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modeling and simulation in signal transduction pathways: a systems biology approach

BIOCHIMIE 2006年第3-4期88卷 277-283页

作者： Babu, CVS Song, EJ Yoo, YS Korea Inst Sci & Technol Bioanal & Biotransformat Res Ctr Seoul 130650 South Korea Univ Sci & Technol Korea Inst Sci & Technol Int R&D Acad Seoul 130650 South Korea

modeling, the heart of systems biology, of complex processes (example: signal transduction) is a wide scientific discipline where many approaches from different areas are confronted with the aim of better understanding, identifying and modeling of complex data coming from various sources. The purpose of this paper is to introduce the basic steps of systems biology view towards signaling pathways. which mainly deals with the computational tools. The paper emphasizes the modeling and simulation approach in the signal transduction pathways using the topologies of the biochemical reactions with an overview of the different types of software platforms. Finally. we demonstrated the epidermal growth factor receptor signaling pathway model as an example to study the growth factor mediated signaling system with biological experiments. This paper will enables new comers to underline the strengths of the computational approaches towards signal transduction, as well as to highlight the systems biology research directions. (c) 2005 Elsevier SAS. All rights reserved.

关键词： biological systems signal transduction systems biology modeling and simulation

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modeling and simulation to Support Phase 2 Dose Selection for RG7652, a Fully Human Monoclonal Antibody Against Proprotein Convertase Subtilisin/Kexin Type 9

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AAPS JOURNAL 2015年第4期17卷 881-890页

作者： Budha, Nageshwar R. Leabman, Maya Jin, Jin Y. Wada, D. Russell Baruch, Amos Peng, Kun Tingley, Whittemore G. Davis, John D. Genentech Inc Clin Pharmacol San Francisco CA 94080 USA Genentech Inc Dev Sci San Francisco CA 94080 USA Quantitat Solut Menlo Pk CA USA Genentech Inc Clin Sci San Francisco CA 94080 USA Genentech Inc BioAnalyt Sci San Francisco CA USA

RG7652 is a fully humanized monoclonal antibody targeting human PCSK9, a regulator of serum low density lipoprotein cholesterol (LDLc) levels. RG7652 prevents degradation of the hepatic LDLc receptors by blocking PCSK9 binding and thereby resulting in efficient LDLc uptake by hepatocytes. The pharmacokinetics of RG7652 have been evaluated in healthy subjects after single and multiple subcutaneous doses. Pharmacokinetic (PK) and pharmacodynamic (PD) models were developed to explain the antibody PK and LDLc time course data. The PK and PD models based on data from healthy subjects were used to simulate the effects of RG7652 on LDLc levels for a range of potential dose regimens in patients with coronary heart disease. A one-compartment PK model combined with an indirect PD response model was able to adequately describe the PK and LDLc data. simulations of 400 mg every 4 weeks or 800 mg every 8 weeks regimens show significant LDLc reduction and suggest that dosing RG7652 once every month or once every 2 months is predicted to be optimal for the treatment of hypercholesterolemia. The PK and PD model successfully described the PK and LDLc data from healthy subjects in a Phase 1 study, and the model-based simulations provided useful insights and quantitative understanding for the selection of Phase 2 study doses in patients with coronary heart disease. The approach used in the case study demonstrates the utility of modeling and simulation in designing dose-ranging studies.

关键词： antibody LDLc modeling and simulation PCSK9 PK/PD

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modeling and simulation of railway vehicle vertical dynamic behavior by considering the effect of passenger-carbody coupling vibration

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International Journal of modeling, simulation, and Scientific Computing 2019年第5期10卷 58-81页

作者： Yuewei Yu Leilei Zhao Changcheng Zhou School of Transportation and Vehicle Engineering Shandong University of Technology ZiboP.R.China

In order to reflect the vertical random vibration characteristics of railway vehicles more truly and effectively,this paper regards the human body as a single-degree-of-freedom system attached to the bottom of the carriage,and establishes a vertical dynamic model of railway vehicles by considering the influence of the coupling vibration effect between the passenger and the car *** correctness of the model is verified by the real vehicle ***,the influence of the passengers on the vertical vibration characteristics of railway vehicles is analyzed,and the influence of the railway vehicle vibration on the vertical vibration characteristics of passengers is discussed in this *** research made in this paper can provide an effective model reference for the analysis of the vertical random vibration characteristics of railway vehicles and passengers,and for the optimization design of the suspension system parameters.

关键词： Railway vehicle passenger-carbody coupling vibration car body elastic vibration vertical dynamic modeling and simulation

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modeling and simulation of Pivotal Clinical Trials Using Linked Models for Multiple Endpoints in Chronic Obstructive Pulmonary Disease With Roflumilast

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JOURNAL OF CLINICAL PHARMACOLOGY 2017年第8期57卷 1042-1052页

作者： Facius, Axel Krause, Andreas Claret, Laurent Bruno, Rene Lahu, Gezim Takeda Pharmaceut Int GmbH Thurgauerstr 130 CH-8152 Zurich Switzerland Pharsight Pharsight Consulting Serv Mountain View CA USA

Roflumilast is a selective phosphodiesterase 4 inhibitor (PDE4i) for the treatment of severe chronic obstructive pulmonary disease (COPD). In 2 large phase 3 trials in a broader population of COPD patients (BY217/M2-111, ***: NCT00076089 and BY217/M2-112, ***: NCT00430729), treatment with roflumilast reduced the rate of exacerbations;however, the reduction did not reach statistical significance. Two linked dose-response models for the primary (annualized COPD exacerbation counts) and secondary (change from baseline in forced expiratory volume in 1 second [FEV1]) end points were therefore developed to characterize and quantify effect sizes and the patient characteristics influencing them. The models showed that disease severity and bronchitis, particularly the severity of bronchitis expressed in cough-and-sputum scores, were good predictors of exacerbation rates and differential benefit of roflumilast in exacerbation reduction. The models were used to support the rational design of 2 phase 3 randomized, placebo-controlled clinical trials (BY217/M2-124, ***: NCT00297102 and BY217/M2-125, ***: NCT00297115) by identifying the most appropriate patient population using clinical trial simulations. Model predictions for both end points were found to be highly accurate - as confirmed by the results from these trials, which led to the approval of roflumilast as the first oral PDE4i for the treatment of COPD in patients associated with chronic bronchitis and a history of exacerbations.

关键词： chronic obstructive pulmonary disease (COPD) roflumilast modeling and simulation FEV1 COPD exacerbation rates phase 3 study design

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modeling and simulation of sexual activity daily diary data of patients with female sexual arousal disorder treated with sildenafil citrate (Viagra^®)

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PHARMACEUTICAL RESEARCH 2006年第8期23卷 1756-1764页

作者： Claret, Laurent Cox, Eugene H. McFadyen, Lynn Pidgen, Alwyn Johnson, Patrick J. Haughie, Scott Boolell, Mitra Bruno, Rene Pfizer Global Res & Dev Clin Res & Dev Sandwich CT13 9NJ Kent England Pharsight Corp Strateg Consulting Serv Mountain View CA USA

Purpose. To develop a model to explore the dose-response of sildenafil citrate in patients with female sexual arousal disorder (FSAD) based on telephone sexual activity daily diary (TSADD) data obtained in double-blind, placebo controlled clinical studies. Materials. Data were available on 614 patients with FSAD. A parametric model (Weibull distribution) was developed to describe the probability density function of the time between sexual events. Orgasm satisfaction scores and overall sexual satisfaction scores were simultaneously modeled as ordered categorical variables. simulations were performed to evaluate the expected clinical response in patients with FSAD. Results. The expected time between sexual events was approximately 3.5 days. Satisfaction scores increased with time to achieve a plateau after 3 to 4 weeks on treatment. The expected probability of satisfying orgasm (score of 3 and higher) ranged from 34.7% for placebo to 41.6% for 100 mg sildenafil citrate. Treatment effect (difference from placebo) was 6.9% for 100 mg sildenafil citrate, ranging from 0.6 to 24.7% for testosterone levels of 0.1 to 4.0 pg/ml. The treatment effect in postmenopausal women was larger than in premenopausal women. Conclusions. A modeling and simulation framework to support drug development in FSAD was developed. Sildenafil citrate demonstrated a dose-dependent effect in patients with FSAD.

关键词： female sexual arousal disorder modeling and simulation NONMEM sildenafil citrate

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modeling and simulation of traction drive dynamics and control

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JOURNAL OF MECHANICAL DESIGN 2001年第4期123卷 556-561页

作者： Zou, Z Zhang, Y Zhang, X Tobler, W Univ Michigan Dept Mech Engn Dearborn MI 48128 USA

This paper presents an analytical model for the simulation of traction drive dynamics and control in ratio change processes. The model systematically incorporates the formulations on the kinematics, dynamics and control characteristics of traction drives. In the model, the motion parameters of traction drive components are coupled to CVT inputs and outputs, torque losses, as well as ratio variations. The characteristics of a dual feedback ratio control system are formulated in Laplace transform and integrated into the overall The model is implemented in Matlab/Simulink block diagrams and is capable of predicting traction drive performances under various ratio change conditions. The effectiveness of the model is illustrated in a numerical example by the comparison between the simulation and experimental data on key CVT performance parameters.

关键词： dynamics Standing Orders control characteristics Laplace transform Traction traction drive simulating loss torque numerical example modeling and simulation modeling

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modeling and simulation of Bone Mineral Density Response From a Phase 2 Study of ONO-5334, a New Cathepsin K Inhibitor, to Support Dose Selection in Osteoporosis

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JOURNAL OF CLINICAL PHARMACOLOGY 2014年第8期54卷 937-948页

作者： Hasegawa, Chihiro Kastrissios, Helen Monteleone, Jonathan Ohno, Tomoya Umemura, Takeo Ohyama, Michiyo Nagase, Shinichi Small, Maria Deacon, Steve Ogawa, Mikio Ieiri, Ichiro Ono Pharmaceut Co Ltd Pharmacokinet Res Labs Tsukuba Ibaraki 3004247 Japan Kyushu Univ Grad Sch Pharmaceut Sci Dept Clin Pharmacokinet Higashi Ku Fukuoka 812 Japan Pharsight Corp Strateg Consulting Serv Sunnyvale CA USA Ono Pharmaceut Co Ltd Clin Dev Planning Chuo Ku Osaka Japan ONO Pharma UK Ltd Drug Dev London England

ONO-5334, a selective inhibitor of cathepsin K, is a potential new treatment for osteoporosis. The objectives of this modeling study were to (1) develop exposure-response (E-R) models to relate ONO-5334 exposure to bone mineral density (BMD), (2) predict BMD responses to various doses of ONO-5334 for both immediate release tablet (IRT) and sustained release tablet (SRT) formulations where only BMD response after administration of IRT had been studied to date, (3) inform selection of appropriate formulation/dose using simulation for future clinical trials. A population pharmacokinetic (PK) model was developed to simultaneously analyze data for both IRT and SRT. The exposure metrics at steady state were estimated by post hoc Bayesian prediction using the final population PK model. E-R models were developed using dose-ranging data with only IRT from postmenopausal females with osteoporosis. Based on the developed model, lumbar spine and total hip BMD after administration of ONO-5334 SRT as well as IRT were simulated. The simulation results showed that ONO-5334 SRT should provide comparable BMD responses at a lower dose relative to IRT (a finding consistent with the results from a previous population PK-PD modeling study with bone resorption markers).

关键词： modeling and simulation cathepsin K inhibitor ONO-5334 bone mineral density osteoporosis

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modeling and simulation of Cooperative Exploration Strategies in Unknown Environments

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Complex System modeling and simulation 2023年第4期3卷 343-356页

作者： Yong Peng Yue Hu Chuan Ai College of Systems Engineering National University of Defense TechnologyChangsha 410073China

Cooperative spatial exploration in initially unknown surroundings is a common embodied task in various applications and requires satisfactory coordination among the *** many other research questions,there is a lack of simulation platforms for the cooperative exploration problem to perform and statistically evaluate different methods before they are deployed in practical *** this end,this paper designs a simulation framework to run different models,which features efficient event scheduling and data *** top of such a framework,we propose and implement two different cooperative exploration strategies,i.e.,the synchronous and asynchronous *** the coordination in the former approach is conducted after gathering the perceptive information from all agents in each round,the latter enables an ad-hoc ***,they exploit different principles for assigning target points for the *** experiments on different types of environments and settings not only validate the scheduling efficiency of our simulation engine,but also demonstrate the respective advantages of the two strategies on different metrics.

关键词： modeling and simulation event scheduling cooperative exploration synchronous strategy asynchronous strategy

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modeling and simulation of twin-tube hydraulic shock absorber thermodynamic characteristics and sensitivity analysis of its influencing factors

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International Journal of modeling, simulation, and Scientific Computing 2020年第2期11卷 49-68页

作者： Yuewei Yu Leilei Zhao Changcheng Zhou Lin Yang School of Transportation and Vehicle Engineering Shandong University of Technology ZiboP.R.China

In order to find out the sensitivity of the thermophysical and structural parameters to the thermodynamic characteristics of twin-tube hydraulic shock absorbers,based on the bench test,a method for calculating the time-varying rate of the external work on the shock absorber oil is *** then,a thermodynamic model of the twin-tube hydraulic shock absorber is established by using the basic thermodynamic *** analyzing the influence of each parameter on the thermodynamic characteristics of the shock absorber,it can be seen that,the radius of the working cylinder outer wall has the greatest influence on the temperature rise of the shock absorber,followed by the thermal conductivity of the oil,the height of the oil,the heat transfer length of the cylinder barrel,the radius of the oil storage cylinder outer wall,the emissivity of the oil storage cylinder outer wall,the height of the nitrogen,the thermal conductivity of the nitrogen,the specific heat capacity of the oil,the density of the oil,the thermal conductivity of the cylinder,and the mass of the working *** kinematic viscosity of the oil has the least influence on the temperature rise of the shock *** research can provide an effective theoretical guidance and reference for the design of the twin-tube hydraulic shock absorber.

关键词： Twin-tube hydraulic shock absorber thermodynamic model thermodynamic characteristics influencing factors sensitivity analysis modeling and simulation

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modeling and simulation of Orlistat to Predict Weight Loss and Weight Maintenance in Obesity Patients

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DRUG METABOLISM AND PHARMACOKINETICS 2014年第3期29卷 278-282页

作者： Nakai, Kiyohiko Wada, Russell Iida, Satofumi Kawanishi, Takehiko Matsumoto, Yoshiaki Chugai Pharmaceut Co Ltd Clin Res Planning Dept Tokyo 1038324 Japan Quantitat Solut Inc Menlo Pk CA USA Nihon Univ Sch Pharm Chiba Japan

Orlistat is used clinically worldwide as anti-obesity drug. It is a chemically synthesized hydrogenated derivative of lipstatin and is an inhibitor of gastric and pancreatic lipases. It has been found to reduce the absorption of dietary fat in the gastrointestinal tract. modeling and simulation based on pharmacokinetic/pharmacodynamic analysis is becoming increasingly used in the design of clinical trials to assure that the trials are of high quality and are conducted efficiently. We developed a clinical trial simulation model for orlistat based on Phase III clinical study data. This innovative weight loss model includes the relationships between orlistat dose, changes in fecal fat excretion, and weight loss, and also incorporates a dropout function. The model guided the dose-finding strategy and allowed simulation of long-term clinical outcomes of orlistat.

关键词： orlistat Xenical modeling and simulation weight loss model population pharmacodynamics obesity

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