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

    Science.gov (United States)

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

    2016-07-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2008-09-29

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

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

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    Valeria Famiglini

    2016-02-01

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

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

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    Nicolas Sluis-Cremer

    2013-11-01

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

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

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    Madhu N. Rao

    2006-01-01

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

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

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

    2016-08-15

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

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

    Institute of Scientific and Technical Information of China (English)

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

    2008-01-01

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

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

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    Driss Cherqaoui

    2004-01-01

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

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

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    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.

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

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    Peter V. Coveney

    2012-07-01

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

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

    DEFF Research Database (Denmark)

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

    2009-01-01

    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...

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

    Institute of Scientific and Technical Information of China (English)

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

    2010-01-01

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

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

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    Van Houtte Margriet

    2011-10-01

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

  14. Exploring isoxazole and carboxamide derivatives as potential non-nucleoside reverse transcriptase inhibitors.

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    Kurup, Sudheer S; Joshi, Kaustubh A

    2016-04-01

    Nonnucleoside reverse transciptase inhibitors (NNRTI) are a class of drug molecules with a specific target of HIV-1 reverse transcriptase (RT). In the present work, we evaluated a set of selected oxazole and carboxamide derivatives to identify potential pharmacophoric features using molecular docking approach. The docking approach employed has been validated by enrichment factor calculation at top 1% (EF1%). It shows a considerable improvement in EF1%value compared to earlier reported study carried out on specific dataset of ligands and decoys for RT, in the directory of useful decoys (DUD). The carboxamide derivatives show better activity as NNRT inhibitors than oxazole derivatives. From this study, four pharmacophoric groups including a triazine ring, an aniline substituent, a benzyl amide moiety and a trimethylphenoxy substituent have been recognized and used for designing new NNRT inhibitors. Newly designed molecules show significant enhancement in docking scores over the native ligand, parent and other training set molecules. In addition, some functional groups have also been identified to assist in improving the activity of these pharmacophores. Thus a nitrile group, an amide and fluoro substitution turn out to be an important requisite for NNRT potential inhibitors. PMID:26973048

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

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    A. M. Bain

    2008-01-01

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

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

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    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

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

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    Markus Hecht

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

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

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    Mastan SK

    2009-10-01

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

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

    Institute of Scientific and Technical Information of China (English)

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

    2009-01-01

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

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

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

    2008-01-01

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

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

    DEFF Research Database (Denmark)

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

    2008-01-01

    BACKGROUND: Interruption of a non-nucleoside reverse transcriptase inhibitor (NNRTI)-regimen is often necessary, but must be performed with caution because NNRTIs have a low genetic barrier to resistance. Limited data exist to guide clinical practice on the best interruption strategy to use....... 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...... mutations (i.e. 69.2%) achieved HIV-RNA of 400 copies/ml or less compared with those in whom no mutations were detected (i.e. 86.7%; P = 0.05). CONCLUSION: In patients who interrupt a suppressive NNRTI-regimen, the choice of interruption strategy may influence resuppression rates when restarting a similar...

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

    Science.gov (United States)

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

    2015-04-01

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

  3. 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

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    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.

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

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

    2016-09-01

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

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

    Science.gov (United States)

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

    2014-07-01

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

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

    Science.gov (United States)

    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.

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

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    Shao Yiming

    2011-05-01

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

  8. Identification of a novel sulfonamide non-nucleoside reverse transcriptase inhibitor by a phenotypic HIV-1 full replication assay.

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    Tae-Hee Kim

    Full Text Available Classical target-based, high-throughput screening has been useful for the identification of inhibitors for known molecular mechanisms involved in the HIV life cycle. In this study, the development of a cell-based assay that uses a phenotypic drug discovery approach based on automated high-content screening is described. Using this screening approach, the antiviral activity of 26,500 small molecules from a relevant chemical scaffold library was evaluated. Among the selected hits, one sulfonamide compound showed strong anti-HIV activity against wild-type and clinically relevant multidrug resistant HIV strains. The biochemical inhibition, point resistance mutations and the activity of structural analogs allowed us to understand the mode of action and propose a binding model for this compound with HIV-1 reverse transcriptase.

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

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    Donna C Davidson

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

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

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    Sonya J Snedecor

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

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

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    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

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

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    Susan A. Eaton

    2008-01-01

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

  13. Second-line protease inhibitor-based highly active antiretroviral therapy after failing non-nucleoside reverse transcriptase inhibitors-based regimens in Asian HIV-infected children

    Science.gov (United States)

    Bunupuradah, Torsak; Puthanakit, Thanyawee; Fahey, Paul; Kariminia, Azar; Yusoff, Nik Khairulddin Nik; Khanh, Truong Huu; Sohn, Annette H.; Chokephaibulkit, Kulkanya; Lumbiganon, Pagakrong; Hansudewechakul, Rawiwan; Razali, Kamarul; Kurniati, Nia; Huy, Bui Vu; Sudjaritruk, Tavitiya; Kumarasamy, Nagalingeswaran; Fong, Siew Moy; Saphonn, Vonthanak; Ananworanich, Jintanat

    2013-01-01

    Background The WHO recommends boosted protease inhibitor (bPI)-based highly active antiretroviral therapy (HAART) after failing non-nucleoside reverse transcriptase inhibitor (NNRTI) treatment. We examined outcomes of this regimen in Asian HIV-infected children. Methods Children from five Asian countries in the TREAT Asia Pediatric HIV Observational Database (TApHOD) with ≥24 weeks of NNRTI-based HAART followed by ≥24 weeks of bPI-based HAART were eligible. Primary outcomes were the proportions with virologic suppression (HIV-RNA <400 copies/ml) and immune recovery (CD4% ≥25% if age <5 years and CD4 count ≥500 cells/mm3 if age ≥5 years) at 48 and 96 weeks. Results Of 3422 children, 153 were eligible; 52% were female. At switch, median age was 10 years, 26% were in WHO stage 4. Median weight-for-age z-score (WAZ) was −1.9 (n=121), CD4% was 12.5% (n=106), CD4 count was 237 (n=112) cells/mm3, and HIV-RNA was 4.6 log10copies/ml (n=61). The most common PI was lopinavir/ritonavir (83%). At 48 weeks, 61% (79/129) had immune recovery, 60% (26/43) had undetectable HIV-RNA and 73% (58/79) had fasting triglycerides ≥130mg/dl. By 96 weeks, 70% (57/82) achieved immune recovery, 65% (17/26) virologic suppression, and hypertriglyceridemia occurred in 66% (33/50). Predictors for virologic suppression at week 48 were longer duration of NNRTI-based HAART (p=0.006), younger age (p=0.007), higher WAZ (p=0.020), and HIV-RNA at switch <10,000 copies/ml (p=0.049). Conclusion In this regional cohort of Asian children on bPI-based second-line HAART, 60% of children tested had immune recovery by one year, and two-thirds had hyperlipidemia, highlighting difficulties in optimizing second-line HAART with limited drug options. PMID:23296119

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

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    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

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

    DEFF Research Database (Denmark)

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

    2006-01-01

    antiretroviral therapy with two nucleoside analogue reverse transcriptase inhibitors (didanosine+stavudine) plus either a non-nucleoside reverse transcriptase inhibitor (efavirenz, EFV) or a protease inhibitor (nelfinavir, NFV), or both (EFV/NFV), in patients with HIV-1 infection who had not previously received...... participants (297 EFV, 311 NFV, 303 EFV/NFV). At 3 years, the proportion with HIV RNA less than 50 copies per mL was highest in the EFV group (188 [74%] EFV, 162 [62%] NFV, 155 [62%] EFV/NFV; p=0.004). Mean (95% CI) increases in CD4 count were 316x10(6) cells per L (288-343) for EFV, 289x10(6) cells per L (262...

  16. 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

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    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.

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

    Science.gov (United States)

    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.

  18. Design, discovery, modelling, synthesis, and biological evaluation of novel and small, low toxicity s-triazine derivatives as HIV-1 non-nucleoside reverse transcriptase inhibitors.

    Science.gov (United States)

    Viira, Birgit; Selyutina, Anastasia; García-Sosa, Alfonso T; Karonen, Maarit; Sinkkonen, Jari; Merits, Andres; Maran, Uko

    2016-06-01

    A set of top-ranked compounds from a multi-objective in silico screen was experimentally tested for toxicity and the ability to inhibit the activity of HIV-1 reverse transcriptase (RT) in cell-free assay and in cell-based assay using HIV-1 based virus-like particles. Detailed analysis of a commercial sample that indicated specific inhibition of HIV-1 reverse transcription revealed that a minor component that was structurally similar to that of the main compound was responsible for the strongest inhibition. As a result, novel s-triazine derivatives were proposed, modelled, discovered, and synthesised, and their antiviral activity and cellular toxicity were tested. Compounds 18a and 18b were found to be efficient HIV-1 RT inhibitors, with an IC50 of 5.6±1.1μM and 0.16±0.05μM in a cell-based assay using infectious HIV-1, respectively. Compound 18b also had no detectable toxicity for different human cell lines. Their binding mode and interactions with the RT suggest that there was strong and adaptable binding in a tight (NNRTI) hydrophobic pocket. In summary, this iterative study produced structural clues and led to a group of non-toxic, novel compounds to inhibit HIV-RT with up to nanomolar potency. PMID:27108399

  19. Synthesis and Biological Evaluation of 2-Thioxopyrimidin-4(1H-one Derivatives as Potential Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors

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    Nagy M. Khalifa

    2014-11-01

    Full Text Available A series of new 5-allyl-6-benzylpyrimidin-4(3H-ones bearing different substituents at the C-2 position of the pyrimidine core have been synthesized and evaluated for their in vitro activities against human immunodeficiency virus type 1 (HIV-1 in the human T-lymphotropic type (MT-4 cell cultures. The majority of the title compounds showed moderate to good activities against HIV-1. Amongst them, 5-allyl-6-benzyl-2-(3-hydroxypropylthiopyrimidin-4(3H-one analogue 11c exhibited the most potent anti-HIV-1 activity (IC50 0.32 µM. The biological testing results clearly indicated that the substitution at C-2 position of the pyrimidine ring could increase the anti-HIV-1 reverse transcriptase (RT activity.

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

    Science.gov (United States)

    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.

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

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    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.

  2. 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.

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    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.

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

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    Viviane D Lima

    2016-08-01

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

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

    Directory of Open Access Journals (Sweden)

    Monique Araújo de Brito

    2012-06-01

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

  5. Pre-incubation of cell-free HIV-1 group M isolates with non-nucleoside reverse transcriptase inhibitors blocks subsequent viral replication in co-cultures of dendritic cells and T cells.

    Science.gov (United States)

    Njai, Harr F; Lewi, Paul J; Janssen, Cornelus G M; Garcia, Sergio; Fransen, Katrien; Kestens, Luc; Vanham, Guido; Janssen, Paul A J

    2005-01-01

    In order to study the inhibitory effect of various reverse transcriptase inhibitors (RTIs) on cell-free HIV, we adapted a recently described in vitro system, based on co-cultures of dendritic cells and resting CD4 T cells, modelling early target cells during sexual transmission. The compounds tested included the second-generation non-nucleoside RTI (NNRTI) TMC-120 (R147681, dapivirine) and TMC-125 (R165335, travertine), as well as the reference nucleoside RTI AZT (zidovudine), the nucleotide RTI PMPA (tenofovir) and the NNRTI UC-781. The virus strains included the reference strain HIV-1Ba-L and six primary isolates, representative of the HIV-1 group M pandemic. They all display the non-syncytium-inducing and CCR5 receptor-using (NSI/R5) phenotype, important in transmission. Cell-free virus was immobilized on a poly-L-lysine (PLL)-treated microwell plate and incubated with compound for 1 h. Afterwards, the compound was thoroughly washed away; target cells were added and cultured for 2 weeks, followed by an extended culture with highly susceptible mitogen-activated T cells. Viral production in the cultures was measured on supernatant with HIV antigen ELISA. Negative results were confirmed by showing absence of proviral DNA in the cells. TMC-120 and TMC-125 inhibited replication of HIV-1Ba-L with average EC50 values of 38 nM and 117 nM, respectively, whereas the EC50 of UC-781 was 517 nM. Complete suppression of virus and provirus was observed at compound concentrations of 100, 300 and 1000 nM, respectively. Inhibition of all primary isolates followed the same pattern as HIV-1Ba-L. In contrast, pre-treating the virus with the nucleotide RTI PMPA and AZT failed to inhibit infection even at a concentration of 100000 nM. These data clearly suggest that NNRTIs inactivate RT enzymatic activity of different viral clades (predominant in the epidemic) and might be proposed for further testing as a sterilizing microbicide worldwide. PMID:15865220

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

    Directory of Open Access Journals (Sweden)

    Jeffrey S A Stringer

    2010-02-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2009-07-10

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

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

    Institute of Scientific and Technical Information of China (English)

    闫寒; 王孝伟; 郭盈; 张志丽; 刘俊义

    2011-01-01

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

  9. 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

    Indian Academy of Sciences (India)

    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.

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

    Institute of Scientific and Technical Information of China (English)

    肖泽云; 李凯; 李爱秀; 王晓辉; 刘勇庆

    2016-01-01

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

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

    Institute of Scientific and Technical Information of China (English)

    曹颖莉; 李少雄; 陈虹; 郭颖

    2009-01-01

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

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

    Institute of Scientific and Technical Information of China (English)

    朱瑞新; 王飞; 刘琦; 康廷国

    2011-01-01

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

  13. Synthesis and biological evaluation of novel 2-arylalkylthio-5-iodo-6-benzyl S-DABOs as potent non-nucleoside HIV-1 reverse transcriptase inhibitors%新型2-芳硫基-5-碘-6-苄基S-DABOs类化合物的合成及作为非核苷类HIV-1RT抑制剂的活性评估

    Institute of Scientific and Technical Information of China (English)

    张亮; 王孝伟; 刘俊义

    2012-01-01

    A series of novel dihydro-alkylthio-benzyl-oxopyrimidines (S-DABOs) 7a-f have been designed and synthesized with an efficient method.Biological evaluation of their HIV-1 reverse transcriptase inhibitory activities was performed using Nevirapine (NVP) as a reference compound.Among the series,compound 7d shows the highest reverse transcriptase inhibitory activity,which is better than Nevirapine.%我们设计了一系列新型S-DABOs类目标化合物7a-f,通过简单有效的方法合成了该系列化合物,并进行了逆转录酶活性检测,发现该类化合物具有较好的生物活性,其中化合物7d的IC50值达到了3.64 μmol/L,是Nevirapine的IC50值的1/2.

  14. Molecular profiling of ADAM12 in human bladder cancer

    DEFF Research Database (Denmark)

    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...

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

    Directory of Open Access Journals (Sweden)

    Christy M Hebner

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

  16. Structural modifications of CH(OH)-DAPYs as new HIV-1 non-nucleoside reverse transcriptase inhibitors.

    Science.gov (United States)

    Yan, Zi-Hong; Huang, Xia-Yun; Wu, Hai-Qiu; Chen, Wen-Xue; He, Qiu-Qin; Chen, Fen-Er; De Clercq, Erik; Pannecouque, Christophe

    2014-04-15

    A series of CR2(OH)-diarylpyrimidine derivatives (CR2(OH)-DAPYs) featuring a hydrophobic group at CH(OH) linker between wing I and the central pyrimidine were synthesized and evaluated for their anti-HIV activity in MT-4 cell cultures. All the target compounds except for compound 3k displayed inhibitory activity against HIV-1 wild-type with EC50 values ranging from 7.21±1.99 to 0.067±0.006 μM. Among them, compound 3d showed the most potent anti-HIV-1 activity (EC50=0.067±0.006 μM, SI>592), which was approximately 2-fold more potent than the reference drugs nevirapine (NVP) and delaviridine (DLV) in the same assay. In addition, the binding modes with HIV-1 RT and the preliminary SAR studies of these new derivatives were also investigated. PMID:24680058

  17. C-2-Aryl O-substituted HI-236 derivatives as non-nucleoside HIV-1 reverse-transcriptase inhibitors

    OpenAIRE

    Hunter, Roger; Younis, Yassir; Muhanji, Clare I; Curtin, Tanith-lea; Naidoo, Kevin J.; Petersen, Melissa; Bailey, Christopher M.; Basavapathruni, Aravind; Anderson, Karen S.

    2008-01-01

    Several novel thiourea derivatives of the NNRTI HI-236 substituted at the C-2 oxygen of the phenyl ring have been synthesized and evaluated for their inhibitory activity against HIV-1 (IIIB) replication in MT-2 cell cultures. The compounds were synthesized in order to fine-tune the activity of HI-236 as well as to gain insight into spatial characteristics in the pocket pertaining to the positional choice of tether in the design of [NRTI]-tether-[HI-236] bifunctional inhibitors. Two of the thi...

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

    DEFF Research Database (Denmark)

    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...

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

    NARCIS (Netherlands)

    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.B. 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.B. 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

    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

  20. Decrease of vitamin D concentration in patients with HIV infection on a non nucleoside reverse transcriptase inhibitor-containing regimen

    Directory of Open Access Journals (Sweden)

    Colebunders Robert

    2010-11-01

    Full Text Available Abstract Background Vitamin D is an important determinant of bone health and also plays a major role in the regulation of the immune system. Interestingly, vitamin D status before the start of highly active antiretroviral therapy (HAART has been recently associated with HIV disease progression and overall mortality in HIV-positive pregnant women. We prospectively studied vitamin D status in HIV individuals on HAART in Belgium. We selected samples from HIV-positive adults starting HAART with a pre-HAART CD4 T-cell count >100 cells/mm3 followed up for at least 12 months without a treatment change. We compared 25-hydroxyvitamin D plasma [25-(OHD] concentration in paired samples before and after 12 months of HAART. 25-(OHD levels are presented using two different cut-offs: Results Vitamin D deficiency was common before HAART, the frequency of plasma 25-(OHD concentrations below 20 ng/ml and 30 below ng/ml was 43.7% and 70.1% respectively. After 12 months on HAART, the frequency increased to 47.1% and 81.6%. HAART for 12 months was associated with a significant decrease of plasma 25-(OHD concentration (p = 0.001. Decreasing plasma 25-(OHD concentration on HAART was associated in the multivariate model with NNRTI-based regimen (p = 0.001 and lower body weight (p = 0.008. Plasma 25-(OHD concentrations decreased significantly in both nevirapine and efavirenz-containing regimens but not in PI-treated patients. Conclusions Vitamin D deficiency is frequent in HIV-positive individuals and NNRTI therapy further decreases 25-(OHD concentrations. Consequently, vitamin D status need to be checked regularly in all HIV-infected patients and vitamin D supplementation should be given when needed.

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

    Science.gov (United States)

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

    2016-04-01

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

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

    Directory of Open Access Journals (Sweden)

    Nadya Urakova

    2016-04-01

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

  3. Det Syriske Adams Testamente

    DEFF Research Database (Denmark)

    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...

  4. Ansel Adams: early works

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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.

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

    Directory of Open Access Journals (Sweden)

    Rubin Donald H

    2011-05-01

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

  7. Was Adam a Real Person?

    Science.gov (United States)

    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…

  8. The Adams Family

    Science.gov (United States)

    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…

  9. ADAM Proteases and Gastrointestinal Function.

    Science.gov (United States)

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

    2016-01-01

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

  10. ADAM Proteases and Gastrointestinal Function

    Science.gov (United States)

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

    2016-01-01

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

  11. ADAM Proteases and Gastrointestinal Function.

    Science.gov (United States)

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

    2016-01-01

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

  12. The role of ADAMs in disease pathophysiology.

    LENUS (Irish Health Repository)

    Duffy, Michael J

    2012-02-01

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

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

    Indian Academy of Sciences (India)

    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.

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

    Science.gov (United States)

    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

  15. Novel (2,6-difluorophenyl)(2-(phenylamino)pyrimidin-4-yl)methanones with restricted conformation as potent non-nucleoside reverse transcriptase inhibitors against HIV-1.

    Science.gov (United States)

    Šimon, Petr; Baszczyňski, Ondřej; Šaman, David; Stepan, George; Hu, Eric; Lansdon, Eric B; Jansa, Petr; Janeba, Zlatko

    2016-10-21

    To elucidate the structure-geometry-activity relationship in diarylpyrimidine family (DAPYs) containing carbonyl linker between the central pyrimidine core and phenyl type B-arm, a series of (2,6-difluorophenyl)(2-(phenylamino)pyrimidin-4-yl)methanones was designed, prepared and tested for their anti-HIV-1 activity. The carbonyl linker bearing B phenyl arm was successfully attached at both C-2 and C-4 positions of the central pyrimidine ring using a new synthetic approach. Further modifications of target compounds are present at C-5 position of the pyrimidine ring. In vitro anti-HIV-1 activity study performed on a series of 22 compounds confirmed the crucial importance of both conformational rigidity between phenyl B arm and the pyrimidine core linked through the carbonyl bridge, as well as presence of fluoro substituents in ortho-positions of phenyl B moiety. The most potent derivative of the series, compound 17, having almost perpendicular angle within the two planes made from the B aromatic arm and the pyrimidine ring, exhibited low nanomolar anti-HIV-1 activity (EC50 = 4 nM) with no significant toxicity (CC50 > 57.1 μM). PMID:27371922

  16. Application of the Huisgen cycloaddition and 'click' reaction toward various 1,2,3-triazoles as HIV non-nucleoside reverse transcriptase inhibitors.

    Science.gov (United States)

    Pribut, Nicole; Veale, Clinton G L; Basson, Adriaan E; van Otterlo, Willem A L; Pelly, Stephen C

    2016-08-01

    The development of novel anti-HIV agents remains an important medicinal chemistry challenge given that no cure for the disease is imminent, and the continued use of current NNRTIs inevitably leads to problems associated with resistance. Inspired by the pyrazole-containing NNRTI lersivirine (LSV), we embarked upon a study to establish whether 1,2,3-triazole heterocycles could be used as a new scaffold for the creation of novel NNRTIs. An especially attractive feature of triazoles used for this purpose is the versatility in accessing variously functionalised systems using either the thermally regulated Huisgen cycloaddition, or the related 'click' reaction. Employing three alternative forms of these reactions, we were able to synthesise a range of triazole compounds and evaluate their efficacy in a phenotypic HIV assay. To our astonishment, even compounds closely mimicking LSV were only moderately effective against HIV. PMID:27287366

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

    Institute of Scientific and Technical Information of China (English)

    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.

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

    Science.gov (United States)

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

    2016-06-15

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

  19. John Adams in 1959

    CERN Document Server

    1959-01-01

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

  20. Changing Perceptions in "Adam Bede."

    Science.gov (United States)

    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…

  1. New Mathematical Dimensions: Adam's Story

    Science.gov (United States)

    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…

  2. A randomized trial comparing initial HAART regimens of nelfinavir/nevirapine and ritonavir/saquinavir in combination with two nucleoside reverse transcriptase inhibitors

    DEFF Research Database (Denmark)

    Kirk, Ole; Lundgren, Jens D; Pedersen, Court;

    2003-01-01

    BACKGROUND: A triple-class HAART regimen may be associated with a better virological effect than conventional regimens, but may also lead to toxicity and more profound resistance. METHODS: Randomized, controlled, open-label trial of 233 protease inhibitor- and non-nucleoside reverse transcriptase...

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

    International Nuclear Information System (INIS)

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2014-04-15

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

  5. John Adams Lecture

    CERN Multimedia

    PH Department

    2010-01-01

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

  6. Adam Smith and dependency.

    Science.gov (United States)

    Ozler, Sule

    2012-06-01

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

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

    Science.gov (United States)

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

    2014-01-01

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

  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.

    Directory of Open Access Journals (Sweden)

    Eliana F Castro

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

  9. Bookshelf. John Adams biography

    International Nuclear Information System (INIS)

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

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

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

    2016-01-01

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

  12. Smith, Adam (1723-90)

    DEFF Research Database (Denmark)

    Bouchet, Dominique

    2015-01-01

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

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

    Institute of Scientific and Technical Information of China (English)

    Sha Guo; Min Peng; Qing Zhao; Wei Zhang

    2012-01-01

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

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

    Science.gov (United States)

    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.

  15. Activation of ADAM 12 protease by copper

    DEFF Research Database (Denmark)

    Loechel, F; Wewer, Ulla M.

    2001-01-01

    Conversion of latent proteases to the active form occurs by various mechanisms characteristic for different protease families. Here we report that the disintegrin metalloprotease ADAM 12-S is activated by Cu(II). Copper activation is distinct from the cysteine switch component of latency: elimina......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...... for ADAM 12 involving both furin cleavage and copper binding....

  16. ADAM: Analyzer for Dialectal Arabic Morphology

    Directory of Open Access Journals (Sweden)

    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.

  17. Adam Smith’s contribution to secularisation

    Directory of Open Access Journals (Sweden)

    Petrus Simons

    2013-06-01

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

  18. ADAM9 Is a Novel Product of Polymorphonuclear Neutrophils

    DEFF Research Database (Denmark)

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

    2014-01-01

    A disintegrin and a metalloproteinase domain (ADAM) 9 is known to be expressed by monocytes and macrophages. In this study, we report that ADAM9 is also a product of human and murine polymorphonuclear neutrophils (PMNs). ADAM9 is not synthesized de novo by circulating PMNs. Rather, ADAM9 protein ...

  19. Kellwood Company Finalizes Acquisition of ADAM

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

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

  20. ADAM: All-Data Asteroid Modeling

    Science.gov (United States)

    Viikinkoski, Matti; Kaasalainen, Mikko; Durech, Josef

    2015-02-01

    ADAM (All-Data Asteroid Modeling) models asteroid shape reconstruction from observations. Developed in MATLAB with core routines in C, its features include general nonconvex and non-starlike parametric 3D shape supports and reconstruction of asteroid shape from any combination of lightcurves, adaptive optics images, HST/FGS data, disk-resolved thermal images, interferometry, and range-Doppler radar images. ADAM does not require boundary contour extraction for reconstruction and can be run in parallel.

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

    Science.gov (United States)

    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.

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  3. A Conversation with Adam Heller.

    Science.gov (United States)

    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. PMID:26247288

  4. 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.

    Science.gov (United States)

    Porter, Danielle P; Daeumer, Martin; Thielen, Alexander; Chang, Silvia; Martin, Ross; Cohen, Cal; Miller, Michael D; White, Kirsten L

    2015-12-01

    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. PMID:26690199

  5. 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

    Directory of Open Access Journals (Sweden)

    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.

  6. Synthesis and Biological Evaluation of Novel 2-Arylalkylthio-5-iodine-6-substituted-benzyl-pyrimidine-4(3H-ones as Potent HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors

    Directory of Open Access Journals (Sweden)

    Liang Zhang

    2014-05-01

    Full Text Available A novel series of 2-arylalkylthio-5-iodine-6-substitutedbenzyl-pyrimidine-4(3H-ones (S-DABOs 8a–x had been synthesized via an efficient method. Their biological activity against HIV virus and RT assay were evaluated. Some compounds, especially 8h, 8l and 8n, displayed promising activity against HIV-1 RT with IC50 values in a range of 0.41 μM to 0.71 μM, which were much better than that of nevirapine. Molecular modeling studies revealed that the binding mode would be affected via forming an additional hydrogen bond by incorporating an oxygen atom on the C-2 side chain. The biological activity was in accordance with the docking results.

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

    Directory of Open Access Journals (Sweden)

    Postina Rolf

    2009-02-01

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

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

    Science.gov (United States)

    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.

  9. MBS Analysis Of Kinetic Structures Using ADAMS

    DEFF Research Database (Denmark)

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

    2009-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Xin Yan

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

  11. Role of ADAMs in cancer formation and progression.

    LENUS (Irish Health Repository)

    Duffy, Michael J

    2012-02-01

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

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

    Science.gov (United States)

    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…

  13. 应用ADAMS/car设计汽车悬架

    Institute of Scientific and Technical Information of China (English)

    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.

  14. J. B. Adams Acting Director-General

    CERN Multimedia

    1960-01-01

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

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

    Science.gov (United States)

    Alexander, Kern

    1983-01-01

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

  16. Adam Smith and the Rhetoric of Style.

    Science.gov (United States)

    Moran, Michael G.

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

  17. Paraprofessional of the Year 2009: Tina Adams

    Science.gov (United States)

    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,"…

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

    OpenAIRE

    Groth, Esther

    2016-01-01

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

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

    Institute of Scientific and Technical Information of China (English)

    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.

  20. Hierarchy of ADAM12 binding to integrins in tumor cells

    DEFF Research Database (Denmark)

    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...

  1. ADAM 12 protease induces adipogenesis in transgenic mice

    DEFF Research Database (Denmark)

    Kawaguchi, Nobuko; Xu, Xiufeng; Tajima, Rie;

    2002-01-01

    ADAM 12 (meltrin-alpha) is a member of the ADAM (a disintegrin and metalloprotease) family. ADAM 12 functions as an active metalloprotease, supports cell adhesion, and has been implicated in myoblast differentiation and fusion. Human ADAM 12 exists in two forms: the prototype membrane......-anchored 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...... 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...

  2. Design of Annulated Pyrazoles As Inhibitors of HIV-1 Reverse Transcriptase

    Energy Technology Data Exchange (ETDEWEB)

    Sweeney, Z.K.; Harris, S.F.; Arora, N.; Javanbakht, H.; Li, Y.; Fretland, J.; Davidson, J.P.; Billedeau, J.R.; Gleason, S.; Hirschfeld, D.; Kennedy-Smith, J.J.; Mirzadegan, T.; Roetz, R.; Smith, M.; Sperry, S.; Suh, J.M.; Wu, J.; Tsing, S.; Villasenor, A.G.; Paul, A.; Su, G.

    2009-05-26

    Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are recommended components of preferred combination antiretroviral therapies used for the treatment of HIV. These regimens are extremely effective in suppressing virus replication. Structure-based optimization of diaryl ether inhibitors led to the discovery of a new series of pyrazolo[3,4-c]pyridazine NNRTIs that bind the reverse transcriptase enzyme of human immunodeficiency virus-1 (HIV-RT) in an expanded volume relative to most other inhibitors in this class. The binding mode maintains the {beta}13 and {beta}14 strands bearing Pro236 in a position similar to that in the unliganded reverse transcriptase structure, and the distribution of interactions creates the opportunity for substantial resilience to single point mutations. Several pyrazolopyridazine NNRTIs were found to be highly effective against wild-type and NNRTI-resistant viral strains in cell culture.

  3. 3d-tuotekuva Case Adams Oy

    OpenAIRE

    Dergaeva, Marija

    2010-01-01

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

  4. ADAMS Q&A%ADAMS问答

    Institute of Scientific and Technical Information of China (English)

    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。

  5. Cellular roles of ADAM12 in health and disease

    DEFF Research Database (Denmark)

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

    2008-01-01

    ADAM12 belongs to the large family of ADAMs (a disintegrin and metalloproteases) and possesses extracellular metalloprotease and cell-binding functions, as well as intracellular signaling capacities. Interest in ADAM12 has increased recently because its expression is related to tumor progression...... 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......, and in epidermal growth factor receptor (EGFR) pathways, via ectodomain shedding of membrane-tethered EGFR ligands. These proteolytic events may regulate diverse cellular responses, such as altered cell differentiation, proliferation, migration, and invasion. ADAM12 may also regulate cell-cell and cell...

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

    DEFF Research Database (Denmark)

    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...... properties. This functional trinity is reflected in the structure of ADAM12, which can be divided into head, body, and tail. The head of the protein (consisting of the pro and catalytic domains) mediates processing of growth factors and cytokines and has been implicated in epidermal growth factor (EGF...... of the cytoplasmic domain) is engaged in interactions with intracellular signaling molecules. In many studies, ADAM12 overexpression has been correlated with disease, and ADAM12 has been shown to promote tumor growth and progression in cancer. On the other hand, protective effects of ADAM12 in disease have also been...

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

    DEFF Research Database (Denmark)

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

    1998-01-01

    The ADAMs (a disintegrin and metalloprotease) are a family of multidomain proteins with structural homology to snake venom metalloproteases. We recently described the cloning and sequencing of human ADAM 12 (meltrin alpha). In this report we provide evidence that the metalloprotease domain of ADAM...... 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...... 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...

  8. Molecular profiling of ADAM12 in human bladder cancer

    DEFF Research Database (Denmark)

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

    2006-01-01

    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...... could be detected in the urine by Western blotting; ADAM12 was present in higher levels in the urine from patients with bladder cancer compared with urine from healthy individuals. Significantly, following removal of tumor by surgery, in most bladder cancer cases examined, the level of ADAM12...

  9. Reduction of the disintegrin and metalloprotease ADAM12 in preeclampsia

    DEFF Research Database (Denmark)

    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...

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

    Index Scriptorium Estoniae

    Michnik, Adam, 1946-

    2009-01-01

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

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

    Science.gov (United States)

    Tooley, James

    2007-01-01

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

  12. Adam Smith on public expenditure and taxation

    Directory of Open Access Journals (Sweden)

    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".

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

    Science.gov (United States)

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

    2012-05-01

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

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

    Science.gov (United States)

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

    2012-05-01

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

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

    DEFF Research Database (Denmark)

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

    2014-01-01

    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...

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

    Science.gov (United States)

    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…

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

    DEFF Research Database (Denmark)

    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...

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

    Science.gov (United States)

    Crossley, Robert

    1979-01-01

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

  19. Shedding of klotho by ADAMs in the kidney

    NARCIS (Netherlands)

    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

  20. Shedding of klotho by ADAMs in the kidney.

    NARCIS (Netherlands)

    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

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

    Directory of Open Access Journals (Sweden)

    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.

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

    DEFF Research Database (Denmark)

    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...

  3. Determination of platinum in Adam's catalyst

    Directory of Open Access Journals (Sweden)

    Anđelić Brankica Č.

    2003-01-01

    Full Text Available Adams's catalyst PtO2 x H2O has an important application in the chemical industry. The method for determination of platinum in Adam's catalyst has been elaborated. It includes the combination of cupellation and gravimetry methods. Considering that platinum oxide is practically insolvent in mineral acids, the sample is alloyed with lead by cupellation method and the separated balls solution procedure has been tested. The ball, platinum and lead alloy, is soluble in mineral acid. The platinum was settled by amonium chloride from solution, and obtained deposit treated by amonium acetate with addition of ethanol for lead removing. The retained platinum was determined by atomic absorption spctrophotometry method in the filtrate (after the platinum separation and the final result of platinum content corrected. It was shown how the combined gravimetric and AAS-Pt determination methods might be used for solving determination of Pt content in practically unsoluble sample of catalyst. Applied procedure enables testing the catalyst quality and proving its characteristics required for chemical industry.

  4. 50 Years of synchrotrons Adams' Memorial lecture

    CERN Document Server

    Lawson, J D; CERN. Geneva

    1996-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Robert V. Brown

    2013-12-01

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

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

    Science.gov (United States)

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

    2016-05-13

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

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

    Science.gov (United States)

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

    2016-05-13

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

  8. John Adams and CERN: Personal Recollections

    CERN Document Server

    Brianti, Giorgio

    2013-01-01

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

  9. Luhmann Receives 2007 John Adam Fleming Medal

    Science.gov (United States)

    Russell, Christopher T.; Luhmann, Janet G.

    2008-02-01

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

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

    DEFF Research Database (Denmark)

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

    2000-01-01

    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 demonstrat...

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2010-10-22

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

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

    Index Scriptorium Estoniae

    Pilli, Toivo, 1962-

    2013-01-01

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

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

    Index Scriptorium Estoniae

    Nestor, Siim, 1974-

    2006-01-01

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

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

    DEFF Research Database (Denmark)

    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...

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

    Science.gov (United States)

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

    2008-02-01

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

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

    Institute of Scientific and Technical Information of China (English)

    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。

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

    Institute of Scientific and Technical Information of China (English)

    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。

  18. Who taught Adam to speak?1

    Directory of Open Access Journals (Sweden)

    Arthur C. Custance

    1994-03-01

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

  19. ADAM SMITH: THE INVISIBLE HAND OR CONFIDENCE

    Directory of Open Access Journals (Sweden)

    Fernando Luis, Gache

    2010-01-01

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

  20. TACE (ADAM17) inhibits Schwann cell myelination.

    Science.gov (United States)

    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.

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

    LENUS (Irish Health Repository)

    Duffy, Michael J

    2011-06-09

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

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

    Directory of Open Access Journals (Sweden)

    Heejin Choi

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

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

    Science.gov (United States)

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

    2016-01-01

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

  4. Adam Smith et les passions musicales

    Directory of Open Access Journals (Sweden)

    Marc Parmentier

    2012-02-01

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

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

    DEFF Research Database (Denmark)

    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...

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

    DEFF Research Database (Denmark)

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

    2011-01-01

    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...

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

    DEFF Research Database (Denmark)

    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...

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

    Index Scriptorium Estoniae

    Velner, Harald-Adam, 1923-2012

    2008-01-01

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

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

    DEFF Research Database (Denmark)

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

    2008-01-01

    The ADAMs (a disintegrin and metalloproteases) are an important class of enzymes in the regulation of human disease. The pro domains of ADAMs are responsible for the latency and secretion of mature enzymes. Unlike other metzincins, ADAM pro domains remain bound to the mature enzyme after secretion....... 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...... and NMR spectroscopy. An ADAM22-P fragment encoding residues 26-199 could be expressed in high amounts, remained soluble above 1 mM, and was suitable for structural studies by NMR spectroscopy. CD spectroscopy and predictions suggest that the secondary structure in ADAM22-P consists of beta...

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

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

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

  11. Replication of association between ADAM33 polymorphisms and psoriasis.

    Directory of Open Access Journals (Sweden)

    Valérie Siroux

    Full Text Available Polymorphisms in ADAM33, the first gene identified in asthma by positional cloning, have been recently associated with psoriasis. No replication study of this association has been published so far. Data available in the French EGEA study (Epidemiological study on Genetics and Environment of Asthma, bronchial hyperresponsivensess and Atopy give the opportunity to attempt to replicate the association between ADAM33 and psoriasis in 2002 individuals. Psoriasis (n = 150 has been assessed by questionnaire administered by an interviewer and a sub-sample of subjects with early-onset psoriasis (n = 74 has been identified based on the age of the subjects at time of interview (<40 years. Nine SNPs in ADAM33 and 11 SNPs in PSORS1 were genotyped. Association analysis was conducted by using two methods, GEE regression-based method and a likelihood-based method (LAMP program. The rs512625 SNP in ADAM33 was found associated with psoriasis at p = 0.01, the usual threshold required for replication (OR [95% CI] for heterozygotes compared to the reference group of homozygotes for the most frequent allele = 0.61 [0.42;0.89]. The rs628977 SNP, which was not in linkage disequilibrium with rs512625, was significantly associated with early-onset psoriasis (p = 0.01, OR [95% CI] for homozygotes for the minor allele compared to the reference group = 2.52 [1.31;4.86]. Adjustment for age, sex, asthma and a PSORS1 SNP associated with psoriasis in the EGEA data did not change the significance of these associations. This suggests independent effects of ADAM33 and PSORS1 on psoriasis. This is the first study that replicates an association between genetic variants in ADAM33 and psoriasis. Interestingly, the 2 ADAM33 SNPs associated with psoriasis in the present analysis were part of the 3-SNPs haplotypes showing the strongest associations in the initial study. The identification of a pleiotropic effect of ADAM33 on asthma and psoriasis may contribute to the understanding of

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

    Science.gov (United States)

    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

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

    DEFF Research Database (Denmark)

    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...

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

    DEFF Research Database (Denmark)

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

    2007-01-01

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

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

    DEFF Research Database (Denmark)

    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...

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

    DEFF Research Database (Denmark)

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

    2007-01-01

    mice (ADAM12(+)) after a knife cut lesion and observed that the regeneration process was significantly impaired. ADAM12 seemed to inhibit the satellite cell response and delay myoblast differentiation. These results discourage long-term therapeutic use of ADAM12. They also point to impaired...

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

    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…

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

    Science.gov (United States)

    Dupont, Brandon

    2014-01-01

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

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

    Science.gov (United States)

    Hamilton, D.

    1980-01-01

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

  1. Adam Smith and the Teaching of English Literature.

    Science.gov (United States)

    Court, Franklin E.

    1985-01-01

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

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

    DEFF Research Database (Denmark)

    Vrangbaek, 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...

  3. Adams operations on higher arithmetic K-theory

    DEFF Research Database (Denmark)

    Feliu, Elisenda

    2010-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Lauren Folgosa Cooley

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

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

    DEFF Research Database (Denmark)

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

    2000-01-01

    We have investigated the trafficking of the membrane-anchored form of human ADAM 12 (ADAM 12-L) fused to a green fluorescence protein tag. Subcellular localization of the protein in transiently transfected cells was determined by fluorescence microscopy and trypsin sensitivity. Full-length ADAM 12...... 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...

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

    Science.gov (United States)

    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

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

    Science.gov (United States)

    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.

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Institute of Scientific and Technical Information of China (English)

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

    2002-01-01

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

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

    DEFF Research Database (Denmark)

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

    2012-01-01

    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 are possibly crucial in these contexts. We here investigated internalization and subsequent recycling or degradation of ADAM12 as a potentially important regulatory mechanism. Our results show that ADAM12 is constitutively internalized primarily via the clathrin-dependent pathway and is subsequently detected...... in both early and recycling endosomes. The protease activity of ADAM12 does not influence this internalization mechanism. Analysis of essential elements for internalization established that proline-rich regions in the cytoplasmic domain of ADAM12, previously shown to interact with Src-homology 3 domains...

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

    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.

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

    Institute of Scientific and Technical Information of China (English)

    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,

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

    Science.gov (United States)

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

    2013-01-01

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

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

    OpenAIRE

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

    2016-01-01

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

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

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

    2015-11-01

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

  18. ADAM33, a new candidate for psoriasis susceptibility.

    Directory of Open Access Journals (Sweden)

    Fabienne Lesueur

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

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

    Institute of Scientific and Technical Information of China (English)

    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。

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

    DEFF Research Database (Denmark)

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

    2004-01-01

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

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

    DEFF Research Database (Denmark)

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

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

    Science.gov (United States)

    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.

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

    OpenAIRE

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

    2007-01-01

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

  4. Reverse Engineering

    International Nuclear Information System (INIS)

    This book gives descriptions of reverse engineering with principle and structure of it, including what reverse engineering is, prospect and concerned laws, basic knowledge for reverse engineering like manual and back to user mode, using tool such as IDA installation, dependency walker and dump bin, network monitoring and universal extractor. It indicates analysis of malignant code, giving explanations of file virus, spy ware, an infection way of malignant code, anti debugging like Find window.

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Index Scriptorium Estoniae

    Heero, Aigi, 1971-

    2013-01-01

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

  7. ADAM33 gene polymorphisms in chronic obstructive pulmonary disease

    Directory of Open Access Journals (Sweden)

    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.

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

    OpenAIRE

    Thomas D. Hall

    2015-01-01

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

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

    OpenAIRE

    Woodhouse, Tom

    2010-01-01

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

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

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

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

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

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

    2016-09-15

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

  13. Nucleoside analogue reverse transcriptase inhibitors differentially inhibit human LINE-1 retrotransposition.

    Directory of Open Access Journals (Sweden)

    R Brad Jones

    Full Text Available BACKGROUND: Intact LINE-1 elements are the only retrotransposons encoded by the human genome known to be capable of autonomous replication. Numerous cases of genetic disease have been traced to gene disruptions caused by LINE-1 retrotransposition events in germ-line cells. In addition, genomic instability resulting from LINE-1 retrotransposition in somatic cells has been proposed as a contributing factor to oncogenesis and to cancer progression. LINE-1 element activity may also play a role in normal physiology. METHODS AND PRINCIPAL FINDINGS: Using an in vitro LINE-1 retrotransposition reporter assay, we evaluated the abilities of several antiretroviral compounds to inhibit LINE-1 retrotransposition. The nucleoside analogue reverse transcriptase inhibitors (nRTIs: stavudine, zidovudine, tenofovir disoproxil fumarate, and lamivudine all inhibited LINE-1 retrotransposition with varying degrees of potencies, while the non-nucleoside HIV-1 reverse transcriptase inhibitor nevirapine showed no effect. CONCLUSIONS/SIGNIFICANCE: Our data demonstrates the ability for nRTIs to suppress LINE-1 retrotransposition. This is immediately applicable to studies aimed at examining potential roles for LINE-1 retrotransposition in physiological processes. In addition, our data raises novel safety considerations for nRTIs based on their potential to disrupt physiological processes involving LINE-1 retrotransposition.

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

    DEFF Research Database (Denmark)

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

    2003-01-01

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

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

    DEFF Research Database (Denmark)

    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...

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

    DEFF Research Database (Denmark)

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

    1999-01-01

    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...

  17. At læse Adam Smith er både befriende og irriterende

    DEFF Research Database (Denmark)

    Larsen, Steen Nepper

    2014-01-01

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

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

    DEFF Research Database (Denmark)

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

    2005-01-01

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

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

    Directory of Open Access Journals (Sweden)

    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.

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

    DEFF Research Database (Denmark)

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

    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...

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

    Science.gov (United States)

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

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

    DEFF Research Database (Denmark)

    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...

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

    DEFF Research Database (Denmark)

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

    2005-01-01

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

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

    Science.gov (United States)

    McCauley, Joseph L.

    2000-10-01

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

  5. Reversible Sterilization

    Science.gov (United States)

    Largey, Gale

    1977-01-01

    Notes that difficult questions arise concerning the use of sterilization for alleged eugenic and euthenic purposes. Thus, how reversible sterilization will be used with relation to the poor, mentally ill, mentally retarded, criminals, and minors, is questioned. (Author/AM)

  6. Vasectomy Reversal

    Medline Plus

    Full Text Available ... improving health. Hello, my name is Harris Nagler. I'm the Chairman of the Sol and Margaret ... Israel Medical Center in New York City. Today I'm going to perform a vasectomy reversal using ...

  7. Vasectomy Reversal

    Medline Plus

    Full Text Available ... Today we are going to go to the operating room and show you microsurgical vasectomy reversal. We ... vas and that will be examined under the operating- under the microscope to see if there’s sperm ...

  8. Vasectomy Reversal

    Medline Plus

    Full Text Available ... is a realistic option for many patients. Today we are going to go to the operating room and show you microsurgical vasectomy reversal. We start the procedure by localizing the site of ...

  9. Vasectomy Reversal

    Medline Plus

    Full Text Available Vasectomy Reversal Beth Israel Medical Center, New York, NY February 19, 2009 Welcome to this "OR Live" Webcast presentation premiering from Beth Israel Medical Center in New York City. ...

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

    DEFF Research Database (Denmark)

    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....

  11. 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

    Institute of Scientific and Technical Information of China (English)

    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.

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

    DEFF Research Database (Denmark)

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

    2010-01-01

    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...

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

    DEFF Research Database (Denmark)

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

    2015-01-01

    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...

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

    Directory of Open Access Journals (Sweden)

    Hu Hanyuan

    2015-01-01

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

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

    Science.gov (United States)

    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.

  16. Econophysical visualization of Adam Smith’s invisible hand

    Science.gov (United States)

    Cohen, Morrel H.; Eliazar, Iddo I.

    2013-02-01

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

  17. Adam Smith and the new era of China

    Directory of Open Access Journals (Sweden)

    Aníbal Carlos Zottele

    2013-01-01

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

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

    Institute of Scientific and Technical Information of China (English)

    LIU Zhi; NI Fusheng; ZHOU Hong

    2007-01-01

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

  19. A Pull Back Theorem in the Adams Spectral Sequence

    Institute of Scientific and Technical Information of China (English)

    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.

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

    Science.gov (United States)

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

    2016-08-15

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

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

    Science.gov (United States)

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

    2016-06-01

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

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

    Science.gov (United States)

    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.

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

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

    DEFF Research Database (Denmark)

    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......% for a screen-positive rate of 3.2% and a 1:400 risk cut-off was found by Monte Carlo estimation using ADAM12 and maternal age as screening markers. CONCLUSION: ADAM12 is a promising marker for Down syndrome....

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

    International Nuclear Information System (INIS)

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

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

    DEFF Research Database (Denmark)

    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......, 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....

  7. The cysteine-rich domain of human ADAM 12 supports cell adhesion through syndecans and triggers signaling events that lead to beta1 integrin-dependent cell spreading

    DEFF Research Database (Denmark)

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

    2000-01-01

    : the cys-teine-rich domain made in Escherichia coli (rADAM 12-cys), the disintegrin-like and cysteine-rich domain made in insect cells (rADAM 12-DC), and full-length human ADAM 12-S tagged with green fluorescent protein made in mammalian cells (rADAM 12-GFP). Mesenchymal cells specifically and in a dose...

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

    Science.gov (United States)

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

    2014-01-01

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

  9. Reversible dementias

    OpenAIRE

    Tripathi, Manjari; Vibha, Deepti

    2009-01-01

    In recent years, more attention has been given to the early diagnostic evaluation of patients with dementia which is essential to identify patients with cognitive symptoms who may have treatable conditions. Guidelines suggest that all patients presenting with dementia or cognitive symptoms should be evaluated with a range of laboratory tests, and with structural brain imaging with computed tomography (CT) or magnetic resonance imaging (MRI). While many of the disorders reported as ‘reversible...

  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

    Institute of Scientific and Technical Information of China (English)

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

    Energy Technology Data Exchange (ETDEWEB)

    None

    2002-11-01

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

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

    Directory of Open Access Journals (Sweden)

    Sara Torres Servín

    2013-01-01

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

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

    Institute of Scientific and Technical Information of China (English)

    ChengjianZHANG; HongbingYU

    2001-01-01

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

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

    DEFF Research Database (Denmark)

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

    1999-01-01

    The ADAMs (a disintegrin and metalloprotease) are a family of multidomain proteins that are believed to play key roles in cell-cell and cell-matrix interactions. We have shown recently that human ADAM 12-S (meltrin alpha) is an active metalloprotease. It is synthesized as a zymogen......, 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...

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

    OpenAIRE

    Wikaningtyas, Dian

    2016-01-01

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

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

    OpenAIRE

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

    2010-01-01

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

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

    OpenAIRE

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

    2014-01-01

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

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

    OpenAIRE

    Darwin

    2016-01-01

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

  19. Adams-Oliver syndrome associated with cutis marmorata telangiectatica congenita and congenital cataract: a case report.

    Science.gov (United States)

    Fayol, Laurence; Garcia, Patricia; Denis, Danièle; Philip, Nicole; Simeoni, Umberto

    2006-04-01

    A female infant presented with Adams-Oliver syndrome (AOS), intrauterine growth retardation, severe cutis marmorata telangiectatica congenita, bilateral congenital cataract, and periventricular lesions. The here-reported association of bilateral congenital cataract with AOS is original. Adams-Oliver syndrome is a genetic defect that causes a vasculopathy and leads to a variety of phenotypes. This observation further supports the current understanding of the physiopathology of AOS. PMID:16586236

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

    OpenAIRE

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

    2002-01-01

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

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

    OpenAIRE

    Viikinkoski, Matti; Kaasalainen, Mikko; Durech, Josef

    2015-01-01

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

  2. XOPÓS = Chorós : the dance of Adam

    DEFF Research Database (Denmark)

    Isar, Nicoletta

    is contained in the very title of the book: “the Dance of Adam.” This dance alone gives ontological meaning to the Byzantine subject, to the whole Byzantine ¿¿¿¿¿¿¿a. In this choral equation, Adam stands for the humanity all-embracing. The book reads ¿¿¿¿¿ from an interdisciplinary perspective, incorporating...

  3. 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

    Institute of Scientific and Technical Information of China (English)

    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.

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

    Institute of Scientific and Technical Information of China (English)

    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.

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

    Science.gov (United States)

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

    2015-01-01

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

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

    Science.gov (United States)

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

    2016-03-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1996-12-31

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

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

    Directory of Open Access Journals (Sweden)

    LeMeur Nolwenn

    2009-09-01

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

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

    Directory of Open Access Journals (Sweden)

    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.

  10. Adam Smith om forholdet mellem moralske fornemmelser og naturen

    DEFF Research Database (Denmark)

    Huggler, Lise Oxenbøll

    2008-01-01

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

  11. ADAM SMITH: LA MANO INVISIBLE O LA CONFIANZA

    Directory of Open Access Journals (Sweden)

    Gache, Fernando Luis

    2010-12-01

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

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

    Directory of Open Access Journals (Sweden)

    Souren A. Takhtajan

    2015-08-01

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

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

    DEFF Research Database (Denmark)

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

    2013-01-01

    ADAM (a disintegrin and metalloproteinase) 12 is a metalloprotease implicated in cancer progression. ADAM12 can activate membrane-anchored proteins, such as sonic hedgehog, Delta-like 1 and certain epidermal growth factor receptor ligands, through a process called ectodomain shedding. We screened...... molecule 1)], of which the latter four are specifically expressed by endothelial cells. We also observed that ADAM12 expression was increased in the tumour vasculature of infiltrating ductal carcinoma of the human breast as compared with little to no expression in normal breast tissue vasculature......, suggesting a role for ADAM12 in tumour vessels. These results prompted us to further evaluate ADAM12-mediated shedding of two endothelial cell proteins, VE-cadherin and Tie-2. Endogenous ADAM12 expression was very low in cultured endothelial cells, but was significantly increased by cytokine stimulation...

  14. Reversible Statistics

    DEFF Research Database (Denmark)

    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...

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2012-07-01

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

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

    International Nuclear Information System (INIS)

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

  17. 2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine (ADAM): an improved serotonin transporter ligand

    Energy Technology Data Exchange (ETDEWEB)

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

    2000-04-01

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

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

    Directory of Open Access Journals (Sweden)

    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

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

    International Nuclear Information System (INIS)

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

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

    DEFF Research Database (Denmark)

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

    2006-01-01

    the first visualization of a full-length ADAM molecule, human ADAM12-S, and report that it appears to be a compact clover composed of four globular domains, one of which is the prodomain. Finally, our data demonstrate that the presence of the metalloprotease domain appears to be sufficient for the prodomain...... to remain associated with the mature ADAM12-S. Thus, we conclude that the prodomain of human ADAM12-S is an integral domain of the mature molecule and as such might have specific biological functions in the extracellular space....

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

    Directory of Open Access Journals (Sweden)

    Weide Thomas

    2010-01-01

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

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

    Science.gov (United States)

    Howard, James Michael

    2002-01-01

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

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

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

    2013-09-01

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

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

    Institute of Scientific and Technical Information of China (English)

    刘爽; 马荣

    2013-01-01

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

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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. PMID:27163463

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

    Directory of Open Access Journals (Sweden)

    Paramita Ayuningtyas

    2011-03-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

    Buhl, M.L. Jr.

    1994-12-01

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

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

    Indian Academy of Sciences (India)

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

    2009-06-01

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

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

    Science.gov (United States)

    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.

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

    Directory of Open Access Journals (Sweden)

    Jianyu Han

    2014-08-01

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

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

    DEFF Research Database (Denmark)

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

    2008-01-01

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

  14. Biodistribution and radiation dosimetry of [{sup 123}I]ADAM in healthy human subjects: preliminary results

    Energy Technology Data Exchange (ETDEWEB)

    Kauppinen, Tomi A.; Ahonen, Aapo K. [Division of Nuclear Medicine, Helsinki University Central Hospital, P.O. Box 340, 00029 Helsinki (Finland); Bergstroem, Kim A. [Division of Nuclear Medicine, Helsinki University Central Hospital, P.O. Box 340, 00029 Helsinki (Finland); MAP Medical Technologies Oy, Helsinki (Finland); Heikman, Pertti [Department of Psychiatry, Helsinki University Central Hospital, Helsinki (Finland); Hiltunen, Jukka [MAP Medical Technologies Oy, Helsinki (Finland)

    2003-01-01

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

  15. PKC Activation Counteracts ADAM10 Deficit in HuD-Silenced Neuroblastoma Cells.

    Science.gov (United States)

    Marchesi, Nicoletta; Amadio, Marialaura; Colombrita, Claudia; Govoni, Stefano; Ratti, Antonia; Pascale, Alessia

    2016-09-01

    Neuronal ELAV/Hu (nELAV) are RNA-binding proteins that mainly regulate gene expression by increasing the stability and/or translation rate of target mRNAs bearing ARE (adenine and uracil-rich elements) sequences. Among nELAV target transcripts there is ADAM10, an α-secretase involved in the non-amyloidogenic processing of the amyloid-β protein precursor (AβPP) which leads to the production of the neuroprotective sAβPPα peptide. The aim of this study was to evaluate if nELAV depletion affects ADAM10 expression in human SH-SY5Y neuroblastoma cells. We also studied the effects of Bryostatin-1, a molecule able to activate nELAV protein cascade. The specific HuD/nELAV gene silencing decreased both nELAV and ADAM10 protein contents; similar results were obtained by Aβ40 treatment in wild-type SH-SY5Y cells. In HuD-silenced cells, the exposure to Bryostatin-1 counteracted both nELAV and ADAM10 proteins downregulation, by restoring nELAV/ADAM10 basal levels. We also found that sAβPPα release, which seemed not to be compromised by Aβ40 challenge or HuD-silencing, was favored by Bryostatin-1. Overall, these findings strongly suggest that a deficiency in nELAV content negatively affects ADAM10 expression and may play a role in neurodegenerative diseases, which may benefit by molecules activating ELAV cascade. PMID:27472877

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

    Epstein, Seymour

    2007-01-01

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

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

    Science.gov (United States)

    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…

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

    Science.gov (United States)

    2015-11-01

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

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

    Directory of Open Access Journals (Sweden)

    Gheorghe POPESCU

    2013-05-01

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

  1. El sujeto económico y la racionalidad en Adam Smith

    Directory of Open Access Journals (Sweden)

    Vanesa Valeria D’Elia

    2009-12-01

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

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

    Directory of Open Access Journals (Sweden)

    Gheorghe Popescu

    2012-05-01

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

  3. 集散式I/O控制系统ADAM-8000系列

    Institute of Scientific and Technical Information of China (English)

    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……

  4. 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

    Institute of Scientific and Technical Information of China (English)

    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.

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

    Science.gov (United States)

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

    2016-08-01

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

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

    DEFF Research Database (Denmark)

    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...

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

    DEFF Research Database (Denmark)

    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...

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

    Institute of Scientific and Technical Information of China (English)

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

    2011-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Qingyu Li

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

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

    Science.gov (United States)

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

    2013-01-01

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

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

    DEFF Research Database (Denmark)

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

    2002-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Slack Barbara E

    2011-05-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2002-11-26

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

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    Stokes, Cloyce

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

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

    Energy Technology Data Exchange (ETDEWEB)

    None

    2002-11-01

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

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

    Science.gov (United States)

    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).

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

    DEFF Research Database (Denmark)

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

    2009-01-01

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

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

    Science.gov (United States)

    Winch, Christopher

    1998-01-01

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

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

    Science.gov (United States)

    Ortmann, Andreas

    1997-01-01

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

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

    Science.gov (United States)

    Mundell, Jean

    1987-01-01

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

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

    Science.gov (United States)

    Purcell, William M.

    1986-01-01

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

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

    Science.gov (United States)

    Weinstein, Jack Russell

    2015-01-01

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

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

    Science.gov (United States)

    Davis, Denis J.

    1981-01-01

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

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

    Science.gov (United States)

    Zayernouri, Mohsen; Matzavinos, Anastasios

    2016-07-01

    We first formulate a fractional class of explicit Adams-Bashforth (A-B) and implicit Adams-Moulton (A-M) methods of first- and second-order accuracy for the time-integration of 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.

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

    LENUS (Irish Health Repository)

    McGowan, P M

    2013-02-01

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

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

    Science.gov (United States)

    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,…

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

    DEFF Research Database (Denmark)

    Feliu, Elisenda

    2010-01-01

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

  9. From Adams to Ziebland via Heidegger: Dimensions of Care (Cura) as a philosophical framework for design

    DEFF Research Database (Denmark)

    Coxon, Ian Robert

    not as simply utopian anticipation (Adams, 2009) but Care as playing a central role at ground zero in everyday human experience (Ziebland, 2012). In a sense the proposed framework also provides another way in which human-centred or anthropocentric design ideals might be revisited or better still, genuinely...

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

    Science.gov (United States)

    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…

  11. Development of a High Fidelity Dynamic Module of the Advanced Resistive Exercise Device (ARED) Using Adams

    Science.gov (United States)

    Humphreys, B. T.; Thompson, W. K.; Lewandowski, B. E.; Cadwell, E. E.; Newby, N. J.; Fincke, R. S.; Sheehan, C.; Mulugeta, L.

    2012-01-01

    NASA's Digital Astronaut Project (DAP) implements well-vetted computational models to predict and assess spaceflight health and performance risks, and enhance countermeasure development. DAP provides expertise and computation tools to its research customers for model development, integration, or analysis. DAP is currently supporting the NASA Exercise Physiology and Countermeasures (ExPC) project by integrating their biomechanical models of specific exercise movements with dynamic models of the devices on which the exercises were performed. This presentation focuses on the development of a high fidelity dynamic module of the Advanced Resistive Exercise Device (ARED) on board the ISS. The ARED module, illustrated in the figure below, was developed using the Adams (MSC Santa Ana, California) simulation package. The Adams package provides the capabilities to perform multi rigid body, flexible body, and mixed dynamic analyses of complex mechanisms. These capabilities were applied to accurately simulate: Inertial and mass properties of the device such as the vibration isolation system (VIS) effects and other ARED components, Non-linear joint friction effects, The gas law dynamics of the vacuum cylinders and VIS components using custom written differential state equations, The ARED flywheel dynamics, including torque limiting clutch. Design data from the JSC ARED Engineering team was utilized in developing the model. This included solid modeling geometry files, component/system specifications, engineering reports and available data sets. The Adams ARED module is importable into LifeMOD (Life Modeler, Inc., San Clemente, CA) for biomechanical analyses of different resistive exercises such as squat and dead-lift. Using motion capture data from ground test subjects, the ExPC developed biomechanical exercise models in LifeMOD. The Adams ARED device module was then integrated with the exercise subject model into one integrated dynamic model. This presentation will describe the

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

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

    International Nuclear Information System (INIS)

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2015-01-02

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

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

    International Nuclear Information System (INIS)

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

  16. 研华全新无线解决方案产品ADAM-2000面市

    Institute of Scientific and Technical Information of China (English)

    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。

  17. Reversible arithmetic logic unit

    OpenAIRE

    zhou, Rigui; Shi, Yang; Zhang, Manqun

    2011-01-01

    Quantum computer requires quantum arithmetic. The sophisticated design of a reversible arithmetic logic unit (reversible ALU) for quantum arithmetic has been investigated in this letter. We provide explicit construction of reversible ALU effecting basic arithmetic operations. By provided the corresponding control unit, the proposed reversible ALU can combine the classical arithmetic and logic operation in a reversible integrated system. This letter provides actual evidence to prove the possib...

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

    Institute of Scientific and Technical Information of China (English)

    张慧芳; 李倩倩; 赵兴鹃; 董妍; 张艳

    2012-01-01

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

  19. Drugs That Fight HIV-1

    Science.gov (United States)

    ... program of the National Institutes of Health Nucleoside Reverse Transcriptase Inhibitors (NRTIs) NRTIs block reverse transcriptase, an enzyme HIV- ... these products are on last page.) Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) NNRTIs bind to and alter reverse transcriptase, ...

  20. FDA-Approved HIV Medicines

    Science.gov (United States)

    ... and acronyms) Brand Name FDA Approval Date Nucleoside Reverse Transcriptase Inhibitors (NRTIs) NRTIs block reverse transcriptase, an enzyme HIV ... AZT, ZDV) Retrovir March 19, 1987 Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) NNRTIs bind to and later alter reverse ...

  1. 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

    Institute of Scientific and Technical Information of China (English)

    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.

  2. Managing Reverse Logistics or Reversing Logistics Management?

    NARCIS (Netherlands)

    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

  3. Discovery and Structure-Based Optimization of 2-Ureidothiophene-3-carboxylic Acids as Dual Bacterial RNA Polymerase and Viral Reverse Transcriptase Inhibitors.

    Science.gov (United States)

    Elgaher, Walid A M; Sharma, Kamal K; Haupenthal, Jörg; Saladini, Francesco; Pires, Manuel; Real, Eleonore; Mély, Yves; Hartmann, Rolf W

    2016-08-11

    We are concerned with the development of novel anti-infectives with dual antibacterial and antiretroviral activities for MRSA/HIV-1 co-infection. To achieve this goal, we exploited for the first time the mechanistic function similarity between the bacterial RNA polymerase (RNAP) "switch region" and the viral non-nucleoside reverse transcriptase inhibitor (NNRTI) binding site. Starting from our previously discovered RNAP inhibitors, we managed to develop potent RT inhibitors effective against several resistant HIV-1 strains with maintained or enhanced RNAP inhibitory properties following a structure-based design approach. A quantitative structure-activity relationship (QSAR) analysis revealed distinct molecular features necessary for RT inhibition. Furthermore, mode of action (MoA) studies revealed that these compounds inhibit RT noncompetitively, through a new mechanism via closing of the RT clamp. In addition, the novel RNAP/RT inhibitors are characterized by a potent antibacterial activity against S. aureus and in cellulo antiretroviral activity against NNRTI-resistant strains. In HeLa and HEK 293 cells, the compounds showed only marginal cytotoxicity. PMID:27339173

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

    Data.gov (United States)

    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...

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

    Data.gov (United States)

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

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

    Data.gov (United States)

    NSGIC GIS Inventory (aka Ramona) — This Soils dataset, published at 1:4800 (1in=400ft) scale as of 2005. It is described as 'Adams Co Soils'. Data by this publisher are often provided in WGS 1984...

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

    Index Scriptorium Estoniae

    Köörna, Arno

    2004-01-01

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

  8. Reversible Thermoset Adhesives

    Science.gov (United States)

    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.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2012-07-01

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

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

    OpenAIRE

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

    2008-01-01

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

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

    CERN Document Server

    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.

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

    Institute of Scientific and Technical Information of China (English)

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

    2013-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Sarah Buhler

    2016-01-01

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

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

    Science.gov (United States)

    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). PMID:22082387

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

    Institute of Scientific and Technical Information of China (English)

    何毅斌; 胡荣博; 刘慧; 杨兵宽; 张雨

    2014-01-01

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

  16. Karakteristik Penderita Tonsilitis Kronis di RSUP Haji Adam Malik Medan Tahun 2012

    OpenAIRE

    Manik, Yosefina Imelda

    2015-01-01

    Chronic tonsillitis is persistent inflammation of tonsils due to recurrent infection, usually caused by inadequate medical treatment of acute tonsillitis. The main cause of chronic tonsillitis is infection of virus and group A β–hemolytic streptococcus. Transmission of infection can be through air borne droplets, hands and kiss. Tonsillitis can occur in any age, especially in children. This study aims to find the characteristics of patients with chronic tonsillitis in Haji Adam Malik General ...

  17. Karakteristik Penderita Tonsilitis Kronis Di RSUP H. Adam Malik Medan Tahun 2009

    OpenAIRE

    Amalia, Nina

    2011-01-01

    Introduction: Chronic Tonsillitis is the most commonest disease in the throat occurring predominantly in the younger age group. It is due to chronic inflammation within the tonsils due to insufficient or inappropriate of the antibiotika for acute tonsillitis. The morbidity rate in children 5-14 year group from the family survey in 1995, chronic tonsillitis was on the fifth. Purpose: This study aimed to find the characteristic of chronic tonsillitis patients in H. Adam Malik General Hosp...

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

    OpenAIRE

    Traoré, Flavia Aiello

    2012-01-01

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

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

    International Nuclear Information System (INIS)

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

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

    OpenAIRE

    Prihartomo, Gatot Aji

    2015-01-01

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

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

    OpenAIRE

    Sembiring, Morel

    2016-01-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2015-07-15

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

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

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

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

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

    OpenAIRE

    Pathmanathan, Hemalatha

    2012-01-01

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

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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…

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

    OpenAIRE

    Burhan, Fatmadina

    2015-01-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2005-07-01

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

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

    OpenAIRE

    Shakir Ariff Bin Zulkifli

    2012-01-01

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

  10. BEA首席软件架构师:Adam Bosworth

    Institute of Scientific and Technical Information of China (English)

    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。

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

    OpenAIRE

    Kakarot-Handtke, Egmont

    2014-01-01

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

  12. Drug Interactions

    Science.gov (United States)

    ... WITH HIV MEDICATIONS? Protease inhibitors and non-nucleoside reverse transcriptase inhibitors are processed by the liver and cause many ... taken with any protease inhibitor or non-nucleoside reverse transcriptase inhibitor. You can also check for drug-drug and ...

  13. Reverse Shoulder Arthroplasty

    Medline Plus

    Full Text Available ... you can use for reverse shoulder replacement. The standard delto-pectoral approach, or the superior approach, which ... that are different between a reverse and a standard total is, first of all, we don't ...

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

    CERN Document Server

    CERN. Geneva

    2009-01-01

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

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

    CERN Document Server

    CERN. Geneva

    2009-01-01

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

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

    Science.gov (United States)

    Viikinkoski, Matti; Kaasalainen, Mikko; Durech, Josef

    2015-04-01

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

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

    CERN Document Server

    Viikinkoski, Matti; Durech, Josef

    2015-01-01

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

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

    Science.gov (United States)

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

    2016-09-01

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

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

    Institute of Scientific and Technical Information of China (English)

    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.

  20. Reverse cholesterol transport revisited

    Institute of Scientific and Technical Information of China (English)

    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.

  1. Reverse logistics - a framework

    NARCIS (Netherlands)

    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

  2. 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

    Institute of Scientific and Technical Information of China (English)

    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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2011-08-21

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

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

    Science.gov (United States)

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

    2011-08-01

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

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

    DEFF Research Database (Denmark)

    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...

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

    Science.gov (United States)

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

    2016-09-01

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

  7. 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

    Institute of Scientific and Technical Information of China (English)

    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 .

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

    Directory of Open Access Journals (Sweden)

    Andrew W Horne

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

  9. First trimester screening for trisomy 21 in gestational week 8-10 by ADAM12-S as a maternal serum marker

    Directory of Open Access Journals (Sweden)

    Guitton Marie

    2010-10-01

    Full Text Available Abstract Background A disintegrin and metalloprotease 12 (ADAM12-S has previously been reported to be significantly reduced in maternal serum from women with fetal aneuploidy early in the first trimester and to significantly improve the quality of risk assessment for fetal trisomy 21 in prenatal screening. The aim of this study was to determine whether ADAM12-S is a useful serum marker for fetal trisomy 21 using the mixture model. Method In this case control study ADAM12-S was measured by KRYPTOR ADAM12-S immunoassay in maternal serum from gestational weeks 8 to 11 in 46 samples of fetal trisomy 21 and in 645 controls. Comparison of sensitivity and specificity of first trimester screening for fetal trisomy 21 with or without ADAM12-S included in the risk assessment using the mixture model. Results The concentration of ADAM12-S increased from week 8 to 11 and was negatively correlated with maternal weight. Log MoM ADAM12-S was positively correlated with log MoM PAPP-A (r = 0.39, P Conclusion The data show moderately decreased levels of ADAM12-S in cases of fetal aneuploidy in gestational weeks 8-11. However, including ADAM12-S in the routine risk does not improve the performance of first trimester screening for fetal trisomy 21.

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

    Directory of Open Access Journals (Sweden)

    Piotr Donizy

    2015-01-01

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

  11. 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

    Institute of Scientific and Technical Information of China (English)

    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.

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

    Directory of Open Access Journals (Sweden)

    Sandifer Tracy

    2007-07-01

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

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

    Directory of Open Access Journals (Sweden)

    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.

  14. Introduction to reversible computing

    CERN Document Server

    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

  15. Design of Reversible Counter

    OpenAIRE

    Md. Selim Al Mamun; B. K. Karmaker

    2014-01-01

    This article presents a research work on the design and synthesis of sequential circuits and flip-flops that are available in digital arena; and describes a new synthesis design of reversible counter that is optimized in terms of quantum cost, delay and garbage outputs compared to the existing designs. We proposed a new model of reversible T flip-flop in designing reversible counter.

  16. 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

    Institute of Scientific and Technical Information of China (English)

    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。

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

    Science.gov (United States)

    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

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

    Institute of Scientific and Technical Information of China (English)

    游建友; 聂红兵; 黄瑛; 陈志颖

    2015-01-01

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

  19. Posterior Reversible Encephalopathy Syndrome

    OpenAIRE

    J Gordon Millichap

    2013-01-01

    Investigators at Children's Hospital of Montefiore, Albert Einstein College of Medicine, NY, determined the incidence of posterior reversible encephalopathy syndrome (PRES) in a pediatric critical care unit.

  20. 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

    Institute of Scientific and Technical Information of China (English)

    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.

  1. Homodimerization of the p51 Subunit of HIV-1 Reverse Transcriptase

    Energy Technology Data Exchange (ETDEWEB)

    Zheng, X.; Mueller, G; Cuneo, M; DeRose, E; London, R

    2010-01-01

    The dimerization of HIV reverse transcriptase (RT), required to obtain the active form of the enzyme, is influenced by mutations, non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleotide substrates, Mg ions, temperature, and specifically designed dimerization inhibitors. In this study, we have utilized nuclear magnetic resonance (NMR) spectroscopy of the [methyl-{sup 13}C]methionine-labeled enzyme and small-angle X-ray scattering (SAXS) to investigate how several of these factors influence the dimerization behavior of the p51 subunit. The {sup 1}H-{sup 13}C HSQC spectrum of p51 obtained at micromolar concentrations indicates that a significant fraction of the p51 adopts a 'p66-like' conformation. SAXS data obtained for p51 samples were used to determine the fractions of monomer and dimer in the sample and to evaluate the conformation of the fingers/thumb subdomain. All of the p51 monomer observed was found to adopt the compact, 'p51C' conformation observed for the p51 subunit in the RT heterodimer. The NMR and SAXS data indicate that the p51 homodimer adopts a structure that is similar to the p66/p51 heterodimer, with one p51C subunit and a second p51 subunit in an extended, 'p51E' conformation that resembles the p66 subunit of the heterodimer. The fractional dimer concentration and the fingers/thumb orientation are found to depend strongly on the experimental conditions and exhibit a qualitative dependence on nevirapine and ionic strength (KCl) that is similar to the behavior reported for the heterodimer and the p66 homodimer. The L289K mutation interferes with p51 homodimer formation as it does with formation of the heterodimer, despite its location far from the dimer interface. This effect is readily interpreted in terms of a conformational selection model, in which p51{sub L289K} has a much greater preference for the compact, p51C conformation. A reduced level of dimer formation then results from the reduced ratio of

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

    OpenAIRE

    Crowder, Rachel E

    2012-01-01

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

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

    Institute of Scientific and Technical Information of China (English)

    Maurizio BRUNETTI; Adriana CIAMPELLA; Luciano A. LOMONACO

    2006-01-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

    Suescun-Diaz, Daniel [Surcolombiana Univ., Neiva (Colombia). Groupo de Fisica Teorica; Narvaez-Paredes, Mauricio [Javeriana Univ., Cali (Colombia). Groupo de Matematica y Estadistica Aplicada Pontificia; Lozano-Parada, Jamie H. [Univ. del Valle, Cali (Colombia). Dept. de Ingenieria

    2016-03-15

    In this paper, the generalisation of the 4th-order Adams-Bashforth-Moulton predictor-corrector method is proposed to numerically solve the point kinetic equations of the nuclear reactivity calculations without using the nuclear power history. Due to the nature of the point kinetic equations, different predictor modifiers are used in order improve the precision of the approximations obtained. The results obtained with the prediction formulas and generalised corrections improve the precision when compared with previous methods and are valid for various forms of nuclear power and different time steps.

  5. The Role of the Imagination in Adam Smith’s Refutation of the Homo Economicus Thesis

    Directory of Open Access Journals (Sweden)

    José de la Cruz Garrido

    2015-12-01

    Full Text Available Adam Smith’s moral philosophy is grounded in the role of the imagination in explaining the social order at a macro level and as a mechanism for affective identification at the micro level. In both cases, the role of the imagination in our moral psychology refutes the homo economicus thesis according to which human beings are motivated to enter into society due to personal interests. This premise serves to refute the Hobbesian position of a historical state of nature that underlies the moral judgments grounding civil society and the need for a magistrate.

  6. The Role of the Imagination in Adam Smith’s Refutation of the Homo Economicus Thesis

    OpenAIRE

    José de la Cruz Garrido

    2015-01-01

    Adam Smith’s moral philosophy is grounded in the role of the imagination in explaining the social order at a macro level and as a mechanism for affective identification at the micro level. In both cases, the role of the imagination in our moral psychology refutes the homo economicus thesis according to which human beings are motivated to enter into society due to personal interests. This premise serves to refute the Hobbesian position of a historical state of nature that underlies the moral j...

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

    Directory of Open Access Journals (Sweden)

    Blekherman Grigoriy

    2011-07-01

    Full Text Available Abstract Background Many biological systems are modeled qualitatively with discrete models, such as probabilistic Boolean networks, logical models, Petri nets, and agent-based models, to gain a better understanding of them. The computational complexity to analyze the complete dynamics of these models grows exponentially in the number of variables, which impedes working with complex models. There exist software tools to analyze discrete models, but they either lack the algorithmic functionality to analyze complex models deterministically or they are inaccessible to many users as they require understanding the underlying algorithm and implementation, do not have a graphical user interface, or are hard to install. Efficient analysis methods that are accessible to modelers and easy to use are needed. Results We propose a method for efficiently identifying attractors and introduce the web-based tool Analysis of Dynamic Algebraic Models (ADAM, which provides this and other analysis methods for discrete models. ADAM converts several discrete model types automatically into polynomial dynamical systems and analyzes their dynamics using tools from computer algebra. Specifically, we propose a method to identify attractors of a discrete model that is equivalent to solving a system of polynomial equations, a long-studied problem in computer algebra. Based on extensive experimentation with both discrete models arising in systems biology and randomly generated networks, we found that the algebraic algorithms presented in this manuscript are fast for systems with the structure maintained by most biological systems, namely sparseness and robustness. For a large set of published complex discrete models, ADAM identified the attractors in less than one second. Conclusions Discrete modeling techniques are a useful tool for analyzing complex biological systems and there is a need in the biological community for accessible efficient analysis tools. ADAM provides

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

    OpenAIRE

    Viprey, Jean-Marie

    2013-01-01

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

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

    CERN Multimedia

    2003-01-01

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

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

    CERN Multimedia

    2003-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Mara Magda Maftei

    2006-09-01

    Full Text Available Adam Smith is thought to be the first economist, his economic considerations being even nowadays valid, no matter the everchanging connotations of capitalism throughtout the world. Unfortunately, only The Wealth of Nations was translated in Romanian, and that is why there is a tendency among us to analyze Smith only by means of his economic paradigma, leaving out his preoccupations of moral philosophy, of finding the connections between political, juridical and economic aspects. Above all, we should insist on his obsession with human nature, obsession to be embbeded within the increasing importance of economic sciences in his time, growing out of moral philosophy and jurisprudence.

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Directory of Open Access Journals (Sweden)

    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.

  15. 宫颈癌组织中ADAM-19、Ki-67的表达及临床意义%The expression and clinical significance of ADAM-19,Ki-67 in cervical cancer

    Institute of Scientific and Technical Information of China (English)

    逯仁波; 王小川; 马荣; 耿晓星

    2011-01-01

    目的 研究早期宫颈癌组织中去整合素基质金属蛋白酶-19(a disintegrin and metalloproteinase,ADAM-19)、癌细胞增殖指数(Ki-67)的表达及临床意义.方法 应用免疫组化SP法检测18例正常宫颈上皮(normal cervical epithelium,NCE)、22例宫颈上皮内瘤变(cervical intraepithelial neoplasm,CIN)和82例宫颈早期浸润癌(invasive cervix carsinoma,ICC)组织中ADAM-19和Ki-67的表达情况.结果 在宫颈癌中ADAM-19表达于癌细胞浆和或细胞膜;Ki-67表达于细胞核.从正常宫颈上皮(normal cervical epithelium,NCE)到宫颈上皮内瘤变(cervical intraepithelial neoplasm,CIN)再到宫颈浸润癌(invasive carsinoma cervix,ICC),ADAM-19、Ki-67的阳性表达率逐步升高(P<0.05).ADAM-19在宫颈浸润癌中的表达与盆腔淋巴结转移、脉管浸润、间质浸润、国际妇产科联盟(FIGO)分期、组织学分级和Ki-67表达有关(P<0.05);但与年龄和组织学类型无明显相关性(P>0.05).有盆腔淋巴结转移、脉管浸润、突破深层间质浸润、FIGO分期为Ⅱ期、组织学分级为Ⅲ级及Ki-67高度表达者,其ADAM-19阳性表达率显著高于无盆腔淋巴结转移、无脉管浸润、浸润深度在浅层间质以内、FIGO分期为Ⅰ期、组织学分级未超过Ⅱ级及Ki-67表达在中度以内者(P<0.05).结论 ADAM-19阳性表达可能在癌细胞增殖和侵袭转移中起重要作用.ADAM-19过度表达者,癌细胞增殖活跃,更易发生侵袭转移,但并非唯一决定因素.检测宫颈癌中ADAM-19表达对进一步了解宫颈癌生物学行为和判断其预后有一定价值.%Objective To evaluate the expression and clinical significance of A disintegrin and metalloproteinase( ADAM - 19 ),Ki - 67 in early invasive cervical cancer. Methods Expression of ADAM - 19 and Ki - 67 in 18 cases of normal cervical epithelium( NCE ),22 cases of cervical intraepithelial neoplasm( CIN ) and 82 cases of invasive carcinoma cervix( ICC )were detected by

  16. 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

    Institute of Scientific and Technical Information of China (English)

    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.

  17. Lack of ADAM2, CALR3 and SAGE1 Cancer/Testis Antigen Expression in Lung and Breast Cancer

    DEFF Research Database (Denmark)

    Maheswaran, Emeaga; Pedersen, Christina B; Ditzel, Henrik J;

    2015-01-01

    and antigenic properties, but the expression patterns of most of the more than 200 identified cancer/testis antigens in various cancers remain largely uncharacterized. In this study, we investigated the expression of the cancer/testis antigens ADAM2, CALR3 and SAGE1 in lung and breast cancer, the two most...... frequent human cancers, with the purpose of providing novel therapeutic targets for these diseases. We used a set of previously uncharacterized antibodies against the cancer/testis antigens ADAM2, CALR3 and SAGE1 to investigate their expression in a large panel of normal tissues as well as breast and lung...... cancers. Staining for the well-characterized MAGE-A proteins was included for comparison. Immunohistochemical staining confirmed previous mRNA analysis demonstrating that ADAM2, CALR3 and SAGE1 proteins are confined to testis in normal individuals. Negative tissues included plancenta, which express many...

  18. Quantum reverse hypercontractivity

    Energy Technology Data Exchange (ETDEWEB)

    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.

  19. Deep sequencing analysis of HIV-1 reverse transcriptase at baseline and time of failure in patients receiving rilpivirine in the phase III studies ECHO and THRIVE.

    Science.gov (United States)

    Van Eygen, Veerle; Thys, Kim; Van Hove, Carl; Rimsky, Laurence T; De Meyer, Sandra; Aerssens, Jeroen; Picchio, Gaston; Vingerhoets, Johan

    2016-05-01

    Minority variants (1.0-25.0%) were evaluated by deep sequencing (DS) at baseline and virological failure (VF) in a selection of antiretroviral treatment-naïve, HIV-1-infected patients from the rilpivirine ECHO/THRIVE phase III studies. Linkage between frequently emerging resistance-associated mutations (RAMs) was determined. DS (llIumina®) and population sequencing (PS) results were available at baseline for 47 VFs and time of failure for 48 VFs; and at baseline for 49 responders matched for baseline characteristics. Minority mutations were accurately detected at frequencies down to 1.2% of the HIV-1 quasispecies. No baseline minority rilpivirine RAMs were detected in VFs; one responder carried 1.9% F227C. Baseline minority mutations associated with resistance to other non-nucleoside reverse transcriptase inhibitors (NNRTIs) were detected in 8/47 VFs (17.0%) and 7/49 responders (14.3%). Baseline minority nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) RAMs M184V and L210W were each detected in one VF (none in responders). At failure, two patients without NNRTI RAMs by PS carried minority rilpivirine RAMs K101E and/or E138K; and five additional patients carried other minority NNRTI RAMs V90I, V106I, V179I, V189I, and Y188H. Overall at failure, minority NNRTI RAMs and NRTI RAMs were found in 29/48 (60.4%) and 16/48 VFs (33.3%), respectively. Linkage analysis showed that E138K and K101E were usually not observed on the same viral genome. In conclusion, baseline minority rilpivirine RAMs and other NNRTI/NRTI RAMs were uncommon in the rilpivirine arm of the ECHO and THRIVE studies. DS at failure showed emerging NNRTI resistant minority variants in seven rilpivirine VFs who had no detectable NNRTI RAMs by PS. PMID:26412111

  20. Neutralization of ADAM8 ameliorates liver injury and accelerates liver repair in carbon tetrachloride-induced acute liver injury.

    Science.gov (United States)

    Li, San-Qiang; Zhu, Sha; Wan, Xue-Dong; Xu, Zheng-Shun; Ma, Zhao

    2014-04-01

    Although some studies have described the function of ADAM8 (a disintegrin and metalloprotease 8) related with rheumatoid arthritis, cancer and asthma, etc., the concrete role of ADAM8 in acute liver injury is still unknown. So mice respectively received anti-ADAM8 monoclonal antibody (mAb) of 100 μg/100 μl, 200 μg/100 μl or 300 μg/100 μl in PBS or PBS pre-injection. Then acute liver injury was induced in the mice by intraperitoneal (i.p.) injection of carbon tetrachloride (CCl₄). Serum AST and ALT level, Haematoxylin-eosin (H&E) staining, the expression level of vascular endothelial growth factor (VEGF), cytochrome P450 1A2 (CYP1A2) and proliferating cell nuclear antigen (PCNA) were detected in the mice after CCl4 administration. Our results showed that anti-ADAM8 mAb pre-injection could effectively lower AST and ALT levels (P < 0.05 or P < 0.01) and reduce liver injury (P < 0.05 or P <0.01), induce the expression of VEGF, CYP1A2 and PCNA (P <0.05 or P < 0.01) in dose-dependent manner compared with the control mice which received PBS pre-injection. In summary, our study suggested that ADAM8 might promote liver injury by inhibiting the proliferation of hepatocytes, angiogenesis and affecting the metabolism function of liver during acute liver injury induced by CCl₄. Anti-ADAM8 mAb injection might be suitable as a potential method for acute liver injury therapy. PMID:24646716

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

    Science.gov (United States)

    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.

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

    Institute of Scientific and Technical Information of China (English)

    SANG; QingXiang; Amy

    2009-01-01

    Human ADAM19 is a recently identified member of the ADAM family.It is highly expressed in human placentas,but its dynamic change and function at the human feto-maternal interface during placentation remain to be elucidated.In this present study,the spatial and temporal expression and cellular localization of ADAM19 in normal human placentas were first demonstrated,and the effects of ADAM19 on trophoblast cell adhesion and invasion were further investigated by using a human choriocarcinoma cell line(JEG-3) as an in vitro model.The data demonstrated that ADAM19 was widely distributed in villous cytotrophoblast cells,syncytiotrophoblast cells,column trophoblasts,and villous capillary endothelial cells during early pregnancy.The mRNA and protein level of ADAM19 in placentas was high at gestational weeks 8-9,but diminished significantly at mid-and term pregnancy.In JEG-3 cells,the overexpression of ADAM19 led to diminished cell invasion,as well as increases in cell adhesiveness and the expression of E-cadherin,with no changes in β-catenin expression observed.These data indicate that ADAM19 may participate in the coordinated regulation of human trophoblast cell behaviors during the process of placentation.

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

    Science.gov (United States)

    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…

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

    DEFF Research Database (Denmark)

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

    2013-01-01

    that there is a positive correlation between MMP-14 and ADAM12 expression in human breast cancer. We demonstrated that in 293-VnR and human breast cancer cells expressing ADAM12 at the cell surface, endogenous MMP-14 was recruited to the cell surface, resulting in its activation. Subsequent to this activation, gelatin...... degradation was stimulated and tumor cell apoptosis was decreased, with reduced expression of the pro-apoptotic proteins BCL2L11 and BIK. The effect on gelatin degradation was abrogated by inhibition of the MMP-14 activity and appeared to be dependent on cell surface αVβ3 integrin localization, but neither...

  5. Gambaran Penderita Demam Berdarah Dengue Pada Anak Di RSUP. H. Adam Malik Medan Tahun 2008-2010

    OpenAIRE

    Maurieza, Keishya

    2011-01-01

    Dengue Hemmoraghic Fever is still a major problem of infectious disease in a various parts of the world. The incidence rate of DHF in the city of medan is also high. The aims of this study to know the descriptions of patients with DHFamong children in RSUP. H. Adam Malik Medan in the year 2008-2010. These type of the researchis a descriptive study. The study was conducted in RSUP. H. Adam Malik Medan between the months of May to November 2010. The source data of this research were secondary d...

  6. Lokalisation und Aktivierung von ADAM-Proteasen im Kontext der Fas-Ligand-Proteolyse in T-Zellen

    OpenAIRE

    Ebsen, Henriette

    2014-01-01

    Die Expression des Fas-Liganden wird u.a. durch posttranslationale Modifikationen reguliert, z.B. durch proteolytische Prozessierung. Die Aktivierung von T-Zellen durch TPA/Ionomycin bzw. T-Zellrezeptor/CD3/CD28-Stimulation führt zum gesteigerten Shedding durch die Metalloproteasen ADAM10 und/oder ADAM17. TZR/CD3/CD28-Aktivierung führt weiterhin zu einer partiellen Translokation der Proteasen und des FasL zu Detergenz-resistenten Membranen (DRMs). The expression of the death factor Fas Lig...

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

    Science.gov (United States)

    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

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

    Science.gov (United States)

    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

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

    Directory of Open Access Journals (Sweden)

    Thomas D. Hall

    2015-08-01

    Full Text Available About sixteen months ago we began discussing commissioning a series of review essays on Arrighi’s Adam Smith in Beijing. The original idea was to publish a collection of essays from various world-systems scholars, and have Arrighi respond. As we all know, Giovanni became ill and sadly passed in summer of 2009. In commissioning the essays as book review editor I faced a special challenge. Some likely writers had already committed to essays for other venues (e.g., Janet Abo-Lughod 2008; Chris Chase-Dunn forthcoming. I also wanted to get a variety of approaches so that the entire collection would represent a diverse set of views. The following essays do that. We are especially fortunate to have an essay from Robert Denemark, who I asked to comment on Andre Gunder Frank’s probable take(s on Adam Smith in Beijing. The remaining essays offer various insights into this important work.

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

    Directory of Open Access Journals (Sweden)

    T. RAFFAELLI

    2013-10-01

    Full Text Available It is the paradigm of political economy as an autonomous science, distinguished from ethics and politics, that Adam Smith is considered to be the "founding father" of. However, this confinement has at time resulted in a distorted of his views with regards to the central themes of later times, making him at times to be the supporter of methodological individualism, of unconditional liaise faire and the minimal state, and of the full coherence between private and public interest. Indeed, he has been pushed out of his historical context to take on almost absurd traits. Stereotypical and anti-historical aspects of these images of Smith were often detected in the past, but only recently have they become the subject of a critique that also involves the paradigmatic character of the Smith’s work. Taking into account this extraordinary wealth of new studies, the author proposes some reasons in favour of the interpretation of Smith as the theorist of capitalism and the father of political economy.  JEL Codes: B12Keywords: Adam Smith, political economy, capitalism

  11. Co-Simulation Control of Robot Arm Dynamics in ADAMS and MATLAB

    Directory of Open Access Journals (Sweden)

    Luo Haitao

    2013-10-01

    Full Text Available The main objective of this study is how to quickly establish the virtual prototyping model of robot arm system and effectively solve trajectory tracking control for a given signal. Taking the 2-DOF robot arm as an example, a co-simulation control method is introduced to research multi-body dynamics. Using Newton-Euler and Lagrange method, respectively establish the dynamics model of robot arm and verify the correctness of equations. Firstly, the physical model of robot arm was built by PROE and ADAMS. Furthermore, a control model was created in MATLAB/SIMULINK. And then, the co-simulation model was established based on ADAMS/Control and MATLAB/SIMULINK. The simulation results indicate that the robot arm system has preferable response characteristics and nicer locus-tracking ability. The co-simulation method is intuitive and effective. It is no need to create dynamics equation of complicated physical system and has the important practical significance to study manipulation and control for robot arm.

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

    DEFF Research Database (Denmark)

    Jakobsen, Ulla; Rohr, Katja; Madsen, Rasmus K;

    2007-01-01

    The synthesis of amphiphilic polyaza crown ether monomers X (palmityl-substituted), Y (cholesteryl-substituted) and Z (dipalmityl-subtituted) and their incorporation into oligonucleotides are described. Their effects on thermal duplex stability were investigated by UV melting curve analysis....... 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....

  13. Adam's Dream

    Science.gov (United States)

    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…

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

    DEFF Research Database (Denmark)

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

    2003-01-01

    the expression and redistribution of several components of the muscle cell-adhesion complexes. First, we analyzed transgenic mice that overexpress ADAM12 and found mild myopathic changes and accelerated regeneration following acute injury. We then analyzed changes in gene-expression profiles in mdx/ADAM12...... in humans. More specifically ADAM12 appeared to prevent muscle cell necrosis in the mdx mice as evidenced by morphological analysis and by the reduced levels of serum creatine kinase. In the present study we demonstrated that ADAM12 may compensate for the dystrophin deficiency in mdx mice by increasing......, and suggested that significant changes in mdx/ADAM12 muscle might occur post-transcriptionally. Indeed, by immunostaining and immunoblotting we found an approximately 2-fold increase in expression, and distinct extrasynaptic localization, of alpha 7B integrin and utrophin, the functional homolog of dystrophin...

  15. An Algebra of Reversible Computation

    OpenAIRE

    Wang, Yong

    2014-01-01

    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.

  16. Analysis of the sediments of the Julian Adame Alatorre dam by the INAA; Analisis de sedimentos de la presa Julian Adame Alatorre por la tecnica de AANI

    Energy Technology Data Exchange (ETDEWEB)

    Oliva, J.E.; Lugo, J.F.; Mireles, F.; Quirino, L.L.; Davila, J.I.; Pinedo, J.L.; Rios, C. [UAZ, Cipres 10, Fracc. La Penuela, 98068 Zacatecas (Mexico); Miller, W.H. [Nuclear Science and Engineering Institute, E2433 Engineering Building East, University of Missouri-Columbia, MO 65211 (United States)]. e-mail: jeolivag@yahoo.com.mx

    2003-07-01

    Its were taken eight samples of sediment of the Julian Adame Alatorre dam located in the Villanueva municipality, in the State of Zacatecas, Mexico; with the end of determining the presence of elements of anthropogenic origin, as well as the concentration of the same ones. It was used the Instrumental neutron activation analysis (AANI) with a flow of thermal neutrons of 8 x 10{sup 13} and 5 x 10{sup 13} n cm{sup -2} s{sup -1}. With the purpose of determining the concentration of these elements at level of traces; finding presence of 32 elements among which its were find elements in greater concentrations and others at level of traces. Of these 32 elements, five of anthropogenic origin were identified which its were: Cr, Co, Zn, As and Mn; but that whose concentration is very low, in comparison with the one reported in other places of the world. In this work there are presented the obtained results of the elementary analysis of this samples. (Author)

  17. On the construction of reversible automata for reversible languages

    OpenAIRE

    Lombardy, Sylvain

    2002-01-01

    International audience Reversible languages occur in many different domains. Although the decision for the membership of reversible languages was solved in 1992 by Pin, an effective construction of a reversible automaton for a reversible language was still unknown. We give in this paper a method to compute a reversible automaton from the minimal automaton of a reversible language. With this intention, we use the universal automaton of the language that can be obtained from the minimal auto...

  18. Reversible flowchart languages and the structured reversible program theorem

    DEFF Research Database (Denmark)

    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....

  19. Reverse Shoulder Arthroplasty

    Medline Plus

    Full Text Available ... stability and soft tissue envelope. In the early days of reverse arthroplasty, it used to be said ... often we'll drain these patients for a day to try to prevent hematoma formation, especially in ...

  20. Purchasing As Reverse Marketing

    OpenAIRE

    Blenkhorn, D L; Banting, P M

    1989-01-01

    This paper describes a new concept called reverse marketing, which is changing the conventional buyer-seller relationship and has important implications for the traditional role of the industrial marketer.

  1. Reversible Data Hiding Techniques

    Directory of Open Access Journals (Sweden)

    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.

  2. Reverse Shoulder Arthroplasty

    Medline Plus

    Full Text Available ... dislocations, although it's also reported to have a higher rate of getting the components in not perfect ... about infection and other things. There is a higher rate of infection with reverse replacement, probably because ...

  3. Reverse Shoulder Arthroplasty

    Medline Plus

    Full Text Available ... here in New York to bring you a video of a recent case of reverse shoulder arthroplasty ... helped design the system that's shown in this video, so I receive royalties and therefore have a ...

  4. Reverse Shoulder Arthroplasty

    Medline Plus

    Full Text Available ... a friction bite that if you try to work it around the corner, you can get an ... stability and soft tissue envelope. In the early days of reverse arthroplasty, it used to be said ...

  5. Reverse Shoulder Arthroplasty

    Medline Plus

    Full Text Available ... with an intact cuff, we would consider a traditional shoulder replacement. There are two basic approaches you ... less limited with the superior reverse versus the traditional. And I assume the question means the approach: ...

  6. Reverse Shoulder Arthroplasty

    Medline Plus

    Full Text Available ... the reverse allow patients to play tennis or sports where the arm swings backward. Our experience has ... who simply wants to be stronger or play sports better. But in terms of the patients that ...

  7. Reverse Shoulder Arthroplasty

    Medline Plus

    Full Text Available ... case of reverse shoulder arthroplasty for cuff deficient arthritis. You should be aware that I helped design ... in the last decade for cuff deficient shoulder arthritis in the United States. The indications are a ...

  8. Vasectomy reversal in humans

    OpenAIRE

    Bernie, Aaron M.; Osterberg, E Charles; Stahl, Peter J.; Ramasamy, Ranjith; Goldstein, Marc

    2012-01-01

    Vasectomy is the most common urological procedure in the United States with 18% of men having a vasectomy before age 45. A significant proportion of vasectomized men ultimately request vasectomy reversal, usually due to divorce and/or remarriage. Vasectomy reversal is a commonly practiced but technically demanding microsurgical procedure that restores patency of the male excurrent ductal system in 80–99.5% of cases and enables unassisted pregnancy in 40–80% of couples. The discrepancy between...

  9. PROCESSING REVERSE LOGISTICS INVENTORIES

    OpenAIRE

    Bajor, Ivona; Novačko, Luka; Ogrizović, Dario

    2014-01-01

    Developed logistics systems have organized reverse logistics flows and are continuously analyzing product returns, tending to detect patterns in oscillations of returning products in certain time periods. Inventory management in reverse logistics systems depends on different criteria, regarding goods categories, formed contracts between subjects of supply chains, uncertainty in manufacturer’s quantities of DOA (dead on arrival) products, etc. The developing logistics systems, such as the Croa...

  10. Reverse vending machine update

    Energy Technology Data Exchange (ETDEWEB)

    Rypins, S.; Papke, C.

    1986-02-01

    The document discusses reverse vending machines. Placed outdoors in supermarket parking lots or indoors in the lobby of the grocery market, these hightech machines exchange aluminum cans (or other containers in more specialized machines) for cash, coupons or redeemable receipts. The placement of reverse venders (RV) in or near supermarkets has made recycling more visible and more convenient, although the machines have yet to fully reach industry goals.

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

    DEFF Research Database (Denmark)

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

    2011-01-01

    a cell-based system of PMA-induced PKC activation coupled with shedding of heparin binding (HB)-EGF. In agreement with previous studies, we demonstrated that PMA triggers a rapid ADAM17-mediated release of HB-EGF. However, PMA-treatment also results in a protease-independent loss of cell surface HB...

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

    Science.gov (United States)

    Adamczyk, Peter G.; Gorsich, David J.; Hudas, Greg R.; Overholt, James

    2003-09-01

    The U.S. Army is seeking to develop autonomous off-road mobile robots to perform tasks in the field such as supply delivery and reconnaissance in dangerous territory. A key problem to be solved with these robots is off-road mobility, to ensure that the robots can accomplish their tasks without loss or damage. We have developed a computer model of one such concept robot, the small-scale "T-1" omnidirectional vehicle (ODV), to study the effects of different control strategies on the robot's mobility in off-road settings. We built the dynamic model in ADAMS/Car and the control system in Matlab/Simulink. This paper presents the template-based method used to construct the ADAMS model of the T-1 ODV. It discusses the strengths and weaknesses of ADAMS/Car software in such an application, and describes the benefits and challenges of the approach as a whole. The paper also addresses effective linking of ADAMS/Car and Matlab for complete control system development. Finally, this paper includes a section describing the extension of the T-1 templates to other similar ODV concepts for rapid development.

  13. Estrogen upregulates MICA/B expression in human non-small cell lung cancer through the regulation of ADAM17.

    Science.gov (United States)

    Ren, Jing; Nie, Yunzhong; Lv, Mingming; Shen, Sunan; Tang, Ruijing; Xu, Yujun; Hou, Yayi; Zhao, Shuli; Wang, Tingting

    2015-11-01

    Estrogen is involved in promoting lung cancer cell division and metastasis. MICA and MICB function as ligands for NKG2D, an important immunoreceptor expressed on natural killer (NK) cells. However, whether estrogen regulates MICA/B expression and affects tumor immune escape remains unknown. In this study, we measured the mRNA levels of MICA, MICB and ADAM17in non-small cell lung cancer (NSCLC) cell lines treated with estrogen. Surface expression of MICA/B on LTEP-a2 and A549 was detected using flow cytometry. We demonstrate that both mRNA and secretory protein levels of MICA/B in lung adenocarcinoma cell lines were upregulated by estradiol. Estradiol enhanced the expression of ADAM17, which was associated with the secretion of MICA/B. This secretion of MICA/B downregulated the NKG2D receptor on the surface of NK92 cells and impaired the cytotoxic activity of NK cells. Estradiol enhanced the expression of ADAM17, which was associated with the secretion of MICA/B. Furthermore, a significant correlation between the concentration of estradiol and the expression of MICA was found in tumor tissues of NSCLC patients. Therefore, we conclude that estrogen can regulate the expression and secretion of MICA/B through ADAM17, which helps lung cancer cells escape NKG2D-mediated immune surveillance.

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

    Science.gov (United States)

    2012-04-27

    ... Surface Transportation Board Adams-Warnock Railway, Inc.--Lease and Operation Exemption-- Norfolk Southern... exemption under ] 49 CFR 1150.31 to lease from Norfolk Southern Railway Company (NSR), and to operate, a... the lease agreement that is expected to be completed prior to the effective date of the...

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

    Directory of Open Access Journals (Sweden)

    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. 78 FR 37791 - In the Matter of: Jose Guadalupe Reyes-Martinez, Inmate Number #85993-279, CI Adams County...

    Science.gov (United States)

    2013-06-24

    ... by successive Presidential Notices, the most recent being that of August 15, 2012 (77 FR 49699..., CI Adams County, Correctional Institution, P.O. Box 1600, Washington, MS 39190; Order Denying Export... November 21, 2021, Jose Guadalupe Reyes-Martinez, with a last known address at: Inmate Number 85993-279,...

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

    Institute of Scientific and Technical Information of China (English)

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

    Index Scriptorium Estoniae

    2011-01-01

    Küsimusele vastasid välisüliõpilased: rahvusvahelisi suhteid õppiv Charina de Asis Filipiinidelt, magistriõppes rahvusvahelist õigust õppiv Adam Luke Vern-Barnett Austraaliast, küberkaitset õppiv Predrag Tasevski Makedooniast ja tarkvara arendust õppiv Shazia Javed Pakistanist

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

    DEFF Research Database (Denmark)

    Kawaguchi, Nobuko; Sundberg, Christina; Kveiborg, Marie;

    2003-01-01

    Changes in cell shape are a morphological hallmark of differentiation. In this study we report that the expression of ADAM12, a disintegrin and metalloprotease, dramatically affects cell morphology in preadipocytes, changing them from a flattened, fibroblastic appearance to a more rounded shape. We...... early adipocyte differentiation....

  20. Side Effects of HIV Medicines: HIV and Hyperlipidemia

    Science.gov (United States)

    ... name: Sustiva), which belongs to the non-nucleoside reverse transcriptase inhibitor (NNRTI) drug class . Efavirenz is one of the ... brand name: Retrovir), which belong to the nucleoside reverse transcriptase inhibitor (NRTI) drug class . Abacavir is a component of ...

  1. Side Effects of HIV Medicines: HIV and Lipodystrophy

    Science.gov (United States)

    ... of the following HIV medicines in the nucleoside reverse transcriptase inhibitor (NRTI) drug class . Stavudine (brand name: Zerit) Zidovudine ( ... is an HIV medicine in the non-nucleoside reverse transcriptase inhibitor (NNRTI) drug class . Efavirenz is one of the ...

  2. Side Effects of HIV Medicines: HIV and Hepatotoxicity

    Science.gov (United States)

    ... the following drug classes can cause hepatotoxicity: Nucleoside reverse transcriptase inhibitors (NRTIs) Hepatotoxicity is a risk with most NRTIs. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) Among NNRTIs, the risk of hepatotoxicity is ...

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

    Science.gov (United States)

    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.

  4. ADAM17 promotes proliferation of collecting duct kidney epithelial cells through ERK activation and increased glycolysis in polycystic kidney disease.

    Science.gov (United States)

    Beck Gooz, Monika; Maldonado, Eduardo N; Dang, Yujing; Amria, May Y; Higashiyama, Shigeki; Abboud, Hanna E; Lemasters, John J; Bell, P Darwin

    2014-09-01

    Polycystic kidney disease (PKD) is a common genetic disorder leading to cyst formation in the kidneys and other organs that ultimately results in kidney failure and death. Currently, there is no therapy for slowing down or stopping the progression of PKD. In this study, we identified the disintegrin metalloenzyme 17 (ADAM17) as a key regulator of cell proliferation in kidney tissues of conditional knockout Ift88(-/-) mice and collecting duct epithelial cells from Ift88°(rpk) mice, animal models of autosomal recessive polycystic kidney disease (ARPKD). Using Western blotting, an enzyme activity assay, and a growth factor-shedding assay in the presence or absence of the specific ADAM17 inhibitor TMI-005, we show that increased expression and activation of ADAM17 in the cystic kidney and in collecting duct epithelial cells originating from the Ift88°(rpk) mice (designated as PKD cells) lead to constitutive shedding of several growth factors, including heparin-binding EGF-like growth factor (HB-EGF), amphiregulin, and transforming growth factor-α (TGF-α). Increased growth factor shedding induces activation of the EGFR/MAPK/ERK pathway and maintains higher cell proliferation rate in PKD cells compared with control cells. PKD cells also displayed increased lactate formation and extracellular acidification indicative of aerobic glycolysis (Warburg effect), which was blocked by ADAM17 inhibition. We propose that ADAM17 is a key promoter of cellular proliferation in PKD cells by activating the EGFR/ERK axis and a proproliferative glycolytic phenotype. PMID:24899059

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

    CERN Document Server

    Hinkelmann, Franziska; Guang, Bonny; McNeill, Rustin; Blekherman, Grigoriy; Veliz-Cuba, Alan; Laubenbacher, Reinhard

    2010-01-01

    Motivation: Many biological systems are modeled qualitatively with discrete models, such as probabilistic Boolean networks, logical models, bounded Petri nets, and agent-based models. Simulation is a common practice for analyzing discrete models, but many systems are far too large to capture all the relevant dynamical features through simulation alone. Results: We convert discrete models into algebraic models and apply tools from computational algebra to analyze their dynamics. The key feature of biological systems that is exploited by our algorithms is their sparsity: while the number of nodes in a biological network may be quite large, each node is affected only by a small number of other nodes. In our experience with models arising in systems biology and random models, this structure leads to fast computations when using algebraic models, and thus efficient analysis. Availability: All algorithms and methods are available in our package Analysis of Dynamic Algebraic Models (ADAM), a user friendly web-interf...

  6. Ontario Hydro`s Sir Adam Beck Pump Generating Station : thrust bearing and runner servomotor rehabilitation

    Energy Technology Data Exchange (ETDEWEB)

    Barbour, J.; Garro, A. [Ontario Hydro, Toronto, ON (Canada)

    1998-12-01

    A study was conducted to examine the reasons for the recurring failure of generator thrust bearings at Ontario Hydro`s Sir Adam Beck Pump Generating Station (Niagara Falls) comprised of six 25 MW Deriaz turbines. The possible causes for the thrust bearing failures were listed and commented upon. The suspected causes include: (1) marginal bearing capacity, (2) shoes not flat, (3) sub standard oil, (4) dirt in bearing, (5) bearing cooling problems. To solve the problem, extra precaution was taken in the assembly of the bearing parts and extra capacity was added to the oil lift system. Following implementation of these measures, the unit has been operating smoothly for 3 years. 3 tabs., 4 figs.

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

    Directory of Open Access Journals (Sweden)

    Gu Yungao

    2015-01-01

    Full Text Available A multi-body dynamics simulation model of CJ20-25 AC contactor was established with Pro/E(Pro/Engineerin this paper. A coupling simulation with machine, electric, magnetic on the contactor has been achieved in this model. Dynamic parameters which were called use the secondary development technology of ADAMS. The dynamic contact pressure signal of an AC contactor was obtained with ADAMS’s own simultaneous solution such as electromagnetic suction, kinematics and dynamics equations. The simulation results and actual measurement of contactor contact pressure signals are very similar. However, the complexity of the measured contacts vibration is greater than the simulation results because the actual working condition is more complex. This result provides a theoretical foundation to the dynamic contacts contact pressure test.

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

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    To improve the braking safety of automobiles, the author studied the effect of differential brake on the stabilities. To analyze the mechanical characteristics of differential brake, automotive subsystem models were built by applying ADAMS/CAR, and automotive mechanics simulation model was built by setting the main subsystems such as body, engine and brake. The simulation model studied the distribution mode of three kinds of differential brake, and beeline braking stability and turning braking stability were simulated. It shows that differential brake can amend turning shortage of automobile brake and improve its braking stability, but the effect of automobile mass on its braking stability is great. So the distribution mode of braking force and the effect of mass change should be considered while differential brake is applied.

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

    Science.gov (United States)

    McCauley, Joseph L.

    2002-11-01

    Neo-classical economic theory is based on the postulated, nonempiric notion of utility. Neo-classical economists assume that prices, dynamics, and market equilibria are supposed to be derived from utility. The results are supposed to represent mathematically the stabilizing action of Adam Smith's invisible hand. In deterministic excess demand dynamics, however, a utility function generally does not exist mathematically due to nonintegrability. Price as a function of demand does not exist and all equilibria are unstable. Qualitatively, and empirically, the neo-classical prediction of price as a function of demand describes neither consumer nor trader demand. We also discuss five inconsistent definitions of equilibrium used in economics and finance, only one of which is correct, and then explain the fallacy in the economists’ notion of ‘temporary price equilibria’.

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

    Institute of Scientific and Technical Information of China (English)

    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

    Directory of Open Access Journals (Sweden)

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

    Directory of Open Access Journals (Sweden)

    Anna Czabanowska-Wróbel

    2012-01-01

    Full Text Available Any interpretation of one of the most personal poems written by Adam Zagajewski provides a good opportunity to reassess in the new light the elegiac, deeply personal body of his poetry, as well as the role of recollections and memory in the poet’s poetical and essayist writing. The work is interpreted not only within the parental context of the literary output of the author of the essay Lekka przesada [A slight exaggeration] (2011, but also against the background of the important theme in Polish poetry, including modern poetry, i.e. the motif of the mother. The title for the present sketch has been drawn from the essay The Fire of Life, the apology of poetry authored by Richard Rorty, and stresses its unique role in expressing human experience, indicated by the American philosopher.

  13. Reversed extension flow

    DEFF Research Database (Denmark)

    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 start-up of elongation for three Hencky strain units and subsequently the reversed flow. The integral molecular stress function formulation within the 'interchain pressure' concept agrees with the experiments. In the experiments the Hencky strain at which the str~ss becomes zero (the recovery strain......) in the reversed flow has been identified. The recovery strain is found to increase with elongational rate, and has a maximum value of approximately 1.45. The Doi Edwards model using any stretch evolution equation is not able to predict the correct level of the recovery strain....

  14. Radiation controlling reversible window

    Energy Technology Data Exchange (ETDEWEB)

    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.

  15. Characterization of hereditarily reversible posets

    OpenAIRE

    Kukieła, Michał

    2013-01-01

    A poset P is called reversible if every order preserving bijective self map of P is an order automorphism. P is called hereditarily reversible if every subposet of P is reversible. We give a complete characterization of hereditarily reversible posets in terms of forbidden subsets. A similar result is stated also for preordered sets. As a corollary we extend the list of known examples of hereditarily reversible topological spaces.

  16. RT-SHIV, an infectious CCR5-tropic chimeric virus suitable for evaluating HIV reverse transcriptase inhibitors in macaque models

    Directory of Open Access Journals (Sweden)

    Emau Peter

    2009-11-01

    Full Text Available Abstract Background Non-nucleoside reverse transcriptase inhibitors (NNRTIs are an important category of drugs for both chemotherapy and prevention of human immunodeficiency virus type 1 (HIV-1 infection. However, current non-human primate (NHP models utilizing simian immunodeficiency virus (SIV or commonly used chimeric SHIV (SIV expressing HIV-1 envelope are inadequate due to the insensitivity to NNRTIs. To develop a NHP model for evaluation of NNRTI compounds, we characterized a RT-SHIV virus that was assembled by replacing the SIVmac239 reverse transcriptase (RT with that of HIV-1HXB2. Since RT-SHIV exhibited in vitro characteristics of high infectivity, CCR5-usage, and sensitivity to HIV-1 specific NNRTIs, this virus was thought to be suitable for mucosal transmission and then was used to carry out a vaginal transmission study in pigtail macaques (Macaca nemestrina. Results RT-SHIV exhibited in vitro characteristics of an infectious CCR5-tropic chimeric virus. This virus was not only highly sensitive to HIV-1 RT specific NNRTIs; its replication was also inhibited by a variety of NRTIs and protease inhibitors. For in vivo vaginal transmission studies, macaques were either pretreated with a single dose of DMPA (depot medroxyprogesterone acetate or left untreated before intravaginal inoculation with 500 or 1,000 TCID50 of RT-SHIV. All macaques became systemically infected by 2 or 3 weeks post-inoculation exhibiting persistent high viremia, marked CD4+T cell depletion, and antiviral antibody response. DMPA-pretreated macaques showed a higher mean plasma viral load after the acute infection stage, highly variable antiviral antibody response, and a higher incidence of AIDS-like disease as compared with macaques without DMPA pretreatment. Conclusion This chimeric RT-SHIV has exhibited productive replication in both macaque and human PBMCs, predominantly CCR5-coreceptor usage for viral entry, and sensitivity to NNRTIs as well as other anti

  17. Reverse Coherent Information

    OpenAIRE

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

    2008-01-01

    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 lead to the definition of a new entanglement distribution capacity that exceeds the unassisted capacity for some interesting channels.

  18. Reverse Coherent Information

    Science.gov (United States)

    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. Reversible focal splenial lesions

    Energy Technology Data Exchange (ETDEWEB)

    Gallucci, Massimo; Limbucci, Nicola [University of L' Aquila, Department of Radiology, S. Salvatore Hospital, L' Aquila (Italy); Paonessa, Amalia [Loreto Nuovo Hospital, Department of Neuroradiology, Napoli (Italy); Caranci, Ferdinando [Federico II University, Department of Neurological Sciences, Napoli (Italy)

    2007-07-15

    Reversible focal lesions in the splenium of the corpus callosum (SCC) have recently been reported.They are circumscribed and located in the median aspect of the SCC. On MRI, they are hyperintense on T2-W and iso-hypointense on T1-W sequences, with no contrast enhancement. On DWI, SCC lesions are hyperintense with low ADC values, reflecting restricted diffusion due to cytotoxic edema. The common element is the disappearance of imaging abnormalities with time, including normalization of DWI. Clinical improvement is often reported. The most established and frequent causes of reversible focal lesions of the SCC are viral encephalitis, antiepileptic drug toxicity/withdrawal and hypoglycemic encephalopathy. Many other causes have been reported, including traumatic axonal injury. The similar clinical and imaging features suggest a common mechanism induced by different pathological events leading to the same results. Edema and diffusion restriction in focal reversible lesions of the SCC have been attributed to excitotoxic mechanisms that can result from different mechanisms; no unifying relationship has been found to explain all the pathologies associated with SCC lesions. In our opinion, the similar imaging, clinical and prognostic aspects of these lesions depend on a high vulnerability of the SCC to excitotoxic edema and are less dependent on the underlying pathology. In this review, the relevant literature concerning reversible focal lesions in the SCC is analyzed and hypotheses about their pathogenesis are proposed. (orig.)

  20. Time reversal communication system

    Science.gov (United States)

    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.

  1. On reverse hypercontractivity

    CERN Document Server

    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...

  2. Reversing insect pollinator decline

    OpenAIRE

    Potts, Simon; Wentworth, Jonathan

    2013-01-01

    Pollination by insects enables the reproduction of flowering plants and is critical to UK agriculture.1 Insect pollinators have declined globally, with implications for food security and wild habitats. This POSTnote summarises the causes for the recent trends, gaps in knowledge and possible strategies for reversing pollinator decline.

  3. Reverse Shoulder Arthroplasty

    Medline Plus

    Full Text Available Reverse Shoulder Arthroplasty Zimmer, Inc. New York City, New York March 17, 2010 Welcome to this OR Live presentation, brought to you by Zimmer. Hi. I'm ... my partner, Brad Parsons. We're here in New York to bring you a video of a ...

  4. 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

    Institute of Scientific and Technical Information of China (English)

    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。

  5. 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

    Institute of Scientific and Technical Information of China (English)

    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.

  6. 基于 ADAMS 的铁路货车滚动轴承建模及故障仿真分析%Modeling and Simulation Analysis of Fault for Railway Freight Rolling Bearings Based on ADAMS

    Institute of Scientific and Technical Information of China (English)

    吴冬; 陈斌; 高宝成

    2015-01-01

    The fault samples for railway freight rolling bearings are usually difficult to obtain in practice.A modeling method for rolling bearings is presented based on Pro /E and ADAMS.The acting forces are analyzed among different elements of railway freight rolling bearings,and the model for railway freight rolling bearings is built by using software Pro /E.The model for bearings is imported into ADAMS to add constraint,contact and driving forces by adding refer-ence axis.By using rigid -flexible construction,the outer ring is set as flexile body,while other elements are taken as rigid body.The experimental result shows that the vibration characteristic of model is consistent with theoretical situa-tion.%针对铁路货车滚动轴承故障样本数据难获取的问题,提出一种基于 Pro /E 和 ADAMS 的滚动轴承仿真建模方法。分析了铁路货车滚动轴承各零件之间作用力关系,并利用 Pro /E 软件建立铁路货车滚动轴承模型。采用添加参考轴线系的装配方法,将轴承模型导入 ADAMS 中添加约束、接触和驱动力;采用刚柔共建方式,将外圈设置为柔性体,其他部件为刚性体。结果表明,仿真模型的振动特性与理论情况基本相符。

  7. N-terminal cleavage and release of the ectodomain of Flt1 is mediated via ADAM10 and ADAM 17 and regulated by VEGFR2 and the Flt1 intracellular domain.

    Directory of Open Access Journals (Sweden)

    Nandita S Raikwar

    Full Text Available Flt is one of the cell surface VEGF receptors which can be cleaved to release an N-terminal extracellular fragment which, like alternately transcribed soluble Flt1 (sFlt1, can antagonize the effects of VEGF. In HUVEC and in HEK293 cells where Flt1 was expressed, metalloprotease inhibitors reduced Flt1 N-terminal cleavage. Overexpression of ADAM10 and ADAM17 increased cleavage while knockdown of ADAM10 and ADAM17 reduced N-terminal cleavage suggesting that these metalloproteases were responsible for Flt1 cleavage. Protein kinase C (PKC activation increased the abundance and the cleavage of Flt1 but this did not require any residues within the intracellular portion of Flt1. ALLN, a proteasomal inhibitor, increased the abundance of Flt1 which was additive to the effect of PKC. Removal of the entire cytosolic region of Flt1 appeared to stimulate cleavage of Flt1 and Flt1 was no longer sensitive to ALLN suggesting that the cytosolic region contained a degradation domain. Knock down of c-CBL, a ring finger ubiquitin ligase, in HEK293 cells increased the expression of Flt1 although it did not appear to require a previously published tyrosine residue (1333Y in the C-terminus of Flt1. Increasing VEGFR2 expression increased VEGF-stimulated sFlt1 expression and progressively reduced the cleavage of Flt1 with Flt1 staying bound to VEGFR2 as a heterodimer. Our results imply that secreted sFlt1 and cleaved Flt1 will tend to have local effects as a VEGF antagonist when released from cells expressing VEGFR2 and more distant effects when released from cells lacking VEGFR2.

  8. Record of Decision for the Final Remedial Action for the Rocky Mountain Arsenal Offpost Unit in southern Adams County, Commerce City, Colorado

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — This decision document presents the selected remedial action for the Rocky Mountain Arsenal (RMA) Offpost Operable Unit (OU) in southern Adams County, east of...

  9. Road and Street Centerlines, Adams Co Street Centerlines, Published in 2005, 1:4800 (1in=400ft) scale, MSA Professional Services.

    Data.gov (United States)

    NSGIC GIS Inventory (aka Ramona) — , 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 Street Centerlines'....

  10. WATER TEMPERATURE and other data from USS CHARLES F. ADAMS from 1989-10-27 to 1989-11-01 (NCEI Accession 9000003)

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The data in this accession was collected in from ship C.F. Adams between October 27, 1989 and November 1, 1989. The real time data of water temperature at varying...

  11. 基于ADAMS的双横臂悬架系统仿真%ADAMS double wishbone suspension system simulation based on

    Institute of Scientific and Technical Information of China (English)

    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.

  12. Characterization of 4-[18F]-ADAM as an imaging agent for SERT in non-human primate brain using PET: a dynamic study

    International Nuclear Information System (INIS)

    Introduction: Serotonin transporter (SERT) has been associated with many psychiatric diseases. This study investigated the biodistribution of a serotonin transporter imaging agent, N,N-dimethyl-2-(2-amino-4-18F-fluorophenylthio)benzylamine (4-[18F]-ADAM), in nonhuman primate brain using positron emission tomography (PET). Methods: Six and four Macaca cyclopis monkeys were used to determine the transit time (i.e., time necessary to reach biodistribution equilibrium) and the reproducibility of 4-[18F]-ADAM biodistribution in the brain, respectively. The sensitivity and specificity of 4-[18F]-ADAM binding to SERT were evaluated in one monkey challenged with different doses of fluoxetine and one monkey treated with 3,4-methylendioxymethamphetamine (MDMA). Dynamic PET imaging was performed for 3 h after 4-[18F]-ADAM intravenous bolus injection. The specific uptake ratios (SURs) in the midbrain (MB), thalamus (TH), striatum (ST) and frontal cortex (FC) were calculated. Results: The distribution of 4-[18F]-ADAM reached equilibrium 120–150 min after injection. The mean SURs were 2.49±0.13 in MB, 1.59±0.17 in TH, 1.35±0.06 in ST and 0.34±0.03 in FC, and the minimum variability was shown 120–150 min after 4-[18F]-ADAM injection. Using SURs and intraclass coefficient of correlation, the test/retest variability was under 8% and above 0.8, respectively, in SERT-rich areas. Challenge with fluoxetin (0.75–2 mg) dose-dependently inhibited the SURs in various brain regions. 4-[18F]-ADAM binding was markedly reduced in the brain of an MDMA-treated monkey compared to that in brains of normal controls. Conclusion: 4-[18F]-ADAM appears to be a highly selective radioligand for imaging SERT in monkey brain.

  13. Involvement of the serine/threonine p70S6 kinase in TGF-beta1-induced ADAM12 expression in cultured human hepatic stellate cells

    DEFF Research Database (Denmark)

    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....

  14. Book Review: Happiness and place: why life is better outside of the city by Adam Okulicz-Kozaryn

    OpenAIRE

    Meyer, William B.

    2015-01-01

    In Happiness and Place: Why Life is Better Outside of the City, Adam Okulicz-Kozaryn challenges the assumption that urban life is most conducive to happiness and wellbeing, arguing that cities are stressful, dissatisfying and inhibit connection with other humans and nature. While William B. Meyer praises this book as a useful and lively challenge to social science orthodoxy that tends to vaunts the urban, he suggests that its thesis, largely centred on the US case, requires further evidence t...

  15. Type II Diabetic Control and Prevalence in Tegucigalpa, Honduras: Patients of the James Moody Adams Clinic at the Baxter Institute

    OpenAIRE

    Magalhaes, Edward Pereira

    2011-01-01

    The purpose of this study was to determine the prevalence of known risk factors associated with diabetes among James Moody Adams (JMA) clinic patients in order to develop and test educational material and clinical interventions to reduce the incidence of pre-diabetes and uncontrolled Type II Diabetes. The research objectives for this study focused on: 1. prevalence of Type II Diabetic patients at the Clinic; 2. pre- and post-test knowledge level of patients regarding their Type II Diabetes; ...

  16. The Inner Man and his Deed: Jerzy Grotowski and the legacy of Adam Mickiewicz and polish romanticism

    Directory of Open Access Journals (Sweden)

    Kris Salata

    2013-03-01

    Full Text Available This article locates Grotowski in a concrete cultural milieu of Polish Romanticism and of the lifework of the Romantic poet Adam Mickiewicz. The bulk of my focus goes towards the notion of the deed and the act of doing that dematerialises the work of art turning it into an inner process – all features of Mickiewicz’s and Grotowski’s projects.

  17. Hubungan Dukungan Keluarga Dengan Harga Diri Pasien Kanker Payudara Yang Menjalani Kemoterapi Di RSUP H. Adam Malik Medan

    OpenAIRE

    Siburian, Christine Handayani

    2013-01-01

    Family support is a valuable support for individuals from his family. Self-esteem is result of acceptance or rejection of the individual against himself. The purpose of this research is to identify family support and self-esteem correlation of patient with chemotherapy breast cancer in RSUP H. Adam Malik Medan during February to March 2012. The research design applied descriptive correlation. Sampling technique in research was Purposive Sampling with 30 respondens. The research instruments us...

  18. Association of ADAM33 gene polymorphisms with adult-onset asthma and its severity in an Indian adult population

    Indian Academy of Sciences (India)

    Priya Tripathi; Shally Awasthi; Rajendra Prasad; Nuzhat Husain; Subramaniam Ganesh

    2011-08-01

    ADAM33, a member of the ADAM (a disintegrin and metalloprotease) gene family, is an asthma susceptibility gene originally identified by positional cloning. In the present study, we investigated the possible association of five single-nucleotide polymorphisms (SNPs) in the ADAM33 (rs511898, rs528557, rs44707, rs597980 and rs2787094) with adult-onset asthma in an Indian population. The study included 175 patients with mild intermittent ($n = 44$), mild persistent ($n = 108$) or moderate persistent ($n = 23$) subgroups of asthma, and 253 nonasthmatic control individuals. SNPs were genotyped with the help of restriction fragment length polymorphism polymerase chain reaction (RFLP-PCR) method, and data were analysed using chi-square test and logistic regression model. Bonferroni’s correction for multiple comparisons was applied for each hypothesis. Genotypes and allele frequencies of SNPs rs511898 and rs528557 were significantly associated with adult-onset asthma ($P = 0.010-\\lt 0.001$). A significant association of the homozygous mutant genotype and mutant alleles of SNPs rs2787094, rs44707 and rs597980 with the asthma was also observed ($P = 0.020-\\lt 0.001$). A positive association between asthma and haplotypes AGCCT, GGCCT, AGACT, GCAGT, GGACT, ACCCC and AGACC were also found ($P = 0.036-\\lt 0.001$, OR $= 2.07-8.49$). Haplotypes AGCGT, GCAGC, ACAGC, ACAGT, GGAGC and GGCGT appear to protect against asthma ($P = 0.013-\\lt 0.0001$, OR $= 0.34-0.10$). Our data suggest that ADAM33 gene polymorphisms serve as genetic risk factors for asthma in Indian adult population.

  19. ADAMS柔性体运动仿真分析及运用%Application of ADAMS flexible body kinetic simulation

    Institute of Scientific and Technical Information of China (English)

    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.

  20. Biodistribution and radioimmunoimage of iodine-125 labeled anti-human ADAM15 polyclonal antibody in nude mice bearing human gastric carcinoma xenografts

    International Nuclear Information System (INIS)

    Objective: To investigate the biodistribution of Iodine-125 labeled anti-human ADAM15 polyclonal antibody in nude mice bearing human gastric carcinoma xenografts. Methods: The anti-human ADAM15 polyclonal antibody was labeled with I-125 using Chloramine-T method. The labeling efficiency and radiochemical purity of 125I-anti-ADAM15 antibody were measured. The SPECT planar imaging of nude mice bearing gastric carcinoma xenografts were performed at 1, 4, 8, 24, and 48 h post-injection and the biodistribution of 125I-anti-ADAM15 antibody was measured at 48 h after injection. Results: The labeling efficiency of 125I-anti-ADAM15 antibody was (75.16±9.43)% and its radiochemical purity was (99.44±0.21)% . Tumors could be cleanly visualized in SPECT planar images, and the radioactivity ratio of tumor to non-tumor tissue was 3.84±0.43 at 48 h post-injection. Conclusion: 125I-anti-ADAM15 antibody can target the gastric carcinoma in vivo, and provide good radioimmunoimages. (authors)