases.

    Tsubota, Yoshiaki; Frey, Jeremy M; Tai, Phillip W L; Welikson, Robert E; Raines, Elaine W

    2013-04-15

    Despite expanded definition of the leukocyte adhesion cascade and mechanisms underlying individual steps, very little is known about regulatory mechanisms controlling sequential shifts between steps. We tested the hypothesis that metalloproteinases provide a mechanism to rapidly transition monocytes between different steps. Our study identifies diapedesis as a step targeted by metalloproteinase activity. Time-lapse video microscopy shows that the presence of a metalloproteinase inhibitor results in a doubling of the time required for human monocytes to complete diapedesis on unactivated or inflamed human endothelium, under both static and physiological-flow conditions. Thus, diapedesis is promoted by metalloproteinase activity. In contrast, neither adhesion of monocytes nor their locomotion over the endothelium is altered by metalloproteinase inhibition. We further demonstrate that metalloproteinase inhibition significantly elevates monocyte cell surface levels of integrins CD11b/CD18 (Mac-1), specifically during transendothelial migration. Interestingly, such alterations are not detected for other endothelial- and monocyte-adhesion molecules that are presumed metalloproteinase substrates. Two major transmembrane metalloproteinases, a disintegrin and metalloproteinase (ADAM)17 and ADAM10, are identified as enzymes that control constitutive cleavage of Mac-1. We further establish that knockdown of monocyte ADAM17, but not endothelial ADAM10 or ADAM17 or monocyte ADAM10, reproduces the diapedesis delay observed with metalloproteinase inhibition. Therefore, we conclude that monocyte ADAM17 facilitates the completion of transendothelial migration by accelerating the rate of diapedesis. We propose that the progression of diapedesis may be regulated by spatial and temporal cleavage of Mac-1, which is triggered upon interaction with endothelium.

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

    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)

  14. Analysis of mixed model in gear transmission based on ADAMS

    Li, Xiufeng; Wang, Yabin

    2012-09-01

    The traditional method of mechanical gear driving simulation includes gear pair method and solid to solid contact method. The former has higher solving efficiency but lower results accuracy; the latter usually obtains higher precision of results while the calculation process is complex, also it is not easy to converge. Currently, most of the researches are focused on the description of geometric models and the definition of boundary conditions. However, none of them can solve the problems fundamentally. To improve the simulation efficiency while ensure the results with high accuracy, a mixed model method which uses gear tooth profiles to take the place of the solid gear to simulate gear movement is presented under these circumstances. In the process of modeling, build the solid models of the mechanism in the SolidWorks firstly; Then collect the point coordinates of outline curves of the gear using SolidWorks API and create fit curves in Adams based on the point coordinates; Next, adjust the position of those fitting curves according to the position of the contact area; Finally, define the loading conditions, boundary conditions and simulation parameters. The method provides gear shape information by tooth profile curves; simulates the mesh process through tooth profile curve to curve contact and offer mass as well as inertia data via solid gear models. This simulation process combines the two models to complete the gear driving analysis. In order to verify the validity of the method presented, both theoretical derivation and numerical simulation on a runaway escapement are conducted. The results show that the computational efficiency of the mixed model method is 1.4 times over the traditional method which contains solid to solid contact. Meanwhile, the simulation results are more closely to theoretical calculations. Consequently, mixed model method has a high application value regarding to the study of the dynamics of gear mechanism.

  15. Unsaturated Fatty Acids Drive Disintegrin and Metalloproteinase (ADAM)-dependent Cell Adhesion, Proliferation, and Migration by Modulating Membrane Fluidity*

    Reiss, Karina; Cornelsen, Isabell; Husmann, Matthias; Gimpl, Gerald; Bhakdi, Sucharit

    2011-01-01

    The disintegrin-metalloproteinases ADAM10 and ADAM17 mediate the release of several cell signaling molecules and cell adhesion molecules such as vascular endothelial cadherin or L-selectin affecting endothelial permeability and leukocyte transmigration. Dysregulation of ADAM activity may contribute to the pathogenesis of vascular diseases, but the mechanisms underlying the control of ADAM functions are still incompletely understood. Atherosclerosis is characterized by lipid plaque formation and local accumulation of unsaturated free fatty acids (FFA). Here, we show that unsaturated FFA increase ADAM-mediated substrate cleavage. We demonstrate that these alterations are not due to genuine changes in enzyme activity, but correlate with changes in membrane fluidity as revealed by measurement of 1,6-diphenyl-1,3,5-hexatriene fluorescence anisotropy and fluorescence recovery after photobleaching analyses. ELISA and immunoblot experiments conducted with granulocytes, endothelial cells, and keratinocytes revealed rapid increase of ectodomain shedding of ADAM10 and ADAM17 substrates upon membrane fluidization. Large amounts of unsaturated FFA may be liberated from cholesteryl esters in LDL that is entrapped in atherosclerotic lesions. Incubation of cells with thus modified LDL resulted in rapid cleavage of ADAM substrates with corresponding functional consequences on cell proliferation, cell migration, and endothelial permeability, events of high significance in atherogenesis. We propose that FFA represent critical regulators of ADAM function that may assume relevance in many biological settings through their influence on mobility of enzyme and substrate in lipid bilayers. PMID:21642425

  16. Unsaturated fatty acids drive disintegrin and metalloproteinase (ADAM)-dependent cell adhesion, proliferation, and migration by modulating membrane fluidity.

    Reiss, Karina; Cornelsen, Isabell; Husmann, Matthias; Gimpl, Gerald; Bhakdi, Sucharit

    2011-07-29

    The disintegrin-metalloproteinases ADAM10 and ADAM17 mediate the release of several cell signaling molecules and cell adhesion molecules such as vascular endothelial cadherin or L-selectin affecting endothelial permeability and leukocyte transmigration. Dysregulation of ADAM activity may contribute to the pathogenesis of vascular diseases, but the mechanisms underlying the control of ADAM functions are still incompletely understood. Atherosclerosis is characterized by lipid plaque formation and local accumulation of unsaturated free fatty acids (FFA). Here, we show that unsaturated FFA increase ADAM-mediated substrate cleavage. We demonstrate that these alterations are not due to genuine changes in enzyme activity, but correlate with changes in membrane fluidity as revealed by measurement of 1,6-diphenyl-1,3,5-hexatriene fluorescence anisotropy and fluorescence recovery after photobleaching analyses. ELISA and immunoblot experiments conducted with granulocytes, endothelial cells, and keratinocytes revealed rapid increase of ectodomain shedding of ADAM10 and ADAM17 substrates upon membrane fluidization. Large amounts of unsaturated FFA may be liberated from cholesteryl esters in LDL that is entrapped in atherosclerotic lesions. Incubation of cells with thus modified LDL resulted in rapid cleavage of ADAM substrates with corresponding functional consequences on cell proliferation, cell migration, and endothelial permeability, events of high significance in atherogenesis. We propose that FFA represent critical regulators of ADAM function that may assume relevance in many biological settings through their influence on mobility of enzyme and substrate in lipid bilayers.

  17. Conformational Plasticity of the NNRTI-Binding Pocket in HIV-1 Reverse Transcriptase: A Fluorine Nuclear Magnetic Resonance Study.

    Sharaf, Naima G; Ishima, Rieko; Gronenborn, Angela M

    2016-07-19

    HIV-1 reverse transcriptase (RT) is a major drug target in the treatment of HIV-1 infection. RT inhibitors currently in use include non-nucleoside, allosteric RT inhibitors (NNRTIs), which bind to a hydrophobic pocket, distinct from the enzyme's active site. We investigated RT-NNRTI interactions by solution (19)F nuclear magnetic resonance (NMR), using singly (19)F-labeled RT proteins. Comparison of (19)F chemical shifts of fluorinated RT and drug-resistant variants revealed that the fluorine resonance is a sensitive probe for identifying mutation-induced changes in the enzyme. Our data show that in the unliganded enzyme, the NNRTI-binding pocket is highly plastic and not locked into a single conformation. Upon inhibitor binding, the binding pocket becomes rigidified. In the inhibitor-bound state, the (19)F signal of RT is similar to that of drug-resistant mutant enzymes, distinct from what is observed for the free state. Our results demonstrate the power of (19)F NMR spectroscopy to characterize conformational properties using selectively (19)F-labeled protein.

  18. Regulated ADAM17-dependent EGF family ligand release by substrate-selecting signaling pathways.

    Dang, Michelle; Armbruster, Nicole; Miller, Miles A; Cermeno, Efrain; Hartmann, Monika; Bell, George W; Root, David E; Lauffenburger, Douglas A; Lodish, Harvey F; Herrlich, Andreas

    2013-06-11

    Ectodomain cleavage of cell-surface proteins by A disintegrin and metalloproteinases (ADAMs) is highly regulated, and its dysregulation has been linked to many diseases. ADAM10 and ADAM17 cleave most disease-relevant substrates. Broad-spectrum metalloprotease inhibitors have failed clinically, and targeting the cleavage of a specific substrate has remained impossible. It is therefore necessary to identify signaling intermediates that determine substrate specificity of cleavage. We show here that phorbol ester or angiotensin II-induced proteolytic release of EGF family members may not require a significant increase in ADAM17 protease activity. Rather, inducers activate a signaling pathway using PKC-α and the PKC-regulated protein phosphatase 1 inhibitor 14D that is required for ADAM17 cleavage of TGF-α, heparin-binding EGF, and amphiregulin. A second pathway involving PKC-δ is required for neuregulin (NRG) cleavage, and, indeed, PKC-δ phosphorylation of serine 286 in the NRG cytosolic domain is essential for induced NRG cleavage. Thus, signaling-mediated substrate selection is clearly distinct from regulation of enzyme activity, an important mechanism that offers itself for application in disease.

  19. Adam33 polymorphisms are associated with COPD and lung function in long-term tobacco smokers

    Meyers Deborah A

    2009-03-01

    Full Text Available Abstract Background Variation in ADAM33 has been shown to be important in the development of asthma and altered lung function. This relationship however, has not been investigated in the population susceptible to COPD; long term tobacco smokers. We evaluated the association between polymorphisms in ADAM33 gene with COPD and lung function in long term tobacco smokers. Methods Caucasian subjects, at least 50 year old, who smoked ≥ 20 pack-years (n = 880 were genotyped for 25 single nucleotide polymorphisms (SNPs in ADAM33. COPD was defined as an FEV1/FVC ratio 1 ≥ 80% (n = 311 despite ≥ 20 pack years of smoking. Logistic and linear regressions were used for the analysis. Age, sex, and smoking status were considered as potential confounders. Results Five SNPs in ADAM33 were associated with COPD (Q-1, intronic: p Conclusion Five SNPs in ADAM33 were associated with COPD and lung function in long-term smokers. Functional studies will be needed to evaluate the biologic significance of these polymorphisms in the pathogenesis of COPD.

  20. Reversal of HIV drug resistance and novel strategies to curb HIV infection: the viral infectivity factor Vif as a target and tool of therapy.

    Mezei, M; Minarovits, J

    2006-07-01

    Due to the high genetic variability of human immunodeficiency virus (HIV), treatment of AIDS (acquired immunodeficiency syndrome) patients with inhibitors of reverse trancriptase (RT) and drugs blocking the viral protease regularly results in the accumulation of drug resistant HIV variants and treatment failure. The sensitivity of clinically derived resistant HIV-1 strains to nucleotide RT inhibitors could be restored, however, in several laboratories by pharmacological depletion of the appropriate endogenous deoxynucleotide triphosphate (dNTP), and such a manipulation (induction of dCTP pool imbalance during reverse transcription in the presence of a non-nucleoside RT inhibitor) altered the mutation spectrum of the HIV-1 genome, resulting in a lower level of HIV resistance to certain drugs. The cytoplasmic single-stranded DNA cytidine deaminases APOBEC3G and APOBEC3F block HIV replication by introducing premature stop codons into the viral genome. We suggest that the resulting crippled, defective HIV (dHIV) variants could interfere with replication of "wild type" viruses and curbe disese progression in long term non-progressor individuals. Vif, an accessory protein encoded by HIV, counteracts APOBEC3G/F action. We speculate that small molecule inhibitors of Vif could permit lethal or sublethal mutagenesis of HIV genomes. We suggest that an artificial dHIV construct carrying a mutated vif gene (coding for a Vif protein unable to block APOBEC3G/F) could have a therapeutic effect as well in HIV infected individuals and AIDS patients.

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

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

    2002-01-01

    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......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......, as 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....

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

    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.

  3. PENETAPAN ‘ADAM WALI NIKAH OLEH PEJABAT KUA DI KOTA SEMARANG

    Rokhmadi

    2016-10-01

    Full Text Available This article is result of the study that describes the determination concept of adam wali nikah by officials of the Religious Affairs Office (KUA in Semarang, on marriage guardian of an ineligible woman, that because of the bride’s birth is less than six months from her parents’ marriage. Having determined adam marriage guardians’ status, then KUA establishes that the marriage guardian is delegated to KUA officials in each region of Semarang. As for the basis used by those who determine the delegation for the reason of deficient condition of marriage guardians for a female to the KUA is the use of the legal basis contained in adam marriage guardians’ determination in the letter of Director General Guidance and Pilgrimage Affairs Number: D/ED/PW.01/03/1992, in which its position is under the Marriage Legislation No. 1 of 1974 and the Islamic Law Compilation (KHI.

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

    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.

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

    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 play an important role in wound healing, including heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) and insulin growth factor (IGF) binding proteins. Here, we report that expression of ADAM12 is fivefold upregulated in the nonhealing edge of chronic ulcers compared to healthy...... skin, based on microarrays of biopsies taken from five patients and from healthy controls (p = 0.013). The increase in ADAM12 expression in chronic ulcers was confirmed by quantitative real-time polymerase chain reaction (RT-PCR). Moreover, immunohistochemical analysis demonstrated a pronounced...

  6. Lytle S. Adams, DDS (1883-1970): Nonstop Airmail Pick-up inventor.

    Christen, Arden G; Christen, Joan A

    2005-11-01

    Between 1923 and 1940, a restless, optimistic, self-styled, inventor, Lytle S. Adams, DDS (1883-1970) was tirelessly working to develop a nonstop, airmail delivery and pick-up system. He believed that his invention would enable air postal services to serve those smaller, more isolated communities that would otherwise be bypassed due to economic and operational reasons. For 17 years, Adams vigorously promoted his pick-up system in both public and private arenas, and he even obtained congressional support for his ideas. However, he was unable to arrange for long-term, hardheaded financial and engineering support. Consequently, the once promising Adams Nonstop Airmail Pick-up System had only temporary and limited success. His endeavor, like others which came before and after, initially appeared to be a sound idea in search of inspired realization.

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

    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.

  8. El sujeto económico y la racionalidad en Adam Smith

    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.

  9. Adam Smith and Liberal Economics: Reading the Minimum Wage Debate of 1795-96

    Christopher Martin

    2011-01-01

    Adam Smith’s outlook still inspires and informs modern sensibilities and argumentation. It is of interest beyond Smith aficionados whether a particular line of modern thought “fits” Smith. One important such dispute involves recent “left Smithian” writers who argue that he was more open to government intervention—especially on behalf of the poor—than had previously been believed. Perhaps the best short statement of this view is Emma Rothschild’s 1992 essay “Adam Smith and Conservative Economi...

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

    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.

  11. 集散式I/O控制系统ADAM-8000系列

    叶丹

    2003-01-01

    @@集散式I/O控制系统ADAM-8000系列是研华科技为增强ADAM产品在控制领域的应用而特别推出的,ADAM-8000系列产品定位于I/O控制系统,可以更好地满足离散、稳定、可靠以及强大功能的需求。随着ADAM-8000系列的问市,研华……

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

    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

  13. Identification of SH3 domain proteins interacting with the cytoplasmic tail of the a disintegrin and metalloprotease 10 (ADAM10.

    Henriette Ebsen

    Full Text Available The a disintegrin and metalloproteases (ADAMs play a pivotal role in the control of development, adhesion, migration, inflammation and cancer. Although numerous substrates of ADAM10 have been identified, the regulation of its surface expression and proteolytic activity is still poorly defined. One current hypothesis is that both processes are in part modulated by protein-protein interactions mediated by the intracellular portion of the protease. For related proteases, especially proline-rich regions serving as docking sites for Src homology domain 3 (SH3 domain-containing proteins proved to be important for mediating regulatory interactions. In order to identify ADAM10-binding SH3 domain proteins, we screened the All SH3 Domain Phager library comprising 305 human SH3 domains using a GST fusion protein with the intracellular region of human ADAM10 as a bait for selection. Of a total of 291 analyzed phage clones, we found 38 SH3 domains that were precipitated with the ADAM10-derived fusion protein but not with GST. We verified the binding to the cytosolic portion of ADAM10 for several candidates by co-immunoprecipitation and/or pull down analyses. Intriguingly, several of the identified proteins have been implicated in regulating surface appearance and/or proteolytic activity of related ADAMs. Thus, it seems likely that they also play a role in ADAM10 biology.

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

    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...

  15. A Reader Response to File and Adams's "The Reality, Robustness, and Possible Superiority of Incidental Vocabulary Acquisition"

    Mason, Beniko; Krashen, Stephen

    2010-01-01

    File and Adams (2010) conclude that their data confirm the superiority of form-focused vocabulary instruction over incidental acquisition. The authors of this response argue that File and Adams's data actually confirm the reality, robustness, and possible superiority of incidental acquisition. Their subjects heard two passages read to them that…

  16. ADAM10 mediates the house dust mite-induced release of chemokine ligand CCL20 by airway epithelium

    Post, S.; Rozeveld, D.; Jonker, M. R.; Bischoff, R.; van Oosterhout, A. J.; Heijink, I. H.

    2015-01-01

    Background: House dust mite (HDM) acts on the airway epithelium to induce airway inflammation in asthma. We previously showed that the ability of HDM to induce allergic sensitization in mice is related to airway epithelial CCL20 secretion. Objective: As a disintegrin and metalloprotease (ADAM)s have

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

    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-PC...

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

    Wewer, Ulla M; Mörgelin, Matthias; Holck, Peter

    2006-01-01

    and 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...

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

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

    2013-01-01

    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...

  20. Modeling and optimization of Macpherson suspension based on ADAMS/CAR%ADAMS/CAR环境下的麦弗逊悬架建模与优化

    石柏军; 朱新涛

    2008-01-01

    为更好地改善麦弗逊独立悬架的性能,在ADAMS/CAR中建立了仿真模型,对影响车辆操稳性的特性参数在汽车行驶中的变化进行了仿真分析,并在ADAMS/Insight模块中对这些参数做出了优化.结果表明,在ADAMS中,通过优化悬架关键硬点坐标参数值可以提高悬架性能,从而为麦弗逊独立悬架的设计和制造提供理论依据.

  1. The level of ADAM12-S in maternal serum is an early first-trimester marker of fetal trisomy 18

    Laigaard, Jennie; Christiansen, Michael; Frohlich, Camilla

    2005-01-01

    (DS) fetus. On the basis of this finding, it was suggested that ADAM12-S might be a useful maternal serum marker of fetal chromosomal disease. OBJECTIVE: Retrospective examination of the use of ADAM12-S as a marker for fetal trisomy 18. METHOD: Serum samples were obtained from ten women during...... the first semester of their pregnancies with fetuses that had trisomy 18. An ELISA was used to determine the levels of ADAM12 in maternal serum. Results were compared to ADAM12-S levels, previously measured in the serum of 170 women carrying normal pregnancies during the first trimester. RESULTS: In all...... cases, the ADAM12-S concentration in maternal serum samples was lower in trisomy 18 pregnancies than in normal pregnancies, with a median multiple of the median (MoM) of 0.28 (p trisomy 18...

  2. A systematic study of modulation of ADAM-mediated ectodomain shedding by site-specific O-glycosylation

    Goth, Christoffer K; Halim, Adnan; Khetarpal, Sumeet A;

    2015-01-01

    -glycosylation is often found and examples of crosstalk between shedding and O-glycosylation have been reported. Here, we systematically investigated the potential of site-specific O-glycosylation mediated by distinct polypeptide GalNAc-transferase (GalNAc-T) isoforms to coregulate ectodomain shedding mediated...... by the A Disintegrin And Metalloproteinase (ADAM) subfamily of proteases and in particular ADAM17. We analyzed 25 membrane proteins that are known to undergo ADAM17 shedding and where the processing sites included Ser/Thr residues within ± 4 residues that could represent O-glycosites. We used in vitro GalNAc-T enzyme...... and ADAM cleavage assays to demonstrate that shedding of at least 12 of these proteins are potentially coregulated by O-glycosylation. Using TNF-α as an example, we confirmed that shedding mediated by ADAM17 is coregulated by O-glycosylation controlled by the GalNAc-T2 isoform both ex vivo in isogenic cell...

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

    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.

  4. 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

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

    2000-01-01

    The ADAMs (a disintegrin and metalloprotease) family of proteins is involved in a variety of cellular interactions, including cell adhesion and ecto- domain shedding. Here we show that ADAM 12 binds to cell surface syndecans. Three forms of recombinant ADAM 12 were used in these experiments: the ...

  5. Springs, streams, and gas vent on and near Mount Adams volcano, Washington

    Nathenson, Manuel; Mariner, Robert H.

    2013-01-01

    Springs and some streams on Mount Adams volcano have been sampled for chemistry and light stable isotopes of water. Spring temperatures are generally cooler than air temperatures from weather stations at the same elevation. Spring chemistry generally reflects weathering of volcanic rock from dissolved carbon dioxide. Water in some springs and streams has either dissolved hydrothermal minerals or has reacted with them to add sulfate to the water. Some samples appear to have obtained their sulfate from dissolution of gypsum while some probably involve reaction with sulfide minerals such as pyrite. Light stable isotope data for water from springs follow a local meteoric water line, and the variation of isotopes with elevation indicate that some springs have very local recharge and others have water from elevations a few hundred meters higher. No evidence was found for thermal or slightly thermal springs on Mount Adams. A sample from a seeping gas vent on Mount Adams was at ambient temperature, but the gas is similar to that found on other Cascade volcanoes. Helium isotopes are 4.4 times the value in air, indicating that there is a significant component of mantle helium. The lack of fumaroles on Mount Adams and the ambient temperature of the gas indicates that the gas is from a hydrothermal system that is no longer active.

  6. The quantitative ADAM questionnaire: a new tool in quantifying the severity of hypogonadism

    Mohamed, O; Freundlich, R E; Dakik, H K; Grober, E D; Najari, B; Lipshultz, L I; Khera, M

    2009-01-01

    Androgen deficiency is a pervasive problem in the older male population and is thought to be responsible for many symptoms once considered to be the result of normal aging. Numerous methods have been proposed to facilitate the detection of men at risk for androgen deficiency. In this article, we propose a novel screening tool, the quantitative Androgen Deficiency in the Aging Male (qADAM) questionnaire and report its successful use in quantifying the severity of androgen deficiency in a group of older men. Fifty-seven males scheduled to undergo radical prostatectomy for prostate cancer completed the qADAM as well as the Sexual Health Inventory for Men (SHIM) and the Expanded Prostate Cancer Index Composite hormonal/sexual (EPICh/EPICs) questionnaires. Thirty-four men also had serum testosterone levels measured for comparison. The qADAM showed statistically significant correlation to the SHIM (P=0.001), EPICh (P=0.016), EPICs (P=<0.001), and serum testosterone (P=0.046). The qADAM represents a viable alternative to existing questionnaires used to detect androgen deficiency and to assess response to treatment. PMID:19657348

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

    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.

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

    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)

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

    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)

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

    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)

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

    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…

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

    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)

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

    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…

  14. Melittin modulates keratinocyte function through P2 receptor-dependent ADAM activation.

    Sommer, Anselm; Fries, Anja; Cornelsen, Isabell; Speck, Nancy; Koch-Nolte, Friedrich; Gimpl, Gerald; Andrä, Jörg; Bhakdi, Sucharit; Reiss, Karina

    2012-07-06

    Melittin, the major component of the bee venom, is an amphipathic, cationic peptide with a wide spectrum of biological properties that is being considered as an anti-inflammatory and anti-cancer agent. It modulates multiple cellular functions but the underlying mechanisms are not clearly understood. Here, we report that melittin activates disintegrin-like metalloproteases (ADAMs) and that downstream events likely contribute to the biological effects evoked by the peptide. Melittin stimulated the proteolysis of ADAM10 and ADAM17 substrates in human neutrophil granulocytes, endothelial cells and murine fibroblasts. In human HaCaT keratinocytes, melittin induced shedding of the adhesion molecule E-cadherin and release of TGF-α, which was accompanied by transactivation of the EGF receptor and ERK1/2 phosphorylation. This was followed by functional consequences such as increased keratinocyte proliferation and enhanced cell migration. Evidence is provided that ATP release and activation of purinergic P2 receptors are involved in melittin-induced ADAM activation. E-cadherin shedding and EGFR phosphorylation were dose-dependently reduced in the presence of ATPases or P2 receptor antagonists. The involvement of P2 receptors was underscored in experiments with HEK cells, which lack the P2X7 receptor and showed strikingly increased response to melittin stimulation after transfection with this receptor. Our study provides new insight into the mechanism of melittin function which should be of interest particularly in the context of its potential use as an anti-inflammatory or anti-cancer agent.

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

    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.

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

    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 0 CD t τ u (x , t) = g (t ; u), τ ∈ (0 , 1 ], where 0 CD t τ 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.

  17. Commentary to Adam Oliver’s 'Incentivising improvements in health care delivery'

    Vrangbæk, Karsten

    2015-01-01

    The commentary discusses key issues for assessment of performance management within health care. It supports the ambition to develop more realistic understandings of performance management based on insights from behavioral economics as suggested by Adam Oliver. However, it also points to several...

  18. Serendipity in the Theater: Maude Adams as James M. Barrie's American Muse.

    Diaz de Chumaceiro, Cora L.

    2003-01-01

    This essay discusses how Maude Adams influenced James M. Barrie's creative process and became his inspiration. Set change theory is underscored as a cognitive explanation for Barrie's illumination. The psychoanalytic theory of transference is proposed as an underlying mechanism for facilitating the change of mental set during the incubation stage.…

  19. VizieR Online Data Catalog: ADAM: 3D asteroid shape reconstruction code (Viikinkoski+, 2015)

    Viikinkoski, M.; Kaasalainen, M.; Durech, J.

    2015-02-01

    About the code: ADAM is a collection of routines for 3D asteroid shape reconstruction from disk-resolved observations. Any combination of lightcurves, adaptive optics images, HST/FGS data, range-Doppler radar images and disk-resolved thermal images may be used as data sources. The routines are implemented in a combination of MATLAB and C. (2 data files).

  20. Boundary Value Technique for Initial Value Problems Based on Adams-Type Second Derivative Methods

    Jator, S. N.; Sahi, R. K.

    2010-01-01

    In this article, we propose a family of second derivative Adams-type methods (SDAMs) of order up to 2k + 2 ("k" is the step number) for initial value problems. The methods are constructed through a continuous approximation of the SDAM which is obtained by multistep collocation. The continuous approximation is used to obtain initial value methods,…

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

    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...

  2. Award for Distinguished Scientific Early Career Contributions to Psychology: Adam K. Anderson

    American Psychologist, 2009

    2009-01-01

    Adam K. Anderson, recipient of the Award for Distinguished Scientific Early Career Contributions to Psychology, is cited for his outstanding contribution to understanding the representation of emotion and its influence on cognition. By combining psychological and neuroscience techniques with rigorous and creative experimental designs, Anderson has…

  3. ADAM in Holland? : Verslag van de Pilot Monitoring van drugsgebruik onder arrestanten bij Politie Haaglanden

    Broek, H. van den; Klerks, P.; Otter, P. den; Zandhuis, E.

    2000-01-01

    Het ADAM-project (Arrestee Drug Abuse Monitoring) afkomstig uit de Verenigde Staten houdt in dat arrestanten op vrijwillige basis meewerken aan een interview over hun drugsgebruik en een urinemonster afstaan dat op drugs wordt getest. Om na te gaan of deze procedure ook in Nederland uitvoerbaar is,

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

    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

  5. Imaging serotonin transporters using [{sup 123}I]ADAM SPECT in a parkinsonian primate model

    Ma, K.-H. [Department of Biology and Anatomy, National Defense Medical Center, No. 161, Section 6, Min-Chuan E. Road, Neihu 114, Taipei, Taiwan (China)], E-mail: kuohsing91@yahoo.com.tw; Huang, W.-S. [Department of Nuclear Medicine, Tri-Service General Hospital, Taipei, Taiwan (China); Huang, S.-Y. [Department of Psychiatry, Tri-Service General Hospital, Taipei, Taiwan (China); Cheng, C.-Y. [Department of Nuclear Medicine, Tri-Service General Hospital, Taipei, Taiwan (China); Chen, C.-Y. [Department of Nuclear Medicine, Taichung Branch of Buddhist Tzu Chi General Hospital, Taichung, Taiwan (China); Shen, L.-H. [Institute of Nuclear Energy Research, Taoyaun, Taiwan (China); Liu, J.-C. [Department of Biology and Anatomy, National Defense Medical Center, No. 161, Section 6, Min-Chuan E. Road, Neihu 114, Taipei, Taiwan (China); Fu, Y.-K. [Institute of Nuclear Energy Research, Taoyaun, Taiwan (China); Department of Chemistry, Chung Yuan Christian University, Chung-Li, Taiwan (China)], E-mail: fufrank@iner.gov.tw

    2008-12-15

    Parkinson's disease (PD) affects multiple neurotransmitter systems. The purpose of this study was to investigate differences in the serotonin transport system between normal and parkinsonian monkeys using 2-([2-([di-methylamino]methyl)phenyl]thio)-5-[{sup 123}I] iodophenyl-amine([{sup 123}I]ADAM), a serotonin transporters (SERT) radioligand. The brain single photon emission computed tomography (SPECT) was performed on two normal and one parkinsonian monkey. The parkinsonian monkey was induced by bilateral injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle under magnetic resonance imaging (MRI) guidance. Each monkey underwent two [{sup 99m}Tc] TRODAT-1 (a dopamine transporters imaging agent) and two [{sup 123}I] ADAM brain SPECT scans. After a bolus injection of the radioligand, the SPECT data were acquired over 4 h using a dual-head gamma camera equipped with ultra-high resolution fan-beam collimators. The striatal uptake of [{sup 99m}Tc]TRODAT-1 was 46% lower in the parkinsonian monkey than those of normal monkeys at 210-240 min post-injection. [{sup 123}I]ADAM uptake in the midbrain of the parkinsonian monkey was comparable to those of the controls. The uptakes of [{sup 123}I]ADAM in the striatum, thalamus, and frontal cortex of the parkinsonian monkey, were 31%, 31%, and 23% lower than those of normal monkeys at 210-240 min post-injection, respectively. Our results suggest that [{sup 123}I]ADAM SPECT has potential for evaluating the serotonin transporter changes in human PD.

  6. Managing Reverse Logistics or Reversing Logistics Management?

    Brito, Marisa

    2004-01-01

    textabstractIn the past, supply chains were busy fine-tuning the logistics from raw material to the end customer. Today an increasing flow of products is going back in the chain. Thus, companies have to manage reverse logistics as well.This thesis contributes to a better understanding of reverse logistics. The thesis brings insights on reverse logistics decision-making and it lays down theoretical principles for reverse logistics as a research field.In particular it puts together a framework ...

  7. Soluble Axl is generated by ADAM10-dependent cleavage and associates with Gas6 in mouse serum.

    Budagian, Vadim; Bulanova, Elena; Orinska, Zane; Duitman, Erwin; Brandt, Katja; Ludwig, Andreas; Hartmann, Dieter; Lemke, Greg; Saftig, Paul; Bulfone-Paus, Silvia

    2005-11-01

    Axl receptor tyrosine kinase exists as a transmembrane protein and as a soluble molecule. We show that constitutive and phorbol 12-myristate 13-acetate-induced generation of soluble Axl (sAxl) involves the activity of disintegrin-like metalloproteinase 10 (ADAM10). Spontaneous and inducible Axl cleavage was inhibited by the broad-spectrum metalloproteinase inhibitor GM6001 and by hydroxamate GW280264X, which is capable of blocking ADAM10 and ADAM17. Furthermore, murine fibroblasts deficient in ADAM10 expression exhibited a significant reduction in constitutive and inducible Axl shedding, whereas reconstitution of ADAM10 restored sAxl production, suggesting that ADAM10-mediated proteolysis constitutes a major mechanism for sAxl generation in mice. Partially overlapping 14-amino-acid stretch deletions in the membrane-proximal region of Axl dramatically affected sAxl generation, indicating that these regions are involved in regulating the access of the protease to the cleavage site. Importantly, relatively high circulating levels of sAxl are present in mouse sera in a heterocomplex with Axl ligand Gas6. Conversely, two other family members, Tyro3 and Mer, were not detected in mouse sera and conditioned medium. sAxl is constitutively released by murine primary cells such as dendritic and transformed cell lines. Upon immobilization, sAxl promoted cell migration and induced the phosphorylation of Axl and phosphatidylinositol 3-kinase. Thus, ADAM10-mediated generation of sAxl might play an important role in diverse biological processes.

  8. Soluble Axl Is Generated by ADAM10-Dependent Cleavage and Associates with Gas6 in Mouse Serum†

    Budagian, Vadim; Bulanova, Elena; Orinska, Zane; Duitman, Erwin; Brandt, Katja; Ludwig, Andreas; Hartmann, Dieter; Lemke, Greg; Saftig, Paul; Bulfone-Paus, Silvia

    2005-01-01

    Axl receptor tyrosine kinase exists as a transmembrane protein and as a soluble molecule. We show that constitutive and phorbol 12-myristate 13-acetate-induced generation of soluble Axl (sAxl) involves the activity of disintegrin-like metalloproteinase 10 (ADAM10). Spontaneous and inducible Axl cleavage was inhibited by the broad-spectrum metalloproteinase inhibitor GM6001 and by hydroxamate GW280264X, which is capable of blocking ADAM10 and ADAM17. Furthermore, murine fibroblasts deficient in ADAM10 expression exhibited a significant reduction in constitutive and inducible Axl shedding, whereas reconstitution of ADAM10 restored sAxl production, suggesting that ADAM10-mediated proteolysis constitutes a major mechanism for sAxl generation in mice. Partially overlapping 14-amino-acid stretch deletions in the membrane-proximal region of Axl dramatically affected sAxl generation, indicating that these regions are involved in regulating the access of the protease to the cleavage site. Importantly, relatively high circulating levels of sAxl are present in mouse sera in a heterocomplex with Axl ligand Gas6. Conversely, two other family members, Tyro3 and Mer, were not detected in mouse sera and conditioned medium. sAxl is constitutively released by murine primary cells such as dendritic and transformed cell lines. Upon immobilization, sAxl promoted cell migration and induced the phosphorylation of Axl and phosphatidylinositol 3-kinase. Thus, ADAM10-mediated generation of sAxl might play an important role in diverse biological processes. PMID:16227584

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

    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.

  10. ADAM12 induces actin cytoskeleton and extracellular matrix reorganization during early adipocyte differentiation by regulating beta1 integrin function

    Kawaguchi, Nobuko; Sundberg, Christina; Kveiborg, Marie

    2003-01-01

    -100 from cells overexpressing ADAM12 than from control cells. Collectively, these results show that surface expression of ADAM12 impairs the function of beta1 integrins and, consequently, alters the organization of the actin cytoskeleton and extracellular matrix. These events may be necessary....... Moreover, ADAM12-expressing cells were more prone to apoptosis, which could be prevented by treating the cells with beta1-activating antibodies. A reduced and re-organized fibronectin-rich extracellular matrix accompanied these changes. In addition, beta1 integrin was more readily extracted with Triton X...

  11. 研华全新无线解决方案产品ADAM-2000面市

    2012-01-01

    研华科技近期推出全新ADAM家族无线解决方案的产品——ADAM-2000系列。其基于IEEE802.15.4/ZIGBEE技术,2.4G全球免费频段,具有可靠、高性价比、低功耗和弹性传输距离等特点,可以与研华ADAM-4000和ADAM-6000等产品集成,提供卓越的全面感知解决方案。

  12. Managing Reverse Logistics or Reversing Logistics Management?

    M.P. de Brito (Marisa)

    2004-01-01

    textabstractIn the past, supply chains were busy fine-tuning the logistics from raw material to the end customer. Today an increasing flow of products is going back in the chain. Thus, companies have to manage reverse logistics as well.This thesis contributes to a better understanding of reverse log

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

    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

  14. Simulation Analysis of Handling Stability for FSAE Racing Car Based on Adams/Car%基于Adams/Car的FSAE赛车操纵稳定性仿真分析

    孙明浩

    2013-01-01

    针对某FSAE赛车样车,利用Adams/Car建立该样车的整车仿真模型,按照GB/T6323-1994进行包括转向盘转角阶跃输入和蛇形试验在内的操纵稳定性仿真试验,分析该样车的操纵稳定性,为进一步提高赛车的瞬态响应性能、急剧转向性能等具体性能,给出更加明确的设计参考.

  15. Application of ADAMS/Car Module in Vehicle's Handling Stability%ADAMS/Car模块在汽车操纵稳定性中的应用

    王凯峰

    2015-01-01

    文中简单介绍了ADAMS/Car模块,利用其建立了包括车身、悬架、转向系统和轮胎等在内的整车多体动力学模型.进行了操纵稳定性的仿真,并将仿真结果与实车试验结果进行对比,验证了所建整车动力学模型的正确性.

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

    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

  17. The Reasearch of Full Car Ride Comfort Based on ADAMS/car%基于ADAMS/Car的整车平顺性仿真研究

    韦辉; 杨竞; 陈兵; 尹忠俊; 李文越

    2008-01-01

    以某轿车为研究对象,借助于ADAMS/Car仿真分析软件建立该车的多体系统动力学整车模型,根据路面理论生成脉冲和随机路面文件,根据国家标准对该车进行整车平顺性仿真并进行客观性评价,结果表明该车的平顺性较好.

  18. Reversible Thermoset Adhesives

    Mac Murray, Benjamin C. (Inventor); Tong, Tat H. (Inventor); Hreha, Richard D. (Inventor)

    2016-01-01

    Embodiments of a reversible thermoset adhesive formed by incorporating thermally-reversible cross-linking units and a method for making the reversible thermoset adhesive are provided. One approach to formulating reversible thermoset adhesives includes incorporating dienes, such as furans, and dienophiles, such as maleimides, into a polymer network as reversible covalent cross-links using Diels Alder cross-link formation between the diene and dienophile. The chemical components may be selected based on their compatibility with adhesive chemistry as well as their ability to undergo controlled, reversible cross-linking chemistry.

  19. Enhanced PK-resistance of the Cu2+-induced recombinant prion protein treated by ADAM10%ADAM10处理增强铜离子诱导的重组朊蛋白的蛋白酶抗性

    陈操; 吕燕; 石琦; 董小平

    2016-01-01

    目的 分析ADAM10对铜离子诱导后的PrP蛋白的剪切特点.方法 常规方法表达、纯化人PrP全长蛋白(aa 23-230),利用氯化铜对纯化后的PrP蛋白进行诱导.用不同浓度的ADAM10对PrP蛋白进行处理,检测诱导后全长蛋白及剪切片段的PK抗性.结果 重组人PrP蛋白经Cu2诱导后具有部分抵抗PK消化的特点.Cu2+诱导后的PrP蛋白可被ADAM10剪切,具有剂量依赖性.ADAM10对Cu2+诱导的PrP蛋白处理后抵抗PK消化的能力明显加强.结论 ADAM10可以剪切Cu2+诱导的PrP蛋白,同时增加了处理后PrP蛋白的PK抗性.%Objective To analyze the characteristics of the ADAM10 cleavage on the Cu2+-induced recombinant prion protein.Methods Recombinant human prion protein (PrP,aa 23-230) was expressed and purified by routine methods.The purified human PrP was induced by copper chloride.Subsequently,the Cu2+-induced recombinant human PrP was treated with various concentrations of ADAM10 and its PK-resistance was assessed by PrP-specific Western Blot after incubating with various concentrations of proteinase K.Results The Cu2 +-induced purified recombinant prion protein has the characteristic of partial PK-resistance.ADAM10 can cleavage the Cu2+-induced purified recombinant prion protein,with a dosedependent manner.The PK-resistance ability of ADAM10-treated Cu2+-induced purified recombinant prion protein is higher than that of ADAM10-untreated one.Conclusions ADAM10 can cleavage the Cu2+ induced purified recombinant prion protein and enhance the PK-resistance ability of the treated prion protein.

  20. Reverse right ventricular structural and extracellular matrix remodeling by estrogen in severe pulmonary hypertension.

    Nadadur, Rangarajan D; Umar, Soban; Wong, Gabriel; Eghbali, Mansour; Iorga, Andrea; Matori, Humann; Partow-Navid, Rod; Eghbali, Mansoureh

    2012-07-01

    Chronic pulmonary hypertension (PH) leads to right-ventricular failure (RVF) characterized by RV remodeling. Ventricular remodeling is emerging as an important process during heart failure and recovery. Remodeling in RVF induced by PH is not fully understood. Recently we discovered that estrogen (E2) therapy can rescue severe preexisting PH. Here, we focused on whether E2 (42.5 μg·kg(-1)·day(-1), 10 days) can reverse adverse RV structural and extracellular matrix (ECM) remodeling induced by PH using monocrotaline (MCT, 60 mg/kg). RV fibrosis was evident in RVF males. Intact females developed less severe RV remodeling compared with males and ovariectomized (OVX) females. Novel ECM-degrading disintegrin-metalloproteinases ADAM15 and ADAM17 transcripts were elevated ∼2-fold in all RVF animals. E2 therapy reversed RV remodeling in all groups. In vitro, E2 directly inhibited ANG II-induced expression of fibrosis markers as well as the metalloproteinases in cultured cardiac fibroblasts. Estrogen receptor-β agonist diarylpropionitrile (DPN) but not estrogen receptor-α agonist 4,4',4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT) was as effective as E2 in inhibiting expression of these genes. Expression of ECM-interacting cardiac fetal-gene osteopontin (OPN) also increased ∼9-fold in RVF males. Intact females were partially protected from OPN upregulation (∼2-fold) but OVX females were not. E2 reversed OPN upregulation in all groups. Upregulation of OPN was also reversed in vitro by E2. Plasma OPN was elevated in RVF (∼1.5-fold) and decreased to control levels in the E2 group. RVF resulted in elevated Akt phosphorylation, but not ERK, in the RV, and E2 therapy restored Akt phosphorylation. In conclusion, E2 therapy reverses adverse RV remodeling associated with PH by reversing fibrosis and upregulation of novel ECM enzymes ADAM15, ADAM17, and OPN. These effects are likely mediated through estrogen receptor-β.

  1. Hydrography, Adams Co Hydro, Published in 2005, 1:4800 (1in=400ft) scale, MSA Professional Services.

    NSGIC GIS Inventory (aka Ramona) — This Hydrography dataset, published at 1:4800 (1in=400ft) scale, was produced all or in part from Orthoimagery information as of 2005. It is described as 'Adams Co...

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

    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...

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

    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

  4. Reverse cholesterol transport revisited

    Astrid; E; van; der; Velde

    2010-01-01

    Reverse cholesterol transport was originally described as the high-density lipoprotein-mediated cholesterol flux from the periphery via the hepatobiliary tract to the intestinal lumen, leading to fecal excretion. Since the introduction of reverse cholesterol transport in the 1970s, this pathway has been intensively investigated. In this topic highlight, the classical reverse cholesterol transport concepts are discussed and the subject reverse cholesterol transport is revisited.

  5. Reverse logistics - a framework

    Brito, Marisa; Dekker, Rommert

    2002-01-01

    textabstractIn this paper we define and compare Reverse Logistics definitions. We start by giving an understanding framework of Reverse Logistics: the why-what-how. By this means, we put in context the driving forces for Reverse Logistics, a typology of return reasons, a classification of products, processes and actors. In addition we provide a decision framework for Reverse Logistics and we present it according to long, medium and short term decisions, i.e. strategic-tactic-operational decis...

  6. Sir John Adams: his legacy to the world of particle accelerators

    Wilson, E J N

    2011-01-01

    John Adams acquired an unrivalled reputation for his leading part in designing and constructing the Proton Synchrotron (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 Super Proton Synchrotron (SPS) project to approval and then to direct its construction. By the time of his early death in 1984 he had built the two flagship proton accelerators at CERN and, during the second of his terms as Director-General, he laid 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? The speaker, who worked many years alongside him, will discuss these questions and speculate on how Sir John Adams might have viewed today’s CERN.

  7. Adam Smith e Francis Ysidro Edgeworth: uma crítica do utilitarismo

    Solange Regina Marin

    2012-01-01

    Full Text Available Sugerimos, nesse trabalho, a investigação das concepções de Adam Smith e a de Francis Ysidro Edgeworth do utilitarismo. Ambas as concepções foram utilizadas para desenvolver a Ciência Econômica. Porém, também apresentaram as limitações da teoria econômica, cujas fronteiras vislumbradas pelos autores remetem para a necessidade de avaliar as ações e condutas humanas com teoria moral diferente do utilitarismo. Entendemos que a teoria moral de Adam Smith, esquecida pela história do pensamento econômico, se apresenta como alternativa e, em decorrência, uma ideia promissora para aperfeiçoar o estudo das ações e condutas ditas econômicas.

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

    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.

  9. Adam M. Grant: Award for Distinguished Scientific Early Career Contributions to Psychology.

    2011-11-01

    Presents Adam M. Grant, the 2011 winner of the American Psychological Association Award for Distinguished Scientific Early Career Contributions to Psychology. "For extensive, elegant, and programmatic research on the power of relational job design in enhancing employee motivation, productivity, and satisfaction; for creative and rigorous studies documenting the profound and surprising effects of connecting employees to their impact on others; for highlighting prosocial motivation, not only extrinsic and intrinsic motivations, as a key force behind employee behavior; and for demonstrating by example the feasibility and benefits of conducting field experiments, yielding studies rich in internal validity, external validity, and practical impact. In addition to his accomplishments, Adam M. Grant is known for his generosity as a scholar, teacher, and colleague." (PsycINFO Database Record (c) 2011 APA, all rights reserved).

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

    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)

  11. 基于ADAMS/Car的轿车悬架分析和优化设计%Simulation and optimization of automobile suspension based on ADAMS/Car

    邹海锋

    2010-01-01

    本文基于ADAMS的虚拟样机技术,把悬架视为多个相互连接、彼此能够相对运动的多体运动系统.用CATIA软件建立轿车前悬架的多体动力学模型,依据双横臂独立前悬架的拓扑关系,利用设计阶段新车基本参数的要求,借助ADAMS/Car建立悬架和转向系统的参数化模型.通过ADAMS/Car进行悬架操纵稳定性和舒适性参数的仿真分析,对车轮跳动和转向时,悬架的各种参数的变化进行分析.可以在新车开发阶段比较全面的了解悬架的各项性能,为悬架进一步优化参数提供相当有效的方法.

  12. Reverse logistics - a framework

    M.P. de Brito (Marisa); R. Dekker (Rommert)

    2002-01-01

    textabstractIn this paper we define and compare Reverse Logistics definitions. We start by giving an understanding framework of Reverse Logistics: the why-what-how. By this means, we put in context the driving forces for Reverse Logistics, a typology of return reasons, a classification of product

  13. Karakteristik Penderita Dispepsia Rawat Inap Di RSUP.H. Adam Malik Medan Tahun 2001-2004

    Sianturi, Chandra D.

    2012-01-01

    Dispepsia sering ditemukan di masyarakat dengan angka morbiditas yang tinggi. Dispepsia merupakan kumpulan keluhan/gejala klinis, rasa tidak nyaman di daerah abdomen bagian atas. Untuk mengetahui distribusi proporsi penderita dispepsia rawat inap di RSUP.H.Adam Malik Medan tahun 2001-2004 dilakukan penelitian bersifat deskriptif dengan desain case series, yang menggunakan data sekunder dengan populasi 484 penderita dan sampel yang diambil dari catatan rekam medik selama tahun 2001-2004 seb...

  14. Rival ecologies of global commerce: Adam Smith and the natural historians.

    Jonsson, Fredrik Albritton

    2010-01-01

    This essay explores how the defense of global commerce pioneered in the Enlightenment was tied to the improvement of the natural order. Two rival ecologies, one made by natural historians and the other developed by Adam Smith and his liberal successors, vied for intellectual precedence as well as for practical application in the metropole and the colonies. Together they constitute the beginnings of an ongoing quarrel over the environmental foundation of capitalism.

  15. Los fundamentos morales de la economía: una relectura del problema de Adam Smith

    José Atilano Pena López; José Manuel Sánchez Santos

    2008-01-01

    This paper offers a reinterpretation of “Adam Smith’s problem” and reconsiders the relation between ethics and economics. It makes a critical revision of the attempts that seek to solve this problem, proposes an alternative framework constructed on the Smithian concepts of sympathy and the impartial spectator, and shows that morality understood as an extension of sympathy relations, constitutes a precondition for the market existence. The analysis clarifies that morality is the base of the ec...

  16. Raymond D. Adams, gigante de la neurología norteamericana

    Leonardo Palacios

    2011-01-01

    Professor Raymond D. Adams (1911-2010) has been one of the most prominent figures in North American neurology in the XX century. He studied medicine at Duke University. He began training in psychiatry but decided to study nervous system pathology and neurology in Boston City Hospital during ten years. Then he became chairman of the neurology department in Massachusetts General Hospital for more than twenty five years. He was Neuropathology Emeritus Professor at Harvard University and has been...

  17. Melittin Modulates Keratinocyte Function through P2 Receptor-dependent ADAM Activation*

    Sommer, Anselm; Fries, Anja; Cornelsen, Isabell; Speck, Nancy; Koch-Nolte, Friedrich; Gimpl, Gerald; Andrä, Jörg; Bhakdi, Sucharit; Reiss, Karina

    2012-01-01

    Melittin, the major component of the bee venom, is an amphipathic, cationic peptide with a wide spectrum of biological properties that is being considered as an anti-inflammatory and anti-cancer agent. It modulates multiple cellular functions but the underlying mechanisms are not clearly understood. Here, we report that melittin activates disintegrin-like metalloproteases (ADAMs) and that downstream events likely contribute to the biological effects evoked by the peptide. Melittin stimulated the proteolysis of ADAM10 and ADAM17 substrates in human neutrophil granulocytes, endothelial cells and murine fibroblasts. In human HaCaT keratinocytes, melittin induced shedding of the adhesion molecule E-cadherin and release of TGF-α, which was accompanied by transactivation of the EGF receptor and ERK1/2 phosphorylation. This was followed by functional consequences such as increased keratinocyte proliferation and enhanced cell migration. Evidence is provided that ATP release and activation of purinergic P2 receptors are involved in melittin-induced ADAM activation. E-cadherin shedding and EGFR phosphorylation were dose-dependently reduced in the presence of ATPases or P2 receptor antagonists. The involvement of P2 receptors was underscored in experiments with HEK cells, which lack the P2X7 receptor and showed strikingly increased response to melittin stimulation after transfection with this receptor. Our study provides new insight into the mechanism of melittin function which should be of interest particularly in the context of its potential use as an anti-inflammatory or anti-cancer agent. PMID:22613720

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

    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.)

  19. Profil Pasien Hipertensi di Poli Jantung Rumah Sakit Umum Pusat Haji Adam Malik Medan Tahun 2013

    Hatta, Rezka Darmawan

    2015-01-01

    Cardiovascular disease is currently the most common cause of death in the world, and the most ignored problem is hypertension. Riset Kesehatan Dasar (RISKESDAS) Kementrian Kesehatan RI 2013 shows that the prevalence of hypertension in Indonesia is very high, which is 31,7% of adults. To view the profile of hypertensive patients in cardiology polyclinic at RSUP H. Adam Malik Medan, a descriptive study is conducted with case series design. The population of this study is all the patients in ...

  20. Museum Quality: A New Museum and Recharged College Bring Creative Energy to North Adams, Massachusetts

    Grant, Mary

    2005-01-01

    Nestled in the valley between the Berkshire hills and the Taconic range, North Adams, Massachusetts, in many ways is typical of old New England mill towns working hard to create a new identity in the global economy. When Sprague Electric left town in 1985, the city of 16,000 reeled from the loss of 4,000 blue-collar jobs. This article describes…

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

    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...

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

    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...

  3. BEA首席软件架构师:Adam Bosworth

    2004-01-01

    对于Adam Bosworth.同事Joel Spolsky一点都不吝惜自己的溢美之词。他俩曾共事于微软.当Joel正在设计所谓的应用程序可编程能力策略时(就是后来演变成为VBA的玩意儿),Adam正在设计Microsoft Access。

  4. Kebutuhan Perawatan Periodontal Pada Perawat Instalasi Rawat Inap RSUP H. Adam Malik Medan

    Pradana, Fadil

    2015-01-01

    Interaction between nurses and their patients will affect each other and may have an impact on each individual. Various impaired quality of life associated with dental health can occur, periodontal disease can indirectly affect the quality of nursing work. To achieve optimal work productivity is also required optimal health, including nurse’s occupational health. The purpose of this study was to determine the needs for periodontal treatment in inpatient nursing installation RSUP H Adam Malik,...

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

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

    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...

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

    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...

  8. ADAM12: a novel first-trimester maternal serum marker for Down syndrome

    Laigaard, Jennie; Sørensen, Tina; Fröhlich, Camilla

    2003-01-01

    /L at week 8 of pregnancy to 670 micro g/L at 16 weeks, and reached 12 000 micro g/L at term. In 18 first-trimester Down syndrome pregnancies, the concentration of ADAM12 was decreased, thus the median multiple of mean (MoM) value was 0.14 (0.01-0.76). A detection rate for foetal Down syndrome of 82...... levels decrease markedly during pregnancy. ADAM12 (A disintegrin and metalloprotease) is an IGFBP-3 and IGFBP-5 protease and is present in human pregnancy serum. The goal of this study was to determine whether ADAM12 concentration in maternal serum is a useful indicator of foetal health. METHODS: We......OBJECTIVES: The concentration of bioavailable insulin-like growth factor (IGF) I and II is important to foetal growth. It is regulated by insulin-like growth factor binding proteins (IGFBP) 1 through 6. Proteolytic cleavage of IGFBP-3 takes place in human pregnancy serum; accordingly, IGFBP-3 serum...

  9. Snake venom metalloproteinases: structure, function and relevance to the mammalian ADAM/ADAMTS family proteins.

    Takeda, Soichi; Takeya, Hiroyuki; Iwanaga, Sadaaki

    2012-01-01

    Metalloproteinases are among the most abundant toxins in many Viperidae venoms. Snake venom metalloproteinases (SVMPs) are the primary factors responsible for hemorrhage and may also interfere with the hemostatic system, thus facilitating loss of blood from the vasculature of the prey. SVMPs are phylogenetically most closely related to mammalian ADAM (a disintegrin and metalloproteinase) and ADAMTS (ADAM with thrombospondin type-1 motif) family of proteins and, together with them, constitute the M12B clan of metalloendopeptidases. Large SVMPs, referred to as the P-III class of SVMPs, have a modular architecture with multiple non-catalytic domains. The P-III SVMPs are characterized by higher hemorrhagic and more diverse biological activities than the P-I class of SVMPs, which only have a catalytic domain. Recent crystallographic studies of P-III SVMPs and their mammalian counterparts shed new light on structure-function properties of this class of enzymes. The present review will highlight these structures, particularly the non-catalytic ancillary domains of P-III SVMPs and ADAMs that may target the enzymes to specific substrates. This article is part of a Special Issue entitled: Proteolysis 50years after the discovery of lysosome.

  10. On the Convergence of Products ~γsh1hn in the Adams Spectral Sequence

    Xiu Gui LIU

    2007-01-01

    Let A be the mod p Steenrod algebra and S the sphere spectrum localized at p,where p is an odd prime. In 2001 Lin detected a new family in the stable homotopy of spheres which isrepresented by (b0hn-h1bn-1)3∈Ext3,A(pn+p)q(Zp,Zp)in the Adams spectral sequence. At the same time, he proved that i*(h1hn)∈Ext2,A(pn+p)q(H*M,Zp)is a permanent cycle in the Adams spectralsequence and converges to a nontrivial element ζn∈π(pn+p)q-2M.in this paper, with Lin's results,family of homotopy elements jj'-γs-ii'ζn in the stable homotopy grops of spheres. The new one is of degree pnq+sp2q+spq+(s-2)q+s-6 and is represented up to a nonzero scalar by h1hn-γs in the Es2+2,*-term of the Adams spectral sequence, where p≥7,q=2(p-1),n≥4 and 3≤s<p.

  11. Expression of ADAM17 and HER-2 in breast cancer and their correlation%ADAM17与HER-2在乳腺癌中表达的意义及相关性

    孙泽辉; 张雪鹏; 韩旭; 胡宝山

    2012-01-01

    目的 探讨解聚素-金属蛋白酶17(a disintegrin and metalloproteinase 17,ADAM17)和原癌基因人表皮生长因子受体2(human epidermal growth factor receptor-2,HER-2)在乳腺癌中的表达及相关性,探索新的乳腺肿瘤标记物.方法 采用免疫组化法检测ADAM17和HER-2在正常乳腺组织及乳腺癌中的表达情况,并分析其表达与临床病理关系.结果 ADAM17和HER-2在正常乳腺组织中的表达以阴性为主,少部分呈弱阳性表达;而在乳腺癌中表达增高,以阳性表达为主,且强阳性占大部分,差异有统计学意义(P<0.05),两者在乳腺癌中的表达存在正相关性.ADAM17与HER-2表达水平与乳腺癌患者的年龄及肿瘤大小无关,而与腋窝淋巴结转移有关.结论 ADAM17和HER-2在乳腺癌中的表达增高,且两者的表达水平均可反映癌细胞的淋巴结转移能力,因此ADAM17可成为一个乳腺癌靶向治疗的新靶点.%Objective To investigate the expressions and clinical significance of a disintegrin and metalloprotein- ase 17 ( ADAM17) and human epidermal growth factor receptor - 2 ( HER - 2) in human breast cancer; and to investigated the correlation between ADAM17 and HER - 2. Methods The expression of ADAM17 and HER - 2 in the normal breast tissue and breast cancer were detected by immunohistochemical staining. Results ADAM17 and HER - 2 were negatively or weakly expressed in normal breast tissue, while the expression was positive in breast cancer. The ADAM17 and HER - 2 positive expression rates in breast cancer were significantly higher than those in normal tissues ( P <0. 05 ). There was no significant correlation between expression of ADAM17 or HER - 2 and the age of patients or tumor size. However, there was significant correlation between the expressions of ADAM17 or HER -2 and lymph node metastasis. Conclusions The expressions of ADAM17 and HER -2 are associated with the biological characteristics of breast cancer, indicating possible lymph

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

    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

  13. Biological evaluation on 125I-ADAM as serotonin transporter ligand

    LEI Bei; ZHU Junqing; LU Chunxiong; JIANG Quanfu; ZOU Meifeng; WANG Songpei; LI Xiaomin; WU Chunying

    2007-01-01

    ADAM (2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine) is suggested as a promising serotonin transporter (SERT) imaging agent for central nervous system. In this paper, biodistribution studies in rats showed that the initial uptake of 131I-ADAM in the brain was high (1.087%ID at 2 min post-injection), and consistently displayed the highest binding (between 60~240 min post-injection) in hypothalamus, a region known with the highest density of SERT. The specific binding((T/CB)-l) of 131I-ADAM in hypothalamus were 2.94, 3.03 and 3.09 at 60, 120 and 240 min post-injection, respectively. The (T/CB)-1 was significantly blocked by pretreatment with paroxetine, which is known as a serotonin site reuptake inhibitor, while another nonselective competing drug (5HT2A antagonist) Ketanserin, showed no block effect. The rat brain autoradiography and analysis showed that there was a high 131I-ADAM uptake in hypothalamus, the ratio of hypothalamus/cerebellum was significantly reduced from 7.94±0.39to 1.30±0.56 by pretreatment with paroxetine at 60 min post-injection. Blood clearance kinetics was performed in rats,and the initial half-life of 13.79 min and late half-life of 357.14 min were obtained. The kinetic equation is:C=3.6147e-0.0725t + 1.0413e-0.0028t. The thyroid uptake was 0.009% ID and 1.421% ID at 2 min and 120 min post-injection, respectively, suggesting that in vivo deiodination may be the major route of metabolism. Toxicity trial showed that the dose per kilogram administered to mice was 1000 times greater than that to humans, assuming a weight of 50kg. These data suggest that 131I-ADAM may be useful for SPECT imaging of SERT binding sites in the brain.

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

    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

  15. Increase of ADAM10 level in coronary artery in-stent restenosis segments in diabetic minipigs: high ADAM10 expression promoting growth and migration in human vascular smooth muscle cells via Notch 1 and 3.

    Ke Yang

    Full Text Available BACKGROUND: This study aimed to identify major proteins in the pathogenesis of coronary artery in-stent restenosis (ISR in diabetic minipigs with sirolimus-eluting stenting, and to investigate the roles of key candidate molecules, particularly ADAM10, in human arterial smooth muscle cells (HASMCs. METHODS AND RESULTS: The stents were implanted in the coronary arteries of 15 diabetic and 26 non-diabetic minipigs, and angiography was repeated at six months. The intima of one vascular segment with significant ISR and one with non-ISR in diabetic minipigs were isolated and cultured in conditioned medium (CM. The CM was analyzed by LC-MS/MS to uncover proteins whose levels were significantly increased (≥ 1.5-fold in ISR than in non-ISR tissues. After literature searching, we focused on the identified proteins, whose biological functions were most potentially related to ISR pathophysiology. Among them, ADAM10 was significantly increased in diabetic and non-diabetic ISR tissues as compared with non-ISR controls. In cell experiments, retrovirus-mediated overexpression of ADAM10 promoted growth and migration of HASMCs. The effects of ADAM10 were more remarkable in high-glucose culture than in low-glucose culture. Using shRNA and an inhibitor of γ-secretase (GSI, we found that the influences of ADAM10 were in part mediated by Notch1 and notch 3 pathway, which up-regulated Notch downstream genes and enhanced nuclear translocation of the small intracellular component of Notch1 and Notch3. CONCLUSIONS: This study has identified significantly increased expression of ADAM10 in the ISR versus non-ISR segment in diabetic minipigs and implicates ADAM10 in the enhanced neointimal formation observed in diabetes after vascular injury.

  16. Simulation of Maize Culm with Harvester Header Based on ADAMS%基于 ADAMS 的玉米茎秆与收获割台仿真

    郭君娣; 伍德林; 陈黎卿

    2016-01-01

    茎秆折断在玉米收获过程中已成为一个迫切需要解决的问题。为此,通过 ADAMS/VIEW 拉伸法建立玉米茎秆柔性体模型,利用Pro/E建立割台三维模型,导入 Adams 后添加相应约束和驱动进行仿真。仿真结果表明:分禾器外表面过渡处越平滑,植株越不易被推倒,减少了玉米茎秆的折断的几率。同时,通过虚拟正交试验,得到拉茎辊转速和机器行走速度的最优组合为n=900r/min,v=2.16km/h,可以降低对玉米茎秆的损伤程度,减少折断玉米茎秆的几率。%Maize culm snapped has become an urgent problem to be solved in the course of the corn harvest .The flexible body of maize culm was being created by ADAMS/VIEW Extrusion .The model of maize harvester header was established with Proe .And then , these models were imported into the ADAMS environment to create the virtual prototyping models including the appropriate constraints and motion , and drive simulation .Simulation results show that: the divider outside the smoother surface transitions ,the plant can not easily be torn down , reducing the chance of snapped the maize culm . Through virtual orthogonal experiment , snapping roller rotational speed and travel speed of the optimal combination for n=900r/min,v=2.16km/h, can reduce the extent of damage to the corn stalk , reducing the chance of snapped the maize culm .

  17. 基于ADAMS/Car的雨天汽车行车安全分析%Analysis of Car Traffic Safety Based on ADAMS/Car in Rainy Days

    房科; 周华; 刘纯志

    2012-01-01

    This paper established a vehicle dynamics model, a road model and a vehicle-road coupling model by using the multi-body dynamics software ADAMS/Car. By changing road friction coefficients, the driving conditions in sunny, dry and rainy roads were simulated respectively. Single lane change text and ramp steering text were carried out, and the response output of lateral displacement was obtained. Computation results in the single lane change indicate that when road friction coefficient in rain weather is 0. 4, vehicle speed is 60 km/h in the single line simulation, and the vehicle will be easily out of control. When vehicle speed is 55 km/h, and the maximum steer value is 70 in the single lane simulation, vehicle will go haywire. In the ramp steer simulation when vehicle speed is 40 km/h, vehicle will also go haywire.%以多刚体动力学仿真软件ADAMS/Car为依托,建立车辆动力学模型、道路模型、车路耦合模型.通过改变ADAMS/Car中道路文件的路面摩擦系数,分别研究了车辆在干燥路面、潮湿路面及雨天路面的行驶状况.通过单移线和斜坡脉冲转向这2种常见工况进行仿真分析,得到了不同的车辆侧向位移曲线和车轮所受的侧向反力曲线,分析雨天对汽车行车安全的影响.单移线仿真试验结果表明:雨天路面摩擦因数为0.4,车速为60 km/h时,车辆变车道容易失去控制发生意外;车速为55km/h,转向盘转角达到70°时,车辆也将失去控制;斜坡阶跃仿真试验结果表明:车速为40 km/h,车辆将会失去控制.

  18. ADAM12 localizes with c-Src to actin-rich structures at the cell periphery and regulates Src kinase activity

    Stautz, Dorte; Sanjay, Archana; Hansen, Matilde Thye;

    2010-01-01

    to enhance Src kinase activity in response to external signals, such as integrin engagement. Thus, we suggest that activated c-Src binds, phosphorylates, and redistributes ADAM12-L to specific sites at the cell periphery, which may in turn promote signalling mechanisms regulating cellular processes...... partners and signalling proteins. We demonstrate here a c-Src-dependent redistribution of ADAM12-L from perinuclear areas to actin-rich Src-positive structures at the cell periphery, and identified two separate c-Src binding sites in the cytoplasmic tail of ADAM12-L that interact with the SH3 domain of c......-Src with different binding affinities. The association between ADAM12-L and c-Src is transient, but greatly stabilized when the c-Src kinase activity is disrupted. In agreement with this observation, kinase-active forms of c-Src induce ADAM12-L tyrosine phosphorylation. Interestingly, ADAM12-L was also found...

  19. Development of an advanced system identification technique for comparing ADAMS analytical results with modal test data for a MICON 65/13 wind turbine

    Bialasiewicz, J.T.

    1995-07-01

    This work uses the theory developed in NREL/TP--442-7110 to analyze simulated data from an ADAMS (Automated Dynamic Analysis of Mechanical Systems) model of the MICON 65/13 wind turbine. The Observer/Kalman Filter identification approach is expanded to use input-output time histories from ADAMS simulations or structural test data. A step by step outline is offered on how the tools developed in this research, can be used for validation of the ADAMS model.

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

    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.

  1. Variation of human immunodeficiency virus type-1 reverse transcriptase within the simian immunodeficiency virus genome of RT-SHIV.

    Debra A Wadford

    Full Text Available RT-SHIV is a chimera of simian immunodeficiency virus (SIV containing the reverse transcriptase (RT-encoding region of human immunodeficiency virus type 1 (HIV-1 within the backbone of SIVmac239. It has been used in a non-human primate model for studies of non-nucleoside RT inhibitors (NNRTI and highly active antiretroviral therapy (HAART. We and others have identified several mutations that arise in the "foreign" HIV-1 RT of RT-SHIV during in vivo replication. In this study we catalogued amino acid substitutions in the HIV-1 RT and in regions of the SIV backbone with which RT interacts that emerged 30 weeks post-infection from seven RT-SHIV-infected rhesus macaques. The virus set points varied from relatively high virus load, moderate virus load, to undetectable virus load. The G196R substitution in RT was detected from 6 of 7 animals at week 4 post-infection and remained in virus from 4 of 6 animals at week 30. Virus from four high virus load animals showed several common mutations within RT, including L74V or V75L, G196R, L214F, and K275R. The foreign RT from high virus load isolates exhibited as much variation as that of the highly variable envelope surface glycoprotein, and 10-fold higher than that of the native RT of SIVmac239. Isolates from moderate virus load animals showed much less variation in the foreign RT than the high virus load isolates. No variation was found in SIVmac239 genes known to interact with RT. Our results demonstrate substantial adaptation of the foreign HIV-1 RT in RT-SHIV-infected macaques, which most likely reflects selective pressure upon the foreign RT to attain optimal activity within the context of the chimeric RT-SHIV and the rhesus macaque host.

  2. Reversible cortical blindness: posterior reversible encephalopathy syndrome.

    Bandyopadhyay, Sabyasachi; Mondal, Kanchan Kumar; Das, Somnath; Gupta, Anindya; Biswas, Jaya; Bhattacharyya, Subir Kumar; Biswas, Gautam

    2010-11-01

    Cortical blindness is defined as visual failure with preserved pupillary reflexes in structurally intact eyes due to bilateral lesions affecting occipital cortex. Bilateral oedema and infarction of the posterior and middle cerebral arterial territory, trauma, glioma and meningioma of the occipital cortex are the main causes of cortical blindness. Posterior reversible encephalopathy syndrome (PRES) refers to the reversible subtype of cortical blindness and is usually associated with hypertension, diabetes, immunosuppression, puerperium with or without eclampsia. Here, 3 cases of PRES with complete or partial visual recovery following treatment in 6-month follow-up are reported.

  3. FoxM1和ADAM17在乳腺癌中的表达及其临床意义%Expression and clinical significance of FoxM1 and ADAM17 in breast cancer

    张艳; 乔炜超; 孙影; 张雪鹏

    2016-01-01

    目的:探讨叉头框蛋白M1(FoxM1)与ADAM17在乳腺癌中的表达、相关性及临床意义。方法采用免疫组织化学法检测2014年6月~2015年12月华北理工大学附属医院浸润性乳腺癌(乳腺癌组)62例、乳腺纤维腺瘤(乳腺纤维腺瘤组)33例和正常乳腺组织(对照组)31例中FoxM1和ADAM17的表达,分析两者之间的关系以及其与乳腺癌临床病理特征的相关性。结果 FoxM1和ADAM17在对照组、乳腺纤维腺瘤组、乳腺癌组中的染色指数分别为0.49±0.11、2.13±0.25、9.58±0.95和0.56±0.17、1.87±0.22、9.40±1.17。乳腺癌组FoxM1和ADAM17表达显著高于乳腺纤维腺瘤组,乳腺纤维腺瘤组FoxM1、ADAM17表达高于对照组,差异均有统计学意义(P0.05)。FoxM1和ADAM17在乳腺癌中的表达呈正相关(r=0.68,P0.05) , but it was associated with the metastasis of axillary lymph nodes (P< 0.05). Correlation analysis showed that the expression of FoxM1 and ADAM17 in breast cancer was positively correlated (r=0.68, P<0.05). Conclusion There is high level of FoxM1 and ADAM17 in inva-sive carcinoma, and a positive correlation between them. Positive expression of FoxM1 and ADAM17 is positive associ-ation with axillary lymph node metastasis, but not with age and tumor size in patients with invasive carcinoma of the breast.

  4. Introduction to reversible computing

    Perumalla, Kalyan S

    2013-01-01

    Few books comprehensively cover the software and programming aspects of reversible computing. Filling this gap, Introduction to Reversible Computing offers an expanded view of the field that includes the traditional energy-motivated hardware viewpoint as well as the emerging application-motivated software approach. Collecting scattered knowledge into one coherent account, the book provides a compendium of both classical and recently developed results on reversible computing. It explores up-and-coming theories, techniques, and tools for the application of rever

  5. Reversible Logic Circuit Synthesis

    Shende, V V; Markov, I L; Prasad, A K; Hayes, John P.; Markov, Igor L.; Prasad, Aditya K.; Shende, Vivek V.

    2002-01-01

    Reversible, or information-lossless, circuits have applications in digital signal processing, communication, computer graphics and cryptography. They are also a fundamental requirement for quantum computation. We investigate the synthesis of reversible circuits that employ a minimum number of gates and contain no redundant input-output line-pairs (temporary storage channels). We propose new constructions for reversible circuits composed of NOT, Controlled-NOT, and TOFFOLI gates (the CNT gate library) based on permutation theory. A new algorithm is given to synthesize optimal reversible circuits using an arbitrary gate library. We also describe much faster heuristic algorithms. We also pursue applications of the proposed techniques to the synthesis of quantum circuits.

  6. ADAM28反义核酸对人牙乳头细胞表达细胞外基质蛋白的影响%The effects of ADAM28 AS-ODN on HDPCs expressing extracellular matrix proteins

    赵征; 徐军明; 赵威丽

    2008-01-01

    目的:研究金属蛋白酶解离素28(ADAM28)反义核酸(AS-ODN)转染人牙乳头细胞(HDPC)后,对其表达多种细胞外基质蛋白(BSP、OPN、DSPP、CollagenⅠ/Ⅲ)的影响.方法:采用细胞培养、基凼转染、免疫细胞化学和图像分析技术检测)ADAM28反义核睃对HDPC表达上述基质蛋白的影响.结果:ADAM28反义核酸转染HDPC后BSP、DSPP、Collagen Ⅰ的表达明显减弱(P<0.01),OPN、CollagenⅢ的表达无明显变化(P>0.05).结论:ADAM28反义核酸可有效封闭人牙乳头细胞内BSP、DSPP、Collagen Ⅰ的表达,ADAM28基冈对BSP、DSPP、Collagen Ⅰ的表达起显著的正向调节作用.

  7. The Analysi s of Incomplete Gear Reversing Mechanism Dynamics%不完全齿轮换向机构的动力学特性分析

    王猛; 李长春; 田希杰

    2012-01-01

    在利用Pro/E4.0对不完全齿轮进行渐开线参数化建模的基础上,使用ADAMS软件对不完全齿轮自动换向机构进行动力学仿真分析,并研究了齿轮作用力和转矩的特性曲线。%In the use of Pro / E 4 on the incomplete gear involute parametric modeling based on ADAMS software, use of incomplete gear automatic reversing mechanism simulation analysis of dynamic is carried out, and the study of the gear force and torque characteristic curve. Base on the incomplete gear involute parametric modeling in the use of Pro/E 4.0, the incomplete gear automatic reversing mechanism simulation analysis of dynamic on ADAMS software is carried out, and the study of the gear force and torque characteristic curve.

  8. Role of ADAM17 in invasion and migration of CD133-expressing liver cancer stem cells after irradiation

    Hong, Sung Woo; Hur, Wonhee; Choi, Jung Eun; Kim, Jung-Hee; Hwang, Daehee; Yoon, Seung Kew

    2016-01-01

    We investigated the biological role of CD133-expressing liver cancer stem cells (CSCs) enriched after irradiation of Huh7 cells in cell invasion and migration. We also explored whether a disintegrin and metalloproteinase-17 (ADAM17) influences the metastatic potential of CSC-enriched hepatocellular carcinoma (HCC) cells after irradiation. A CD133-expressing Huh7 cell subpopulation showed greater resistance to sublethal irradiation and specifically enhanced cell invasion and migration capabilities. We also demonstrated that the radiation-induced MMP-2 and MMP-9 enzyme activities as well as the secretion of vascular endothelial growth factor were increased more predominantly in Huh7CD133+ cell subpopulations than Huh7CD133− cell subpopulations. Furthermore, we showed that silencing ADAM17 significantly inhibited the migration and invasiveness of enriched Huh7CD133+ cells after irradiation; moreover, Notch signaling was significantly reduced in irradiated CD133-expressing liver CSCs following stable knockdown of the ADAM17 gene. In conclusion, our findings indicate that CD133-expressing liver CSCs have considerable metastatic capabilities after irradiation of HCC cells, and their metastatic capabilities might be maintained by ADAM17. Therefore, suppression of ADAM17 shows promise for improving the efficiency of current radiotherapies and reducing the metastatic potential of liver CSCs during HCC treatment. PMID:26993601

  9. Conditional Knockout Adam10 Gene of Neuronal Cell in Mouse Leads to Cortical Dysplasia%选择性敲除小鼠神经细胞 Adam10基因导致大脑皮质发育不良

    王义辉; 李秀娟; 渠文生

    2015-01-01

    Objective: To investigate the role of Adam10 gene in mouse central nervous system (CNS) develop-ment. Methods: Gfapcre mice were mated to Adam10lox/lox mice using cre-loxp conditional gene knockout technique, and mice of conditional knockout Adam10 gene of neuronal cells(Gfapcre-Adam10lox/lox) were produced. At postnatal day of fourteen, mouse brain sections were prepared and HE staining was used to observe CNS development in Adam10 gene knockout mice. Results: By conditional knockout Adam10 gene of neuronal cell in mice (Gfapcre-Adam10lox/lox), mice could survive to about three weeks after birth. A tiny fraction of mice showed cortical defect,and developed cerebral cortex showed disorders of cortical lamination by HE staining. Conclusion: Adam10 gene plays an important role in CNS development. Conditional knockout Adam10 gene of neuronal cell in mouse leads to cortical defect or dysplasia.%目的:研究 Adam10基因在小鼠神经系统发育中的作用。方法:利用 Cre-loxp 转基因鼠技术,将 Gfapcre转基因鼠和 Adam10lox/lox 转基因鼠杂交,得到神经细胞特异性 Adam10基因敲除鼠(Gfapcre-Adam10lox/lox),在出生后第14天对大脑切片行 HE 染色,观察 Adam10基因敲除后神经系统发育情况。结果:选择性敲除小鼠神经细胞 Adam10基因(Gfapcre-Adam10lox/lox),小鼠可存活至出生后3周左右,部份小鼠大脑皮质单侧或双侧缺失,未出现皮质缺失的小鼠大脑皮质经 HE 染色提示出现层次结构紊乱。结论:Adam10基因在小鼠神经系统发育中具有重要作用,选择性敲除神经细胞 Adam10基因后导致小鼠大脑皮质缺失或层次结构紊乱。

  10. Reversible cerebral vasoconstriction syndrome

    Saini Monica

    2009-01-01

    Full Text Available Reversible cerebral vasoconstriction syndromes (RCVS are a group of disorders that have in common an acute presentation with headache, reversible vasoconstriction of cerebral arteries, with or without neurological signs and symptoms. In contrast to primary central nervous system vasculitis, they have a relatively benign course. We describe here a patient who was diagnosed with RCVS.

  11. Quantum reverse hypercontractivity

    Cubitt, Toby [Department of Computer Science, University College London, London, United Kingdom and Centre for Quantum Information and Foundations, DAMTP, University of Cambridge, Cambridge (United Kingdom); Kastoryano, Michael [NBIA, Niels Bohr Institute, University of Copenhagen, 2100 Copenhagen (Denmark); Montanaro, Ashley [School of Mathematics, University of Bristol, Bristol (United Kingdom); Temme, Kristan [Institute for Quantum Information and Matter, California Institute of Technology, Pasadena, California 91125 (United States)

    2015-10-15

    We develop reverse versions of hypercontractive inequalities for quantum channels. By generalizing classical techniques, we prove a reverse hypercontractive inequality for tensor products of qubit depolarizing channels. We apply this to obtain a rapid mixing result for depolarizing noise applied to large subspaces and to prove bounds on a quantum generalization of non-interactive correlation distillation.

  12. ADAMS/CAR与EASY5在车辆主动悬架动力学研究中的应用%ADAMS/CAR AND EASY5 CO-SIMULATION TECHNOLOGY IN ACTIVE SUSPENSION VEHICLE RESEARCH

    张晓芬; 丛华; 晁志强; 刘相波

    2007-01-01

    概括介绍了ADAMS/CAR与EASY5仿真软件在车辆主动悬架研究中的应用,通过ADAMS/CAR建立了整车主动悬架的多体动力学模型,采用EASY5软件设计了主动悬架的液压系统,并提出了ADAMS/CAR与EASY5联合仿真的方案,对联合仿真技术应用于主动悬架进行了可行性分析.同时,车辆平顺性的仿真结果表明,采用液压主动悬架的车辆与采用被动悬架的车辆相比平顺性有了明显的改善.

  13. APPLICATION OF MSC ADAMS – NX NASTRAN/FEMAP INTERFACE IN STRENGTH CALCULATIONS OF TRUCK FRAMES

    Adam PRZEMYK

    2016-06-01

    Full Text Available In this paper, the finite element method (FEM is used to calculate the strength of truck frames by integrating the MSC Adams software, for dynamics analysis of mechanical systems, and the NX Nastran/Femap software. At the same time, a method for reducing degrees of freedom is been developed based on the Craig–Bampton method. The interface is applied in order to calculate the strength of the frame in the selected truck, which runs on the test track. The selected model of truck can be treated as the virtual prototype that is useful in the design process.

  14. ADAM: Analysis of Discrete Models of Biological Systems Using Computer Algebra

    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

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

    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

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

    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

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

    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.

  18. Karakteristik Penderita Otitis Media Supuratif Kronik Di RSUP Haji Adam Malik Medan Pada Tahun 2012

    Batubara, Muhammad Akbar

    2014-01-01

    Chronic Suppurative Otitis Media (CSOM) is included in one of the major health problem which can be found in many population in the world and it is one of the cause of significant morbidity and motility. The prevalence rate of CSOM in the world states 1 to 46% in the middle to low class in developing countries . This research is conducted in order to recognize the char acteristic of patients with CSOM at RSUP Haji Adam Malik Medan in 201 2. The samples of this research are the patients of thi...

  19. Adam Smith's conceptual contributions to international economics: Based on the Wealth of Nations

    Ismail Kucukaksoy

    2011-01-01

    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 ...

  20. ADAM SMITH Y ALEXIS DE TOCQUEVILLE: DOS IMAGINARIOS POLÍTICOS DE LA SOCIEDAD CIVIL

    JORGE VELÁZQUEZ DELGADO

    2008-01-01

    La riqueza de las naciones de Adam Smith y La democracia en América de Alexis de Tocqueville son dos importantes e invaluables aportaciones en el debate en torno a la democracia y la sociedad civil. Sin dejar de ser dos trascendentes análisis socioeconómico y político de su tiempo su relevancia actual radica en la estrecha relación que guardan con respecto a la tradición liberal y con respecto a la necesidad de comprender, desde ese horizonte crítico abierto por estos grandes pensadores, la r...

  1. Calculation of nuclear reactivity using the generalised Adams-Bashforth-Moulton predictor corrector method

    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.

  2. MORPHOLOGICAL AND ANATOMICAL STUDY OF ZIZIPHORA PUSHKINII ADAMS. OF LAMINACEAE LINDL. FAMILY

    F. K. Serebryanaya

    2014-01-01

    Full Text Available Morphological and anatomical study of Ziziphora puschkinii Adams. was carried out. It resulted on the revelation of diagnostic signs of a stem, leafstalk and lamina structure. According to the present results, the nodal and caulifoliar morphology in Ziziphora may be helpful in systematic researches. Stomatal apparatus of diacytic type and big unicellular trichomes presence may be considered to be diagnostic signs of lamina epidermis. The data reseived may be uded in further systematic researches of Ziziphora L. genus.

  3. The Co-simulation of Humanoid Robot Based on Solidworks, ADAMS and Simulink

    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.

  4. References to Africa in Adam Smith's Wealth of Nations and Some Key Propositions Surrounding Them

    Amavilah, Voxi Heinrich

    2010-01-01

    Adam Smith sought to illustrate some of his propositions in The Wealth of Nations (WON) with examples from Africa. However, the examples were few, and many were neither profound nor instructive from a principles viewpoint. I find that Africa figures very little in the WON, and nearly every time it appears cursory. With 20/20 hindsight, one may conclude that opinions about Africa have remained invariant with respect to time. Final value-judgment about whether that is a good or bad thing rests...

  5. The Prevailing of the Human Nature in the Economics of Adam Smith

    Mara Magda Maftei

    2006-07-01

    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.

  6. The Prevailing of the Human Nature in the Economics of Adam Smith

    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.

  7. Polyaza crown ether as non-nucleosidic building blocks in DNA-conjugates

    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....... Thermal denaturation experiments showed remarkable stabilization of dsDNA by polyaza crown ether monomers when incorporated in opposite positions. The series of polyaza crown ether monomers (X, Y, and Z) with different lipophilicity showed a trend of increased stability of the corresponding ds......DNA with increasing lipophilicity of the polyaza crown ether monomer....

  8. A mechanism of male germ cell apoptosis induced by bisphenol-A and nonylphenol involving ADAM17 and p38 MAPK activation.

    Paulina Urriola-Muñoz

    Full Text Available Germ cell apoptosis regulation is pivotal in order to maintain proper daily sperm production. Several reports have shown that endocrine disruptors such as Bisphenol-A (BPA and Nonylphenol (NP induce germ cell apoptosis along with a decrease in sperm production. Given their ubiquitous distribution in plastic products used by humans it is important to clarify their mechanism of action. TACE/ADAM17 is a widely distributed extracellular metalloprotease and participates in the physiological apoptosis of germ cells during spermatogenesis. The aims of this work were: 1 to determine whether BPA and NP induce ADAM17 activation; and 2 to study whether ADAM17 and/or ADAM10 are involved in germ cell apoptosis induced by BPA and NP in the pubertal rat testis. A single dose of BPA or NP (50 mg/kg induces germ cell apoptosis in 21-day-old male rats, which was prevented by a pharmacological inhibitor of ADAM17, but not by an inhibitor of ADAM10. In vitro, we showed that BPA and NP, at similar concentrations to those found in human samples, induce the shedding of exogenous and endogenous (TNF-α ADAM17 substrates in primary rat Sertoli cell cultures and TM4 cell line. In addition, pharmacological inhibitors of metalloproteases and genetic silencing of ADAM17 prevent the shedding induced in vitro by BPA and NP. Finally, we showed that in vivo BPA and NP induced early activation (phosphorylation of p38 MAPK and translocation of ADAM17 to the cell surface. Interestingly, the inhibition of p38 MAPK prevents germ cell apoptosis and translocation of ADAM17 to the cell surface. These results show for the first time that xenoestrogens can induce activation of ADAM17 at concentrations similar to those found in human samples, suggesting a mechanism by which they could imbalance para/juxtacrine cell-to-cell-communication and induce germ cell apoptosis.

  9. Evaluación de la expresión génica de mica, micb, adam10, adam17 y mmp14 en lesiones intraepiteliales cervicales en pacientes residentes en Bogotá

    García Lesmes, Laura Alejandra

    2014-01-01

    NKG2D es un receptor activador expresado en las células naturales asesinas involucrado en la eliminación de células transformadas y/o infectadas por virus. Dentro de los ligandos descritos para este receptor están MICA y MICB y la familia de las ULBPs (ULBP1-ULBP6). Por otro lado, uno de los mecanismos de evasión por parte de la célula tumoral es el clivaje de éstas proteínas por parte de metaloproteinasas como ADAM10, ADAM17 y MMP14. Por lo anterior en este estudio analizamos ...

  10. 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

    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

  11. Adams/Car与Insight在汽车前悬架仿真与优化中的联合应用%Co-application of adams/car and insight in simulation and optimization for an automobile front suspension

    廖抒华; 段守焱; 王金波

    2010-01-01

    应用Adams/Car建立了某微型车的麦弗逊前悬架模型,分析了其轮跳对前轮定位参数的影响,找出了其不合理性,并采用Adams/Insight对该悬架的部分硬点位置进行了优化,优化结果表明,所做的优化设计正确有效,改善了悬架系统的运动学特性.

  12. The disintegrin and metalloproteinase ADAM12 contributes to TGF-beta signaling through interaction with the type II receptor

    Atfi, Azeddine; Dumont, Emmanuelle; Colland, Frédéric;

    2007-01-01

    Transforming growth factor-beta (TGF-beta) regulates a wide variety of biological processes through two types of Ser/Thr transmembrane receptors: the TGF-beta type I receptor and the TGF-beta type II receptor (TbetaRII). Upon ligand binding, TGF-beta type I receptor activated by TbetaRII propagates...... signals to Smad proteins, which mediate the activation of TGF-beta target genes. In this study, we identify ADAM12 (a disintegrin and metalloproteinase 12) as a component of the TGF-beta signaling pathway that acts through association with TbetaRII. We found that ADAM12 functions by a mechanism...... 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...

  13. ADAM10 overexpression shifts lympho- and myelopoiesis by dysregulating site 2/site 3 cleavage products of Notch.

    Gibb, David R; Saleem, Sheinei J; Kang, Dae-Joong; Subler, Mark A; Conrad, Daniel H

    2011-04-01

    Although the physiological consequences of Notch signaling in hematopoiesis have been extensively studied, the differential effects of individual notch cleavage products remain to be elucidated. Given that ADAM10 is a critical regulator of Notch and that its deletion is embryonically lethal, we generated mice that overexpress ADAM10 (ADAM10 transgenic [A10Tg]) at early stages of lympho- and myeloid development. Transgene expression resulted in abrogated B cell development, delayed T cell development in the thymus, and unexpected systemic expansion of CD11b(+)Gr-1(+) cells, also known as myeloid-derived suppressor cells. Mixed bone marrow reconstitution assays demonstrated that transgene expression altered hematopoiesis via a cell-intrinsic mechanism. Consistent with previously reported observations, we hypothesized that ADAM10 overexpression dysregulated Notch by uncoupling the highly regulated proteolysis of Notch receptors. This was confirmed using an in vitro model of hematopoiesis via culturing A10Tg hematopoietic Lineage(-)Sca-1(+)c-Kit(+) cells with OP-9 stromal cells in the presence or absence of Delta-like 1, a primary ligand for Notch. Blockade of the site 2 (S2) and site 3 (S3) cleavage of the Notch receptor demonstrated differential effects on hematopoiesis. OP9-DL1 cultures containing the ADAM10 inhibitor (S2 cleavage site) enhanced and rescued B cell development from wild-type and A10Tg Lineage(-)Sca-1(+)c-Kit(+) cells, respectively. In contrast, blockade of γ-secretase at the S3 cleavage site induced accumulation of the S2 product and consequently prevented B cell development and resulted in myeloid cell accumulation. Collectively, these findings indicate that the differential cleavage of Notch into S2 and S3 products regulated by ADAM10 is critical to hematopoietic cell-fate determination.

  14. Adam's Dream

    Piacenti, Alexandria

    2011-01-01

    Growing up as a young girl, summer camp was a typical affair. Packed lunches kept cold with frozen freezer packs, seemingly endless slip n' slides, activities, games, contests. Every morning, the author was eager to wake up and head off to hours and hours of fun with friends and counselors. However, one may think the camping experience could not…

  15. ADAM28: a potential oncogene involved in asbestos-related lung adenocarcinomas.

    Wright, Casey M; Larsen, Jill E; Hayward, Nicholas K; Martins, Maria U; Tan, Maxine E; Davidson, Morgan R; Savarimuthu, Santiyagu M; McLachlan, Rebecca E; Passmore, Linda H; Windsor, Morgan N; Clarke, Belinda E; Duhig, Edwina E; Yang, Ian A; Bowman, Rayleen V; Fong, Kwun M

    2010-08-01

    Asbestos-related lung cancer accounts for 4-12% of all lung cancers worldwide. Since putative mechanisms of carcinogenesis differ between asbestos and tobacco induced lung cancers, tumors induced by the two agents may be genetically distinct. To identify gene expression biomarkers associated with asbestos-related lung tumorigenicity we performed gene expression array analysis on tumors of 36 patients with primary lung adenocarcinoma, comparing 12 patients with lung asbestos body counts above levels associated with urban dwelling (ARLC-AC: asbestos-related lung cancer-adenocarcinoma) with 24 patients with no asbestos bodies (NARLC-AC: non-asbestos related lung cancer-adenocarcinoma). Genes differentially expressed between ARLC-AC and NARLC-AC were identified on fold change and P value, and then prioritized using gene ontology. Candidates included ZNRF3, ADAM28, PPP1CA, IRF6, RAB3D, and PRDX1. Expression of these six genes was technically and biologically replicated by qRT-PCR in the training set and biologically validated in three independent test sets. ADAM28, encoding a disintegrin and metalloproteinase domain protein that interacts with integrins, was consistently upregulated in ARLC across all four datasets. Further studies are being designed to investigate the possible role of this gene in asbestos lung tumorigenicity, its potential utility as a marker of asbestos related lung cancer for purposes of causal attribution, and its potential as a treatment target for lung cancers arising in asbestos exposed persons.

  16. PAX2 regulates ADAM10 expression and mediates anchorage-independent cell growth of melanoma cells.

    Sophia Boyoung Lee

    Full Text Available PAX transcription factors play an important role during development and carcinogenesis. In this study, we investigated PAX2 protein levels in melanocytes and melanoma cells by Western Blot and immunofluorescence analysis and characterized the role of PAX2 in the pathogenesis of melanoma. In vitro we found weak PAX2 protein expression in keratinocytes and melanocytes. Compared to melanocytes increased PAX2 protein levels were detectable in melanoma cell lines. Interestingly, in tissue sections of melanoma patients nuclear PAX2 expression strongly correlated with nuclear atypia and the degree of prominent nucleoli, indicating an association of PAX2 with a more atypical cellular phenotype. In addition, with chromatin immunoprecipitation assay, PAX2 overexpression and PAX2 siRNA we present compelling evidence that PAX2 can regulate ADAM10 expression, a metalloproteinase known to play important roles in melanoma metastasis. In human tissue samples we found co-expression of PAX2 and ADAM10 in melanocytes of benign nevi and in melanoma cells of patients with malignant melanoma. Importantly, the downregulation of PAX2 by specific siRNA inhibited the anchorage independent cell growth and decreased the migratory and invasive capacity of melanoma cells. Furthermore, the downregulation of PAX2 abrogated the chemoresistance of melanoma cells against cisplatin, indicating that PAX2 expression mediates cell survival and plays important roles during melanoma progression.

  17. Dalla teoria delle passioni al nuovo ordine: mercato e capitalismo in Adam Smith

    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

  18. Introduction: REVIEW SYMPOSIUM ON GIOVANNI ARRIGHI’S ADAM SMITH IN BEIJING

    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.

  19. ADAM13 cleavage of cadherin-11 promotes CNC migration independently of the homophilic binding site.

    Abbruzzese, Genevieve; Becker, Sarah F; Kashef, Jubin; Alfandari, Dominique

    2016-07-15

    The cranial neural crest (CNC) is a highly motile population of cells that is responsible for forming the face and jaw in all vertebrates and perturbing their migration can lead to craniofacial birth defects. Cell motility requires a dynamic modification of cell-cell and cell-matrix adhesion. In the CNC, cleavage of the cell adhesion molecule cadherin-11 by ADAM13 is essential for cell migration. This cleavage generates a shed extracellular fragment of cadherin-11 (EC1-3) that possesses pro-migratory activity via an unknown mechanism. Cadherin-11 plays an important role in modulating contact inhibition of locomotion (CIL) in the CNC to regulate directional cell migration. Here, we show that while the integral cadherin-11 requires the homophilic binding site to promote CNC migration in vivo, the EC1-3 fragment does not. In addition, we show that increased ADAM13 activity or expression of the EC1-3 fragment increases CNC invasiveness in vitro and blocks the repulsive CIL response in colliding cells. This activity requires the presence of an intact homophilic binding site on the EC1-3 suggesting that the cleavage fragment may function as a competitive inhibitor of cadherin-11 adhesion in CIL but not to promote cell migration in vivo.

  20. In vivo quantification by SPECT of [{sup 123}I] ADAM bound to serotonin transporters in the brains of rabbits

    Ye, X.-X. [Institute of Radiological Sciences, National Yang-Ming University, Taipei 112, Taiwan (China); Hwang, J.-J. [Institute of Radiological Sciences, National Yang-Ming University, Taipei 112, Taiwan (China); Hsieh, J.-F. [Department of Nuclear Medicine, Chi-Mei Foundation Medical Center, Yungkang City 710, Taiwan (China); Chen, J.-C. [Institute of Radiological Sciences, National Yang-Ming University, Taipei 112, Taiwan (China)]. E-mail: jcchen@ym.edu.tw; Chou, Y.-T. [Institute of Physiology, National Yang-Ming University, Taipei 112, Taiwan (China); Tu, K.-Y. [Department of Nuclear Medicine, Mackey Memorial Hospital, Taipei, Taiwan 104 (China); Wey, S.-P. [Department of Medical Imaging and Radiological Sciences, Chang-Gung University, Taoyuan, Taiwan 333 (China); Ting Gann [Institute of Nuclear Energy Research, Tao- Yuan 335, Taiwan (China)

    2004-11-01

    Background: A novel radioiodine ligand [{sup 123}I] ADAM (2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine) has been suggested as a promising serotonin transporter (SERT) imaging agent for the central nervous system. In this study, the biodistribution of SERTs in the rabbit brain was investigated using [{sup 123}I] ADAM and mapping images of the same animal produced by both single-photon emission computed tomography (SPECT) and microautoradiography. A semiquantification method was adopted to deduce the optimum time for SPECT imaging, whereas the input for a simple fully quantitative tracer kinetic model was provided from arterial blood sampling data. Methods: SPECT imaging was performed on female rabbits postinjection of 185 MBq [{sup 123}I] ADAM. The time-activity curve obtained from the SPECT images was used to quantify the SERTs, for which the binding potential was calculated from the kinetic modeling of [{sup 123}I] ADAM. The kinetic data were analyzed by the nonlinear least squares method. The effects of the selective serotonin reuptake inhibitors fluoxetine and p-chloroamphetamine (PCA) on rabbits were also evaluated. After scanning, the same animal was sacrificed and the brain was removed for microautoradiography. Regions-of-interest were analyzed using both SPECT and microautoradiography images. The SPECT images were coregistered manually with the corresponding microautoradiography images for comparative study. Results: During the time interval 90-100 min postinjection, the peak specific binding levels in different brain regions were compared and the brain stem was shown to have the highest activity. The target-to-background ratio was 1.89{+-}0.02. Similar studies with fluoxetine and PCA showed a background level for SERT occupation. Microautoradiography demonstrated a higher level of anatomical details of the [{sup 123}I] ADAM distribution than that obtained by SPECT imaging of the rabbit brain. Conclusion: SPECT imaging of the rabbit brain with

  1. Isotopic and trace element constraints on the petrogenesis of lavas from the Mount Adams volcanic field, Washington

    Jicha, B.R.; Hart, G.L.; Johnson, C.M.; Hildreth, W.; Beard, B.L.; Shirey, S.B.; Valley, J.W.

    2009-01-01

    Strontium, Nd, Pb, Hf, Os, and O isotope compositions for 30 Quaternary lava flows from the Mount Adams stratovolcano and its basaltic periphery in the Cascade arc, southern Washington, USA indicate a major component from intraplate mantle sources, a relatively small subduction component, and interaction with young mafic crust at depth. Major- and trace-element patterns for Mount Adams lavas are distinct from the rear-arc Simcoe volcanic field and other nearby volcanic centers in the Cascade arc such as Mount St. Helens. Radiogenic isotope (Sr, Nd, Pb, and Hf) compositions do not correlate with geochemical indicators of slab-fluids such as (Sr/P)n and Ba/Nb. Mass-balance modeling calculations, coupled with trace-element and isotopic data, indicate that although the mantle source for the calc-alkaline Adams basalts has been modified with a fluid derived from subducted sediment, the extent of modification is significantly less than what is documented in the southern Cascades. The isotopic and trace-element compositions of most Mount Adams lavas require the presence of enriched and depleted mantle sources, and based on volume-weighted chemical and isotopic compositions for Mount Adams lavas through time, an intraplate mantle source contributed the major magmatic mass of the system. Generation of basaltic andesites to dacites at Mount Adams occurred by assimilation and fractional crystallization in the lower crust, but wholesale crustal melting did not occur. Most lavas have Tb/Yb ratios that are significantly higher than those of MORB, which is consistent with partial melting of the mantle in the presence of residual garnet. ??18O values for olivine phenocrysts in Mount Adams lavas are within the range of typical upper mantle peridotites, precluding involvement of upper crustal sedimentary material or accreted terrane during magma ascent. The restricted Nd and Hf isotope compositions of Mount Adams lavas indicate that these isotope systems are insensitive to crustal

  2. Isotopic and trace element constraints on the petrogenesis of lavas from the Mount Adams volcanic field, Washington

    Jicha, Brian R.; Hart, Garret L.; Johnson, Clark M.; Hildreth, Wes; Beard, Brian L.; Shirey, Steven B.; Valley, John W.

    2009-02-01

    Strontium, Nd, Pb, Hf, Os, and O isotope compositions for 30 Quaternary lava flows from the Mount Adams stratovolcano and its basaltic periphery in the Cascade arc, southern Washington, USA indicate a major component from intraplate mantle sources, a relatively small subduction component, and interaction with young mafic crust at depth. Major- and trace-element patterns for Mount Adams lavas are distinct from the rear-arc Simcoe volcanic field and other nearby volcanic centers in the Cascade arc such as Mount St. Helens. Radiogenic isotope (Sr, Nd, Pb, and Hf) compositions do not correlate with geochemical indicators of slab-fluids such as (Sr/P) n and Ba/Nb. Mass-balance modeling calculations, coupled with trace-element and isotopic data, indicate that although the mantle source for the calc-alkaline Adams basalts has been modified with a fluid derived from subducted sediment, the extent of modification is significantly less than what is documented in the southern Cascades. The isotopic and trace-element compositions of most Mount Adams lavas require the presence of enriched and depleted mantle sources, and based on volume-weighted chemical and isotopic compositions for Mount Adams lavas through time, an intraplate mantle source contributed the major magmatic mass of the system. Generation of basaltic andesites to dacites at Mount Adams occurred by assimilation and fractional crystallization in the lower crust, but wholesale crustal melting did not occur. Most lavas have Tb/Yb ratios that are significantly higher than those of MORB, which is consistent with partial melting of the mantle in the presence of residual garnet. δ 18O values for olivine phenocrysts in Mount Adams lavas are within the range of typical upper mantle peridotites, precluding involvement of upper crustal sedimentary material or accreted terrane during magma ascent. The restricted Nd and Hf isotope compositions of Mount Adams lavas indicate that these isotope systems are insensitive to crustal

  3. Dynamic change of Adamalysin 19 (ADAM19) in human placentas and its effects on cell invasion and adhesion in human trophoblastic cells

    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.

  4. Towards the "Informed Use" of Information and Communication Technology in Education: A Response to Adams' "Powerpoint, Habits of Mind, and Classroom Culture"

    Vallance, Michael; Towndrow, Phillip A.

    2007-01-01

    PowerPoint, the widely-used slide-show software package, is finding increasing currency in lecture halls and classrooms as the preferred method of communicating and presenting information. But, as Adams [Adams, C. (2006) "PowerPoint, habits of mind, and classroom culture." "Journal of Curriculum Studies," 38(4), 389-411] attempts to show, users…

  5. ADAM in Holland? : Verslag van het onderzoek naar de haalbaarheid van de pilot monitoring van drugsgebruik onder arrestanten bij de politie Haaglanden

    Broek, Hans van den; Klerks, Peter; Otter, Paul den

    1999-01-01

    In de VS worden sinds 1987 systematisch gegevens verzameld over drugsgebruik onder aangehouden verdachten in het kader van het ADAM-programma. Als eerst stap naar een mogelijke Nederlandse ADAM wil het ministerie bezien in hoeverre er draagvlak bestaat voor een pilot in de politieregio Haaglanden.

  6. An algebra of reversible computation.

    Wang, Yong

    2016-01-01

    We design an axiomatization for reversible computation called reversible ACP (RACP). It has four extendible modules: basic reversible processes algebra, algebra of reversible communicating processes, recursion and abstraction. Just like process algebra ACP in classical computing, RACP can be treated as an axiomatization foundation for reversible computation.

  7. An algebra of reversible computation

    2016-01-01

    We design an axiomatization for reversible computation called reversible ACP (RACP). It has four extendible modules, basic reversible processes algebra (BRPA), algebra of reversible communicating processes (ARCP), recursion and abstraction. Just like process algebra ACP in classical computing, RACP can be treated as an axiomatization foundation for reversible computation.

  8. Reversible flowchart languages and the structured reversible program theorem

    Yokoyama, Tetsuo; Axelsen, Holger Bock; Glück, Robert

    2008-01-01

    Many irreversible computation models have reversible counterparts, but these are poorly understood at present. We introduce reversible flowcharts with an assertion operator and show that any reversible flowchart can be simulated by a structured reversible flowchart using only three control flow o...... justification for low-level machine code for reversible microprocessors as well as high-level block-structured reversible languages. We give examples for both such languages and illustrate them with a lossless encoder for permutations given by Dijkstra....

  9. Reversible Data Hiding Techniques

    Dhananjay Yadav

    2012-03-01

    Full Text Available Reversible data hiding is a technique that is used to hide data inside an image. The data is hidden in such a way that the exact or original data is not visible. The hidden data can be retrieved as and when required. There are several methods that are used in reversible data hiding techniques like Watermarking, Lossless embedding and encryption. In this paper we present a review of reversible watermarking techniques and show different methods that are used to get reversible data hiding technique with higher embedding capacity and invisible objects. Watermark need not be hidden. Watermarking can be applied to 1. Images, 2. Text, 3. Audio/video, 4. Software.

  10. Adaptive Pairing Reversible Watermarking.

    Dragoi, Ioan-Catalin; Coltuc, Dinu

    2016-05-01

    This letter revisits the pairwise reversible watermarking scheme of Ou et al., 2013. An adaptive pixel pairing that considers only pixels with similar prediction errors is introduced. This adaptive approach provides an increased number of pixel pairs where both pixels are embedded and decreases the number of shifted pixels. The adaptive pairwise reversible watermarking outperforms the state-of-the-art low embedding bit-rate schemes proposed so far.

  11. 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

    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)

  12. ADAM28 is expressed by epithelial cells in human normal tissues and protects from C1q-induced cell death.

    Miyamae, Yuka; Mochizuki, Satsuki; Shimoda, Masayuki; Ohara, Kentaro; Abe, Hitoshi; Yamashita, Shuji; Kazuno, Saiko; Ohtsuka, Takashi; Ochiai, Hiroki; Kitagawa, Yuko; Okada, Yasunori

    2016-05-01

    ADAM28 (disintegrin and metalloproteinase 28), which was originally reported to be lymphocyte-specific, is over-expressed by carcinoma cells and plays a key role in cell proliferation and progression in human lung and breast carcinomas. We studied ADAM28 expression in human normal tissues and examined its biological function. By using antibodies specific to ADAM28, ADAM28 was immunolocalized mainly to epithelial cells in several tissues, including epididymis, bronchus and stomach, whereas lymphocytes in lymph nodes and spleen were negligibly immunostained. RT-PCR, immunoblotting and ELISA analyses confirmed the expression in these tissues, and low or negligible expression by lymphocytes was found in the lymph node and spleen. C1q was identified as a candidate ADAM28-binding protein from a human lung cDNA library by yeast two-hybrid system, and specific binding was demonstrated by binding assays, immunoprecipitation and surface plasmon resonance. C1q treatment of normal bronchial epithelial BEAS-2B and NHBE cells, both of which showed low-level expression of ADAM28, caused apoptosis through activation of p38 and caspase-3, and cell death with autophagy through accumulation of LC3-II and autophagosomes, respectively. C1q-induced cell death was attenuated by treatment of the cells with antibodies against the C1q receptor gC1qR/p33 or cC1qR/calreticulin. Treatment of C1q with recombinant ADAM28 prior to addition to culture media reduced C1q-induced cell death, and knockdown of ADAM28 using siRNAs increased cell death. These data demonstrate that ADAM28 is expressed by epithelial cells of several normal organs, and suggest that ADAM28 plays a role in cell survival by suppression of C1q-induced cytotoxicity in bronchial epithelial cells.

  13. On thermodynamic and microscopic reversibility

    Crooks, Gavin E.

    2011-07-12

    The word 'reversible' has two (apparently) distinct applications in statistical thermodynamics. A thermodynamically reversible process indicates an experimental protocol for which the entropy change is zero, whereas the principle of microscopic reversibility asserts that the probability of any trajectory of a system through phase space equals that of the time reversed trajectory. However, these two terms are actually synonymous: a thermodynamically reversible process is microscopically reversible, and vice versa.

  14. 77 FR 25229 - Adams-Warnock Railway, Inc.-Lease and Operation Exemption-Norfolk Southern Railway Company

    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...

  15. ADAM9 up-regulates N-cadherin via miR-218 suppression in lung adenocarcinoma cells.

    Yuh-Pyng Sher

    Full Text Available Lung cancer is the leading cause of cancer death worldwide, and brain metastasis is a major cause of morbidity and mortality in lung cancer. CDH2 (N-cadherin, a mesenchymal marker of the epithelial-mesenchymal transition and ADAM9 (a type I transmembrane protein are related to lung cancer brain metastasis; however, it is unclear how they interact to mediate this metastasis. Because microRNAs regulate many biological functions and disease processes (e.g., cancer by down-regulating their target genes, microRNA microarrays were used to identify ADAM9-regulated miRNAs that target CDH2 in aggressive lung cancer cells. Luciferase assays and western blot analysis showed that CDH2 is a target gene of miR-218. MiR-218 was generated from pri-mir-218-1, which is located in SLIT2, in non-invasive lung adenocarcinoma cells, whereas its expression was inhibited in aggressive lung adenocarcinoma. The down-regulation of ADAM9 up-regulated SLIT2 and miR-218, thus down-regulating CDH2 expression. This study revealed that ADAM9 activates CDH2 through the release of miR-218 inhibition on CDH2 in lung adenocarcinoma.

  16. PKCa and PKCd regulate ADAM17-mediated ectodomain shedding of heparin binding-EGF through separate pathways

    Kveiborg, Marie; Instrell, Rachael; Rowlands, Christina;

    2011-01-01

    -EGF. We identified PKCa as the key participant in the activation of ADAM17 and suggest that it acts in parallel with a pathway linking PKCd and ERK activity. While PKCa specifically regulated PMA-induced shedding, PKCd and ERK influenced both constitutive and inducible shedding by apparently affecting...

  17. Analysis of the Oscillating Mechanism of an Aerial Work Platform Based on ADAMS Hydraulic-Mechanical Coupling Simulation

    GU De-jun; TENG Ru-min; GAO Shun-de; BAI Ri; GAO Kai-qing

    2008-01-01

    Rigid model of the aerial work platform and hydraulic model of the oscillating mechanism were established with ADAMS. The simulation of two parameters, cy-linder force and oil chamber pressure, was carried out. The simulation result is useful to the design of the oscillating mechanism.

  18. Lightweight robotic mobility: template-based modeling for dynamics and controls using ADAMS/car and MATLAB

    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.

  19. Loss of the metalloprotease ADAM9 leads to cone-rod dystrophy in humans and retinal degeneration in mice.

    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; Johnson, Colin A; Booth, Adam P; Jafri, Hussain; Rashid, Yasmin; Banin, Eyal; Strom, Tim M; Farber, Debora B; Sharon, Dror; Blobel, Carl P; Pugh, Edward N; Pierce, Eric A; Inglehearn, Chris F

    2009-05-01

    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 processes of the retinal pigment epithelium (RPE) cells are disorganized and contact between photoreceptor outer segments (POSs) and the RPE apical surface is compromised. In 20-month-old mice, there is clear evidence of progressive retinal degeneration with disorganized POS and thinning of the outer nuclear layer (ONL) in addition to the anomaly at the POS-RPE junction. RPE basal deposits and macrophages were also apparent in older mice. These findings therefore not only identify ADAM9 as a CRD gene but also identify a form of pathology wherein retinal disease first manifests at the POS-RPE junction.

  20. Kuidas meeldib välismaalastele Eestis [õppida]? / Shazia Javed, Charina de Asis, Adam Luke Vern-Barnett, Predrag Tasevski

    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

  1. A new approach to sharp Moser-Trudinger and Adams type inequalities: A rearrangement-free argument

    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 αAdams inequalities 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]).

  2. Reversible Communicating Processes

    Geoffrey Brown

    2016-02-01

    Full Text Available Reversible distributed programs have the ability to abort unproductive computation paths and backtrack, while unwinding communication that occurred in the aborted paths. While it is natural to assume that reversibility implies full state recovery (as with traditional roll-back recovery protocols, an interesting alternative is to separate backtracking from local state recovery. For example, such a model could be used to create complex transactions out of nested compensable transactions where a programmer-supplied compensation defines the work required to "unwind" a transaction. Reversible distributed computing has received considerable theoretical attention, but little reduction to practice; the few published implementations of languages supporting reversibility depend upon a high degree of central control. The objective of this paper is to demonstrate that a practical reversible distributed language can be efficiently implemented in a fully distributed manner. We discuss such a language, supporting CSP-style synchronous communication, embedded in Scala. While this language provided the motivation for the work described in this paper, our focus is upon the distributed implementation. In particular, we demonstrate that a "high-level" semantic model can be implemented using a simple point-to-point protocol.

  3. ADAM: Analysis of Discrete Models of Biological Systems Using Computer Algebra

    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...

  4. The allegorical meditation on the base of The Fasciculus of various prayer by Adam Opatowiusz

    Marcin Godawa

    2009-03-01

    Full Text Available This article undertakes the issues of applying the allegorical method of withdrawing meanings from the biblical text during the meditation. It bases on The Fasciculus of various prayer (Fascykuł nabożeństwa różnego by Adam Opatowiusz (1574–1647. The author used the ways of rhetorical allegorization and biblical theory of senses in order to realize the persuasive aims of prayer comprehended as means of spiritual growth. The rhetorical allegorization includes the relation between biblical senses and human experience, which results in four kinds of allegory: the biblical-biblical, biblical-experimental, experimental-biblical and experimental-experimental allegory. It helps in explaining, developing and referring the biblical meanings to spiritual life being also a pivot of reflection whereas the literary elements are subordinated to the spiritual matter.

  5. Adam Smith's invisible hand is unstable: physics and dynamics reasoning applied to economic theorizing

    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’.

  6. ADAM Project – A generic web interface for retrieval and display of ATLAS TDAQ information.

    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...

  7. Raymond D. Adams, gigante de la neurología norteamericana

    Palacios, Leonardo

    2011-01-01

    El profesor Raymond D. Adams (1911-2010) fue una de las figuras más prominentes de la neurología norteamericana en el siglo XX. Realizó sus estudios de medicina en la Universidad de Duke. Posteriormente, inició especialización en psiquiatría, pero optó por dedicarse al estudio de la patología del sistema nervioso y a la neurología en el Hospital de Boston durante 10 años. Luego fue contratado por el Hospital General de Massachusetts, donde dirigió del Departamento de Neurología por más de 25 ...

  8. "Solutio theorematum" by Adam Adamandy Kocha\\'nski -- Latin text with annotated English translation

    Fukś, Henryk

    2011-01-01

    Annotated parallel text in Latin and English of the paper of Adam Adamandy Kocha\\'nski "Solutio Theorematum Ab illustri Viro in Actis hujus Anni Mense Januario, pag. 28. propositorum", Acta Eruditorum, Lipsiae 1682, pp. 230-236, in which he presented solutions of two geometric problems proposed by an anonymous author in the same journal in January 1682. The Latin text of "Solutio theorematum" presented here closely follows the original text published in "Acta Eruditorum". Punctuation, capitalization, and mathematical notation have been preserved. Several misprints which appeared in the original are also reproduced unchanged, but with a footnote indicating correction. Every effort has been made to preserve the layout of original tables. The translation is as faithful as possible, often literal, and it is mainly intended to be of help to those who wish to study the original Latin text. In the appendix, all propositions from Euclid's "Elements" mentioned in the text are listed in both Latin and English.

  9. The Fire of Life. Adam Zagajewski’s poem “About My Mother”

    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.

  10. Function of ADAMs in Mammalian Fertilization%ADAMs与哺乳动物受精

    徐存拴; 熊蕾; 卢龙斗

    2001-01-01

    ADAMs是近几年发现的一类具有多个结构区和广泛生物学功能的糖蛋白,它们在哺乳动物受精中的作用日益得到实验结果的支持,本文简要总结了近几年ADAMs在哺乳动物受精中作用的研究进展。%ADAMs are a group of transmembrane glycoproteins found recently, which possess multidomain and function. Their action in mammalian fertilization was confirmed by more and more experiments. The progress that got from research on their action in mammalian fertilization were summarized in this paper.

  11. Kinematic and Dynamic Simulation Analysis of Hydraulic Excavator’s Working Equipment based on ADAMS

    Yu Hong Yan

    2016-01-01

    Full Text Available This paper establishes the 3D excavator model according to the actual size in UG firstly. Then based on the virtual simulation software ADAMS, the virtual prototype of the working device is built by adding interrelated constraints(kinematic pair and hydraulic cylinder driving function and load secondly. This paper gets the main parameters of the excavator working scope and the pressure situation change curves of point of each hydraulic cylinder by making kinematic and dynamic simulation analysis of hydraulic excavator’s working equipment at last. The conclusion providing design theory and improvement for the excavator’s working device, which also play an important role in improving the level of China’s excavator design, enhancing excavator’s performance and promoting the rapid development of excavator industry.

  12. Simulation Study of AC Contactor Dynamic Contacts Contact Pressure Based on ADAMS

    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.

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

    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.

  14. Heightened cleavage of Axl receptor tyrosine kinase by ADAM metalloproteases may contribute to disease pathogenesis in SLE.

    Orme, Jacob J; Du, Yong; Vanarsa, Kamala; Mayeux, Jessica; Li, Li; Mutwally, Azza; Arriens, Cristina; Min, Soyoun; Hutcheson, Jack; Davis, Laurie S; Chong, Benjamin F; Satterthwaite, Anne B; Wu, Tianfu; Mohan, Chandra

    2016-08-01

    Systemic lupus erythematosus (SLE) is characterized by antibody-mediated chronic inflammation in the kidney, lung, skin, and other organs to cause inflammation and damage. Several inflammatory pathways are dysregulated in SLE, and understanding these pathways may improve diagnosis and treatment. In one such pathway, Axl tyrosine kinase receptor responds to Gas6 ligand to block inflammation in leukocytes. A soluble form of the Axl receptor ectodomain (sAxl) is elevated in serum from patients with SLE and lupus-prone mice. We hypothesized that sAxl in SLE serum originates from the surface of leukocytes and that the loss of leukocyte Axl contributes to the disease. We determined that macrophages and B cells are a source of sAxl in SLE and in lupus-prone mice. Shedding of the Axl ectodomain from the leukocytes of lupus-prone mice is mediated by the matrix metalloproteases ADAM10 and TACE (ADAM17). Loss of Axl from lupus-prone macrophages renders them unresponsive to Gas6-induced anti-inflammatory signaling in vitro. This phenotype is rescued by combined ADAM10/TACE inhibition. Mice with Axl-deficient macrophages develop worse disease than controls when challenged with anti-glomerular basement membrane (anti-GBM) sera in an induced model of nephritis. ADAM10 and TACE also mediate human SLE PBMC Axl cleavage. Collectively, these studies indicate that increased metalloprotease-mediated cleavage of leukocyte Axl may contribute to end organ disease in lupus. They further suggest dual ADAM10/TACE inhibition as a potential therapeutic modality in SLE.

  15. [Adam hammer (1818 - 1878) - remarks on a forgotten pioneer of ether anaesthesia in obstetrics].

    Goerig, M; Streckfuss, W

    2004-05-01

    Adam Hammer, born in 1818, and working as a doctor for the poor since 1847 in Mannheim, was the first person in the German speaking world to use ether for pain relief during labor on February 18th 1847. He took part in the abortive April 1848 Revolution in Mannheim - a pinnacle of German liberalism and later of political radicalism, which attented to abolish the Monarchy and introduce a democratic Republic. After the revolution was put down, Hammer emigrated to the United States and settled down in St. Louis, Missouri. Remaining politically active, he joined the Republican Party, founded in 1854 and served as a military surgeon in the Union Army during the American Civil War. Even before the war, he was engaged in efforts to improve the level of medical training in America and was involved with the foundation of High Schools which offered training courses along the lines of German universities. His ideas and innovations were not introduced immediately, but had a significant impact on medical training methology later on in the US. During a visit in Europe in 1876, he was the first to diagnose a coronary thombosis as the cause of a heart attack on a live patient. The diagnosis was later confirmed by post-morten autopsy on the patient. In 1877 he returned to Germany and died one year later. The biography of Adam Hammer mirrows that of many other German-Americans whose emigration proved to be a gain for America but a loss for Germany. This story was destinated to be repeated in terrible circumstances some decades later.

  16. Radiation controlling reversible window

    Gell, H.A. Jr.

    1980-01-01

    A coated glass glazing system is presented including a transparent glass substrate having one surface coated with a radiation absorptive film which is overcoated with a radiation reflective film by a technique which renders the radiation reflective film radiation absorptive at the surface contracting the radiating absorptive film. The coated glass system is used as glazing for storm windows which are adapted to be reversible so that the radiation reflective surface may be exposed to the outside of the dwelling during the warm seasons to prevent excessive solar radiation from entering a dwelling and reversed during cold seasons to absorb solar radiation and utilize it to aid in keeping the dwelling interior warm.

  17. Sequential Polarity-Reversing Circuit

    Labaw, Clayton C.

    1994-01-01

    Proposed circuit reverses polarity of electric power supplied to bidirectional dc motor, reversible electro-mechanical actuator, or other device operating in direction depending on polarity. Circuit reverses polarity each time power turned on, without need for additional polarity-reversing or direction signals and circuitry to process them.

  18. Reverse Coherent Information

    García-Patrón, Raúl; Pirandola, Stefano; Lloyd, Seth; Shapiro, Jeffrey H.

    2009-05-01

    In this Letter we define a family of entanglement distribution protocols assisted by feedback classical communication that gives an operational interpretation to reverse coherent information, i.e., the symmetric counterpart of the well-known coherent information. This leads to the definition of a new entanglement distribution capacity that exceeds the unassisted capacity for some interesting channels.

  19. Time reversal communication system

    Candy, James V.; Meyer, Alan W.

    2008-12-02

    A system of transmitting a signal through a channel medium comprises digitizing the signal, time-reversing the digitized signal, and transmitting the signal through the channel medium. The channel medium may be air, earth, water, tissue, metal, and/or non-metal.

  20. On reverse hypercontractivity

    Mossel, Elchanan; Sen, Arnab

    2011-01-01

    We study the notion of reverse hypercontractivity. We show that reverse hypercontractive inequalities are implied by standard hypercontractive inequalities as well as by the modified log-Sobolev inequality. Our proof is based on a new comparison lemma for Dirichlet forms and an extension of the Strook-Varapolos inequality. A consequence of our analysis is that {\\em all} simple operators $L=Id-\\E$ as well as their tensors satisfy uniform reverse hypercontractive inequalities. That is, for all $qreverse hypercontractive inequalities established here imply new mixing and isoperimetric results for short random walks in product spaces, for certain card-shufflings, for Glauber dynamics in high-temperat...

  1. REVERSE SUPPLY CHAIN

    Tomasz DOMAGAŁA

    2013-10-01

    Full Text Available The paper focuses on the presentation of the reverse supply chain, of which the role in the modern business grows along with the increasing number of environmental regulations and possibilities of reducing an operating cost. The paper also describes main problems in developing the profitable chain and possibilities to take an action in order to overcome them.

  2. Reversed extension flow

    Nielsen, Jens Kromann; Rasmussen, Henrik K.

    2008-01-01

    Afilament stretching rheometer (FSR) was used for measuring the start-up of uni-axial elongational flow followed by reversed bi-axial flow, both with a constant elongational rate. A narrow molecular mass distribution linear polystyrene with a molecular weight of 145 kg / mole wis subjected to the...

  3. 基于Matlab/Simulink与Adams/Car的车辆稳定性控制系统联合仿真%Co-simulation of Vehicle Stability Control System Based on Matlab/Simulink and Adams/Car

    周红妮; 袁浩文

    2012-01-01

    利用Adams/CAR建立整车动力学仿真模型,在Matlab/Simulink中建立一种车辆稳定性控制器,并通过Adams/Control模块实现两者之间的联合仿真.阶跃仿真和正弦仿真结果表明:设计的控制器能有效控制车辆的稳定性,验证了联合仿真方法的可行性,为车辆稳定性控制系统控制策略的快速开发提供参考.

  4. 基于ADAMS/Car Ride的整车平顺性建模与仿真%Modeling and simulation of vehicle ride based on ADAMS/Car Ride

    王南; 平恩顺; 岳龙山; 李伟

    2010-01-01

    利用机械系统动力学分析软件ADAMS/Car Ride模块建立整车虚拟样机模型,应用虚拟四柱试验台对整车模型进行随机输入和脉冲输入下的平顺性仿真试验.仿真结果表明:ADAMS/Car Ride可简洁有效地进行整车平顺性仿真试验,实现了在设计阶段对汽车进行平顺性预测与分析的目标,从而为车辆的前期开发提供设计依据.

  5. 基于Adams-AMESim的平台吊机升沉补偿系统联合仿真技术%The Co-simulation Technique of Active-heave Compensation System of Platform Crane Based on Adams and AMESim

    杨诚; 邓智勇; 高磊; 唐国元

    2014-01-01

    利用Adams的虚拟样机弥补AMESim的不足,建立基于Adams-AMESim的虚拟样机联合仿真模型,完成主被动一体式平台吊机升沉补偿系统的联合仿真,不同波浪条件下的仿真结果表明该系统具有很好的补偿效果,波浪频率对补偿效果的影响较大,说明基于Adams-AMESim的联合仿真系统能够可靠实现多领域联合仿真,可以为海上平台吊机升沉补偿系统的分析提供良好的虚拟试验平台.

  6. Optimization of Alignment Parameters of Automotive Suspension based on ADAMS/INSIGHT%基于 ADAMS/INSIGHT 的汽车悬架定位参数优化设计

    丁亚康; 翟润国; 井绪文

    2011-01-01

    运用 ADAMS/CAR 建立某车型前悬架的精确模型,并分析了该悬架定位参数随车轮跳动的变化情况.针对分析中存在前束角和外倾角变化范围较大问题,运用 ADAMS/INSIGHT,通过对悬架部分硬点坐标和优化目标多次修改和迭代计算,系统可自动找出最优结果.对比优化前、后车轮定位参数可知,不仅前束角和外倾角优化目标达到,其它车轮定位参数的变化范围也有所缩小.%A precise model of a car front suspension is established with ADAMS/CAR, and the change of alignment parameters of the suspension with the bump of the wheels is analyzed.To solve the problem of excessive change of toe-in and camber existing in the analysis, ADAMS/INSIGHT is applied.By repeated correction and iterative calculation of suspension hard point coordinate and optimization target, the optimum result can be identified by the system automatically.It is concluded by comparing the front/rear wheel alignment parameter before and after optimization that not only the optimization objective of toe-in and camber is achieved, but also the scope of change of other wheel alignment parameters is limited down.

  7. 基于 ADAMS 的方程式赛车前悬架分析与优化%Th e Analysis and Optimization on the Front Su spension Syts em of a Formula Racing Vehicle Based on ADAMS

    骆阳; 智淑亚; 张劼

    2014-01-01

    It introduces the analysis and optimization of front suspension system for a certain type of Formula Student China (FSC) racing vehicle.It establishes the flexible multi -body model of the front suspension system for racing vehicle and obtains the elastic kinematics mode with dynamic software ADAMS/CAR, analyzes the ki-nematic characteristics of suspension system in the test of parallel wheel travel and the steering handiness and an -ti-dive performance in test of braking .The analysis results show that the laws of kingpin inclination angle , cam-ber angle , steering wheel torque and scrub radius are unfit for designation requirements .It defines the multi -objectively optimization system by ADAMS/INSIGHT and gives each parameter finally .This optimization design improves the system's kinematic characteristics and steering handiness.%针对某型大学生方程式赛车前悬架系统进行分析与优化。利用动力学软件ADAMS/CAR建立该赛车前悬架多柔体模型,并在弹性运动学模式下进行仿真。分析了双轮平行跳动时悬架运动特性和赛车制动时的转向轻便性与抗点头性,结果显示主销内倾角、车轮外倾角、转向盘力矩与磨胎半径变化规律不符合设计要求。运用ADAMS/INSIGHT对原系统进行多目标优化,最终各参数均得到优化,改善了悬架系统的运动学特性与赛车的转向轻便性。

  8. Reversible quantum cellular automata

    Schumacher, B

    2004-01-01

    We define quantum cellular automata as infinite quantum lattice systems with discrete time dynamics, such that the time step commutes with lattice translations and has strictly finite propagation speed. In contrast to earlier definitions this allows us to give an explicit characterization of all local rules generating such automata. The same local rules also generate the global time step for automata with periodic boundary conditions. Our main structure theorem asserts that any quantum cellular automaton is structurally reversible, i.e., that it can be obtained by applying two blockwise unitary operations in a generalized Margolus partitioning scheme. This implies that, in contrast to the classical case, the inverse of a nearest neighbor quantum cellular automaton is again a nearest neighbor automaton. We present several construction methods for quantum cellular automata, based on unitaries commuting with their translates, on the quantization of (arbitrary) reversible classical cellular automata, on quantum c...

  9. 基于ADAMS的双横臂悬架系统仿真%ADAMS double wishbone suspension system simulation based on

    赵妞

    2013-01-01

      本文运用ADAMS/Car对双横臂独立悬架进行建模并仿真,在观察悬架运动过程中,初步验证了运用ADAMS/Car进行汽车悬架建模仿真的合理性,从而为悬架的设计提供了一种新的可行性方案。%in this paper, using ADAMS/Car modeling and Simulation of the double wishbone independent suspension, in the observation of suspension movement process, preliminary validate the rationality of the use of ADAMS/Car vehicle suspension system modeling and simulation, which provides a new feasible scheme for suspension design.

  10. Record of Decision for the Final Remedial Action for the Rocky Mountain Arsenal Offpost Unit in southern Adams County, Commerce City, Colorado

    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...

  11. Reversible multi-head finite automata characterize reversible logarithmic space

    Axelsen, Holger Bock

    2012-01-01

    Deterministic and non-deterministic multi-head finite automata are known to characterize the deterministic and non- deterministic logarithmic space complexity classes, respectively. Recently, Morita introduced reversible multi-head finite automata (RMFAs), and posed the question of whether RMFAs...... characterize reversible logarithmic space as well. Here, we resolve the question affirmatively, by exhibiting a clean RMFA simulation of logarithmic space reversible Turing machines. Indirectly, this also proves that reversible and deterministic multi-head finite automata recognize the same languages....

  12. Choreography is a technology of presence, and desire. Adam Linder as told to Anaïs Nony

    Anaïs Nony

    2016-11-01

    Full Text Available In an interview conducted on October, 26 2015 at the FD13 Residency for the Arts in Saint- Paul, Minnesota, Adam Linder talks about choreography as being both a technology of presence and desire. Starting off with a reflection concerning the diverse languages he uses in his artwork, Linder quickly turns his attention to the complex relationships between body movements, abstraction, and diverse forms of codification. He underlines how cultural influences are shaping production of languages and their commodification, and describes the technics he deploys for the body to remain a central mode of expression. Recipient of the Mohn Prize for artistic excellence in 2016, Adam Linder (b. 1983, Sydney is a choreographer and dancer based in Los Angeles and Berlin.

  13. Tumor necrosis factor α-converting enzyme (TACE/ADAM17) mediates ectodomain shedding of the scavenger receptor CD163

    Etzerodt, Anders; Maniecki, Maciej Bogdan; Møller, Kirsten;

    2010-01-01

    is seen between the sCD163 plasma level and the severity of various infectious and inflammatory diseases. In the present analysis of the phorbol ester-induced shedding of sCD163 in CD163 cDNA-transfected HEK293 cells, we used metalloproteinase inhibitors and siRNA-mediated inhibition of metalloproteinases...... to identify TACE/ADAM17 as an enzyme responsible for PMA-induced cleavage of the membrane-proximal region of CD163. As TACE/ADAM17-mediated shedding of TNF-α is up-regulated in macrophages subjected to inflammatory stimuli, the present results now provide a likely explanation for the strong empirical...

  14. Tumor necrosis factor α-converting enzyme (TACE/ADAM17) mediates ectodomain shedding of the scavenger receptor CD163

    Etzerodt, Anders; Maniecki, Maciej Bogdan; Møller, Kirsten;

    2010-01-01

    is seen between the sCD163 plasma level and the severity of various infectious and inflammatory diseases. In the present analysis of the phorbol ester-induced shedding of sCD163 in CD163 cDNA-transfected HEK293 cells, we used metalloproteinase inhibitors and siRNA-mediated inhibition of metalloproteinases...... to identify TACE/ADAM17 as an enzyme responsible for PMA-induced cleavage of the membrane-proximal region of CD163. As TACE/ADAM17-mediated shedding of TNF-alpha is up-regulated in macrophages subjected to inflammatory stimuli, the present results now provide a likely explanation for the strong empirical...

  15. Involvement of the serine/threonine p70S6 kinase in TGF-beta1-induced ADAM12 expression in cultured human hepatic stellate cells

    Le Pabic, Hélène; L'Helgoualc'h, Annie; Coutant, Alexandre;

    2005-01-01

    In chronic liver injury, quiescent hepatic stellate cells change into proliferative myofibroblast-like cells, which are a main source of fibrosis. We have recently reported that these cells synthesize ADAM12, a disintegrin and metalloprotease whose expression is up-regulated by TGF-beta1 in liver...... cancers. Here, we studied the role of the serine/threonine p70S6 kinase (p70S6K) in regulating TGF-beta1-induced ADAM12 expression....

  16. [Reverse Chaddock sign].

    Tashiro, Kunio

    2011-08-01

    It is widely accepted that the Babinski reflex is the most well-known and important pathological reflex in clinical neurology. Among many other pathological reflexes that elicit an upgoing great toe, such as Chaddock, Oppenheim, Gordon, Schaefer, and Stransky, only the Chaddock reflex is said to be as sensitive as the Babinski reflex. The optimal receptive fields of the Babinski and Chaddock reflexes are the lateral plantar surface and the external inframalleolar area of the dorsum, respectively. It has been said that the Babinski reflex, obtained by stroking the sole, is by far the best and most reliable method of eliciting an upgoing great toe. However, the Chaddock reflex, the external malleolar sign, is also considered sensitive and reliable according to the literature and everyday neurological practice. The major problems in eliciting the Babinski reflex by stroking the lateral part of the sole are false positive or negative responses due to foot withdrawal, tonic foot response, or some equivocal movements. On the other hand, according to my clinical experience, the external inframalleolar area, which is the receptive field of the Chaddock reflex, is definitely suitable for eliciting the upgoing great toe. In fact, the newly proposed method to stimulate the dorsum of the foot from the medial to the lateral side, which I term the "reversed Chaddock method," is equally sensitive to demonstrate pyramidal tract involvement. With the "reversed Chaddock method", the receptive field of the Chaddock reflex may be postulated to be in the territory of the sural nerve, which could be supported by the better response obtained on stimulation of the postero-lateral calf than the anterior shin. With regard to the receptive fields of the Babinski and Chaddock reflexes, the first sacral dermatome (S1) is also considered a reflexogenous zone, but since the dermatome shows marked overlapping, the zones vary among individuals. As upgoing toe responses are consistently observed in

  17. Karakteristik Abses Leher Dalam Di SMF THT-KL RSUP. H. Adam Malik Medan Tahun 2006-2012.

    2015-01-01

    Introduction: A deep neck infection is a neck infection at the space (a potential) between the fascia of the neck, consists of peritonsil, parapharynx, retropharynx and submandibular abscesses. Currently, the case of deep neck infection is rarely found since the discovering of antibiotics. Deep neck infection is still a case of emergency in ENT-HNS cause resulting a fatal complications. Purpose: To identify the characteristic of deep neck infection at H. Adam Malik General Hospital Medan ...

  18. The Inner Man and his Deed: Jerzy Grotowski and the legacy of Adam Mickiewicz and polish romanticism

    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.

  19. Prevalensi Malnutrisi Berdasarkan Antropometri pada Pasien Lansia di Rumah Sakit Umum Pusat Haji Adam Malik Tahun 2016

    Arif, Shafira Hazmi

    2017-01-01

    Malnutrition is one of numerous problems happening to the elderly. High prevalence of malnutrition in the elderly and with plenty of impacts caused make grading nutrition status crucial to undergo as an initial step to maintain or improve nutrition status of the elderly. This research aimed to figure out nutrition status of the elderly in RSUP H. Adam Malik Medan. The research design used was descriptive involving 57 people. Data collection was carried out by consecutive sampling technique...

  20. Association study on ADAM33 polymorphisms in mite-sensitized persistent allergic rhinitis in a Chinese population.

    Ruo-Xi Chen

    Full Text Available BACKGROUND: The ADAM33 gene has been identified as a potentially important asthma candidate gene and polymorphisms in this gene have been shown to be associated with asthma and seasonal allergic rhinitis. OBJECTIVE: To assess whether the ADAM33 polymorphisms are associated with persistent allergic rhinitis (PER due to house dust mites in a Chinese population. METHODS: In a hospital-based case-control study of 515 patients with mite-sensitized PER and 495 healthy controls, we genotyped seven single nucleotide polymorphisms (SNPs in ADAM33. Serum levels of eosinophil cationic protein, total IgE and allergen-specific IgE against Dermatophagoides pteronyssinus and Dermatophagoides farinae were measured by the ImmunoCAP assays. RESULTS: In the single-locus analysis, three polymorphisms, rs3918392 (F1, rs528557 (S2 and rs2787093, were significantly associated with mite-sensitized PER. SNP S2 was associated with significantly increased risk both of asthmatic and nonasthmatic mite-sensitized PER. In the combined genotypes analysis, individuals with 2-4 risk alleles had a significantly higher risk of mite-sensitized PER (adjusted OR = 1.99, 95% CI = 1.50-2.62 than those with 0-1 risk alleles. Haplotype-based association analysis revealed that the ACAGCCT haplotype might have potential to protect against mite-sensitized PER (adjusted OR = 0.67; 95% CI = 0.49-0.90. CONCLUSIONS: Polymorphisms in the ADAM33 gene may contribute to susceptibility of mite-sensitized PER in this Chinese population.

  1. Association of ADAM33 gene polymorphisms with adult-onset asthma and its severity in an Indian adult population

    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.

  2. Karakteristik Penyakit Jantung Bawaan pada Neonatus di unit Neonatologi RSUP Haji Adam Malik Medan Periode 2011 – 2013

    Ameen, Asna Hidaya Binti Mohammed

    2015-01-01

    Background: Congenital Heart Disease is a congenital disorder with abnormalities in the cardiac structure or the function of the heart’s circulation, caused when the cardiac structures failed to develop in the early phase of fetal development. Objective: This study aims to investigate the characteristic of Congenital Heart Disease in neonates in the neonatology unit of RSUP Haji Adam Malik from 2011-2013. Method: The population in this study is all neonates with Congenital Heart Disease...

  3. ADAMS柔性体运动仿真分析及运用%Application of ADAMS flexible body kinetic simulation

    焦广发; 周兰英

    2007-01-01

    介绍机械系统自动动力学分析软件(ADAMS)柔性体基本理论及在ADAMS中生成柔性体的几种方法,并构建机械系统仿真模型,通过一个实例验证ADAMS柔性体运动仿真分析的实效.

  4. Increased abundance of ADAM9 transcripts in the blood is associated with tissue damage [version 2; referees: 2 approved, 1 approved with reservations

    Darawan Rinchai

    2016-10-01

    Full Text Available Background: Members of the ADAM (a disintegrin and metalloprotease domain family have emerged as critical regulators of cell-cell signaling during development and homeostasis. ADAM9 is consistently overexpressed in various human cancers, and has been shown to play an important role in tumorigenesis. However, little is known about the involvement of ADAM9 during immune-mediated processes. Results: Mining of an extensive compendium of transcriptomic datasets identified important gaps in knowledge regarding the possible role of ADAM9 in immunological homeostasis and inflammation: 1 The abundance of ADAM9 transcripts in the blood was increased in patients with acute infection but, 2 changed very little after in vitro exposure to a wide range of pathogen-associated molecular patterns (PAMPs. 3 Furthermore it was found to increase significantly in subjects as a result of tissue injury or tissue remodeling, in absence of infectious processes. Conclusions: Our findings indicate that ADAM9 may constitute a valuable biomarker for the assessment of tissue damage, especially in clinical situations where other inflammatory markers are confounded by infectious processes.

  5. Fisetin suppresses ADAM9 expression and inhibits invasion of glioma cancer cells through increased phosphorylation of ERK1/2.

    Chen, Chien-Min; Hsieh, Yi-Hsien; Hwang, Jin-Ming; Jan, Hsun-Jin; Hsieh, Shu-Ching; Lin, Shin-Huey; Lai, Chung-Yu

    2015-05-01

    Fisetin (3,3',4',7-tetrahydroxyflavone) is a naturally occurring flavonoid which is widely distributed in plants. It has been reported to possess some anticancer and anti-invasive capabilities. We set out to explore the effects of fisetin on antimetastatic and its mechanism of action in GBM8401 cells. The results indicated that fisetin exhibited effective inhibition of cell migration and inhibited the invasion of GBM8401 cells under non-cytotoxic concentrations. To identify the potential targets of fisetin, human proteinase antibody array analysis was performed, and the results indicated that the fisetin treatment inhibited the expression of ADAM9 protein and mRNA, which are known to contribute to the progression of glioma cancer. Our results showed that fisetin phosphorylated ERK1/2 in a sustained way that contributed to the inhibited ADAM9 protein and mRNA expression determined by Western blot and RT-PCR. Moreover, inhibition of ERK1/2 by U0126 or transfection with the siERK plasmid significantly abolished the fisetin-inhibited migration and invasion through activation of the ERK1/2 pathway. In summary, our results suggest that fisetin might be a potential therapeutic agent against human glioma cells based on its capacity to activate ERK1/2 and to inhibit ADAM9 expression.

  6. Mid-trimester maternal ADAM12 levels differ according to fetal gender in pregnancies complicated by preeclampsia.

    Myers, Jenny E; Thomas, Grégoire; Tuytten, Robin; Van Herrewege, Yven; Djiokep, Raoul O; Roberts, Claire T; Kenny, Louise C; Simpson, Nigel A B; North, Robyn A; Baker, Philip N

    2015-02-01

    An overrepresentation of adverse pregnancy outcomes has been observed in pregnancies associated with a male fetus. We investigated the association between fetal gender and candidate biomarkers for preeclampsia. Proteins were quantified in samples taken at 20 weeks from women recruited to the SCreening fOr Pregnancy Endpoints (SCOPE) study (preeclampsia n = 150; no preeclampsia n = 450). In contrast to placental growth factor, soluble endoglin, and insulin-like growth factor acid labile subunit, levels of metallopeptidase domain 12 (ADAM12) at 20 weeks were dependent on fetal gender in pregnancies complicated by preeclampsia, for male (n = 73) fetuses the multiples of the median (MoM; interquartile range [IQR] 1.1-1.5) was 1.3, whereas for female fetuses (n = 75) MoM was 1.1 (1.0-1.3); P preeclampsia using ADAM12 levels was improved for pregnancies associated with a male fetus (area under receiver-operator curve [AUC] 0.73 [95% confidence interval [CI] 0.67-0.80]) than that of a female fetus (AUC 0.62 [0.55-0.70]); P = .03. The data presented here fit a contemporary hypothesis that there is a difference between the genders in response to an adverse maternal environment and suggest that an alteration in ADAM12 may reflect an altered placental response in pregnancies subsequently complicated by preeclampsia.

  7. Platelet integrin α6β1 controls lung metastasis through direct binding to cancer cell–derived ADAM9

    Mammadova-Bach, Elmina; Zigrino, Paola; Brucker, Camille; Bourdon, Catherine; Freund, Monique; Abrams, Scott I.; Orend, Gertaud; Gachet, Christian

    2016-01-01

    Metastatic dissemination of cancer cells, which accounts for 90% of cancer mortality, is the ultimate hallmark of malignancy. Growing evidence suggests that blood platelets have a predominant role in tumor metastasis; however, the molecular mechanisms involved remain elusive. Here, we demonstrate that genetic deficiency of integrin α6β1 on platelets markedly decreases experimental and spontaneous lung metastasis. In vitro and in vivo assays reveal that human and mouse platelet α6β1 supports platelet adhesion to various types of cancer cells. Using a knockdown approach, we identified ADAM9 as the major counter receptor of α6β1 on both human and mouse tumor cells. Static and flow-based adhesion assays of platelets binding to DC-9, a recombinant protein covering the disintegrin-cysteine domain of ADAM9, demonstrated that this receptor directly binds to platelet α6β1. In vivo studies showed that the interplay between platelet α6β1 and tumor cell–expressed ADAM9 promotes efficient lung metastasis. The integrin α6β1–dependent platelet-tumor cell interaction induces platelet activation and favors the extravasation process of tumor cells. Finally, we demonstrate that a pharmacological approach targeting α6β1 efficiently impairs tumor metastasis through a platelet-dependent mechanism. Our study reveals a mechanism by which platelets promote tumor metastasis and suggests that integrin α6β1 represents a promising target for antimetastatic therapies. PMID:27699237

  8. 基于VC++和ADAMS/Car的汽车制动性能仿真分析系统%Simulation and analysis of automotive braking system based on VC++ and ADAMS/Car

    张杰; 孙虎; 杨波; 王斌

    2012-01-01

    To speed up the virtual development of the automobile braking system, VC++6.0 programming environment and the Junction of ADAMS are applied to execute the batch files based on the ADAMS/ CAR software,and the simulation and analysis system for automotive braking system is developed as well. Then a friendly convenient and the flexible man-machine conversation interface are developed by VC++ foreground.When the software is used,the user only is required to input the vehicle parameters and set the simulation parameters, which will be obtained from the backstage of the system and transformed to the ADAMS operating commands and encapsulated in acar.cmd file.ADAMS will automatically create a virtual model and simulate after executing the acar.cmd file, so that the data of the simulation is got.With the application of the system the modeling efficiency for virtual model is improved,which reduce the work load on study and design of braking system greatly.%为了提高汽车制动系统的虚拟研发速度,利用VC++6.0的编程环境和ADAMS可执行批处理文件的功能,以ADAMS/CAR软件为基础平台,开发了汽车制动性能仿真分析系统.通过VC++前台开发出友好、方便、易用的人机交互界面,用户在使用此软件时,只需在此界面中输入整车结构参数及仿真设置参数,系统在后台获取这些参数并转换为需要对ADAMS进行的操作命令后封装入acar.cmd文件中,ADAMS调用此文件后即可自动实现整车虚拟模型建立及计算仿真,并获取仿真试验数据.设计人员利用此系统,可提高虚拟模型的建模效率,大大减少汽车制动系统研究与设计的工作量.

  9. Number of discernible colors for color-deficient observers estimated from the MacAdam limits.

    Perales, Esther; Martínez-Verdú, Francisco Miguel; Linhares, João Manuel Maciel; Nascimento, Sérgio Miguel Cardoso

    2010-10-01

    We estimated the number of colors perceived by color normal and color-deficient observers when looking at the theoretic limits of object-color stimuli. These limits, the optimal color stimuli, were computed for a color normal observer and CIE standard illuminant D65, and the resultant colors were expressed in the CIELAB and DIN99d color spaces. The corresponding color volumes for abnormal color vision were computed using models simulating for normal trichromatic observers the appearance for dichromats and anomalous trichomats. The number of colors perceived in each case was then computed from the color volumes enclosed by the optimal colors also known as MacAdam limits. It was estimated that dichromats perceive less than 1% of the colors perceived by normal trichromats and that anomalous trichromats perceive 50%-60% for anomalies in the medium-wavelength-sensitive and 60%-70% for anomalies in the long-wavelength-sensitive cones. Complementary estimates obtained similarly for the spectral locus of monochromatic stimuli suggest less impairment for color-deficient observers, a fact that is explained by the two-dimensional nature of the locus.

  10. The Eroticism of Artificial Flesh in Villiers de L'Isle Adam's L'Eve Future

    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.

  11. A turning point in the concept of justice: from Adam Smith to John Stuart Mill

    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.

  12. Desperately seeking social approval: Adam Smith, Thorstein Veblen and the moral limits of capitalist culture.

    Watson, Matthew

    2012-09-01

    Adam Smith and Thorstein Veblen shared much in matters of economic ontology. Both dismissed the very notion of an autonomous economic self and instead investigated the processes through which self and other are mutually constituted under changing cultural traditions of individual aspiration. Their strikingly similar critiques of status-oriented consumption and concern for the moral basis of the market economy are established in this manner. However, the political implications of their analyses point in different directions, with Veblen being the more radical. The Smithian individual can always use spectatorial insights to assert through genuinely praiseworthy behaviour personal moral distance from social norms of status-oriented consumption. The Veblenian individual, by contrast, has no such capacity for elevating abstract moral principles above socially-situated conduct, as mind and environment co-evolve in line with changing material circumstances of life. For Veblen, the rise of status-oriented consumption itself acted as a form of moral self-education that more deeply entrenched the social norms of ownership out of which it arose, thus the impossibility of an autonomous economic self was matched by the impossibility of an autonomous moral self. To his way of thinking, moral degradation in conspicuous consumption was irredeemably inscribed into the whole cultural structure of capitalism.

  13. Raymond D. Adams, gigante de la neurología norteamericana

    Leonardo Palacios

    2011-12-01

    Full Text Available Professor Raymond D. Adams (1911-2010 has been one of the most prominent figures in North American neurology in the XX century. He studied medicine at Duke University. He began training in psychiatry but decided to study nervous system pathology and neurology in Boston City Hospital during ten years. Then he became chairman of the neurology department in Massachusetts General Hospital for more than twenty five years. He was Neuropathology Emeritus Professor at Harvard University and has been recognized by other universities and scientific associations in United States and in other countries. His contribution to North American Neurology consolidation has been crucial. He described various syndromes and contributed to the development of other fields in neuroscience. He wrote and published many scientific articles and since 1977 with his colleague Maurice Victor the books “Principles of Neurology” a classic in the field, being traduced to many languages. He has been the chairman of a Department where many important neurologists from different parts of the world where trained and brighten neurology worldwide.

  14. Adam Smith's conceptual contributions to international economics: Based on the Wealth of Nations

    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.

  15. Dalla teoria delle passioni al nuovo ordine: mercato e capitalismo in Adam Smith

    T. RAFFAELLI

    1994-06-01

    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.

  16. Kinematic characterization and optimization of vehicle front-suspension design based on ADAMS

    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.

  17. A turning point in the concept of justice: from Adam Smith to John Stuart Mill

    Estrella Trincado Aznar

    2012-01-01

    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.

  18. [Effects of piracetam therapy in a case of Lance-Adams syndrome].

    Hoshino, Ai; Kumada, Satoko; Yokochi, Fusako; Hachiya, Yasuo; Hanafusa, Yukiko; Tomita, Sunao; Okiyama, Ryoich; Kurihara, Eiji

    2009-09-01

    We report a 17-year-old female patient with Lance-Adams syndrome caused by anoxic encephalopathy during a severe attack of bronchial asthma. She had difficulty in writing because of action myoclonus in her arms. She also exhibited freezing gait and was unable to walk without cane. Although her gait disturbance resembled those seen in patients with parkinsonism secondary to anoxic encephalopathy, surface electromyography revealed that it was caused by action myoclonus in her legs. The presence of giant somatosensory evoked potentials and enhanced cortical reflexes in response to the electrical stimulation to her posterior tibial nerves supported our diagnosis. A combined therapy with valproate sodium, clonazepam and piracetam (15 g/day) was not effective. However, her freezing gait remarkably improved and she was able to walk without help, after the treatment with sufficient dose of piracetam (21 g/day). Cortical hyperexcitability as revealed by electrophysiological examination also improved. We concluded that the combined therapy with antiepileptic drugs and piracetam was effective in the treatment for action myoclonus. However, because the effects seemed dose-related, the dosage of piracetam needed to be increased until the optimum effects were obtained.

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

    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. Inhibitory role of TACE/ADAM17 cytotail in protein ectodomain shedding

    Liliana; Pérez

    2011-01-01

    AIM:To determine if the cytotail of the principal sheddase tumor necrosis factor-α converting enzyme (TACE;ADAM17) controls protein ectodomain shedding.METHODS:Site-directed mutagenesis was performed to derive TACE variants. The resulting TACE expression plasmids with amino acid substitutions in the extracel-lular,cysteine-rich disintegrin domain (CRD) and/or deleted cytotail,along with an expression vector for the enhanced green fluorescence protein were transfected into shedding-defective M1 mutants stably expressing transmembrane L-selectin or transforming growth factor (TGF)-α. The expression levels of the TACE substrates at the cell surface were determined by flow cytometry. RESULTS:Consistent with published data,a single point mutation (C600Y) in the CRD led to shedding defi-ciency. However,removal of the cytotail from the C600Y TACE variant partially restored ectodomain cleavage of TGF-α and L-selectin. Cytotail-deleted mutants with any other substituting amino acid residues in place of Cys600 displayed similar function compared with tail-less C600Y TACE.CONCLUSION:The cytotail plays an inhibitory role,which becomes evident when it is removed from an enzyme with another mutation that affects the enzyme function.