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Sample records for therapeutic models final

  1. Physiologically Based Pharmacokinetic Modeling of Therapeutic Proteins.

    Science.gov (United States)

    Wong, Harvey; Chow, Timothy W

    2017-09-01

    Biologics or therapeutic proteins are becoming increasingly important as treatments for disease. The most common class of biologics are monoclonal antibodies (mAbs). Recently, there has been an increase in the use of physiologically based pharmacokinetic (PBPK) modeling in the pharmaceutical industry in drug development. We review PBPK models for therapeutic proteins with an emphasis on mAbs. Due to their size and similarity to endogenous antibodies, there are distinct differences between PBPK models for small molecules and mAbs. The high-level organization of a typical mAb PBPK model consists of a whole-body PBPK model with organ compartments interconnected by both blood and lymph flows. The whole-body PBPK model is coupled with tissue-level submodels used to describe key mechanisms governing mAb disposition including tissue efflux via the lymphatic system, elimination by catabolism, protection from catabolism binding to the neonatal Fc (FcRn) receptor, and nonlinear binding to specific pharmacological targets of interest. The use of PBPK modeling in the development of therapeutic proteins is still in its infancy. Further application of PBPK modeling for therapeutic proteins will help to define its developing role in drug discovery and development. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  2. A therapeutic gain model for brachytherapy

    International Nuclear Information System (INIS)

    Wigg, D.R.

    2003-01-01

    When treating with continuous irradiation the potential therapeutic gain or loss depends on several treatment, normal tissue and tumour variables. There are similarities between equations defining tissue effects with fractionated treatment and brachytherapy. The former is sensitive to dose per fraction (and incomplete repair for short intervals between treatments) and the later is sensitive to dose rate and continuous repair factors. Because of these similarities, for typical tumours and normal tissues, dose per fraction and dose rates generally work in similar directions. As the dose per fraction or dose rate increases the therapeutic gain falls. With continuous irradiation the dose rates effects are determined by Beta cell kill and hence the absolute value of Beta . Minimal sensitivity occurs at very low and very high dose rates. The magnitude of cell kill also depends on the Continuous Repair Factor (g) which is a function of the treatment time and the Repair Half Time (in hours) of the tissues (Repair Half Time T 1/2Ln(2)/h, when h the Repair Constant). An interactive optimising model has been written to predict the therapeutic gain or loss as the parameter values are varied. This model includes the tumour and normal tissue parameters alpha and beta Gy (or individual values), their Repair Half Times, dose rates and overall treatment time. The model is based on the Linear-Quadratic equation and the Total Effect (TE) method of Thames and Hendry although the Extrapolated Response Dose (ERD) method of Barendsen produces the same results. The model is written so that the gain or loss may be seen when treatment is always to normal tissue tolerance doses. The magnitude of the therapeutic loss as the dose rate increases and its sensitivity to changes in normal tissue and tumour parameter values is clearly demonstrated

  3. Huntington disease: Experimental models and therapeutic perspectives

    International Nuclear Information System (INIS)

    Serrano Sanchez, Teresa; Blanco Lezcano, Lisette; Garcia Minet, Rocio; Alberti Amador, Esteban; Diaz Armesto, Ivan and others

    2011-01-01

    Huntington's disease (HD) is a degenerative dysfunction of hereditary origin. Up to date there is not, an effective treatment to the disease which having lapsed 15 or 20 years advances inexorably, in a slow form, toward the total inability or death. This paper reviews the clinical and morphological characteristics of Huntington's disease as well as the experimental models more commonly used to study this disease, having as source the articles indexed in Medline data base, published in the last 20 years. Advantages and disadvantages of all experimental models to reproduce the disease as well as the perspectives to therapeutic assay have been also considered. the consent of outline reported about the toxic models, those induced by neurotoxins such as quinolinic acid, appears to be the most appropriate to reproduce the neuropathologic characteristic of the disease, an genetic models contributing with more evidence to the knowledge of the disease etiology. Numerous treatments ameliorate clinical manifestations, but none of them has been able to stop or diminish the affectations derived from neuronal loss. At present time it is possible to reproduce, at least partially, the characteristics of the disease in experimentation animals that allow therapy evaluation in HD. from the treatment view point, the more promissory seems to be transplantation of no neuronal cells, taking into account ethical issues and factibility. On the other hand the new technology of interference RNA emerges as a potential therapeutic tool for treatment in HD, and to respond basic questions on the development of the disease.

  4. Pig models on intestinal development and therapeutics.

    Science.gov (United States)

    Yin, Lanmei; Yang, Huansheng; Li, Jianzhong; Li, Yali; Ding, Xueqing; Wu, Guoyao; Yin, Yulong

    2017-12-01

    The gastrointestinal tract plays a vital role in nutrient supply, digestion, and absorption, and has a crucial impact on the entire organism. Much attention is being paid to utilize animal models to study the pathogenesis of gastrointestinal diseases in response to intestinal development and health. The piglet has a body size similar to that of the human and is an omnivorous animal with comparable anatomy, nutritional requirements, and digestive and associated inflammatory processes, and displays similarities to the human intestinal microbial ecosystem, which make piglets more appropriate as an animal model for human than other non-primate animals. Therefore, the objective of this review is to summarize key attributes of the piglet model with which to study human intestinal development and intestinal health through probing into the etiology of several gastrointestinal diseases, thus providing a theoretical and hopefully practical, basis for further studies on mammalian nutrition, health, and disease, and therapeutics. Given the comparable nutritional requirements and strikingly similar brain developmental patterns between young piglets and humans, the piglet has been used as an important translational model for studying neurodevelopmental outcomes influenced by pediatric nutrition. Because of similarities in anatomy and physiology between pigs and mankind, more emphasises are put on how to use the piglet model for human organ transplantation research.

  5. Immunogenicity of therapeutic proteins: the use of animal models.

    Science.gov (United States)

    Brinks, Vera; Jiskoot, Wim; Schellekens, Huub

    2011-10-01

    Immunogenicity of therapeutic proteins lowers patient well-being and drastically increases therapeutic costs. Preventing immunogenicity is an important issue to consider when developing novel therapeutic proteins and applying them in the clinic. Animal models are increasingly used to study immunogenicity of therapeutic proteins. They are employed as predictive tools to assess different aspects of immunogenicity during drug development and have become vital in studying the mechanisms underlying immunogenicity of therapeutic proteins. However, the use of animal models needs critical evaluation. Because of species differences, predictive value of such models is limited, and mechanistic studies can be restricted. This review addresses the suitability of animal models for immunogenicity prediction and summarizes the insights in immunogenicity that they have given so far.

  6. Repository simulation model: Final report

    International Nuclear Information System (INIS)

    1988-03-01

    This report documents the application of computer simulation for the design analysis of the nuclear waste repository's waste handling and packaging operations. The Salt Repository Simulation Model was used to evaluate design alternatives during the conceptual design phase of the Salt Repository Project. Code development and verification was performed by the Office of Nuclear Waste Isolation (ONWL). The focus of this report is to relate the experience gained during the development and application of the Salt Repository Simulation Model to future repository design phases. Design of the repository's waste handling and packaging systems will require sophisticated analysis tools to evaluate complex operational and logistical design alternatives. Selection of these design alternatives in the Advanced Conceptual Design (ACD) and License Application Design (LAD) phases must be supported by analysis to demonstrate that the repository design will cost effectively meet DOE's mandated emplacement schedule and that uncertainties in the performance of the repository's systems have been objectively evaluated. Computer simulation of repository operations will provide future repository designers with data and insights that no other analytical form of analysis can provide. 6 refs., 10 figs

  7. Therapeutic Enactment: Integrating Individual and Group Counseling Models for Change

    Science.gov (United States)

    Westwood, Marvin J.; Keats, Patrice A.; Wilensky, Patricia

    2003-01-01

    The purpose of this article is to introduce the reader to a group-based therapy model known as therapeutic enactment. A description of this multimodal change model is provided by outlining the relevant background information, key concepts related to specific change processes, and the differences in this model compared to earlier psychodrama…

  8. A Zebrafish Heart Failure Model for Assessing Therapeutic Agents.

    Science.gov (United States)

    Zhu, Xiao-Yu; Wu, Si-Qi; Guo, Sheng-Ya; Yang, Hua; Xia, Bo; Li, Ping; Li, Chun-Qi

    2018-03-20

    Heart failure is a leading cause of death and the development of effective and safe therapeutic agents for heart failure has been proven challenging. In this study, taking advantage of larval zebrafish, we developed a zebrafish heart failure model for drug screening and efficacy assessment. Zebrafish at 2 dpf (days postfertilization) were treated with verapamil at a concentration of 200 μM for 30 min, which were determined as optimum conditions for model development. Tested drugs were administered into zebrafish either by direct soaking or circulation microinjection. After treatment, zebrafish were randomly selected and subjected to either visual observation and image acquisition or record videos under a Zebralab Blood Flow System. The therapeutic effects of drugs on zebrafish heart failure were quantified by calculating the efficiency of heart dilatation, venous congestion, cardiac output, and blood flow dynamics. All 8 human heart failure therapeutic drugs (LCZ696, digoxin, irbesartan, metoprolol, qiliqiangxin capsule, enalapril, shenmai injection, and hydrochlorothiazide) showed significant preventive and therapeutic effects on zebrafish heart failure (p failure model developed and validated in this study could be used for in vivo heart failure studies and for rapid screening and efficacy assessment of preventive and therapeutic drugs.

  9. Preclinical models used for immunogenicity prediction of therapeutic proteins.

    Science.gov (United States)

    Brinks, Vera; Weinbuch, Daniel; Baker, Matthew; Dean, Yann; Stas, Philippe; Kostense, Stefan; Rup, Bonita; Jiskoot, Wim

    2013-07-01

    All therapeutic proteins are potentially immunogenic. Antibodies formed against these drugs can decrease efficacy, leading to drastically increased therapeutic costs and in rare cases to serious and sometimes life threatening side-effects. Many efforts are therefore undertaken to develop therapeutic proteins with minimal immunogenicity. For this, immunogenicity prediction of candidate drugs during early drug development is essential. Several in silico, in vitro and in vivo models are used to predict immunogenicity of drug leads, to modify potentially immunogenic properties and to continue development of drug candidates with expected low immunogenicity. Despite the extensive use of these predictive models, their actual predictive value varies. Important reasons for this uncertainty are the limited/insufficient knowledge on the immune mechanisms underlying immunogenicity of therapeutic proteins, the fact that different predictive models explore different components of the immune system and the lack of an integrated clinical validation. In this review, we discuss the predictive models in use, summarize aspects of immunogenicity that these models predict and explore the merits and the limitations of each of the models.

  10. Using an experimental model for the study of therapeutic touch.

    Science.gov (United States)

    dos Santos, Daniella Soares; Marta, Ilda Estéfani Ribeiro; Cárnio, Evelin Capellari; de Quadros, Andreza Urba; Cunha, Thiago Mattar; de Carvalho, Emilia Campos

    2013-02-01

    to verify whether the Paw Edema Model can be used in investigations about the effects of Therapeutic Touch on inflammation by measuring the variables pain, edema and neutrophil migration. this is a pilot and experimental study, involving ten male mice of the same genetic strain and divided into experimental and control group, submitted to the chemical induction of local inflammation in the right back paw. The experimental group received a daily administration of Therapeutic Touch for 15 minutes during three days. the data showed statistically significant differences in the nociceptive threshold and in the paw circumference of the animals from the experimental group on the second day of the experiment. the experiment model involving animals can contribute to study the effects of Therapeutic Touch on inflammation, and adjustments are suggested in the treatment duration, number of sessions and experiment duration.

  11. [Identification of novel therapeutically effective antibiotics using silkworm infection model].

    Science.gov (United States)

    Hamamoto, Hiroshi; Urai, Makoto; Paudel, Atmika; Horie, Ryo; Murakami, Kazuhisa; Sekimizu, Kazuhisa

    2012-01-01

    Most antibiotics obtained by in vitro screening with antibacterial activity have inappropriate properties as medicines due to their toxicity and pharmacodynamics in animal bodies. Thus, evaluation of the therapeutic effects of these samples using animal models is essential in the crude stage. Mammals are not suitable for therapeutic evaluation of a large number of samples due to high costs and ethical issues. We propose the use of silkworms (Bombyx mori) as model animals for screening therapeutically effective antibiotics. Silkworms are infected by various pathogenic bacteria and are effectively treated with similar ED(50) values of clinically used antibiotics. Furthermore, the drug metabolism pathways, such as cytochrome P450 and conjugation systems, are similar between silkworms and mammals. Silkworms have many advantages compared with other infection models, such as their 1) low cost, 2) few associated ethical problems, 3) adequate body size for easily handling, and 4) easier separation of organs and hemolymph. These features of the silkworm allow for efficient screening of therapeutically effective antibiotics. In this review, we discuss the advantages of the silkworm model in the early stages of drug development and the screening results of some antibiotics using the silkworm infection model.

  12. Therapeutic action of ghrelin in a mouse model of colitis.

    Science.gov (United States)

    Gonzalez-Rey, Elena; Chorny, Alejo; Delgado, Mario

    2006-05-01

    Ghrelin is a novel growth hormone-releasing peptide with potential endogenous anti-inflammatory activities ameliorating some pathologic inflammatory conditions. Crohn's disease is a chronic debilitating disease characterized by severe T helper cell (Th)1-driven inflammation of the colon. The aim of this study was to investigate the therapeutic effect of ghrelin in a murine model of colitis. We examined the anti-inflammatory action of ghrelin in the colitis induced by intracolonic administration of trinitrobenzene sulfonic acid. Diverse clinical signs of the disease were evaluated, including weight loss, diarrhea, colitis, and histopathology. We also investigated the mechanisms involved in the potential therapeutic effect of ghrelin, such as inflammatory cytokines and chemokines, Th1-type response, and regulatory factors. Ghrelin ameliorated significantly the clinical and histopathologic severity of the trinitrobenzene sulfonic acid-induced colitis; abrogating body weight loss, diarrhea, and inflammation; and increasing survival. The therapeutic effect was associated with down-regulation of both inflammatory and Th1-driven autoimmune response through the regulation of a wide spectrum of inflammatory mediators. In addition, a partial involvement of interluekin-10/transforming growth factor-beta1-secreting regulatory T cells in this therapeutic effect was demonstrated. Importantly, the ghrelin treatment was therapeutically effective in established colitis and avoided the recurrence of the disease. Our data demonstrate novel anti-inflammatory actions for ghrelin in the gastrointestinal tract, ie, the capacity to deactivate the intestinal inflammatory response and to restore mucosal immune tolerance at multiple levels. Consequently, ghrelin administration represents a novel possible therapeutic approach for the treatment of Crohn's disease and other Th1-mediated inflammatory diseases, such as rheumatoid arthritis and multiple sclerosis.

  13. Mathematical models for therapeutic approaches to control HIV disease transmission

    CERN Document Server

    Roy, Priti Kumar

    2015-01-01

    The book discusses different therapeutic approaches based on different mathematical models to control the HIV/AIDS disease transmission. It uses clinical data, collected from different cited sources, to formulate the deterministic as well as stochastic mathematical models of HIV/AIDS. It provides complementary approaches, from deterministic and stochastic points of view, to optimal control strategy with perfect drug adherence and also tries to seek viewpoints of the same issue from different angles with various mathematical models to computer simulations. The book presents essential methods and techniques for students who are interested in designing epidemiological models on HIV/AIDS. It also guides research scientists, working in the periphery of mathematical modeling, and helps them to explore a hypothetical method by examining its consequences in the form of a mathematical modelling and making some scientific predictions. The model equations, mathematical analysis and several numerical simulations that are...

  14. Temperature Buffer Test. Final THM modelling

    International Nuclear Information System (INIS)

    Aakesson, Mattias; Malmberg, Daniel; Boergesson, Lennart; Hernelind, Jan; Ledesma, Alberto; Jacinto, Abel

    2012-01-01

    The Temperature Buffer Test (TBT) is a joint project between SKB/ANDRA and supported by ENRESA (modelling) and DBE (instrumentation), which aims at improving the understanding and to model the thermo-hydro-mechanical behavior of buffers made of swelling clay submitted to high temperatures (over 100 deg C) during the water saturation process. The test has been carried out in a KBS-3 deposition hole at Aespoe HRL. It was installed during the spring of 2003. Two heaters (3 m long, 0.6 m diameter) and two buffer arrangements have been investigated: the lower heater was surrounded by bentonite only, whereas the upper heater was surrounded by a composite barrier, with a sand shield between the heater and the bentonite. The test was dismantled and sampled during the winter of 2009/2010. This report presents the final THM modelling which was resumed subsequent to the dismantling operation. The main part of this work has been numerical modelling of the field test. Three different modelling teams have presented several model cases for different geometries and different degree of process complexity. Two different numerical codes, Code B right and Abaqus, have been used. The modelling performed by UPC-Cimne using Code B right, has been divided in three subtasks: i) analysis of the response observed in the lower part of the test, by inclusion of a number of considerations: (a) the use of the Barcelona Expansive Model for MX-80 bentonite; (b) updated parameters in the vapour diffusive flow term; (c) the use of a non-conventional water retention curve for MX-80 at high temperature; ii) assessment of a possible relation between the cracks observed in the bentonite blocks in the upper part of TBT, and the cycles of suction and stresses registered in that zone at the start of the experiment; and iii) analysis of the performance, observations and interpretation of the entire test. It was however not possible to carry out a full THM analysis until the end of the test due to

  15. Temperature Buffer Test. Final THM modelling

    Energy Technology Data Exchange (ETDEWEB)

    Aakesson, Mattias; Malmberg, Daniel; Boergesson, Lennart; Hernelind, Jan [Clay Technology AB, Lund (Sweden); Ledesma, Alberto; Jacinto, Abel [UPC, Universitat Politecnica de Catalunya, Barcelona (Spain)

    2012-01-15

    The Temperature Buffer Test (TBT) is a joint project between SKB/ANDRA and supported by ENRESA (modelling) and DBE (instrumentation), which aims at improving the understanding and to model the thermo-hydro-mechanical behavior of buffers made of swelling clay submitted to high temperatures (over 100 deg C) during the water saturation process. The test has been carried out in a KBS-3 deposition hole at Aespoe HRL. It was installed during the spring of 2003. Two heaters (3 m long, 0.6 m diameter) and two buffer arrangements have been investigated: the lower heater was surrounded by bentonite only, whereas the upper heater was surrounded by a composite barrier, with a sand shield between the heater and the bentonite. The test was dismantled and sampled during the winter of 2009/2010. This report presents the final THM modelling which was resumed subsequent to the dismantling operation. The main part of this work has been numerical modelling of the field test. Three different modelling teams have presented several model cases for different geometries and different degree of process complexity. Two different numerical codes, Code{sub B}right and Abaqus, have been used. The modelling performed by UPC-Cimne using Code{sub B}right, has been divided in three subtasks: i) analysis of the response observed in the lower part of the test, by inclusion of a number of considerations: (a) the use of the Barcelona Expansive Model for MX-80 bentonite; (b) updated parameters in the vapour diffusive flow term; (c) the use of a non-conventional water retention curve for MX-80 at high temperature; ii) assessment of a possible relation between the cracks observed in the bentonite blocks in the upper part of TBT, and the cycles of suction and stresses registered in that zone at the start of the experiment; and iii) analysis of the performance, observations and interpretation of the entire test. It was however not possible to carry out a full THM analysis until the end of the test due to

  16. Physiologically-based PK/PD modelling of therapeutic macromolecules.

    Science.gov (United States)

    Thygesen, Peter; Macheras, Panos; Van Peer, Achiel

    2009-12-01

    Therapeutic proteins are a diverse class of drugs consisting of naturally occurring or modified proteins, and due to their size and physico-chemical properties, they can pose challenges for the pharmacokinetic and pharmacodynamic studies. Physiologically-based pharmacokinetics (PBPK) modelling has been effective for early in silico prediction of pharmacokinetic properties of new drugs. The aim of the present workshop was to discuss the feasibility of PBPK modelling of macromolecules. The classical PBPK approach was discussed with a presentation of the successful example of PBPK modelling of cyclosporine A. PBPK model was performed with transport of the cyclosporine across cell membranes, affinity to plasma proteins and active membrane transporters included to describe drug transport between physiological compartments. For macromolecules, complex PBPK modelling or permeability-limited and/or target-mediated distribution was discussed. It was generally agreed that PBPK modelling was feasible and desirable. The role of the lymphatic system should be considered when absorption after extravascular administration is modelled. Target-mediated drug disposition was regarded as an important feature for generation of PK models. Complex PK-models may not be necessary when a limited number of organs are affected. More mechanistic PK/PD models will be relevant when adverse events/toxicity are included in the PK/PD modelling.

  17. Fleet replacement modeling : final report, July 2009.

    Science.gov (United States)

    2009-07-01

    This project focused on two interrelated areas in equipment replacement modeling for fleets. The first area was research-oriented and addressed a fundamental assumption in engineering economic replacement modeling that all assets providing a similar ...

  18. Final Project Report Load Modeling Transmission Research

    Energy Technology Data Exchange (ETDEWEB)

    Lesieutre, Bernard [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Bravo, Richard [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Yinger, Robert [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Chassin, Dave [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Huang, Henry [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Lu, Ning [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Hiskens, Ian [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Venkataramanan, Giri [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)

    2012-03-31

    The research presented in this report primarily focuses on improving power system load models to better represent their impact on system behavior. The previous standard load model fails to capture the delayed voltage recovery events that are observed in the Southwest and elsewhere. These events are attributed to stalled air conditioner units after a fault. To gain a better understanding of their role in these events and to guide modeling efforts, typical air conditioner units were testing in laboratories. Using data obtained from these extensive tests, new load models were developed to match air conditioner behavior. An air conditioner model is incorporated in the new WECC composite load model. These models are used in dynamic studies of the West and can impact power transfer limits for California. Unit-level and systemlevel solutions are proposed as potential solutions to the delayed voltage recovery problem.

  19. Tocopherol And Tocotrienol: Therapeutic Potential In Animal Models of Stress.

    Science.gov (United States)

    Azlina, Mohd Fahami Nur; Kamisah, Yusof; Qodriyah, Mohd Saad

    2017-11-22

    Scientific reports had shown that stress is related to numerous pathological changes in the body. These pathological changes can bring about numerous diseases and can significantly cause negative effects in an individual. These include gastric ulcer, liver pathology and neurobehavioral changes. A common pathogenesis in many diseases related to stress involves oxidative damage. Therefore, the administration of antioxidants such as vitamin E is a reasonable therapeutic approach. However, there is conflicting evidence about antioxidant supplementation. The aim of this work was to summarize documented reports on the effects of tocopherol and tocotrienol on various pathological changes induced by stress. This review will reveal the scientific evidence of enteral supplementation of vitamin E in the forms of tocotrienol and tocopherol in animal models of stress. These models mimic the stress endured by critically ill patients in a clinical setting and psychological stress in individuals. Positive outcomes from enteral feeding of vitamin E in reducing the occurrence of stress-induced pathological changes are discussed in this review. These positive findings include their ability to reduced stress-induced gastric ulcers, elevated liver enzymes and improved locomotors activity. Evidences showing tocotrienol and tocopherol effects are not just related to its ability to reduce oxidative stress but also acting on other mechanism are discussed. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  20. Mathematical models for atmospheric pollutants. Final report

    International Nuclear Information System (INIS)

    Drake, R.L.; Barrager, S.M.

    1979-08-01

    The present and likely future roles of mathematical modeling in air quality decisions are described. The discussion emphasizes models and air pathway processes rather than the chemical and physical behavior of specific anthropogenic emissions. Summarized are the characteristics of various types of models used in the decision-making processes. Specific model subclasses are recommended for use in making air quality decisions that have site-specific, regional, national, or global impacts. The types of exposure and damage models that are currently used to predict the effects of air pollutants on humans, other animals, plants, ecosystems, property, and materials are described. The aesthetic effects of odor and visibility and the impact of pollutants on weather and climate are also addressed. Technical details of air pollution meteorology, chemical and physical properties of air pollutants, solution techniques, and air quality models are discussed in four appendices bound in separate volumes

  1. Respiratory trace deposition models. Final report

    International Nuclear Information System (INIS)

    Yeh, H.C.

    1980-03-01

    Respiratory tract characteristics of four mammalian species (human, dog, rat and Syrian hamster) were studied, using replica lung casts. An in situ casting techniques was developed for making the casts. Based on an idealized branch model, over 38,000 records of airway segment diameters, lengths, branching angles and gravity angles were obtained from measurements of two humans, two Beagle dogs, two rats and one Syrian hamster. From examination of the trimmed casts and morphometric data, it appeared that the structure of the human airway is closer to a dichotomous structure, whereas for dog, rat and hamster, it is monopodial. Flow velocity in the trachea and major bronchi in living Beagle dogs was measured using an implanted, subminiaturized, heated film anemometer. A physical model was developed to simulate the regional deposition characteristics proposed by the Task Group on Lung Dynamics of the ICRP. Various simulation modules for the nasopharyngeal (NP), tracheobronchial (TB) and pulmonary (P) compartments were designed and tested. Three types of monodisperse aerosols were developed for animal inhalation studies. Fifty Syrian hamsters and 50 rats were exposed to five different sizes of monodisperse fused aluminosilicate particles labeled with 169 Yb. Anatomical lung models were developed for four species (human, Beagle dog, rat and Syrian hamster) that were based on detailed morphometric measurements of replica lung casts. Emphasis was placed on developing a lobar typical-path lung model and on developing a modeling technique which could be applied to various mammalian species. A set of particle deposition equations for deposition caused by inertial impaction, sedimentation, and diffusion were developed. Theoretical models of particle deposition were developed based on these equations and on the anatomical lung models

  2. Therapeutic strategies in an animal model of neurodegeneration

    NARCIS (Netherlands)

    Borre, Y.E.

    2013-01-01

    Neurodegenerative diseases have complex and multifactorial etiologies, creating an enormous burden on society without an effective treatment. This thesis utilized olfactory bulbectomized rats to investigate therapeutic approaches to neurodegenerative disorders. Removal of the olfactory bulbs, leads

  3. Final model of multicriterionevaluation of animal welfare

    DEFF Research Database (Denmark)

    Bonde, Marianne; Botreau, R; Bracke, MBM

    One major objective of Welfare Quality® is to propose harmonized methods for the overall assessment of animal welfare on farm and at slaughter that are science based and meet societal concerns. Welfare is a multidimensional concept and its assessment requires measures of different aspects. Welfar......, acceptable welfare and not classified. This evaluation model is tuned according to the views of experts from animal and social sciences, and stakeholders....... Quality® proposes a formal evaluation model whereby the data on animals or their environment are transformed into value scores that reflect compliance with 12 subcriteria and 4 criteria of good welfare. Each animal unit is then allocated to one of four categories: excellent welfare, enhanced welfare...

  4. Integrating School-Based and Therapeutic Conflict Management Models at School.

    Science.gov (United States)

    D'Oosterlinck, Franky; Broekaert, Eric

    2003-01-01

    Explores the possibility of integrating school-based and therapeutic conflict management models, comparing two management models: a school-based conflict management program, "Teaching Students To Be Peacemakers"; and a therapeutic conflict management program, "Life Space Crisis Intervention." The paper concludes that integration might be possible…

  5. Modeling Marrow Failure and MDS for Novel Therapeutics

    Science.gov (United States)

    2017-03-01

    syndrome (MDS) and leukemia is also markedly elevated in patients with inherited marrow failure syndromes compared to age-matched controls. Prognosis of...Novel Therapeutics W81XWH-16-1-0054 1. Introduction Clonal evolution is a potentially life threatening long-term complication of inherited and...The risk of early progression to myelodysplastic syndrome (MDS) and leukemia is also markedly elevated in patients with inherited marrow failure

  6. Factors associated with therapeutic inertia in hypertension: validation of a predictive model.

    Science.gov (United States)

    Redón, Josep; Coca, Antonio; Lázaro, Pablo; Aguilar, Ma Dolores; Cabañas, Mercedes; Gil, Natividad; Sánchez-Zamorano, Miguel Angel; Aranda, Pedro

    2010-08-01

    To study factors associated with therapeutic inertia in treating hypertension and to develop a predictive model to estimate the probability of therapeutic inertia in a given medical consultation, based on variables related to the consultation, patient, physician, clinical characteristics, and level of care. National, multicentre, observational, cross-sectional study in primary care and specialist (hospital) physicians who each completed a questionnaire on therapeutic inertia, provided professional data and collected clinical data on four patients. Therapeutic inertia was defined as a consultation in which treatment change was indicated (i.e., SBP >or= 140 or DBP >or= 90 mmHg in all patients; SBP >or= 130 or DBP >or= 80 in patients with diabetes or stroke), but did not occur. A predictive model was constructed and validated according to the factors associated with therapeutic inertia. Data were collected on 2595 patients and 13,792 visits. Therapeutic inertia occurred in 7546 (75%) of the 10,041 consultations in which treatment change was indicated. Factors associated with therapeutic inertia were primary care setting, male sex, older age, SPB and/or DBP values close to normal, treatment with more than one antihypertensive drug, treatment with an ARB II, and more than six visits/year. Physician characteristics did not weigh heavily in the association. The predictive model was valid internally and externally, with acceptable calibration, discrimination and reproducibility, and explained one-third of the variability in therapeutic inertia. Although therapeutic inertia is frequent in the management of hypertension, the factors explaining it are not completely clear. Whereas some aspects of the consultations were associated with therapeutic inertia, physician characteristics were not a decisive factor.

  7. Washington State Nursing Home Administrator Model Curriculum. Final Report.

    Science.gov (United States)

    Cowan, Florence Kelly

    The course outlines presented in this final report comprise a proposed Fort Steilacoom Community College curriculum to be used as a statewide model two-year associate degree curriculum for nursing home administrators. The eight courses described are introduction to nursing, home administration, financial management of nursing homes, nursing home…

  8. Final Report Fermionic Symmetries and Self consistent Shell Model

    International Nuclear Information System (INIS)

    Zamick, Larry

    2008-01-01

    In this final report in the field of theoretical nuclear physics we note important accomplishments.We were confronted with 'anomoulous' magnetic moments by the experimetalists and were able to expain them. We found unexpected partial dynamical symmetries--completely unknown before, and were able to a large extent to expain them. The importance of a self consistent shell model was emphasized.

  9. Model validation studies of solar systems, Phase III. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Lantz, L.J.; Winn, C.B.

    1978-12-01

    Results obtained from a validation study of the TRNSYS, SIMSHAC, and SOLCOST solar system simulation and design are presented. Also included are comparisons between the FCHART and SOLCOST solar system design programs and some changes that were made to the SOLCOST program. Finally, results obtained from the analysis of several solar radiation models are presented. Separate abstracts were prepared for ten papers.

  10. Calculation of extreme wind atlases using mesoscale modeling. Final report

    DEFF Research Database (Denmark)

    Larsén, Xiaoli Guo; Badger, Jake

    This is the final report of the project PSO-10240 "Calculation of extreme wind atlases using mesoscale modeling". The overall objective is to improve the estimation of extreme winds by developing and applying new methodologies to confront the many weaknesses in the current methodologies as explai...

  11. Photovoltaic subsystem marketing and distribution model: programming manual. Final report

    Energy Technology Data Exchange (ETDEWEB)

    1982-07-01

    Complete documentation of the marketing and distribution (M and D) computer model is provided. The purpose is to estimate the costs of selling and transporting photovoltaic solar energy products from the manufacturer to the final customer. The model adjusts for the inflation and regional differences in marketing and distribution costs. The model consists of three major components: the marketing submodel, the distribution submodel, and the financial submodel. The computer program is explained including the input requirements, output reports, subprograms and operating environment. The program specifications discuss maintaining the validity of the data and potential improvements. An example for a photovoltaic concentrator collector demonstrates the application of the model.

  12. Therapeutic budget modelling: a possible road to budgetary ...

    African Journals Online (AJOL)

    ... modelling: a possible road to budgetary allocations in the public health care ... on the public health care sector (especially the primary health care structure) for ... budgetary policies for better medicine formulary and resource management.

  13. Clinical Prediction Model for Time in Therapeutic Range While on Warfarin in Newly Diagnosed Atrial Fibrillation.

    Science.gov (United States)

    Williams, Brent A; Evans, Michael A; Honushefsky, Ashley M; Berger, Peter B

    2017-10-12

    Though warfarin has historically been the primary oral anticoagulant for stroke prevention in newly diagnosed atrial fibrillation (AF), several new direct oral anticoagulants may be preferred when anticoagulation control with warfarin is expected to be poor. This study developed a prediction model for time in therapeutic range (TTR) among newly diagnosed AF patients on newly initiated warfarin as a tool to assist decision making between warfarin and direct oral anticoagulants. This electronic medical record-based, retrospective study included newly diagnosed, nonvalvular AF patients with no recent warfarin exposure receiving primary care services through a large healthcare system in rural Pennsylvania. TTR was estimated as the percentage of time international normalized ratio measurements were between 2.0 and 3.0 during the first year following warfarin initiation. Candidate predictors of TTR were chosen from data elements collected during usual clinical care. A TTR prediction model was developed and temporally validated and its predictive performance was compared with the SAMe-TT 2 R 2 score (sex, age, medical history, treatment, tobacco, race) using R 2 and c-statistics. A total of 7877 newly diagnosed AF patients met study inclusion criteria. Median (interquartile range) TTR within the first year of starting warfarin was 51% (32, 67). Of 85 candidate predictors evaluated, 15 were included in the final validated model with an R 2 of 15.4%. The proposed model showed better predictive performance than the SAMe-TT 2 R 2 score ( R 2 =3.0%). The proposed prediction model may assist decision making on the proper mode of oral anticoagulant among newly diagnosed AF patients. However, predicting TTR on warfarin remains challenging. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

  14. Therapeutic Implications from Sensitivity Analysis of Tumor Angiogenesis Models

    Science.gov (United States)

    Poleszczuk, Jan; Hahnfeldt, Philip; Enderling, Heiko

    2015-01-01

    Anti-angiogenic cancer treatments induce tumor starvation and regression by targeting the tumor vasculature that delivers oxygen and nutrients. Mathematical models prove valuable tools to study the proof-of-concept, efficacy and underlying mechanisms of such treatment approaches. The effects of parameter value uncertainties for two models of tumor development under angiogenic signaling and anti-angiogenic treatment are studied. Data fitting is performed to compare predictions of both models and to obtain nominal parameter values for sensitivity analysis. Sensitivity analysis reveals that the success of different cancer treatments depends on tumor size and tumor intrinsic parameters. In particular, we show that tumors with ample vascular support can be successfully targeted with conventional cytotoxic treatments. On the other hand, tumors with curtailed vascular support are not limited by their growth rate and therefore interruption of neovascularization emerges as the most promising treatment target. PMID:25785600

  15. Translational Mouse Models of Autism: Advancing Toward Pharmacological Therapeutics

    Science.gov (United States)

    Kazdoba, Tatiana M.; Leach, Prescott T.; Yang, Mu; Silverman, Jill L.; Solomon, Marjorie

    2016-01-01

    Animal models provide preclinical tools to investigate the causal role of genetic mutations and environmental factors in the etiology of autism spectrum disorder (ASD). Knockout and humanized knock-in mice, and more recently knockout rats, have been generated for many of the de novo single gene mutations and copy number variants (CNVs) detected in ASD and comorbid neurodevelopmental disorders. Mouse models incorporating genetic and environmental manipulations have been employed for preclinical testing of hypothesis-driven pharmacological targets, to begin to develop treatments for the diagnostic and associated symptoms of autism. In this review, we summarize rodent behavioral assays relevant to the core features of autism, preclinical and clinical evaluations of pharmacological interventions, and strategies to improve the translational value of rodent models of autism. PMID:27305922

  16. Aligning Animal Models of Clinical Germinal Matrix Hemorrhage, From Basic Correlation to Therapeutic Approach.

    Science.gov (United States)

    Lekic, Tim; Klebe, Damon; Pichon, Pilar; Brankov, Katarina; Sultan, Sally; McBride, Devin; Casel, Darlene; Al-Bayati, Alhamza; Ding, Yan; Tang, Jiping; Zhang, John H

    2017-01-01

    Germinal matrix hemorrhage is a leading cause of mortality and morbidity from prematurity. This brain region is vulnerable to bleeding and re-bleeding within the first 72 hours of preterm life. Cerebroventricular expansion of blood products contributes to the mechanisms of brain injury. Consequences include lifelong hydrocephalus, cerebral palsy, and intellectual disability. Unfortunately little is known about the therapeutic needs of this patient population. This review discusses the mechanisms of germinal matrix hemorrhage, the animal models utilized, and the potential therapeutic targets. Potential therapeutic approaches identified in pre-clinical investigations include corticosteroid therapy, iron chelator administration, and transforming growth factor-β pathway modulation, which all warrant further investigation. Thus, effective preclinical modeling is essential for elucidating and evaluating novel therapeutic approaches, ahead of clinical consideration. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  17. PARALLEL MODELS OF ASSESSMENT: INFANT MENTAL HEALTH AND THERAPEUTIC ASSESSMENT MODELS INTERSECT THROUGH EARLY CHILDHOOD CASE STUDIES.

    Science.gov (United States)

    Gart, Natalie; Zamora, Irina; Williams, Marian E

    2016-07-01

    Therapeutic Assessment (TA; S.E. Finn & M.E. Tonsager, 1997; J.D. Smith, 2010) is a collaborative, semistructured model that encourages self-discovery and meaning-making through the use of assessment as an intervention approach. This model shares core strategies with infant mental health assessment, including close collaboration with parents and caregivers, active participation of the family, a focus on developing new family stories and increasing parents' understanding of their child, and reducing isolation and increasing hope through the assessment process. The intersection of these two theoretical approaches is explored, using case studies of three infants/young children and their families to illustrate the application of TA to infant mental health. The case of an 18-month-old girl whose parents fear that she has bipolar disorder illustrates the core principles of the TA model, highlighting the use of assessment intervention sessions and the clinical approach to preparing assessment feedback. The second case follows an infant with a rare genetic syndrome from ages 2 to 24 months, focusing on the assessor-parent relationship and the importance of a developmental perspective. Finally, assessment of a 3-year-old boy illustrates the development and use of a fable as a tool to provide feedback to a young child about assessment findings and recommendations. © 2016 Michigan Association for Infant Mental Health.

  18. Non-Clinical Models for Neurodegenerative Diseases: Therapeutic Approach and Drug Validation in Animal Models

    Directory of Open Access Journals (Sweden)

    Caridad Ivette Fernandez

    2017-12-01

    Full Text Available In 2016, 19.8% of the Cuban population was aged 60 or over. As a result, age-associated degenerative diseases and other diseases have become priority targets from a prophylactic, diagnostic and therapeutic perspective. As a result, the Cuban biomedical scientific community has addressed its basic, preclinical and epidemiological research in order to rise up to the challenge. A firm step in this direction has been the international congress “State of the art in non-clinical models for neurodegenerative diseases” which has brought together preclinical and clinical researchers, technicians and regulatory staff members from different countries to review the state of the art in neurodegenerations, find unifying ideas, objectives and collaborations or partnership. The objective is to expose the perspectives of new biotechnological products from Cuba and other countries from the diagnostic, therapeutic and neuroprotective point of view. It is crucial, therefore, that the irreplaceable role of laboratory animals in achieving these objectives is understood but they must be used in rational, adequate and ethical manner. We expose the current development trends in this field, being of common interest to the work directed to the search for potential drugs, diagnostic tools and the promotion of changes in lifestyle as a preventive projection.

  19. Integrating school-based and therapeutic conflict management models at schools.

    Science.gov (United States)

    D'Oosterlinck, Franky; Broekaert, Eric

    2003-08-01

    Including children with emotional and behavioral needs in mainstream school systems leads to growing concern about the increasing number of violent and nonviolent conflicts. Schools must adapt to this evolution and adopt a more therapeutic dimension. This paper explores the possibility of integrating school-based and therapeutic conflict management models and compares two management models: a school-based conflict management program. Teaching Students To Be Peacemakers; and a therapeutic conflict management program, Life Space Crisis Intervention. The authors conclude that integration might be possible, but depends on establishing a positive school atmosphere, the central position of the teacher, and collaborative and social learning for pupils. Further implementation of integrated conflict management models can be considered but must be underpinned by appropriate scientific research.

  20. A Mathematical Model of the Effect of Immunogenicity on Therapeutic Protein Pharmacokinetics

    OpenAIRE

    Chen, Xiaoying; Hickling, Timothy; Kraynov, Eugenia; Kuang, Bing; Parng, Chuenlei; Vicini, Paolo

    2013-01-01

    A mathematical pharmacokinetic/anti-drug-antibody (PK/ADA) model was constructed for quantitatively assessing immunogenicity for therapeutic proteins. The model is inspired by traditional pharmacokinetic/pharmacodynamic (PK/PD) models, and is based on the observed impact of ADA on protein drug clearance. The hypothesis for this work is that altered drug PK contains information about the extent and timing of ADA generation. By fitting drug PK profiles while accounting for ADA-mediated drug cle...

  1. Therapeutic Effects of Extinction Learning as a Model of Exposure Therapy in Rats

    Science.gov (United States)

    Fucich, Elizabeth A; Paredes, Denisse; Morilak, David A

    2016-01-01

    Current treatments for stress-related psychiatric disorders, such as depression and posttraumatic stress disorder (PTSD), are inadequate. Cognitive behavioral psychotherapies, including exposure therapy, are an alternative to pharmacotherapy, but the neurobiological mechanisms are unknown. Preclinical models demonstrating therapeutic effects of behavioral interventions are required to investigate such mechanisms. Exposure therapy bears similarity to extinction learning. Thus, we investigated the therapeutic effects of extinction learning as a behavioral intervention to model exposure therapy in rats, testing its effectiveness in reversing chronic stress-induced deficits in cognitive flexibility and coping behavior that resemble dimensions of depression and PTSD. Rats were fear-conditioned by pairing a tone with footshock, and then exposed to chronic unpredictable stress (CUS) that induces deficits in cognitive set-shifting and active coping behavior. They then received an extinction learning session as a therapeutic intervention by repeated exposure to the tone with no shock. Effects on cognitive flexibility and coping behavior were assessed 24 h later on the attentional set-shifting test or shock-probe defensive burying test, respectively. Extinction reversed the CUS-induced deficits in cognitive flexibility and coping behavior, and increased phosphorylation of ribosomal protein S6 in the medial prefrontal cortex (mPFC) of stress-compromised rats, suggesting a role for activity-dependent protein synthesis in the therapeutic effect. Inhibiting protein synthesis by microinjecting anisomycin into mPFC blocked the therapeutic effect of extinction on cognitive flexibility. These results demonstrate the utility of extinction as a model by which to study mechanisms underlying exposure therapy, and suggest these mechanisms involve protein synthesis in the mPFC, the further study of which may identify novel therapeutic targets. PMID:27417516

  2. A generic whole body physiologically based pharmacokinetic model for therapeutic proteins in PK-Sim.

    Science.gov (United States)

    Niederalt, Christoph; Kuepfer, Lars; Solodenko, Juri; Eissing, Thomas; Siegmund, Hans-Ulrich; Block, Michael; Willmann, Stefan; Lippert, Jörg

    2018-04-01

    Proteins are an increasingly important class of drugs used as therapeutic as well as diagnostic agents. A generic physiologically based pharmacokinetic (PBPK) model was developed in order to represent at whole body level the fundamental mechanisms driving the distribution and clearance of large molecules like therapeutic proteins. The model was built as an extension of the PK-Sim model for small molecules incorporating (i) the two-pore formalism for drug extravasation from blood plasma to interstitial space, (ii) lymph flow, (iii) endosomal clearance and (iv) protection from endosomal clearance by neonatal Fc receptor (FcRn) mediated recycling as especially relevant for antibodies. For model development and evaluation, PK data was used for compounds with a wide range of solute radii. The model supports the integration of knowledge gained during all development phases of therapeutic proteins, enables translation from pre-clinical species to human and allows predictions of tissue concentration profiles which are of relevance for the analysis of on-target pharmacodynamic effects as well as off-target toxicity. The current implementation of the model replaces the generic protein PBPK model available in PK-Sim since version 4.2 and becomes part of the Open Systems Pharmacology Suite.

  3. Microwave modeling of laser plasma interactions. Final report

    International Nuclear Information System (INIS)

    1983-08-01

    For a large laser fusion targets and nanosecond pulse lengths, stimulated Brillouin scattering (SBS) and self-focusing are expected to be significant problems. The goal of the contractual effort was to examine certain aspects of these physical phenomena in a wavelength regime (lambda approx.5 cm) more amenable to detailed diagnostics than that characteristic of laser fusion (lambda approx.1 micron). The effort was to include the design, fabrication and operation of a suitable experimental apparatus. In addition, collaboration with Dr. Neville Luhmann and his associates at UCLA and with Dr. Curt Randall of LLNL, on analysis and modelling of the UCLA experiments was continued. Design and fabrication of the TRW experiment is described under ''Experiment Design'' and ''Experimental Apparatus''. The design goals for the key elements of the experimental apparatus were met, but final integration and operation of the experiment was not accomplished. Some theoretical considerations on the interaction between Stimulated Brillouin Scattering and Self-Focusing are also presented

  4. Nanoparticle-mediated delivery of pioglitazone enhances therapeutic neovascularization in a murine model of hindlimb ischemia.

    Science.gov (United States)

    Nagahama, Ryoji; Matoba, Tetsuya; Nakano, Kaku; Kim-Mitsuyama, Shokei; Sunagawa, Kenji; Egashira, Kensuke

    2012-10-01

    Critical limb ischemia is a severe form of peripheral artery disease (PAD) for which neither surgical revascularization nor endovascular therapy nor current medicinal therapy has sufficient therapeutic effects. Peroxisome proliferator activated receptor-γ agonists present angiogenic activity in vitro; however, systemic administration of peroxisome proliferator-activated receptor-γ agonists is hampered by its side effects, including heart failure. Here, we demonstrate that the nanoparticle (NP)-mediated delivery of the peroxisome proliferator activated receptor-γ agonist pioglitazone enhances its therapeutic efficacy on ischemia-induced neovascularization in a murine model. In a nondiabetic murine model of hindlimb ischemia, a single intramuscular injection of pioglitazone-incorporated NP (1 µg/kg) into ischemic muscles significantly improved the blood flow recovery in the ischemic limbs, significantly increasing the number of CD31-positive capillaries and α-smooth muscle actin-positive arterioles. The therapeutic effects of pioglitazone-incorporated NP were diminished by the peroxisome proliferator activated receptor-γ antagonist GW9662 and were not observed in endothelial NO synthase-deficient mice. Pioglitazone-incorporated NP induced endothelial NO synthase phosphorylation, as demonstrated by Western blot analysis, as well as expression of multiple angiogenic growth factors in vivo, including vascular endothelial growth factor-A, vascular endothelial growth factor-B, and fibroblast growth factor-1, as demonstrated by real-time polymerase chain reaction. Intramuscular injection of pioglitazone (1 µg/kg) was ineffective, and oral administration necessitated a >500 μg/kg per day dose to produce therapeutic effects equivalent to those of pioglitazone-incorporated NP. NP-mediated drug delivery is a novel modality that may enhance the effectiveness of therapeutic neovascularization, surpassing the effectiveness of current treatments for peripheral artery

  5. Avastin exhibits therapeutic effects on collagen-induced arthritis in rat model.

    Science.gov (United States)

    Wang, Yong; Da, Gula; Li, Hongbin; Zheng, Yi

    2013-12-01

    Avastin is the monoclonal antibody for vascular endothelial growth factor (VEGF). This study aimed to investigate therapeutic effect of Avastin on type II collagen-induced arthritis. Type II chicken collagen was injected into the tails of Wistar rats, and 60 modeled female rats were randomly divided into three groups (n = 20): Avastin group, Etanercept group, and control group. Arthritis index and joint pad thickness were scored, and the pathology of back metapedes was analyzed. The results showed that compared to control group, the arthritis index, target-to-non-target ratio, synovial pathological injury index, serum levels of VEGF and tumor necrosis factor alpha, and VEGF staining were decreased significantly 14 days after Avastin or Etanercept treatment, but there were no significant differences between Avastin group and Etanercept group. These data provide evidence that Avastin exhibits similar effects to Etanercept to relieve rheumatoid arthritis in rat model and suggest that Avastin is a promising therapeutic agent for rheumatoid arthritis.

  6. Glioblastoma, a brief review of history, molecular genetics, animal models and novel therapeutic strategies.

    Science.gov (United States)

    Agnihotri, Sameer; Burrell, Kelly E; Wolf, Amparo; Jalali, Sharzhad; Hawkins, Cynthia; Rutka, James T; Zadeh, Gelareh

    2013-02-01

    Glioblastoma (GBM) is the most common and lethal primary brain tumor. Over the past few years tremendous genomic and proteomic characterization along with robust animal models of GBM have provided invaluable data that show that "GBM", although histologically indistinguishable from one another, are comprised of molecularly heterogenous diseases. In addition, robust pre-clinical models and a better understanding of the core pathways disrupted in GBM are providing a renewed optimism for novel strategies targeting these devastating tumors. Here, we summarize a brief history of the disease, our current molecular knowledge, lessons from animal models and emerging concepts of angiogenesis, invasion, and metabolism in GBM that may lend themselves to therapeutic targeting.

  7. EXPERIMENTS AND COMPUTATIONAL MODELING OF PULVERIZED-COAL IGNITION; FINAL

    International Nuclear Information System (INIS)

    Samuel Owusu-Ofori; John C. Chen

    1999-01-01

    Under typical conditions of pulverized-coal combustion, which is characterized by fine particles heated at very high rates, there is currently a lack of certainty regarding the ignition mechanism of bituminous and lower rank coals as well as the ignition rate of reaction. furthermore, there have been no previous studies aimed at examining these factors under various experimental conditions, such as particle size, oxygen concentration, and heating rate. Finally, there is a need to improve current mathematical models of ignition to realistically and accurately depict the particle-to-particle variations that exist within a coal sample. Such a model is needed to extract useful reaction parameters from ignition studies, and to interpret ignition data in a more meaningful way. The authors propose to examine fundamental aspects of coal ignition through (1) experiments to determine the ignition temperature of various coals by direct measurement, and (2) modeling of the ignition process to derive rate constants and to provide a more insightful interpretation of data from ignition experiments. The authors propose to use a novel laser-based ignition experiment to achieve their first objective. Laser-ignition experiments offer the distinct advantage of easy optical access to the particles because of the absence of a furnace or radiating walls, and thus permit direct observation and particle temperature measurement. The ignition temperature of different coals under various experimental conditions can therefore be easily determined by direct measurement using two-color pyrometry. The ignition rate-constants, when the ignition occurs heterogeneously, and the particle heating rates will both be determined from analyses based on these measurements

  8. Drug-releasing nano-engineered titanium implants: therapeutic efficacy in 3D cell culture model, controlled release and stability

    Energy Technology Data Exchange (ETDEWEB)

    Gulati, Karan [School of Chemical Engineering, The University of Adelaide, SA 5005 (Australia); Kogawa, Masakazu; Prideaux, Matthew; Findlay, David M. [Discipline of Orthopaedics and Trauma, The University of Adelaide, SA 5005 (Australia); Atkins, Gerald J., E-mail: gerald.atkins@adelaide.edu.au [Discipline of Orthopaedics and Trauma, The University of Adelaide, SA 5005 (Australia); Losic, Dusan, E-mail: dusan.losic@adelaide.edu.au [School of Chemical Engineering, The University of Adelaide, SA 5005 (Australia)

    2016-12-01

    There is an ongoing demand for new approaches for treating localized bone pathologies. Here we propose a new strategy for treatment of such conditions, via local delivery of hormones/drugs to the trauma site using drug releasing nano-engineered implants. The proposed implants were prepared in the form of small Ti wires/needles with a nano-engineered oxide layer composed of array of titania nanotubes (TNTs). TNTs implants were inserted into a 3D collagen gel matrix containing human osteoblast-like, and the results confirmed cell migration onto the implants and their attachment and spread. To investigate therapeutic efficacy, TNTs/Ti wires loaded with parathyroid hormone (PTH), an approved anabolic therapeutic for the treatment of severe bone fractures, were inserted into 3D gels containing osteoblast-like cells. Gene expression studies revealed a suppression of SOST (sclerostin) and an increase in RANKL (receptor activator of nuclear factor kappa-B ligand) mRNA expression, confirming the release of PTH from TNTs at concentrations sufficient to alter cell function. The performance of the TNTs wire implants using an example of a drug needed at relatively higher concentrations, the anti-inflammatory drug indomethacin, is also demonstrated. Finally, the mechanical stability of the prepared implants was tested by their insertion into bovine trabecular bone cores ex vivo followed by retrieval, which confirmed the robustness of the TNT structures. This study provides proof of principle for the suitability of the TNT/Ti wire implants for localized bone therapy, which can be customized to cater for specific therapeutic requirements. - Highlights: • Ti wire with titania nanotubes (TNTs) are proposed as ‘in-bone’ therapeutic implants. • 3D cell culture model is used to confirm therapeutic efficacy of drug releasing implants. Osteoblasts migrated and firmly attached to the TNTs and the micro-scale cracks. • Tailorable drug loading from few nanograms to several hundred

  9. Catalytic immunoglobulin gene delivery in a mouse model of Alzheimer's disease: prophylactic and therapeutic applications.

    Science.gov (United States)

    Kou, Jinghong; Yang, Junling; Lim, Jeong-Eun; Pattanayak, Abhinandan; Song, Min; Planque, Stephanie; Paul, Sudhir; Fukuchi, Ken-Ichiro

    2015-02-01

    Accumulation of amyloid beta-peptide (Aβ) in the brain is hypothesized to be a causal event leading to dementia in Alzheimer's disease (AD). Aβ vaccination removes Aβ deposits from the brain. Aβ immunotherapy, however, may cause T cell- and/or Fc-receptor-mediated brain inflammation and relocate parenchymal Aβ deposits to blood vessels leading to cerebral hemorrhages. Because catalytic antibodies do not form stable immune complexes and Aβ fragments produced by catalytic antibodies are less likely to form aggregates, Aβ-specific catalytic antibodies may have safer therapeutic profiles than reversibly-binding anti-Aβ antibodies. Additionally, catalytic antibodies may remove Aβ more efficiently than binding antibodies because a single catalytic antibody can hydrolyze thousands of Aβ molecules. We previously isolated Aβ-specific catalytic antibody, IgVL5D3, with strong Aβ-hydrolyzing activity. Here, we evaluated the prophylactic and therapeutic efficacy of brain-targeted IgVL5D3 gene delivery via recombinant adeno-associated virus serotype 9 (rAAV9) in an AD mouse model. One single injection of rAAV9-IgVL5D3 into the right ventricle of AD model mice yielded widespread, high expression of IgVL5D3 in the unilateral hemisphere. IgVL5D3 expression was readily detectable in the contralateral hemisphere but to a much lesser extent. IgVL5D3 expression was also confirmed in the cerebrospinal fluid. Prophylactic and therapeutic injection of rAAV9-IgVL5D3 reduced Aβ load in the ipsilateral hippocampus of AD model mice. No evidence of hemorrhages, increased vascular amyloid deposits, increased proinflammatory cytokines, or infiltrating T-cells in the brains was found in the experimental animals. AAV9-mediated anti-Aβ catalytic antibody brain delivery can be prophylactic and therapeutic options for AD.

  10. Macromolecular therapeutics.

    Science.gov (United States)

    Yang, Jiyuan; Kopeček, Jindřich

    2014-09-28

    This review covers water-soluble polymer-drug conjugates and macromolecules that possess biological activity without attached low molecular weight drugs. The main design principles of traditional and backbone degradable polymer-drug conjugates as well as the development of a new paradigm in nanomedicines - (low molecular weight) drug-free macromolecular therapeutics are discussed. To address the biological features of cancer, macromolecular therapeutics directed to stem/progenitor cells and the tumor microenvironment are deliberated. Finally, the future perspectives of the field are briefly debated. Copyright © 2014 Elsevier B.V. All rights reserved.

  11. A reduced-order, single-bubble cavitation model with applications to therapeutic ultrasound.

    Science.gov (United States)

    Kreider, Wayne; Crum, Lawrence A; Bailey, Michael R; Sapozhnikov, Oleg A

    2011-11-01

    Cavitation often occurs in therapeutic applications of medical ultrasound such as shock-wave lithotripsy (SWL) and high-intensity focused ultrasound (HIFU). Because cavitation bubbles can affect an intended treatment, it is important to understand the dynamics of bubbles in this context. The relevant context includes very high acoustic pressures and frequencies as well as elevated temperatures. Relative to much of the prior research on cavitation and bubble dynamics, such conditions are unique. To address the relevant physics, a reduced-order model of a single, spherical bubble is proposed that incorporates phase change at the liquid-gas interface as well as heat and mass transport in both phases. Based on the energy lost during the inertial collapse and rebound of a millimeter-sized bubble, experimental observations were used to tune and test model predictions. In addition, benchmarks from the published literature were used to assess various aspects of model performance. Benchmark comparisons demonstrate that the model captures the basic physics of phase change and diffusive transport, while it is quantitatively sensitive to specific model assumptions and implementation details. Given its performance and numerical stability, the model can be used to explore bubble behaviors across a broad parameter space relevant to therapeutic ultrasound.

  12. Characterize and Model Final Waste Formulations and Offgas Solids from Thermal Treatment Processes - FY-98 Final Report for LDRD 2349

    Energy Technology Data Exchange (ETDEWEB)

    Kessinger, Glen Frank; Nelson, Lee Orville; Grandy, Jon Drue; Zuck, Larry Douglas; Kong, Peter Chuen Sun; Anderson, Gail

    1999-08-01

    The purpose of LDRD #2349, Characterize and Model Final Waste Formulations and Offgas Solids from Thermal Treatment Processes, was to develop a set of tools that would allow the user to, based on the chemical composition of a waste stream to be immobilized, predict the durability (leach behavior) of the final waste form and the phase assemblages present in the final waste form. The objectives of the project were: • investigation, testing and selection of thermochemical code • development of auxiliary thermochemical database • synthesis of materials for leach testing • collection of leach data • using leach data for leach model development • thermochemical modeling The progress toward completion of these objectives and a discussion of work that needs to be completed to arrive at a logical finishing point for this project will be presented.

  13. Animal models and therapeutic molecular targets of cancer: utility and limitations

    Directory of Open Access Journals (Sweden)

    Cekanova M

    2014-10-01

    Full Text Available Maria Cekanova, Kusum Rathore Department of Small Animal Clinical Sciences, College of Veterinary Medicine, The University of Tennessee, Knoxville, TN, USA Abstract: Cancer is the term used to describe over 100 diseases that share several common hallmarks. Despite prevention, early detection, and novel therapies, cancer is still the second leading cause of death in the USA. Successful bench-to-bedside translation of basic scientific findings about cancer into therapeutic interventions for patients depends on the selection of appropriate animal experimental models. Cancer research uses animal and human cancer cell lines in vitro to study biochemical pathways in these cancer cells. In this review, we summarize the important animal models of cancer with focus on their advantages and limitations. Mouse cancer models are well known, and are frequently used for cancer research. Rodent models have revolutionized our ability to study gene and protein functions in vivo and to better understand their molecular pathways and mechanisms. Xenograft and chemically or genetically induced mouse cancers are the most commonly used rodent cancer models. Companion animals with spontaneous neoplasms are still an underexploited tool for making rapid advances in human and veterinary cancer therapies by testing new drugs and delivery systems that have shown promise in vitro and in vivo in mouse models. Companion animals have a relatively high incidence of cancers, with biological behavior, response to therapy, and response to cytotoxic agents similar to those in humans. Shorter overall lifespan and more rapid disease progression are factors contributing to the advantages of a companion animal model. In addition, the current focus is on discovering molecular targets for new therapeutic drugs to improve survival and quality of life in cancer patients. Keywords: mouse cancer model, companion animal cancer model, dogs, cats, molecular targets

  14. Mass transfer of therapeutics through natural human plaque biofilms: a model for therapeutic delivery to pathological bacterial biofilms.

    Science.gov (United States)

    Robinson, Colin

    2011-09-01

    Bacterial biofilms in the mouth are prime mediators of the destruction of the dental and oral tissues. This brief review summarises recent work using a device for generating intact plaque in the mouth on natural enamel surfaces such that quantitative studies of mass transfer through natural plaque biofilms could be carried out in relation to plaque architecture. This data is discussed against the background of existing information. The device revealed complex plaque architecture with high a surface area to mass ratio decreasing from the exterior of the biofilm towards the tissue surface. Fluoride, a potent inhibitor of caries was concentrated in the outer regions of the biofilm. This implies some restriction of diffusion and possibly binding to the high surface area of the outer biofilm. Whilst all components examined conformed to this distribution pattern, some relatively uncharged materials penetrated the bacterial biomass whilst other, more highly charged materials tended to be restricted to the channels or biomass surface. Plaque architecture was robust but could be altered using detergent indicating that biomass architecture and chemistry could be manipulated as a possible means of facilitating mass transport of therapeutics. Copyright © 2011 Elsevier Ltd. All rights reserved.

  15. Therapeutic Targets for Neurodevelopmental Disorders Emerging from Animal Models with Perinatal Immune Activation

    Directory of Open Access Journals (Sweden)

    Daisuke Ibi

    2015-11-01

    Full Text Available Increasing epidemiological evidence indicates that perinatal infection with various viral pathogens enhances the risk for several psychiatric disorders. The pathophysiological significance of astrocyte interactions with neurons and/or gut microbiomes has been reported in neurodevelopmental disorders triggered by pre- and postnatal immune insults. Recent studies with the maternal immune activation or neonatal polyriboinosinic polyribocytidylic acid models of neurodevelopmental disorders have identified various candidate molecules that could be responsible for brain dysfunction. Here, we review the functions of several candidate molecules in neurodevelopment and brain function and discuss their potential as therapeutic targets for psychiatric disorders.

  16. Non-adversarial justice and the coroner's court: a proposed therapeutic, restorative, problem-solving model.

    Science.gov (United States)

    King, Michael S

    2008-12-01

    Increasingly courts are using new approaches that promote a more comprehensive resolution of legal problems, minimise any negative effects that legal processes have on participant wellbeing and/or that use legal processes to promote participant wellbeing. Therapeutic jurisprudence, restorative justice, mediation and problem-solving courts are examples. This article suggests a model for the use of these processes in the coroner's court to minimise negative effects of coroner's court processes on the bereaved and to promote a more comprehensive resolution of matters at issue, including the determination of the cause of death and the public health and safety promotion role of the coroner.

  17. Modeling the Pan-Arctic terrestrial and atmospheric water cycle. Final report; FINAL

    International Nuclear Information System (INIS)

    Gutowski, W.J. Jr.

    2001-01-01

    This report describes results of DOE grant DE-FG02-96ER61473 to Iowa State University (ISU). Work on this grant was performed at Iowa State University and at the University of New Hampshire in collaboration with Dr. Charles Vorosmarty and fellow scientists at the University of New Hampshire's (UNH's) Institute for the Study of the Earth, Oceans, and Space, a subcontractor to the project. Research performed for the project included development, calibration and validation of a regional climate model for the pan-Arctic, modeling river networks, extensive hydrologic database development, and analyses of the water cycle, based in part on the assembled databases and models. Details appear in publications produced from the grant

  18. Treatment Model in Children with Speech Disorders and Its Therapeutic Efficiency

    Directory of Open Access Journals (Sweden)

    Barberena, Luciana

    2014-05-01

    Full Text Available Introduction Speech articulation disorders affect the intelligibility of speech. Studies on therapeutic models show the effectiveness of the communication treatment. Objective To analyze the progress achieved by treatment with the ABAB—Withdrawal and Multiple Probes Model in children with different degrees of phonological disorders. Methods The diagnosis of speech articulation disorder was determined by speech and hearing evaluation and complementary tests. The subjects of this research were eight children, with the average age of 5:5. The children were distributed into four groups according to the degrees of the phonological disorders, based on the percentage of correct consonants, as follows: severe, moderate to severe, mild to moderate, and mild. The phonological treatment applied was the ABAB—Withdrawal and Multiple Probes Model. The development of the therapy by generalization was observed through the comparison between the two analyses: contrastive and distinctive features at the moment of evaluation and reevaluation. Results The following types of generalization were found: to the items not used in the treatment (other words, to another position in the word, within a sound class, to other classes of sounds, and to another syllable structure. Conclusion The different types of generalization studied showed the expansion of production and proper use of therapy-trained targets in other contexts or untrained environments. Therefore, the analysis of the generalizations proved to be an important criterion to measure the therapeutic efficacy.

  19. Therapeutic effect of angiogenesis inhibitor combined with radiotherapy on liver metastasis model of colon cancer

    International Nuclear Information System (INIS)

    Jin Liugen; Zhou Shifu

    2005-01-01

    Objective: To observe the therapeutic effect of angiogenesis inhibitor combined with radiotherapy on liver metastasis model of colon cancer. Methods: Nude mice liver metastasis model of colon cancer was established with human colon cancer cells line (LS174T) inoculated into mice' spleen and followed by splenectomy. Angiogenesis inhibitor 2-ME and radiotherapy were administered after-wads. The growth inhibition effect on metastases and neovessel was examined. Results: The incidences of liver metastasis were 100% in this intrasplenic injection model. The mean weight and microvessel density 4 weeks after inoculation were 53.6 ± 4.7 mg, 8.4 ± 1.7 in treatment group as compared to 173.9 ± 11.6 mg, 41.2 ± 6.3 in control group respectively. Conclusion: 2-ME combined with radiotherapy has significant inhibition on the growth of liver metastases. Angiogenesis inhibition is one of the mechanisms of its efficiency. (authors)

  20. Distress modeling for DARWin-ME : final report.

    Science.gov (United States)

    2013-12-01

    Distress prediction models, or transfer functions, are key components of the Pavement M-E Design and relevant analysis. The accuracy of such models depends on a successful process of calibration and subsequent validation of model coefficients in the ...

  1. Increased Plasma Colloid Osmotic Pressure Facilitates the Uptake of Therapeutic Macromolecules in a Xenograft Tumor Model

    Directory of Open Access Journals (Sweden)

    Matthias Hofmann

    2009-08-01

    Full Text Available Elevated tumor interstitial fluid pressure (TIFP is a characteristic of most solid tumors. Clinically, TIFP may hamper the uptake of chemotherapeutic drugs into the tumor tissue reducing their therapeutic efficacy. In this study, a means of modulating TIFP to increase the flux of macromolecules into tumor tissue is presented, which is based on the rationale that elevated plasma colloid osmotic pressure (COP pulls water from tumor interstitium lowering the TIFP. Concentrated human serum albumin: (20% HSA, used as an agent to enhance COP, reduced the TIFP time-dependently from 8 to 2 mm Hg in human tumor xenograft models bearing A431 epidermoid vulva carcinomas. To evaluate whether this reduction facilitates the uptake of macromolecules, the intratumoral distribution of fluorescently conjugated dextrans (2.5 mg/ml and cetuximab (2.0 mg/ml was probed using novel time domain nearinfrared fluorescence imaging. This method permitted discrimination and semiquantification of tumor-accumulated conjugate from background and unspecific probe fluorescence. The coadministration of 20% HSA together with either dextrans or cetuximab was found to lower the TIFP significantly and increase the concentration of the substances within the tumor tissue in comparison to control tumors. Furthermore, combined administration of 20%HSA plus cetuximab reduced the tumor growth significantly in comparison to standard cetuximab treatment. These data demonstrate that increased COP lowers the TIFP within hours and increases the uptake of therapeutic macromolecules into the tumor interstitium leading to reduced tumor growth. This model represents a novel approach to facilitate the delivery of therapeutics into tumor tissue, particularly monoclonal antibodies.

  2. Quantitative Phosphoproteomics Reveals Wee1 Kinase as a Therapeutic Target in a Model of Proneural Glioblastoma.

    Science.gov (United States)

    Lescarbeau, Rebecca S; Lei, Liang; Bakken, Katrina K; Sims, Peter A; Sarkaria, Jann N; Canoll, Peter; White, Forest M

    2016-06-01

    Glioblastoma (GBM) is the most common malignant primary brain cancer. With a median survival of about a year, new approaches to treating this disease are necessary. To identify signaling molecules regulating GBM progression in a genetically engineered murine model of proneural GBM, we quantified phosphotyrosine-mediated signaling using mass spectrometry. Oncogenic signals, including phosphorylated ERK MAPK, PI3K, and PDGFR, were found to be increased in the murine tumors relative to brain. Phosphorylation of CDK1 pY15, associated with the G2 arrest checkpoint, was identified as the most differentially phosphorylated site, with a 14-fold increase in phosphorylation in the tumors. To assess the role of this checkpoint as a potential therapeutic target, syngeneic primary cell lines derived from these tumors were treated with MK-1775, an inhibitor of Wee1, the kinase responsible for CDK1 Y15 phosphorylation. MK-1775 treatment led to mitotic catastrophe, as defined by increased DNA damage and cell death by apoptosis. To assess the extensibility of targeting Wee1/CDK1 in GBM, patient-derived xenograft (PDX) cell lines were also treated with MK-1775. Although the response was more heterogeneous, on-target Wee1 inhibition led to decreased CDK1 Y15 phosphorylation and increased DNA damage and apoptosis in each line. These results were also validated in vivo, where single-agent MK-1775 demonstrated an antitumor effect on a flank PDX tumor model, increasing mouse survival by 1.74-fold. This study highlights the ability of unbiased quantitative phosphoproteomics to reveal therapeutic targets in tumor models, and the potential for Wee1 inhibition as a treatment approach in preclinical models of GBM. Mol Cancer Ther; 15(6); 1332-43. ©2016 AACR. ©2016 American Association for Cancer Research.

  3. Multifactorial causal model of brain (dis)organization and therapeutic intervention: Application to Alzheimer's disease.

    Science.gov (United States)

    Iturria-Medina, Yasser; Carbonell, Félix M; Sotero, Roberto C; Chouinard-Decorte, Francois; Evans, Alan C

    2017-05-15

    Generative models focused on multifactorial causal mechanisms in brain disorders are scarce and generally based on limited data. Despite the biological importance of the multiple interacting processes, their effects remain poorly characterized from an integrative analytic perspective. Here, we propose a spatiotemporal multifactorial causal model (MCM) of brain (dis)organization and therapeutic intervention that accounts for local causal interactions, effects propagation via physical brain networks, cognitive alterations, and identification of optimum therapeutic interventions. In this article, we focus on describing the model and applying it at the population-based level for studying late onset Alzheimer's disease (LOAD). By interrelating six different neuroimaging modalities and cognitive measurements, this model accurately predicts spatiotemporal alterations in brain amyloid-β (Aβ) burden, glucose metabolism, vascular flow, resting state functional activity, structural properties, and cognitive integrity. The results suggest that a vascular dysregulation may be the most-likely initial pathologic event leading to LOAD. Nevertheless, they also suggest that LOAD it is not caused by a unique dominant biological factor (e.g. vascular or Aβ) but by the complex interplay among multiple relevant direct interactions. Furthermore, using theoretical control analysis of the identified population-based multifactorial causal network, we show the crucial advantage of using combinatorial over single-target treatments, explain why one-target Aβ based therapies might fail to improve clinical outcomes, and propose an efficiency ranking of possible LOAD interventions. Although still requiring further validation at the individual level, this work presents the first analytic framework for dynamic multifactorial brain (dis)organization that may explain both the pathologic evolution of progressive neurological disorders and operationalize the influence of multiple interventional

  4. Trehalose upregulates progranulin expression in human and mouse models of GRN haploinsufficiency: a novel therapeutic lead to treat frontotemporal dementia.

    Science.gov (United States)

    Holler, Christopher J; Taylor, Georgia; McEachin, Zachary T; Deng, Qiudong; Watkins, William J; Hudson, Kathryn; Easley, Charles A; Hu, William T; Hales, Chadwick M; Rossoll, Wilfried; Bassell, Gary J; Kukar, Thomas

    2016-06-24

    Progranulin (PGRN) is a secreted growth factor important for neuronal survival and may do so, in part, by regulating lysosome homeostasis. Mutations in the PGRN gene (GRN) are a common cause of frontotemporal lobar degeneration (FTLD) and lead to disease through PGRN haploinsufficiency. Additionally, complete loss of PGRN in humans leads to neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease. Importantly, Grn-/- mouse models recapitulate pathogenic lysosomal features of NCL. Further, GRN variants that decrease PGRN expression increase the risk of developing Alzheimer's disease (AD) and Parkinson's disease (PD). Together these findings demonstrate that insufficient PGRN predisposes neurons to degeneration. Therefore, compounds that increase PGRN levels are potential therapeutics for multiple neurodegenerative diseases. Here, we performed a cell-based screen of a library of known autophagy-lysosome modulators and identified multiple novel activators of a human GRN promoter reporter including several common mTOR inhibitors and an mTOR-independent activator of autophagy, trehalose. Secondary cellular screens identified trehalose, a natural disaccharide, as the most promising lead compound because it increased endogenous PGRN in all cell lines tested and has multiple reported neuroprotective properties. Trehalose dose-dependently increased GRN mRNA as well as intracellular and secreted PGRN in both mouse and human cell lines and this effect was independent of the transcription factor EB (TFEB). Moreover, trehalose rescued PGRN deficiency in human fibroblasts and neurons derived from induced pluripotent stem cells (iPSCs) generated from GRN mutation carriers. Finally, oral administration of trehalose to Grn haploinsufficient mice significantly increased PGRN expression in the brain. This work reports several novel autophagy-lysosome modulators that enhance PGRN expression and identifies trehalose as a promising therapeutic for raising PGRN levels to treat

  5. Mathematical modeling of tumor-induced immunosuppression by myeloid-derived suppressor cells: Implications for therapeutic targeting strategies.

    Science.gov (United States)

    Shariatpanahi, Seyed Peyman; Shariatpanahi, Seyed Pooya; Madjidzadeh, Keivan; Hassan, Moustapha; Abedi-Valugerdi, Manuchehr

    2018-04-07

    Myeloid-derived suppressor cells (MDSCs) belong to immature myeloid cells that are generated and accumulated during the tumor development. MDSCs strongly suppress the anti-tumor immunity and provide conditions for tumor progression and metastasis. In this study, we present a mathematical model based on ordinary differential equations (ODE) to describe tumor-induced immunosuppression caused by MDSCs. The model consists of four equations and incorporates tumor cells, cytotoxic T cells (CTLs), natural killer (NK) cells and MDSCs. We also provide simulation models that evaluate or predict the effects of anti-MDSC drugs (e.g., l-arginine and 5-Fluorouracil (5-FU)) on the tumor growth and the restoration of anti-tumor immunity. The simulated results obtained using our model were in good agreement with the corresponding experimental findings on the expansion of splenic MDSCs, immunosuppressive effects of these cells at the tumor site and effectiveness of l-arginine and 5-FU on the re-establishment of antitumor immunity. Regarding this latter issue, our predictive simulation results demonstrated that intermittent therapy with low-dose 5-FU alone could eradicate the tumors irrespective of their origins and types. Furthermore, at the time of tumor eradication, the number of CTLs prevailed over that of cancer cells and the number of splenic MDSCs returned to the normal levels. Finally, our predictive simulation results also showed that the addition of l-arginine supplementation to the intermittent 5-FU therapy reduced the time of the tumor eradication and the number of iterations for 5-FU treatment. Thus, the present mathematical model provides important implications for designing new therapeutic strategies that aim to restore antitumor immunity by targeting MDSCs. Copyright © 2018 Elsevier Ltd. All rights reserved.

  6. Simulation modeling analysis of sequential relations among therapeutic alliance, symptoms, and adherence to child-centered play therapy between a child with autism spectrum disorder and two therapists.

    Science.gov (United States)

    Goodman, Geoff; Chung, Hyewon; Fischel, Leah; Athey-Lloyd, Laura

    2017-07-01

    This study examined the sequential relations among three pertinent variables in child psychotherapy: therapeutic alliance (TA) (including ruptures and repairs), autism symptoms, and adherence to child-centered play therapy (CCPT) process. A 2-year CCPT of a 6-year-old Caucasian boy diagnosed with autism spectrum disorder was conducted weekly with two doctoral-student therapists, working consecutively for 1 year each, in a university-based community mental-health clinic. Sessions were video-recorded and coded using the Child Psychotherapy Process Q-Set (CPQ), a measure of the TA, and an autism symptom measure. Sequential relations among these variables were examined using simulation modeling analysis (SMA). In Therapist 1's treatment, unexpectedly, autism symptoms decreased three sessions after a rupture occurred in the therapeutic dyad. In Therapist 2's treatment, adherence to CCPT process increased 2 weeks after a repair occurred in the therapeutic dyad. The TA decreased 1 week after autism symptoms increased. Finally, adherence to CCPT process decreased 1 week after autism symptoms increased. The authors concluded that (1) sequential relations differ by therapist even though the child remains constant, (2) therapeutic ruptures can have an unexpected effect on autism symptoms, and (3) changes in autism symptoms can precede as well as follow changes in process variables.

  7. Utility of immunodeficient mouse models for characterizing the preclinical pharmacokinetics of immunogenic antibody therapeutics.

    Science.gov (United States)

    Myzithras, Maria; Bigwarfe, Tammy; Li, Hua; Waltz, Erica; Ahlberg, Jennifer; Giragossian, Craig; Roberts, Simon

    Prior to clinical studies, the pharmacokinetics (PK) of antibody-based therapeutics are characterized in preclinical species; however, those species can elicit immunogenic responses that can lead to an inaccurate estimation of PK parameters. Immunodeficient (SCID) transgenic hFcRn and C57BL/6 mice were used to characterize the PK of three antibodies that were previously shown to be immunogenic in mice and cynomolgus monkeys. Four mouse strains, Tg32 hFcRn SCID, Tg32 hFcRn, SCID and C57BL/6, were administered adalimumab (Humira®), mAbX and mAbX-YTE at 1 mg/kg, and in SCID strains there was no incidence of immunogenicity. In non-SCID strains, drug-clearing ADAs appeared after 4-7 days, which affected the ability to accurately calculate PK parameters. Single species allometric scaling of PK data for Humira® in SCID and hFcRn SCID mice resulted in improved human PK predictions compared to C57BL/6 mice. Thus, the SCID mouse model was demonstrated to be a useful tool for assessing the preclinical PK of immunogenic therapeutics.

  8. Therapeutic Potential of Umbilical Cord Blood Stem Cells on Brain Damage of a Model of Stroke

    Directory of Open Access Journals (Sweden)

    Mohammad Reza Nikravesh

    2011-11-01

    Full Text Available Introduction: Human cord blood-derived stem cells are a rich source of stem cells as well as precursors. With regard to the researchers have focused on the therapeutic potential of stem cell in the neurological disease such as stroke, the aim of this study was the investiga-tion of the therapeutic effects of human cord blood-derived stem cells in cerebral ischemia on rat. Methods: This study was carried out on young rats. Firstly, to create a laboratory model of ischemic stroke, carotid artery of animals was occluded for 30 minutes. Then, umbilical cord blood cells were isolated and labeled using bromodeoxyuridine and 2×105 cells were injected into the experimental group via the tail vein. Rats with hypoxic condi-tions were used as a sham group. A group of animals did not receive any injection or sur-geries were used as a control. Results: Obtained results were evaluated based on behavior-al responses and immunohistochemistry, with emphasis on areas of putamen and caudate nucleus in the control, sham and experimental groups. Our results indicated that behavioral recovery was observed in the experimental group compared to the either the sham or the control group. However, histological studies demonstrated a low percent of tissue injury in the experimental group in comparison with the sham group. Conclusion: Stem cell trans-plantation is beneficial for the brain tissue reparation after hypoxic ischemic cell death.

  9. A predictive mathematical model for the calculation of the final mass of Graves' disease thyroids treated with 131I

    Science.gov (United States)

    Traino, Antonio C.; Di Martino, Fabio; Grosso, Mariano; Monzani, Fabio; Dardano, Angela; Caraccio, Nadia; Mariani, Giuliano; Lazzeri, Mauro

    2005-05-01

    Substantial reductions in thyroid volume (up to 70-80%) after radioiodine therapy of Graves' hyperthyroidism are common and have been reported in the literature. A relationship between thyroid volume reduction and outcome of 131I therapy of Graves' disease has been reported by some authors. This important result could be used to decide individually the optimal radioiodine activity A0 (MBq) to administer to the patient, but a predictive model relating the change in gland volume to A0 is required. Recently, a mathematical model of thyroid mass reduction during the clearance phase (30-35 days) after 131I administration to patients with Graves' disease has been published and used as the basis for prescribing the therapeutic thyroid absorbed dose. It is well known that the thyroid volume reduction goes on until 1 year after therapy. In this paper, a mathematical model to predict the final mass of Graves' diseased thyroids submitted to 131I therapy is presented. This model represents a tentative explanation of what occurs macroscopically after the end of the clearance phase of radioiodine in the gland (the so-called second-order effects). It is shown that the final thyroid mass depends on its basal mass, on the radiation dose absorbed by the gland and on a constant value α typical of thyroid tissue. α has been evaluated based on a set of measurements made in 15 reference patients affected by Graves' disease and submitted to 131I therapy. A predictive equation for the calculation of the final mass of thyroid is presented. It is based on macroscopic parameters measurable after a diagnostic 131I capsule administration (0.37-1.85 MBq), before giving the therapy. The final mass calculated using this equation is compared to the final mass of thyroid measured 1 year after therapy administration in 22 Graves' diseased patients. The final masses calculated and measured 1 year after therapy are in fairly good agreement (R = 0.81). The possibility, for the physician, to decide a

  10. A predictive mathematical model for the calculation of the final mass of Graves' disease thyroids treated with 131I

    International Nuclear Information System (INIS)

    Traino, Antonio C; Martino, Fabio Di; Grosso, Mariano; Monzani, Fabio; Dardano, Angela; Caraccio, Nadia; Mariani, Giuliano; Lazzeri, Mauro

    2005-01-01

    Substantial reductions in thyroid volume (up to 70-80%) after radioiodine therapy of Graves' hyperthyroidism are common and have been reported in the literature. A relationship between thyroid volume reduction and outcome of 131 I therapy of Graves' disease has been reported by some authors. This important result could be used to decide individually the optimal radioiodine activity A 0 (MBq) to administer to the patient, but a predictive model relating the change in gland volume to A 0 is required. Recently, a mathematical model of thyroid mass reduction during the clearance phase (30-35 days) after 131 I administration to patients with Graves' disease has been published and used as the basis for prescribing the therapeutic thyroid absorbed dose. It is well known that the thyroid volume reduction goes on until 1 year after therapy. In this paper, a mathematical model to predict the final mass of Graves' diseased thyroids submitted to 131 I therapy is presented. This model represents a tentative explanation of what occurs macroscopically after the end of the clearance phase of radioiodine in the gland (the so-called second-order effects). It is shown that the final thyroid mass depends on its basal mass, on the radiation dose absorbed by the gland and on a constant value α typical of thyroid tissue. α has been evaluated based on a set of measurements made in 15 reference patients affected by Graves' disease and submitted to 131 I therapy. A predictive equation for the calculation of the final mass of thyroid is presented. It is based on macroscopic parameters measurable after a diagnostic 131 I capsule administration (0.37-1.85 MBq), before giving the therapy. The final mass calculated using this equation is compared to the final mass of thyroid measured 1 year after therapy administration in 22 Graves' diseased patients. The final masses calculated and measured 1 year after therapy are in fairly good agreement (R = 0.81). The possibility, for the physician, to

  11. Dynamic process model of a plutonium oxalate precipitator. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Miller, C.L.; Hammelman, J.E.; Borgonovi, G.M.

    1977-11-01

    In support of LLL material safeguards program, a dynamic process model was developed which simulates the performance of a plutonium (IV) oxalate precipitator. The plutonium oxalate precipitator is a component in the plutonium oxalate process for making plutonium oxide powder from plutonium nitrate. The model is based on state-of-the-art crystallization descriptive equations, the parameters of which are quantified through the use of batch experimental data. The dynamic model predicts performance very similar to general Hanford oxalate process experience. The utilization of such a process model in an actual plant operation could promote both process control and material safeguards control by serving as a baseline predictor which could give early warning of process upsets or material diversion. The model has been incorporated into a FORTRAN computer program and is also compatible with the DYNSYS 2 computer code which is being used at LLL for process modeling efforts.

  12. Dynamic process model of a plutonium oxalate precipitator. Final report

    International Nuclear Information System (INIS)

    Miller, C.L.; Hammelman, J.E.; Borgonovi, G.M.

    1977-11-01

    In support of LLL material safeguards program, a dynamic process model was developed which simulates the performance of a plutonium (IV) oxalate precipitator. The plutonium oxalate precipitator is a component in the plutonium oxalate process for making plutonium oxide powder from plutonium nitrate. The model is based on state-of-the-art crystallization descriptive equations, the parameters of which are quantified through the use of batch experimental data. The dynamic model predicts performance very similar to general Hanford oxalate process experience. The utilization of such a process model in an actual plant operation could promote both process control and material safeguards control by serving as a baseline predictor which could give early warning of process upsets or material diversion. The model has been incorporated into a FORTRAN computer program and is also compatible with the DYNSYS 2 computer code which is being used at LLL for process modeling efforts

  13. Mathematical Models of Elementary Mathematics Learning and Performance. Final Report.

    Science.gov (United States)

    Suppes, Patrick

    This project was concerned with the development of mathematical models of elementary mathematics learning and performance. Probabilistic finite automata and register machines with a finite number of registers were developed as models and extensively tested with data arising from the elementary-mathematics strand curriculum developed by the…

  14. Regional forecasting with global atmospheric models; Final report

    Energy Technology Data Exchange (ETDEWEB)

    Crowley, T.J.; Smith, N.R. [Applied Research Corp., College Station, TX (United States)

    1994-05-01

    The purpose of the project was to conduct model simulations for past and future climate change with respect to the proposed Yucca Mtn. repository. The authors report on three main topics, one of which is boundary conditions for paleo-hindcast studies. These conditions are necessary for the conduction of three to four model simulations. The boundary conditions have been prepared for future runs. The second topic is (a) comparing the atmospheric general circulation model (GCM) with observations and other GCMs; and (b) development of a better precipitation data base for the Yucca Mtn. region for comparisons with models. These tasks have been completed. The third topic is preliminary assessments of future climate change. Energy balance model (EBM) simulations suggest that the greenhouse effect will likely dominate climate change at Yucca Mtn. for the next 10,000 years. The EBM study should improve rational choice of GCM CO{sub 2} scenarios for future climate change.

  15. Experimental Models of Status Epilepticus and Neuronal Injury for Evaluation of Therapeutic Interventions

    Directory of Open Access Journals (Sweden)

    Ramkumar Kuruba

    2013-09-01

    Full Text Available This article describes current experimental models of status epilepticus (SE and neuronal injury for use in the screening of new therapeutic agents. Epilepsy is a common neurological disorder characterized by recurrent unprovoked seizures. SE is an emergency condition associated with continuous seizures lasting more than 30 min. It causes significant mortality and morbidity. SE can cause devastating damage to the brain leading to cognitive impairment and increased risk of epilepsy. Benzodiazepines are the first-line drugs for the treatment of SE, however, many people exhibit partial or complete resistance due to a breakdown of GABA inhibition. Therefore, new drugs with neuroprotective effects against the SE-induced neuronal injury and degeneration are desirable. Animal models are used to study the pathophysiology of SE and for the discovery of newer anticonvulsants. In SE paradigms, seizures are induced in rodents by chemical agents or by electrical stimulation of brain structures. Electrical stimulation includes perforant path and self-sustaining stimulation models. Pharmacological models include kainic acid, pilocarpine, flurothyl, organophosphates and other convulsants that induce SE in rodents. Neuronal injury occurs within the initial SE episode, and animals exhibit cognitive dysfunction and spontaneous seizures several weeks after this precipitating event. Current SE models have potential applications but have some limitations. In general, the experimental SE model should be analogous to the human seizure state and it should share very similar neuropathological mechanisms. The pilocarpine and diisopropylfluorophosphate models are associated with prolonged, diazepam-insensitive seizures and neurodegeneration and therefore represent paradigms of refractory SE. Novel mechanism-based or clinically relevant models are essential to identify new therapies for SE and neuroprotective interventions.

  16. Therapeutic activity of two xanthones in a xenograft murine model of human chronic lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    Berthou Christian

    2010-12-01

    Full Text Available Abstract Background We previously reported that allanxanthone C and macluraxanthone, two xanthones purified from Guttiferae trees, display in vitro antiproliferative and proapoptotic activities in leukemic cells from chronic lymphocytic leukemia (CLL and leukemia B cell lines. Results Here, we investigated the in vivo therapeutic effects of the two xanthones in a xenograft murine model of human CLL, developed by engrafting CD5-transfected chronic leukemia B cells into SCID mice. Treatment of the animals with five daily injections of either allanxanthone C or macluraxanthone resulted in a significant prolongation of their survival as compared to control animals injected with the solvent alone (p = 0.0006 and p = 0.0141, respectively. The same treatment of mice which were not xenografted induced no mortality. Conclusion These data show for the first time the in vivo antileukemic activities of two plant-derived xanthones, and confirm their potential interest for CLL therapy.

  17. Defining New Therapeutics Using a More Immunocompetent Mouse Model of Antibody-Enhanced Dengue Virus Infection.

    Science.gov (United States)

    Pinto, Amelia K; Brien, James D; Lam, Chia-Ying Kao; Johnson, Syd; Chiang, Cindy; Hiscott, John; Sarathy, Vanessa V; Barrett, Alan D; Shresta, Sujan; Diamond, Michael S

    2015-09-15

    With over 3.5 billion people at risk and approximately 390 million human infections per year, dengue virus (DENV) disease strains health care resources worldwide. Previously, we and others established models for DENV pathogenesis in mice that completely lack subunits of the receptors (Ifnar and Ifngr) for type I and type II interferon (IFN) signaling; however, the utility of these models is limited by the pleotropic effect of these cytokines on innate and adaptive immune system development and function. Here, we demonstrate that the specific deletion of Ifnar expression on subsets of murine myeloid cells (LysM Cre(+) Ifnar(flox/flox) [denoted as Ifnar(f/f) herein]) resulted in enhanced DENV replication in vivo. The administration of subneutralizing amounts of cross-reactive anti-DENV monoclonal antibodies to LysM Cre(+) Ifnar(f/f) mice prior to infection with DENV serotype 2 or 3 resulted in antibody-dependent enhancement (ADE) of infection with many of the characteristics associated with severe DENV disease in humans, including plasma leakage, hypercytokinemia, liver injury, hemoconcentration, and thrombocytopenia. Notably, the pathogenesis of severe DENV-2 or DENV-3 infection in LysM Cre(+) Ifnar(f/f) mice was blocked by pre- or postexposure administration of a bispecific dual-affinity retargeting molecule (DART) or an optimized RIG-I receptor agonist that stimulates innate immune responses. Our findings establish a more immunocompetent animal model of ADE of infection with multiple DENV serotypes in which disease is inhibited by treatment with broad-spectrum antibody derivatives or innate immune stimulatory agents. Although dengue virus (DENV) infects hundreds of millions of people annually and results in morbidity and mortality on a global scale, there are no approved antiviral treatments or vaccines. Part of the difficulty in evaluating therapeutic candidates is the lack of small animal models that are permissive to DENV and recapitulate the clinical features

  18. Mechanistic Systems Modeling to Improve Understanding and Prediction of Cardiotoxicity Caused by Targeted Cancer Therapeutics

    Directory of Open Access Journals (Sweden)

    Jaehee V. Shim

    2017-09-01

    Full Text Available Tyrosine kinase inhibitors (TKIs are highly potent cancer therapeutics that have been linked with serious cardiotoxicity, including left ventricular dysfunction, heart failure, and QT prolongation. TKI-induced cardiotoxicity is thought to result from interference with tyrosine kinase activity in cardiomyocytes, where these signaling pathways help to control critical processes such as survival signaling, energy homeostasis, and excitation–contraction coupling. However, mechanistic understanding is limited at present due to the complexities of tyrosine kinase signaling, and the wide range of targets inhibited by TKIs. Here, we review the use of TKIs in cancer and the cardiotoxicities that have been reported, discuss potential mechanisms underlying cardiotoxicity, and describe recent progress in achieving a more systematic understanding of cardiotoxicity via the use of mechanistic models. In particular, we argue that future advances are likely to be enabled by studies that combine large-scale experimental measurements with Quantitative Systems Pharmacology (QSP models describing biological mechanisms and dynamics. As such approaches have proven extremely valuable for understanding and predicting other drug toxicities, it is likely that QSP modeling can be successfully applied to cardiotoxicity induced by TKIs. We conclude by discussing a potential strategy for integrating genome-wide expression measurements with models, illustrate initial advances in applying this approach to cardiotoxicity, and describe challenges that must be overcome to truly develop a mechanistic and systematic understanding of cardiotoxicity caused by TKIs.

  19. The therapeutic effect of PLAG against oral mucositis in hamster and mouse model

    Directory of Open Access Journals (Sweden)

    Ha-Reum Lee

    2016-10-01

    Full Text Available Chemotherapy-induced mucositis can limit the effectiveness of cancer therapy and increase the risk of infections. However, no specific therapy for protection against mucositis is currently available. In this study, we investigated the therapeutic effect of PLAG (1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol, acetylated diglyceride in 5-fluorouracil (5-FU-induced oral mucositis animal models. Hamsters were administered 5-FU (80 mg/kg intraperitoneally on days 0, 6, and 9. The animals’ cheek pouches were then scratched equally with the tip of an 18-gauge needle on days 1, 2, and 7. PLAG was administered daily at 250 mg/kg/day. PLAG administration significantly reduced 5-FU/scratching–induced mucositis. Dramatic reversal of weight loss in PLAG-treated hamsters with mucositis was observed. Histochemical staining data also revealed newly differentiated epidermis and blood vessels in the cheek pouches of PLAG-treated hamsters, indicative of recovery. Whole blood analyses indicated that PLAG prevents 5-FU–induced excessive neutrophil transmigration to the infection site and eventually stabilizes the number of circulating neutrophils. In a mouse mucositis model, mice with 5-FU–induced disease treated with PLAG exhibited resistance to body-weight loss compared with mice that received 5-FU or 5-FU/scratching alone. PLAG also dramatically reversed mucositis-associated weight loss and inhibited mucositis-induced inflammatory responses in the tongue and serum. These data suggest that PLAG enhances recovery from 5-FU–induced oral mucositis and may therefore be a useful therapeutic agent for treating side effects of chemotherapy, such as mucositis and cachexia.

  20. Ultrasound enhanced delivery of molecular imaging and therapeutic agents in Alzheimer's disease mouse models.

    Directory of Open Access Journals (Sweden)

    Scott B Raymond

    Full Text Available Alzheimer's disease is a neurodegenerative disorder typified by the accumulation of a small protein, beta-amyloid, which aggregates and is the primary component of amyloid plaques. Many new therapeutic and diagnostic agents for reducing amyloid plaques have limited efficacy in vivo because of poor transport across the blood-brain barrier. Here we demonstrate that low-intensity focused ultrasound with a microbubble contrast agent may be used to transiently disrupt the blood-brain barrier, allowing non-invasive, localized delivery of imaging fluorophores and immunotherapeutics directly to amyloid plaques. We administered intravenous Trypan blue, an amyloid staining red fluorophore, and anti-amyloid antibodies, concurrently with focused ultrasound therapy in plaque-bearing, transgenic mouse models of Alzheimer's disease with amyloid pathology. MRI guidance permitted selective treatment and monitoring of plaque-heavy anatomical regions, such as the hippocampus. Treated brain regions exhibited 16.5+/-5.4-fold increase in Trypan blue fluorescence and 2.7+/-1.2-fold increase in anti-amyloid antibodies that localized to amyloid plaques. Ultrasound-enhanced delivery was consistently reproduced in two different transgenic strains (APPswe:PSEN1dE9, PDAPP, across a large age range (9-26 months, with and without MR guidance, and with little or no tissue damage. Ultrasound-mediated, transient blood-brain barrier disruption allows the delivery of both therapeutic and molecular imaging agents in Alzheimer's mouse models, which should aid pre-clinical drug screening and imaging probe development. Furthermore, this technique may be used to deliver a wide variety of small and large molecules to the brain for imaging and therapy in other neurodegenerative diseases.

  1. Predictive Software Cost Model Study. Volume I. Final Technical Report.

    Science.gov (United States)

    1980-06-01

    development phase to identify computer resources necessary to support computer programs after transfer of program manangement responsibility and system... classical model development with refinements specifically applicable to avionics systems. The refinements are the result of the Phase I literature search

  2. Modeling future power plant location patterns. Final report

    International Nuclear Information System (INIS)

    Eagles, T.W.; Cohon, J.L.; ReVelle, C.

    1979-04-01

    The locations of future energy facilities must be specified to assess the potential environmental impact of those facilities. A computer model was developed to generate probable locations for the energy facilities needed to meet postulated future energy requirements. The model is designed to cover a very large geographical region. The regional demand for baseload electric generating capacity associated with a postulated demand growth rate over any desired time horizon is specified by the user as an input to the model. The model uses linear programming to select the most probable locations within the region, based on physical and political factors. The linear program is multi-objective, with four objective functions based on transmission, coal supply, population proximity, and water supply considerations. Minimizing each objective function leads to a distinct set of locations. The user can select the objective function or weighted combination of objective functions most appropriate to his interest. Users with disparate interests can use the model to see the locational changes which result from varying weighting of the objective functions. The model has been implemented in a six-state mid-Atlantic region. The year 2000 was chosen as the study year, and a test scenario postulating 2.25% growth in baseload generating capacity between 1977 and 2000 was chosen. The scenario stipulatedthat this capacity be 50% nuclear and 50% coal-fired. Initial utility reaction indicates the objective based on transmission costs is most important for such a large-scale analysis

  3. Neuroprotective and Therapeutic Effect of Caffeine on the Rat Model of Parkinson's Disease Induced by Rotenone.

    Science.gov (United States)

    Khadrawy, Yasser A; Salem, Ahmed M; El-Shamy, Karima A; Ahmed, Emad K; Fadl, Nevein N; Hosny, Eman N

    2017-09-03

    The present study aimed to investigate the protective and therapeutic effects of caffeine on rotenone-induced rat model of Parkinson's disease (PD). Rats were divided into control, PD model induced by rotenone (1.5 mg/kg intraperitoneally (i.p.) for 45 days), protected group injected with caffeine (30 mg/kg, i.p.) and rotenone for 45 days (during the development of PD model), and treated group injected with caffeine (30 mg/kg, i.p.) for 45 days after induction of PD model. The data revealed a state of oxidative and nitrosative stress in the midbrain and the striatum of animal model of PD as indicated from the increased lipid peroxidation and nitric oxide levels and the decreased reduced glutathione level and activities of glutathione-S-transferase and superoxide dismutase. Rotenone induced a decrease in acetylcholinesterase and Na + /K + -ATPase activities and an increase in tumor necrosis factor-α level in the midbrain and the striatum. Protection and treatment with caffeine ameliorated the oxidative stress and the changes in acetylcholinesterase and Na + /K + -ATPase activities induced by rotenone in the midbrain and the striatum. This was associated with improvement in the histopathological changes induced in the two areas of PD model. Caffeine protection and treatment restored the depletion of midbrain and striatal dopamine induced by rotenone and prevented decline in motor activities (assessed by open field test) and muscular strength (assessed by traction and hanging tests) and improved norepinephrine level in the two areas. The present study showed that caffeine offered a significant neuroprotection and treatment against neurochemical, histopathological, and behavioral changes in a rotenone-induced rat model of PD.

  4. Predictive markers of efficacy for an angiopoietin-2 targeting therapeutic in xenograft models.

    Directory of Open Access Journals (Sweden)

    Gallen Triana-Baltzer

    Full Text Available The clinical efficacy of anti-angiogenic therapies has been difficult to predict, and biomarkers that can predict responsiveness are sorely needed in this era of personalized medicine. CVX-060 is an angiopoietin-2 (Ang2 targeting therapeutic, consisting of two peptides that bind Ang2 with high affinity and specificity, covalently fused to a scaffold antibody. In order to optimize the use of this compound in the clinic the construction of a predictive model is described, based on the efficacy of CVX-060 in 13 cell line and 2 patient-derived xenograft models. Pretreatment size tumors from each of the models were profiled for the levels of 27 protein markers of angiogenesis, SNP haplotype in 5 angiogenesis genes, and somatic mutation status for 11 genes implicated in tumor growth and/or vascularization. CVX-060 efficacy was determined as tumor growth inhibition (TGI% at termination of each study. A predictive statistical model was constructed based on the correlation of these efficacy data with the marker profiles, and the model was subsequently tested by prospective analysis in 11 additional models. The results reveal a range of CVX-060 efficacy in xenograft models of diverse tissue types (0-64% TGI, median = 27% and define a subset of 3 proteins (Ang1, EGF, Emmprin, the levels of which may be predictive of TGI by Ang2 blockade. The direction of the associations is such that better efficacy correlates with high levels of target and low levels of compensatory/antagonizing molecules. This effort has revealed a set of candidate predictive markers for CVX-060 efficacy that will be further evaluated in ongoing clinical trials.

  5. Alligator Rivers Analogue project. Hydrogeological modelling. Final Report - Volume 6

    International Nuclear Information System (INIS)

    Townley, L.R.; Trefry, M.G.; Barr, A.D.; Braumiller, S.

    1992-01-01

    This volume describes hydrogeological modelling carried out as part of the Alligator Rivers Analogue Project. Hydrogeology has played a key integrating role in the Project, largely because water movement is believed to have controlled the evolution of the Koongarra uranium Orebody and therefore affects field observations of all types at all scales. Aquifer testing described uses the concept of transmissivity in its interpretation of aquifer response to pumping. The concept of an aquifer, a layer transmitting significant quantities of water in a mainly horizontal direction, seems hard to accept in an environment as heterogeneous as that at Koongarra. But modelling of aquifers both in one dimension and two dimensionally in plan has contributed significantly to our understanding of the site. A one-dimensional model with three layers (often described as a quasi two dimensional model) was applied to flow between the Fault and Koongarra Creek. Being a transient model, this model was able to show that reverse flows can indeed occur back towards the Fault, but only if there is distributed recharge over the orebody as well as a mechanism for the Fault, or a region near the Fault, to remove water from the simulated cross-section. The model also showed clearly that the response of the three-layered system, consisting of a highly weathered zone, a fractured transmissive zone and a less conductive lower schist zone, is governed mainly by the transmissivity and storage coefficient of the middle layer. The storage coefficient of the higher layer has little effect. A two-dimensional model in plan used a description of anisotropy to show that reverse flows can also occur even without a conducting Fault. Modelling of a three-dimensional region using discrete fractures showed that it is certainly possible to simulate systems like that observed at Koongarra, but that large amounts of data are probably needed to obtain realistic descriptions of the fracture networks. Inverse modelling

  6. Alligator Rivers Analogue project. Hydrogeological modelling. Final Report - Volume 6

    Energy Technology Data Exchange (ETDEWEB)

    Townley, L R; Trefry, M G; Barr, A D [CSIRO Div of Water Resources, PO Wembley, WA (Australia); Braumiller, S [Univ of Arizona, Tucson, AZ (United States). Dept of Hydrology and Water Resources; Kawanishi, M [Central Research Institute of Electric Power Industry, Abiko-Shi, Chiba-Ken (Japan); and others

    1993-12-31

    This volume describes hydrogeological modelling carried out as part of the Alligator Rivers Analogue Project. Hydrogeology has played a key integrating role in the Project, largely because water movement is believed to have controlled the evolution of the Koongarra uranium Orebody and therefore affects field observations of all types at all scales. Aquifer testing described uses the concept of transmissivity in its interpretation of aquifer response to pumping. The concept of an aquifer, a layer transmitting significant quantities of water in a mainly horizontal direction, seems hard to accept in an environment as heterogeneous as that at Koongarra. But modelling of aquifers both in one dimension and two dimensionally in plan has contributed significantly to our understanding of the site. A one-dimensional model with three layers (often described as a quasi two dimensional model) was applied to flow between the Fault and Koongarra Creek. Being a transient model, this model was able to show that reverse flows can indeed occur back towards the Fault, but only if there is distributed recharge over the orebody as well as a mechanism for the Fault, or a region near the Fault, to remove water from the simulated cross-section. The model also showed clearly that the response of the three-layered system, consisting of a highly weathered zone, a fractured transmissive zone and a less conductive lower schist zone, is governed mainly by the transmissivity and storage coefficient of the middle layer. The storage coefficient of the higher layer has little effect. A two-dimensional model in plan used a description of anisotropy to show that reverse flows can also occur even without a conducting Fault. Modelling of a three-dimensional region using discrete fractures showed that it is certainly possible to simulate systems like that observed at Koongarra, but that large amounts of data are probably needed to obtain realistic descriptions of the fracture networks. Inverse modelling

  7. Systems Perturbation Analysis of a Large-Scale Signal Transduction Model Reveals Potentially Influential Candidates for Cancer Therapeutics

    Science.gov (United States)

    Puniya, Bhanwar Lal; Allen, Laura; Hochfelder, Colleen; Majumder, Mahbubul; Helikar, Tomáš

    2016-01-01

    -related components and tumor-suppressor genes, suggesting that this combinatorial perturbation may lead to a better target for decreasing cell proliferation and inducing apoptosis. Finally, our approach shows a potential to identify and prioritize therapeutic targets through systemic perturbation analysis of large-scale computational models of signal transduction. Although some components of the presented computational results have been validated against independent gene expression data sets, more laboratory experiments are warranted to more comprehensively validate the presented results. PMID:26904540

  8. Modeling Results For the ITER Cryogenic Fore Pump. Final Report

    Energy Technology Data Exchange (ETDEWEB)

    Pfotenhauer, John M. [University of Wisconsin, Madison, WI (United States); Zhang, Dongsheng [University of Wisconsin, Madison, WI (United States)

    2014-03-31

    A numerical model characterizing the operation of a cryogenic fore-pump (CFP) for ITER has been developed at the University of Wisconsin – Madison during the period from March 15, 2011 through June 30, 2014. The purpose of the ITER-CFP is to separate hydrogen isotopes from helium gas, both making up the exhaust components from the ITER reactor. The model explicitly determines the amount of hydrogen that is captured by the supercritical-helium-cooled pump as a function of the inlet temperature of the supercritical helium, its flow rate, and the inlet conditions of the hydrogen gas flow. Furthermore the model computes the location and amount of hydrogen captured in the pump as a function of time. Throughout the model’s development, and as a calibration check for its results, it has been extensively compared with the measurements of a CFP prototype tested at Oak Ridge National Lab. The results of the model demonstrate that the quantity of captured hydrogen is very sensitive to the inlet temperature of the helium coolant on the outside of the cryopump. Furthermore, the model can be utilized to refine those tests, and suggests methods that could be incorporated in the testing to enhance the usefulness of the measured data.

  9. A new emergency response model for MACCS. Final report

    International Nuclear Information System (INIS)

    Chanin, D.I.

    1992-01-01

    Under DOE sponsorship, as directed by the Los Alamos National Laboratory (LANL), the MACCS code (version 1.5.11.1) [Ch92] was modified to implement a series of improvements in its modeling of emergency response actions. The purpose of this effort has been to aid the Westinghouse Savannah River Company (WSRC) in its performance of the Level III analysis for the Savannah River Site (SRS) probabilistic risk analysis (PRA) of K Reactor [Wo90]. To ensure its usefulness to WSRC, and facilitate the new model's eventual merger with other MACCS enhancements, close cooperation with WSRC and the MACCS development team at Sandia National Laboratories (SNL) was maintained throughout the project. These improvements are intended to allow a greater degree of flexibility in modeling the mitigative actions of evacuation and sheltering. The emergency response model in MACCS version 1.5.11.1 was developed to support NRC analyses of consequences from severe accidents at commercial nuclear power plants. The NRC code imposes unnecessary constraints on DOE safety analyses, particularly for consequences to onsite worker populations, and it has therefore been revamped. The changes to the code have been implemented in a manner that preserves previous modeling capabilities and therefore prior analyses can be repeated with the new code

  10. Model of the final borehole geometry for helical laser drilling

    Science.gov (United States)

    Kroschel, Alexander; Michalowski, Andreas; Graf, Thomas

    2018-05-01

    A model for predicting the borehole geometry for laser drilling is presented based on the calculation of a surface of constant absorbed fluence. It is applicable to helical drilling of through-holes with ultrashort laser pulses. The threshold fluence describing the borehole surface is fitted for best agreement with experimental data in the form of cross-sections of through-holes of different shapes and sizes in stainless steel samples. The fitted value is similar to ablation threshold fluence values reported for laser ablation models.

  11. Patient-Centered Prescription Model to improve therapeutic adherence in patients with multimorbidity

    Directory of Open Access Journals (Sweden)

    Javier González-Bueno

    2018-05-01

    Full Text Available To date, interventions to improve medication adherence in patients with multimorbidity have shown modest and inconsistent efficacy among available studies. Thereby, we should define new approaches aimed at improving medication adherence tailored to effective prescribing, with a multidisciplinary approach and patient-centered. In this regard, the Patient-Centered Prescription Model has shown its usefulness on improving appropriateness of drug treatments in patients with clinical complexity. For that, this strategy addresses the following four steps: 1 Patient-Centered assessment; 2 Diagnosis-Centered assessment; 3 Medication-Centered assessment; and 4 Therapeutic Plan. We propose through a clinical case an adaptation of the Patient-Centered Prescription Model to enhance both appropriateness and medication adherence in patients with multimorbidity. To this end, we have included on its first step the Spanish version of a cross-culturally adapted scale for the multidimensional assessment of medication adherence. Furthermore, we suggest a set of interventions to be applied in the three remaining steps of the model. These interventions were firstly identified by an overview of systematic reviews and then selected by a panel of experts based on Delphi methodology. All of these elements have been considered appropriate in patients with multimorbidity according to three criteria: strength of their supporting evidence, usefulness in the target population and feasibility of implementation in clinical practice. The proposed approach intends to lay the foundations for an innovative way in tackling medication adherence in patients with multimorbidity.

  12. Therapeutic effect of frankincense in a rat model of Alzheimer’s disease

    Directory of Open Access Journals (Sweden)

    Siamak Beheshti

    2016-06-01

    Full Text Available Objective: Frankincense improves memory in different models of learning. However, its influence on models of Alzheimer's disease (AD has not been studied widely. In the present study, the therapeutic effect of frankincense was evaluated in a model of AD induced by i.c.v administration of streptozotocin. Materials and Methods: Under stereotaxic surgery, two guide cannulas were implanted in the lateral ventricles of adult male Wistar rats weighing 230-270 g. One group received streptozotocin (1.5 mg/kg/2μl/side bilaterally on the first and third day of surgery. Another group received artificial cerebro-spinal fluid. Fourteen days after surgery, learning was evaluated using the passive avoidance paradigm. Four other groups of animals received frankincense (50 mg/kg or its solvent after establishment of AD for 21 or 42 consecutive days, and then, memory retrieval was assessed. Results: Streptozotocin increased the number of stimulations required for induction of short-term memory and decreased step-through latency on the test day, significantly (p

  13. Dendritic cell-based vaccination in cancer: therapeutic implications emerging from murine models

    Directory of Open Access Journals (Sweden)

    Soledad eMac Keon

    2015-05-01

    Full Text Available Dendritic cells (DCs play a pivotal role in the orchestration of immune responses, and are thus key targets in cancer vaccine design. Since the 2010 FDA approval of the first cancer DC-based vaccine (Sipuleucel T there has been a surge of interest in exploiting these cells as a therapeutic option for the treatment of tumors of diverse origin. In spite of the encouraging results obtained in the clinic, many elements of DC-based vaccination strategies need to be optimized. In this context, the use of experimental cancer models can help direct efforts towards an effective vaccine design. This paper reviews recent findings in murine models regarding the antitumoral mechanisms of DC-based vaccination, covering issues related to antigen sources, the use of adjuvants and maturing agents, and the role of DC subsets and their interaction in the initiation of antitumoral immune responses. The summary of such diverse aspects will highlight advantages and drawbacks in the use of murine models, and contribute to the design of successful DC-based translational approaches for cancer treatment.

  14. The Role of Aggregates of Therapeutic Protein Products in Immunogenicity: An Evaluation by Mathematical Modeling

    Directory of Open Access Journals (Sweden)

    Liusong Yin

    2015-01-01

    Full Text Available Therapeutic protein products (TPP have been widely used to treat a variety of human diseases, including cancer, hemophilia, and autoimmune diseases. However, TPP can induce unwanted immune responses that can impact both drug efficacy and patient safety. The presence of aggregates is of particular concern as they have been implicated in inducing both T cell-independent and T cell-dependent immune responses. We used mathematical modeling to evaluate several mechanisms through which aggregates of TPP could contribute to the development of immunogenicity. Modeling interactions between aggregates and B cell receptors demonstrated that aggregates are unlikely to induce T cell-independent immune responses by cross-linking B cell receptors because the amount of signal transducing complex that can form under physiologically relevant conditions is limited. We systematically evaluate the role of aggregates in inducing T cell-dependent immune responses using a recently developed multiscale mechanistic mathematical model. Our analysis indicates that aggregates could contribute to T cell-dependent immune response by inducing high affinity epitopes which may not be present in the nonaggregated TPP and/or by enhancing danger signals to break tolerance. In summary, our computational analysis is suggestive of novel insights into the mechanisms underlying aggregate-induced immunogenicity, which could be used to develop mitigation strategies.

  15. Diagnostic modeling of the ARM experimental configuration. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Somerville, R.C.J.

    1998-04-01

    A major accomplishment of this work was to demonstrate the viability of using in-situ data in both mid-continent North America (SGP CART site) and Tropical Western Pacific (TOGA-COARE) locations to provide the horizontal advective flux convergences which force and constrain the Single-Column Model (SCM) which was the main theoretical tool of this work. The author has used TOGA-COARE as a prototype for the ARM TWP site. Results show that SCMs can produce realistic budgets over the ARM sites without relying on parameterization-dependent operational numerical weather prediction objective analyses. The single-column model is diagnostic rather than prognostic. It is numerically integrated in time as an initial value problem which is forced and constrained by observational data. The input is an observed initial state, plus observationally derived estimates of the time-dependent advection terms in the conservation equations, provided at all model layers. Its output is a complete heat and water budget, including temperature and moisture profiles, clouds and their radiative properties, diabatic heating terms, surface energy balance components, and hydrologic cycle elements, all specified as functions of time. These SCM results should be interpreted in light of the original motivation and purpose of ARM and its goal to improve the treatment of cloud-radiation interactions in climate models.

  16. Efforts - Final technical report on task 4. Physical modelling calidation

    DEFF Research Database (Denmark)

    Andreasen, Jan Lasson; Olsson, David Dam; Christensen, T. W.

    The present report is documentation for the work carried out in Task 4 at DTU Physical modelling-validation on the Brite/Euram project No. BE96-3340, contract No. BRPR-CT97-0398, with the title Enhanced Framework for forging design using reliable three-dimensional simulation (EFFORTS). The report...

  17. Traffic congestion forecasting model for the INFORM System. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Azarm, A.; Mughabghab, S.; Stock, D.

    1995-05-01

    This report describes a computerized traffic forecasting model, developed by Brookhaven National Laboratory (BNL) for a portion of the Long Island INFORM Traffic Corridor. The model has gone through a testing phase, and currently is able to make accurate traffic predictions up to one hour forward in time. The model will eventually take on-line traffic data from the INFORM system roadway sensors and make projections as to future traffic patterns, thus allowing operators at the New York State Department of Transportation (D.O.T.) INFORM Traffic Management Center to more optimally manage traffic. It can also form the basis of a travel information system. The BNL computer model developed for this project is called ATOP for Advanced Traffic Occupancy Prediction. The various modules of the ATOP computer code are currently written in Fortran and run on PC computers (pentium machine) faster than real time for the section of the INFORM corridor under study. The following summarizes the various routines currently contained in the ATOP code: Statistical forecasting of traffic flow and occupancy using historical data for similar days and time (long term knowledge), and the recent information from the past hour (short term knowledge). Estimation of the empirical relationships between traffic flow and occupancy using long and short term information. Mechanistic interpolation using macroscopic traffic models and based on the traffic flow and occupancy forecasted (item-1), and the empirical relationships (item-2) for the specific highway configuration at the time of simulation (construction, lane closure, etc.). Statistical routine for detection and classification of anomalies and their impact on the highway capacity which are fed back to previous items.

  18. Transplantation of autologous adipose stem cells lacks therapeutic efficacy in the experimental autoimmune encephalomyelitis model.

    Directory of Open Access Journals (Sweden)

    Xiujuan Zhang

    Full Text Available Multiple sclerosis (MS, characterized by chronic inflammation, demyelination, and axonal damage, is a complicated neurological disease of the human central nervous system. Recent interest in adipose stromal/stem cell (ASCs for the treatment of CNS diseases has promoted further investigation in order to identify the most suitable ASCs. To investigate whether MS affects the biologic properties of ASCs and whether autologous ASCs from MS-affected sources could serve as an effective source for stem cell therapy, cells were isolated from subcutaneous inguinal fat pads of mice with established experimental autoimmune encephalomyelitis (EAE, a murine model of MS. ASCs from EAE mice and their syngeneic wild-type mice were cultured, expanded, and characterized for their cell morphology, surface antigen expression, osteogenic and adipogenic differentiation, colony forming units, and inflammatory cytokine and chemokine levels in vitro. Furthermore, the therapeutic efficacy of the cells was assessed in vivo by transplantation into EAE mice. The results indicated that the ASCs from EAE mice displayed a normal phenotype, typical MSC surface antigen expression, and in vitro osteogenic and adipogenic differentiation capacity, while their osteogenic differentiation capacity was reduced in comparison with their unafflicted control mice. The ASCs from EAE mice also demonstrated increased expression of pro-inflammatory cytokines and chemokines, specifically an elevation in the expression of monocyte chemoattractant protein-1 and keratin chemoattractant. In vivo, infusion of wild type ASCs significantly ameliorate the disease course, autoimmune mediated demyelination and cell infiltration through the regulation of the inflammatory responses, however, mice treated with autologous ASCs showed no therapeutic improvement on the disease progression.

  19. Final Report: Center for Programming Models for Scalable Parallel Computing

    Energy Technology Data Exchange (ETDEWEB)

    Mellor-Crummey, John [William Marsh Rice University

    2011-09-13

    As part of the Center for Programming Models for Scalable Parallel Computing, Rice University collaborated with project partners in the design, development and deployment of language, compiler, and runtime support for parallel programming models to support application development for the “leadership-class” computer systems at DOE national laboratories. Work over the course of this project has focused on the design, implementation, and evaluation of a second-generation version of Coarray Fortran. Research and development efforts of the project have focused on the CAF 2.0 language, compiler, runtime system, and supporting infrastructure. This has involved working with the teams that provide infrastructure for CAF that we rely on, implementing new language and runtime features, producing an open source compiler that enabled us to evaluate our ideas, and evaluating our design and implementation through the use of benchmarks. The report details the research, development, findings, and conclusions from this work.

  20. Computational modeling of drug-resistant bacteria. Final report

    International Nuclear Information System (INIS)

    2015-01-01

    Initial proposal summary: The evolution of antibiotic-resistant mutants among bacteria (superbugs) is a persistent and growing threat to public health. In many ways, we are engaged in a war with these microorganisms, where the corresponding arms race involves chemical weapons and biological targets. Just as advances in microelectronics, imaging technology and feature recognition software have turned conventional munitions into smart bombs, the long-term objectives of this proposal are to develop highly effective antibiotics using next-generation biomolecular modeling capabilities in tandem with novel subatomic feature detection software. Using model compounds and targets, our design methodology will be validated with correspondingly ultra-high resolution structure-determination methods at premier DOE facilities (single-crystal X-ray diffraction at Argonne National Laboratory, and neutron diffraction at Oak Ridge National Laboratory). The objectives and accomplishments are summarized.

  1. Computational modeling of drug-resistant bacteria. Final report

    Energy Technology Data Exchange (ETDEWEB)

    MacDougall, Preston [Middle Tennessee State Univ., Murfreesboro, TN (United States)

    2015-03-12

    Initial proposal summary: The evolution of antibiotic-resistant mutants among bacteria (superbugs) is a persistent and growing threat to public health. In many ways, we are engaged in a war with these microorganisms, where the corresponding arms race involves chemical weapons and biological targets. Just as advances in microelectronics, imaging technology and feature recognition software have turned conventional munitions into smart bombs, the long-term objectives of this proposal are to develop highly effective antibiotics using next-generation biomolecular modeling capabilities in tandem with novel subatomic feature detection software. Using model compounds and targets, our design methodology will be validated with correspondingly ultra-high resolution structure-determination methods at premier DOE facilities (single-crystal X-ray diffraction at Argonne National Laboratory, and neutron diffraction at Oak Ridge National Laboratory). The objectives and accomplishments are summarized.

  2. Advanced numerical modelling of a fire. Final report

    International Nuclear Information System (INIS)

    Heikkilae, L.; Keski-Rahkonen, O.

    1996-03-01

    Experience and probabilistic risk assessments show that fires present a major hazard in a nuclear power plant (NPP). The PALOME project (1988-92) improved the quality of numerical simulation of fires to make it a useful tool for fire safety analysis. Some of the most advanced zone model fire simulation codes were acquired. The performance of the codes was studied through literature and personal interviews in earlier studies and BRI2 code from the Japanese Building Research Institute was selected for further use. In PALOME 2 project this work was continued. Information obtained from large-scale fire tests at the German HDR facility allowed reliable prediction of the rate of heat release and was used for code validation. BRI2 code was validated particularly by participation in the CEC standard problem 'Prediction of effects caused by a cable fire experiment within the HDR-facility'. Participation in the development of a new field model code SOFIE specifically for fire applications as British-Swedish-Finnish cooperation was one of the goals of the project. SOFIE code was implemented at VTT and the first results of validation simulations were obtained. Well instrumented fire tests on electronic cabinets were carried out to determine source terms for simulation of room fires and to estimate fire spread to adjacent cabinets. The particular aim of this study was to measure the rate of heat release from a fire in an electronic cabinet. From the three tests, differing mainly in the amount of the fire load, data was obtained for source terms in numerical modelling of fires in rooms containing electronic cabinets. On the basis of these tests also a simple natural ventilation model was derived. (19 refs.)

  3. Theory, Modeling and Simulation Annual Report 2000; FINAL

    International Nuclear Information System (INIS)

    Dixon, David A; Garrett, Bruce C; Straatsma, TP; Jones, Donald R; Studham, Scott; Harrison, Robert J; Nichols, Jeffrey A

    2001-01-01

    This annual report describes the 2000 research accomplishments for the Theory, Modeling, and Simulation (TM and S) directorate, one of the six research organizations in the William R. Wiley Environmental Molecular Sciences Laboratory (EMSL) at Pacific Northwest National Laboratory (PNNL). EMSL is a U.S. Department of Energy (DOE) national scientific user facility and is the centerpiece of the DOE commitment to providing world-class experimental, theoretical, and computational capabilities for solving the nation's environmental problems

  4. Experimental Benchmarking of Fire Modeling Simulations. Final Report

    International Nuclear Information System (INIS)

    Greiner, Miles; Lopez, Carlos

    2003-01-01

    A series of large-scale fire tests were performed at Sandia National Laboratories to simulate a nuclear waste transport package under severe accident conditions. The test data were used to benchmark and adjust the Container Analysis Fire Environment (CAFE) computer code. CAFE is a computational fluid dynamics fire model that accurately calculates the heat transfer from a large fire to a massive engulfed transport package. CAFE will be used in transport package design studies and risk analyses

  5. Mathematical modeling of the voloxidation process. Final report

    International Nuclear Information System (INIS)

    Stanford, T.G.

    1979-06-01

    A mathematical model of the voloxidation process, a head-end reprocessing step for the removal of volatile fission products from spent nuclear fuel, has been developed. Three types of voloxidizer operation have been considered; co-current operation in which the gas and solid streams flow in the same direction, countercurrent operation in which the gas and solid streams flow in opposite directions, and semi-batch operation in which the gas stream passes through the reactor while the solids remain in it and are processed batch wise. Because of the complexity of the physical ahd chemical processes which occur during the voloxidation process and the lack of currently available kinetic data, a global kinetic model has been adapted for this study. Test cases for each mode of operation have been simulated using representative values of the model parameters. To process 714 kgm/day of spent nuclear fuel, using an oxidizing atmosphere containing 20 mole percent oxygen, it was found that a reactor 0.7 m in diameter and 2.49 m in length would be required for both cocurrent and countercurrent modes of operation while for semibatch operation a 0.3 m 3 reactor and an 88200 sec batch processing time would be required

  6. Modelling the cancer growth process by Stochastic Differential Equations with the effect of Chondroitin Sulfate (CS) as anticancer therapeutics

    Science.gov (United States)

    Syahidatul Ayuni Mazlan, Mazma; Rosli, Norhayati; Jauhari Arief Ichwan, Solachuddin; Suhaity Azmi, Nina

    2017-09-01

    A stochastic model is introduced to describe the growth of cancer affected by anti-cancer therapeutics of Chondroitin Sulfate (CS). The parameters values of the stochastic model are estimated via maximum likelihood function. The numerical method of Euler-Maruyama will be employed to solve the model numerically. The efficiency of the stochastic model is measured by comparing the simulated result with the experimental data.

  7. Neuroprotective efficacy and therapeutic window of curcuma oil: in rat embolic stroke model

    Science.gov (United States)

    Dohare, Preeti; Garg, Puja; sharma, Uma; Jagannathan, NR; Ray, Madhur

    2008-01-01

    Background Among the naturally occurring compounds, turmeric from the dried rhizome of the plant Curcuma longa has long been used extensively as a condiment and a household remedy all over Southeast Asia. Turmeric contains essential oil, yellow pigments (curcuminoids), starch and oleoresin. The present study was designed for investigating the neuroprotective efficacy and the time window for effective therapeutic use of Curcuma oil (C. oil). Method In the present study, the effect of post ischemic treatment of C.oil after ischemia induced by occlusion of the middle cerebral artery in the rat was observed. C.oil (500 mg/kg body wt) was given 4 hrs post ischemia. The significant effect on lesion size as visualized by using diffusion-weighted magnetic resonance imaging and neuroscore was still evident when treatment was started 4 hours after insult. Animals were assessed for behavioral deficit scores after 5 and 24 hours of ischemia. Subsequently, the rats were sacrificed for evaluation of infarct and edema volumes and other parameters. Results C.oil ameliorated the ischemia induced neurological functional deficits and the infarct and edema volumes measured after 5 and 24 hrs of ischemia. After 24 hrs, immunohistochemical and Western blot analysis demonstrated that the expression of iNOS, cytochrome c and Bax/Bcl-2 were altered after the insult, and antagonized by treatment with C.oil. C.oil significantly reduced nitrosative stress, tended to correct the decreased mitochondrial membrane potential, and also affected caspase-3 activation finally apoptosis. Conclusion Here we demonstrated that iNOS-derived NO produced during ischemic injury was crucial for the up-regulation of ischemic injury targets. C.oil down-regulates these targets this coincided with an increased survival rate of neurons. PMID:18826584

  8. Therapeutic effects of D-aspartate in a mouse model of multiple sclerosis

    Directory of Open Access Journals (Sweden)

    Sanaz Afraei

    2017-07-01

    Full Text Available Experimental autoimmune encephalomyelitis (EAE is an animal model of multiple sclerosis. EAE is mainly mediated by adaptive and innate immune responses that leads to an inflammatory demyelization and axonal damage. The aim of the present research was to examine the therapeutic efficacy of D-aspartic acid (D-Asp on a mouse EAE model. EAE induction was performed in female C57BL/6 mice by myelin 40 oligodendrocyte glycoprotein (35-55 in a complete Freund's adjuvant emulsion, and D-Asp was used to test its efficiency in the reduction of EAE. During the course of study, clinical evaluation was assessed, and on Day 21, post-immunization blood samples were taken from the heart of mice for the evaluation of interleukin 6 and other chemical molecules. The mice were sacrificed, and their brain and cerebellum were removed for histological analysis. Our findings indicated that D-Asp had beneficial effects on EAE by attenuation in the severity and delay in the onset of the disease. Histological analysis showed that treatment with D-Asp can reduce inflammation. Moreover, in D-Asp-treated mice, the serum level of interleukin 6 was significantly lower than that in control animals, whereas the total antioxidant capacity was significantly higher. The data indicates that D-Asp possess neuroprotective property to prevent the onset of the multiple sclerosis.

  9. Final model independent result of DAMA/LIBRA-phase1

    Energy Technology Data Exchange (ETDEWEB)

    Bernabei, R.; D' Angelo, S.; Di Marco, A. [Universita di Roma ' ' Tor Vergata' ' , Dipartimento di Fisica, Rome (Italy); INFN, sez. Roma ' ' Tor Vergata' ' , Rome (Italy); Belli, P. [INFN, sez. Roma ' ' Tor Vergata' ' , Rome (Italy); Cappella, F.; D' Angelo, A.; Prosperi, D. [Universita di Roma ' ' La Sapienza' ' , Dipartimento di Fisica, Rome (Italy); INFN, sez. Roma, Rome (Italy); Caracciolo, V.; Castellano, S.; Cerulli, R. [INFN, Laboratori Nazionali del Gran Sasso, Assergi (Italy); Dai, C.J.; He, H.L.; Kuang, H.H.; Ma, X.H.; Sheng, X.D.; Wang, R.G. [Chinese Academy, IHEP, Beijing (China); Incicchitti, A. [INFN, sez. Roma, Rome (Italy); Montecchia, F. [INFN, sez. Roma ' ' Tor Vergata' ' , Rome (Italy); Universita di Roma ' ' Tor Vergata' ' , Dipartimento di Ingegneria Civile e Ingegneria Informatica, Rome (Italy); Ye, Z.P. [Chinese Academy, IHEP, Beijing (China); University of Jing Gangshan, Jiangxi (China)

    2013-12-15

    The results obtained with the total exposure of 1.04 ton x yr collected by DAMA/LIBRA-phase1 deep underground at the Gran Sasso National Laboratory (LNGS) of the I.N.F.N. during 7 annual cycles (i.e. adding a further 0.17 ton x yr exposure) are presented. The DAMA/LIBRA-phase1 data give evidence for the presence of Dark Matter (DM) particles in the galactic halo, on the basis of the exploited model independent DM annual modulation signature by using highly radio-pure NaI(Tl) target, at 7.5{sigma} C.L. Including also the first generation DAMA/NaI experiment (cumulative exposure 1.33 ton x yr, corresponding to 14 annual cycles), the C.L. is 9.3{sigma} and the modulation amplitude of the single-hit events in the (2-6) keV energy interval is: (0.0112{+-}0.0012) cpd/kg/keV; the measured phase is (144{+-}7) days and the measured period is (0.998{+-}0.002) yr, values well in agreement with those expected for DM particles. No systematic or side reaction able to mimic the exploited DM signature has been found or suggested by anyone over more than a decade. (orig.)

  10. Modelling and Evaluation of Aircraft Emissions. Final report

    International Nuclear Information System (INIS)

    Savola, M.

    1996-01-01

    An application was developed to calculate the emissions and fuel consumption of a jet and turboprop powered aircraft in Finnair's scheduled and charter traffic both globally and in the Finnish flight information regions. The emissions calculated are nitrogen oxides, unburnt hydrocarbons and carbon monoxide. The study is based on traffic statistics of one week taken from three scheduled periods in 1993. Each flight was studied by dividing the flight profile into sections. The flight profile data are based on aircraft manufacturers' manuals, and they serve as initial data for engine manufacturers' emission calculation programs. In addition, the study includes separate calculations on air traffic emissions at airports during the so-called LTO cycle. The fuel consumption calculated for individual flights is 419,395 tonnes globally, and 146,142 tonnes in the Finnish flight information regions. According to Finnair's statistics the global fuel consumption is 0.97-fold compared with the result given by the model. The results indicate that in 1993 the global nitrogen oxide emissions amounted to 5,934 tonnes, the unburnt hydrocarbon emissions totalled 496 tonnes and carbon monoxide emissions 1,664 tonnes. The corresponding emissions in the Finnish flight information regions were as follows: nitrogen oxides 2,105 tonnes, unburnt hydrocarbons 177 tonnes and carbon monoxide 693 tonnes. (orig.)

  11. Community Earth System Model (CESM) Tutorial 2016 Final Report

    Energy Technology Data Exchange (ETDEWEB)

    Lamarque, Jean-Francois [Univ. Corporation for Atmospheric Research (UCAR) and National Center for Atmospheric Research (NCAR) and Climate and Global Dynamics Laboratory (CGD), Boulder, CO (United States)

    2017-05-09

    For the 2016 tutorial, NCAR/CGD requested a total budget of $70,000 split equally between DOE and NSF. The funds were used to support student participation (travel, lodging, per diem, etc.). Lectures and practical session support was primarily provided by local participants at no additional cost (see list below). The seventh annual Community Earth System Model (CESM) tutorial (2016) for students and early career scientists was held 8 – 12 August 2016. As has been the case over the last few years, this event was extremely successful and there was greater demand than could be met. There was continued interest in support of the NSF’s EaSM Infrastructure awards, to train these awardees in the application of the CESM. Based on suggestions from previous tutorial participants, the 2016 tutorial experience again provided direct connection to Yellowstone for each individual participant (rather than pairs), and used the NCAR Mesa Library. The 2016 tutorial included lectures on simulating the climate system and practical sessions on running CESM, modifying components, and analyzing data. These were targeted to the graduate student level. In addition, specific talks (“Application” talks) were introduced this year to provide participants with some in-depth knowledge of some specific aspects of CESM.

  12. An experimental Toxoplasma gondii dose response challenge model to study therapeutic or vaccine efficacy in cats.

    Directory of Open Access Journals (Sweden)

    Jan B W J Cornelissen

    Full Text Available High numbers of Toxoplasma gondii oocysts in the environment are a risk factor to humans. The environmental contamination might be reduced by vaccinating the definitive host, cats. An experimental challenge model is necessary to quantitatively assess the efficacy of a vaccine or drug treatment. Previous studies have indicated that bradyzoites are highly infectious for cats. To infect cats, tissue cysts were isolated from the brains of mice infected with oocysts of T. gondii M4 strain, and bradyzoites were released by pepsin digestion. Free bradyzoites were counted and graded doses (1000, 100, 50, 10, and 250 intact tissue cysts were inoculated orally into three cats each. Oocysts shed by these five groups of cats were collected from faeces by flotation techniques, counted microscopically and estimated by real time PCR. Additionally, the number of T. gondii in heart, tongue and brains were estimated, and serology for anti T. gondii antibodies was performed. A Beta-Poisson dose-response model was used to estimate the infectivity of single bradyzoites and linear regression was used to determine the relation between inoculated dose and numbers of oocyst shed. We found that real time PCR was more sensitive than microscopic detection of oocysts, and oocysts were detected by PCR in faeces of cats fed 10 bradyzoites but by microscopic examination. Real time PCR may only detect fragments of T. gondii DNA without the presence of oocysts in low doses. Prevalence of tissue cysts of T. gondii in tongue, heart and brains, and anti T. gondii antibody concentrations were all found to depend on the inoculated bradyzoite dose. The combination of the experimental challenge model and the dose response analysis provides a suitable reference for quantifying the potential reduction in human health risk due to a treatment of domestic cats by vaccination or by therapeutic drug application.

  13. In vitro validation of bioluminescent monitoring of disease progression and therapeutic response in leukaemia model animals

    International Nuclear Information System (INIS)

    Inoue, Yusuke; Okubo, Toshiyuki; Tojo, Arinobu; Sekine, Rieko; Soda, Yasushi; Kobayashi, Seiichiro; Nomura, Akiko; Izawa, Kiyoko; Kitamura, Toshio; Ohtomo, Kuni

    2006-01-01

    The application of in vivo bioluminescence imaging to non-invasive, quantitative monitoring of tumour models relies on a positive correlation between the intensity of bioluminescence and the tumour burden. We conducted cell culture studies to investigate the relationship between bioluminescent signal intensity and viable cell numbers in murine leukaemia model cells. Interleukin-3 (IL-3)-dependent murine pro-B cell line Ba/F3 was transduced with firefly luciferase to generate cells expressing luciferase stably under the control of a retroviral long terminal repeat. The luciferase-expressing cells were transduced with p190 BCR-ABL to give factor-independent proliferation. The cells were cultured under various conditions, and bioluminescent signal intensity was compared with viable cell numbers and the cell cycle stage. The Ba/F3 cells showed autonomous growth as well as stable luciferase expression following transduction with both luciferase and p190 BCR-ABL, and in vivo bioluminescence imaging permitted external detection of these cells implanted into mice. The bioluminescence intensities tended to reflect cell proliferation and responses to imatinib in cell culture studies. However, the luminescence per viable cell was influenced by the IL-3 concentration in factor-dependent cells and by the stage of proliferation and imatinib concentration in factor-independent cells, thereby impairing the proportionality between viable cell number and bioluminescent signal intensity. Luminescence per cell tended to vary in association with the fraction of proliferating cells. Although in vivo bioluminescence imaging would allow non-invasive monitoring of leukaemia model animals, environmental factors and therapeutic interventions may cause some discrepancies between tumour burden and bioluminescence intensity. (orig.)

  14. Effective Classroom Management and Instruction: An Exploration of Models. Executive Summary of Final Report.

    Science.gov (United States)

    Evertson, Carolyn M.; And Others

    A summary is presented of the final report, "Effective Classroom Management and Instruction: An Exploration of Models." The final report presents a set of linked investigations of the effects of training teachers in effective classroom management practices in a series of school-based workshops. Four purposes were addressed by the study: (1) to…

  15. A final size relation for epidemic models of vector-transmitted diseases

    OpenAIRE

    Fred Brauer

    2017-01-01

    We formulate and analyze an age of infection model for epidemics of diseases transmitted by a vector, including the possibility of direct transmission as well. We show how to determine a basic reproduction number. While there is no explicit final size relation as for diseases transmitted directly, we are able to obtain estimates for the final size of the epidemic.

  16. [Caffeine: traditional and new therapeutic indications and use as a dermatological model drug].

    Science.gov (United States)

    Bors, Luca; Bajza, Ágnes; Kocsis, Dorottya; Erdő, Franciska

    2018-03-01

    Coffee consumption had already been described in the 15th century. The spreading of coffee drinking was not only a consequence of its delicious aromatic taste, but also of its pharmacological effects, especially due to its caffeine content. In this review, the mechanisms behind its complex stimulatory effects and the latest studies on the possible new therapeutic indications of caffeine are summarized. Several papers reported the neuroprotective (in Alzheimer's and Parkinson's disease) and hepatoprotective profiles of caffeine, and we show the most promising new results about its preventive properties in dermal malignancies. These findings were described both in cell cultures and in vivo. The application of caffeine and coffee in cosmetology and dermatological products is based on their antioxidant property and on the above-mentioned beneficial effects. Caffeine is also presented here as a dermatological model drug due to its hydrophilic profile. It can be used for designing and comparing different novel drug formulations, although beside the transcellular route, the follicular and transappendageal pathways play also important roles in its skin penetration. Taken together, caffeine molecule has many recently discovered beneficial pharmacological effects, but one should be careful with its excessive consumption. It can result in several adverse events if overdosed and in case of regular intake of high doses, after abandonment, withdrawal symptoms may appear. Orv Hetil. 2018; 159(10): 384-390.

  17. Constraint based modeling of metabolism allows finding metabolic cancer hallmarks and identifying personalized therapeutic windows.

    Science.gov (United States)

    Bordel, Sergio

    2018-04-13

    In order to choose optimal personalized anticancer treatments, transcriptomic data should be analyzed within the frame of biological networks. The best known human biological network (in terms of the interactions between its different components) is metabolism. Cancer cells have been known to have specific metabolic features for a long time and currently there is a growing interest in characterizing new cancer specific metabolic hallmarks. In this article it is presented a method to find personalized therapeutic windows using RNA-seq data and Genome Scale Metabolic Models. This method is implemented in the python library, pyTARG. Our predictions showed that the most anticancer selective (affecting 27 out of 34 considered cancer cell lines and only 1 out of 6 healthy mesenchymal stem cell lines) single metabolic reactions are those involved in cholesterol biosynthesis. Excluding cholesterol biosynthesis, all the considered cell lines can be selectively affected by targeting different combinations (from 1 to 5 reactions) of only 18 metabolic reactions, which suggests that a small subset of drugs or siRNAs combined in patient specific manners could be at the core of metabolism based personalized treatments.

  18. Dapoxetine: An Innovative Approach in the Therapeutic Management In Animal Model of Depression

    Directory of Open Access Journals (Sweden)

    Hira Rafi

    2016-01-01

    Full Text Available Stress is a complicated condition that effects on person’s mental and physical health, and it is the precursor of other psychological disorders mainly depression. Serotonin (5-Hydroxytryptamine; 5-HT is well known to have hypofunction in unpredictable chronic mild stress whereas, unpredictable chronic mild stress (UCMS has produced the most steady and continuous results of anhedonia and learned helplessness particularly in rats. The stress-induced depressive like behavior can be reversed by many antidepressants such as SSRIs. Selective serotonin [5-hydroxytryptamine (5-HT] reuptake inhibitors (SSRIs is mostly prescribed antidepressant that can deplete neurochemical and behavioral deficits. The present study was designed to investigate whether repeated administration of dapoxetine at dose (1.0 mg/kg could reverse the behavioral deficits induced by UCMS in rat model of depression. UCMS induced behavioral deficits. Locomotor  activity in familiar environment (home cage, novel (open field environment and anxiolytic behavior in light/dark activity box were greater in unstressed group than stressed group. The inhibition of serotonin reuptake at pre-synaptic receptors by repeated dapoxetine administration is mainly the mechanism involved and discussed. This particular study may assist in novel approach for understanding the interaction between stress and behavioral functions and extending the therapeutic use of dapoxetine.

  19. Neural stem cells for disease modeling of Wolman disease and evaluation of therapeutics.

    Science.gov (United States)

    Aguisanda, Francis; Yeh, Charles D; Chen, Catherine Z; Li, Rong; Beers, Jeanette; Zou, Jizhong; Thorne, Natasha; Zheng, Wei

    2017-06-28

    Wolman disease (WD) is a rare lysosomal storage disorder that is caused by mutations in the LIPA gene encoding lysosomal acid lipase (LAL). Deficiency in LAL function causes accumulation of cholesteryl esters and triglycerides in lysosomes. Fatality usually occurs within the first year of life. While an enzyme replacement therapy has recently become available, there is currently no small-molecule drug treatment for WD. We have generated induced pluripotent stem cells (iPSCs) from two WD patient dermal fibroblast lines and subsequently differentiated them into neural stem cells (NSCs). The WD NSCs exhibited the hallmark disease phenotypes of neutral lipid accumulation, severely deficient LAL activity, and increased LysoTracker dye staining. Enzyme replacement treatment dramatically reduced the WD phenotype in these cells. In addition, δ-tocopherol (DT) and hydroxypropyl-beta-cyclodextrin (HPBCD) significantly reduced lysosomal size in WD NSCs, and an enhanced effect was observed in DT/HPBCD combination therapy. The results demonstrate that these WD NSCs are valid cell-based disease models with characteristic disease phenotypes that can be used to evaluate drug efficacy and screen compounds. DT and HPBCD both reduce LysoTracker dye staining in WD cells. The cells may be used to further dissect the pathology of WD, evaluate compound efficacy, and serve as a platform for high-throughput drug screening to identify new compounds for therapeutic development.

  20. Preclinical models for an innovative glioblastoma therapeutical strategy by 188Re-SSS encapsulated in nano-tools: translational view

    International Nuclear Information System (INIS)

    Cikankowitz, A.; Belloche, C.; Verger, E.; Garcion, E.; Hindre, F.; Chassain, G.; Fellah, B.; Abadie, J.; Chouin, N.; Ibisch, C.; Davodeau, F.; Couez, D.; Lepareur, N.; Lacoeuille, F.; Menei, P.

    2015-01-01

    Full text of publication follows. Aim: Glioblastoma (GBM) is the most frequent cancer of the nervous system and therapies currently used cannot treat definitively this disease. By the way of NucSan (Nuclear for health) program which supports research development about the use of radio pharmaceutics in oncology, the aim of the proposed work is to provide evidences that internal radiotherapy through lipid nanocapsules loaded with Rhenium-188 (LNC 188 Re-SSS) is an alternative therapeutic strategy for GBM that can be translated to human medicine. Previous works have shown a remarkable efficiency of this tool among syngeneic rats linked with local and peripheral recruitments of the immune system's effectors. In this context, two animal models have been chosen to validate the feasibility of this new innovative therapy design (LNC 188 Re-SSS stereotactic injection). Materials and methods: the syngeneic six weeks old C57BL/6J female mice were treated 6 or 12 days after stereotactic GL261 cells implantation, by a single injection of increasing activities of LNC 188 Re-SSS (0,925; 1,85 and 2,7 MBq/5μl). MRI was used to follow tumor progression to determine the mass volume through the selection of regions of interest. The increased median survival time (IMST) was also assessed for treated mice versus control mice (stereotactic injection of saline solution). For long time survival animals (3 times the median survival time), they were rechallenged through the same procedure in the other hemisphere. The brachy-cephalic dog bearing spontaneous tumor will lead to additional evidences to specifically highlight the potential of this innovative technology for GBM treatment. In order to validate procedures of intracerebral injections, a stereotactic head frame specially designed for dog has been conceived which allow both images acquisition (MRI-SPECT and PET) and the achievement of biopsies. Results/Perspectives: as previously observed on rat models, the preliminary data show

  1. Therapeutic effects of topical doxycycline in a benzalkonium chloride-induced mouse dry eye model.

    Science.gov (United States)

    Zhang, Zhen; Yang, Wen-Zhao; Zhu, Zhen-Zhen; Hu, Qian-Qian; Chen, Yan-Feng; He, Hui; Chen, Yong-Xiong; Liu, Zu-Guo

    2014-05-06

    We investigated the therapeutic effects and underlying mechanisms of topical doxycycline in a benzalkonium chloride (BAC)-induced mouse dry eye model. Eye drops containing 0.025%, 0.1% doxycycline or solvent were administered to a BAC-induced dry eye model four times daily. The clinical evaluations, including tear break-up time (BUT), fluorescein staining, inflammatory index, and tear volume, were performed on days 0, 1, 4, 7, and 10. Global specimens were collected on day 10 and processed for immunofluorescent staining, TUNEL, and periodic acid-Schiff assay. The levels of inflammatory mediators in the corneas were determined by real-time PCR. The total and phosphorylated nuclear factor-κB (NF-κB) were detected by Western blot. Both 0.025% and 0.1% doxycycline treatments resulted in increased BUT, lower fluorescein staining scores, and inflammatory index on days 4, 7, and 10, while no significant change in tear volume was observed. The 0.1% doxycycline-treated group showed more improvements in decreasing fluorescein staining scores, increasing Ki-67-positive cells, and decreasing TUNEL- and keratin-10-positive cells than other groups. The mucin-filled goblet cells in conjunctivas were increased, and the expression of CD11b and levels of matrix metalloproteinase-9, IL-1β, IL-6, TNF-α, macrophage inflammatory protein-2, and cytokine-induced neutrophil chemoattractant in corneas were decreased in both doxycycline-treated groups. In addition, doxycycline significantly reduced the phosphorylation of NF-κB activated in the BAC-treated corneas. Topical doxycycline showed clinical improvements and alleviated ocular surface inflammation on BAC-induced mouse dry eye, suggesting a potential as an anti-inflammatory agent in the clinical treatment of dry eye.

  2. Validation of limited sampling models (LSM) for estimating AUC in therapeutic drug monitoring - is a separate validation group required?

    NARCIS (Netherlands)

    Proost, J. H.

    Objective: Limited sampling models (LSM) for estimating AUC in therapeutic drug monitoring are usually validated in a separate group of patients, according to published guidelines. The aim of this study is to evaluate the validation of LSM by comparing independent validation with cross-validation

  3. Model Orlando regionally efficient travel management coordination center (MORE TMCC), phase II : final report.

    Science.gov (United States)

    2012-09-01

    The final report for the Model Orlando Regionally Efficient Travel Management Coordination Center (MORE TMCC) presents the details of : the 2-year process of the partial deployment of the original MORE TMCC design created in Phase I of this project...

  4. Concise review : Developing best-practice models for the therapeutic use of extracellular vesicles

    NARCIS (Netherlands)

    Reiner, Agnes T.; Witwer, Kenneth W.; Van Balkom, Bas W.M.; De Beer, Joel; Brodie, Chaya; Corteling, Randolph L.; Gabrielsson, Susanne; Gimona, Mario; Ibrahim, Ahmed G.; De Kleijn, Dominique; Lai, Charles P.; Tvall, Jan Lo; Del Portillo, Hernando A; Reischl, Ilona G; Riazifar, Milad; Salomon, Carlos; Tahara, Hidetoshi; Toh, Wei Seong; Wauben, Marca H M; Yang, Vicky K.; Yang, Yijun; Yeo, Ronne Wee Yeh; Yin, Hang; Giebel, Bernd; Rohde, Eva; Lim, Sai Kiang

    2017-01-01

    Growing interest in extracellular vesicles (EVs, including exosomes and microvesicles) as therapeutic entities, particularly in stem cell-related approaches, has underlined the need for standardization and coordination of development efforts. Members of the International Society for Extracellular

  5. Incorporation of FcRn-mediated disposition model to describe the population pharmacokinetics of therapeutic monoclonal IgG antibody in clinical patients.

    Science.gov (United States)

    Ng, Chee M

    2016-03-01

    The two-compartment linear model used to describe the population pharmacokinetics (PK) of many therapeutic monoclonal antibodies (TMAbs) offered little biological insight to antibody disposition in humans. The purpose of this study is to develop a semi-mechanistic FcRn-mediated IgG disposition model to describe the population PK of TMAbs in clinical patients. A standard two-compartment linear PK model from a previously published population PK model of pertuzumab was used to simulate intensive PK data of 100 subjects for model development. Two different semi-mechanistic FcRn-mediated IgG disposition models were developed and First Order Conditional Estimation (FOCE) with the interaction method in NONMEM was used to obtain the final model estimates. The performances of these models were then compared with the two-compartment linear PK model used to simulate the data for model development. A semi-mechanistic FcRn-mediated IgG disposition model consisting of a peripheral tissue compartment and FcRn-containing endosomes in the central compartment best describes the simulated pertuzumab population PK data. This developed semi-mechanistic population PK model had the same number of model parameters, produced very similar concentration-time profiles but provided additional biological insight to the FcRn-mediated IgG disposition in human subjects compared with the standard linear two-compartment linear PK model. This first reported semi-mechanistic model may serve as an important model framework for developing future population PK models of TMAbs in clinical patients. Copyright © 2015 John Wiley & Sons, Ltd.

  6. Therapeutic efficacy of fibroblast growth factor 10 in a rabbit model of dry eye.

    Science.gov (United States)

    Zheng, Wenjing; Ma, Mingming; Du, Ergang; Zhang, Zhengwei; Jiang, Kelimu; Gu, Qing; Ke, Bilian

    2015-11-01

    The aim of the present study was to investigate the therapeutic efficacy of fibroblast growth factor 10 (FGF10) in the promotion of healing, survival and expression of mucin in corneal epithelial cells in a rabbit dry eye model. A total of 12 healthy female New Zealand white rabbits were divided randomly into three groups. The lacrimal glands were injected with saline either alone (normal control group) or with concanavalin A (Con A), with either topical phosphate‑buffered saline (PBS; PBS control group) or 25 µg/ml FGF10 (FGF10 treatment group). Lacrimal gland inflammation, tear function, corneal epithelial cell integrity, cell apoptosis and mucin expression were subsequently assessed. Lacrimal gland tissue biopsies were performed in conjunction with histology and electron microscopy observations. Tear meniscus height (TMH) and tear meniscus area (TMA) were measured using Fourier domain‑optical coherence tomography. Tear membrane break‑up time (TBUT) was also assessed and corneal fluorescein staining was performed. The percentages of apoptotic corneal and conjunctival (Cj) epithelial cells (ECs) were counted using a terminal deoxynucleotidyl transferase‑mediated dUTP nick end labeling method. The mRNA expression levels of Muc1 were determined using reverse transcription‑quantitative polymerase chain reaction analyses. The TMH and TMA values of the PBS and treatment groups were found to be significantly reduced, compared with those of the normal control group 3 days after Con A injection. However, the TMH and TMA of the FGF10 treatment group were higher, compared with those of the PBS group 3 and 7 days after treatment, respectively. Furthermore, the FGF10 treatment group exhibited prolonged TBUT, reduced corneal fluorescein staining and repaired epithelial cell ultrastructure7 days after treatment. The percentages of apoptotic corneal‑ and Cj‑ECs in the FGF10 treatment group were significantly reduced, compared with those in the PBS group. FGF10

  7. A model measuring therapeutic inertia and the associated factors among diabetes patients: A nationwide population-based study in Taiwan.

    Science.gov (United States)

    Huang, Li-Ying; Shau, Wen-Yi; Yeh, Hseng-Long; Chen, Tsung-Tai; Hsieh, Jun Yi; Su, Syi; Lai, Mei-Shu

    2015-01-01

    This article presents an analysis conducted on the patterns related to therapeutic inertia with the aim of uncovering how variables at the patient level and the healthcare provider level influence the intensification of therapy when it is clinically indicated. A cohort study was conducted on 899,135 HbA1c results from 168,876 adult diabetes patients with poorly controlled HbA1c levels. HbA1c results were used to identify variations in the prescription of hypoglycemic drugs. Logistic regression and hierarchical linear models (HLMs) were used to determine how differences among healthcare providers and patient characteristics influence therapeutic inertia. We estimated that 38.5% of the patients in this study were subject to therapeutic inertia. The odds ratio of cardiologists choosing to intensify therapy was 0.708 times that of endocrinologists. Furthermore, patients in medical centers were shown to be 1.077 times more likely to be prescribed intensified treatment than patients in primary clinics. The HLMs presented results similar to those of the logistic model. Overall, we determined that 88.92% of the variation in the application of intensified treatment was at the within-physician level. Reducing therapeutic inertia will likely require educational initiatives aimed at ensuring adherence to clinical practice guidelines in the care of diabetes patients. © 2014, The American College of Clinical Pharmacology.

  8. The special effects of hypnosis and hypnotherapy: A contribution to an ecological model of therapeutic change.

    Science.gov (United States)

    Mende, Matthias

    2006-04-01

    There is ample evidence that hypnosis enhances the effectiveness of psychotherapy and produces some astounding effects of its own. In this paper, the effective components and principles of hypnosis and hypnotherapy are analyzed. The "special" hypnotic and hypnotherapeutic effects are linked to the fact that the ecological requirements of therapeutic change are taken into account implicitly and/or explicitly when working with hypnotic trances in a therapeutic setting. The hypnotic situation is described--theoretically and in case examples--as a therapeutic modality that gratifies and aligns the basic emotional needs to feel autonomous, related, competent, and oriented. It is shown how the hypnotic relationship can help promote a sound ecological balance between these needs--a balance that is deemed to be a necessary prerequisite for salutogenesis. Practical implications for planning hypnotherapeutic interventions are discussed.

  9. Vibration Stabilization of a Mechanical Model of a X-Band Linear Collider Final Focus Magnet

    CERN Document Server

    Frisch, J; Decker, V; Hendrickson, L; Markiewicz, T W; Partridge, R; Seryi, Andrei

    2004-01-01

    The small beam sizes at the interaction point of a X-band linear collider require mechanical stabilization of the final focus magnets at the nanometer level. While passive systems provide adequate performance at many potential sites, active mechanical stabilization is useful if the natural or cultural ground vibration is higher than expected. A mechanical model of a room temperature linear collider final focus magnet has been constructed and actively stabilized with an accelerometer based system.

  10. Vibration Stabilization of a Mechanical Model of a X-Band Linear Collider Final Focus Magnet

    International Nuclear Information System (INIS)

    Frisch, Josef; Chang, Allison; Decker, Valentin; Doyle, Eric; Eriksson, Leif; Hendrickson, Linda; Himel, Thomas; Markiewicz, Thomas; Partridge, Richard; Seryi, Andrei; SLAC

    2006-01-01

    The small beam sizes at the interaction point of a X-band linear collider require mechanical stabilization of the final focus magnets at the nanometer level. While passive systems provide adequate performance at many potential sites, active mechanical stabilization is useful if the natural or cultural ground vibration is higher than expected. A mechanical model of a room temperature linear collider final focus magnet has been constructed and actively stabilized with an accelerometer based system

  11. Therapeutic immunization strategies against cervical cancer : induction of cell-mediated immunity in murine models

    NARCIS (Netherlands)

    Bungener, Laura Barbara

    2004-01-01

    The aim of the study described in this thesis is the development of a therapeutic immunization strategy against cervical cancer and pre-malignant precursor lesions of cervical cancer (CIN lesions). Cervical cancer is caused by high risk human papillomavirus (HPV). Two of the early proteins of high

  12. Potential therapeutic effect of nanobased formulation of rivastigmine on rat model of Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Ismail MF

    2013-01-01

    Full Text Available Manal Fouad Ismail,1 Aliaa Nabil ElMeshad,2 Neveen Abdel-Hameed Salem31Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt; 2Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt; 3Department of Narcotics and Ergogenic Aids and Poisons, National Research Center, Giza, EgyptBackground: To sustain the effect of rivastigmine, a hydrophilic cholinesterase inhibitor, nanobased formulations were prepared. The efficacy of the prepared rivastigmine liposomes (RLs in comparison to rivastigmine solution (RS was assessed in an aluminium chloride (AlCl3-induced Alzheimer’s model.Methods: Liposomes were prepared by lipid hydration (F1 and heating (F2 methods. Rats were treated with either RS or RLs (1 mg/kg/day concomitantly with AlCl3 (50 mg/kg/day.Results: The study showed that the F1 method produced smaller liposomes (67.51 ± 14.2 nm than F2 (528.7 ± 15.5 nm, but both entrapped the same amount of the drug (92.1% ± 1.4%. After 6 hours, 74.2% ± 1.5% and 60.8% ± 2.3% of rivastigmine were released from F1 and F2, respectively. Both RLs and RS improved the deterioration of spatial memory induced by AlCl3, with RLs having a superior effect. Further biochemical measurements proved that RS and RLs were able to lower plasma C-reactive protein, homocysteine and asymmetric dimethylarginine levels. RS significantly attenuated acetylcholinesterase (AChE activity, whereas Na+/K+-adenosine triphosphatase (ATPase activity was enhanced compared to the AlCl3-treated animals; however, RLs succeeded in normalization of AChE and Na+/K+ ATPase activities. Gene-expression profile showed that cotreatment with RS to AlCl3-treated rats succeeded in exerting significant decreases in BACE1, AChE, and IL1B gene expression. Normalization of the expression of the aforementioned genes was achieved by coadministration of RLs to AlCl3-treated rats. The profound therapeutic effect of RLs over RS was

  13. Janez Rugelj's alternative therapeutic community after the five-factor model of personality

    Directory of Open Access Journals (Sweden)

    Judita Bagon

    2000-12-01

    Full Text Available The Alternative Therapeutic Community (ATC of Dr. J. Rugelj is a specific social community consisting of people in distress (always consisting of about 120 people, who have all been handicapped in their lives in one way or another. The group is also specific because of their way towards recovery, i.e., intensively reactivating the mecanisms of healthy life to surmount their psychical and social deficiency. The results of measuring the structure of personality according to BFQ – the "Big Five" model of personality – show that the ATC as a whole achieves lower scores than the normal population on all dimensions and subdimensions. The difference is statistically significant regarding the dimension of Emotional stability as well as the subdimension Emotional control. The ATC is not a uniform group, so the results differ according to the diagnosis. The members with the diagnosis of 'a neurotic' or 'a psychotic' achieve below-average results, while the accompanying members achieve similar results as the control group (selected from the non-members of the ATC. The results of the members diagnosed as 'an alcoholic' are somewhat surprising – they do not differ considerably on any dimension or subdimension from the results achieved by the control group – not even on the Emotional stability scale. As regards the total period of staying in the program, the results of subdimensions remain mostly unchanged. However, during the time spent in the program the results on the subdimensions change: the group which has been in the program for 1 to 2 years generally scores higher than the group of beginners (the difference is statistically significant only for the dimension Emotional control, but the results of the group participating in the program for longer time (more than three years are lower again, until they stabilize in the central position (T=50. The results on theHonesty scale (which may also show positive or negative self-image show no

  14. Transcriptional Profiling Confirms the Therapeutic Effects of Mast Cell Stabilization in a Dengue Disease Model.

    Science.gov (United States)

    Morrison, Juliet; Rathore, Abhay P S; Mantri, Chinmay K; Aman, Siti A B; Nishida, Andrew; St John, Ashley L

    2017-09-15

    There are no approved therapeutics for the treatment of dengue disease despite the global prevalence of dengue virus (DENV) and its mosquito vectors. DENV infections can lead to vascular complications, hemorrhage, and shock due to the ability of DENV to infect a variety of immune and nonimmune cell populations. Increasingly, studies have implicated the host response as a major contributor to severe disease. Inflammatory products of various cell types, including responding T cells, mast cells (MCs), and infected monocytes, can contribute to immune pathology. In this study, we show that the host response to DENV infection in immunocompetent mice recapitulates transcriptional changes that have been described in human studies. We found that DENV infection strongly induced metabolic dysregulation, complement signaling, and inflammation. DENV also affected the immune cell content of the spleen and liver, enhancing NK, NKT, and CD8 + T cell activation. The MC-stabilizing drug ketotifen reversed many of these responses without suppressing memory T cell formation and induced additional changes in the transcriptome and immune cell composition of the spleen, consistent with reduced inflammation. This study provides a global transcriptional map of immune activation in DENV target organs of an immunocompetent host and supports the further development of targeted immunomodulatory strategies to treat DENV disease. IMPORTANCE Dengue virus (DENV), which causes febrile illness, is transmitted by mosquito vectors throughout tropical and subtropical regions of the world. Symptoms of DENV infection involve damage to blood vessels and, in rare cases, hemorrhage and shock. Currently, there are no targeted therapies to treat DENV infection, but it is thought that drugs that target the host immune response may be effective in limiting symptoms that result from excessive inflammation. In this study, we measured the host transcriptional response to infection in multiple DENV target organs

  15. Optimization of production and quality control of therapeutic radionuclides and radiopharmaceuticals. Final report of a co-ordinated research project 1994-1998

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1999-09-01

    The `renaissance` of the therapeutic applications of radiopharmaceuticals during the last few years was in part due to a greater availability of radionuclides with appropriate nuclear decay properties, as well as to the development of carrier molecules with improved characteristics. Although radionuclides such as {sup 32}P, {sup 89}Sr and {sup 131}I, were used from the early days of nuclear medicine in the late 1930s and early 1940s, the inclusion of other particle emitting radionuclides into the nuclear medicine armamentarium was rather late. Only in the early 1980s did the specialized scientific literature start to show the potential for using other beta emitting nuclear reactor produced radionuclides such as {sup 153}Sm, {sup 166} Ho, {sup 165}Dy and {sup 186-188}Re. Bone seeking agents radiolabelled with the above mentioned beta emitting radionuclides demonstrated clear clinical potential in relieving intense bone pain resulting from metastases of the breast, prostate and lung of cancer patients. Therefore, upon the recommendation of a consultants meeting held in Vienna in 1993, the Co-ordinated Research Project (CRP) on Optimization of the Production and quality control of Radiotherapeutic Radionuclides and Radiopharmaceuticals was established in 1994. The CRP aimed at developing and improving existing laboratory protocols for the production of therapeutic radionuclides using existing nuclear research reactors including the corresponding radiolabelling, quality control procedures; and validation in experimental animals. With the participation of ten scientists from IAEA Member States, several laboratory procedures for preparation and quality control were developed, tested and assessed as potential therapeutic radiopharmaceuticals for bone pain palliation. In particular, the CRP optimised the reactor production of {sup 153}Sm and the preparation of the radiopharmaceutical {sup 153}Sm-EDTMP (ethylene diamine tetramethylene phosphonate), as well as radiolabelling

  16. Optimization of production and quality control of therapeutic radionuclides and radiopharmaceuticals. Final report of a co-ordinated research project 1994-1998

    International Nuclear Information System (INIS)

    1999-09-01

    The 'renaissance' of the therapeutic applications of radiopharmaceuticals during the last few years was in part due to a greater availability of radionuclides with appropriate nuclear decay properties, as well as to the development of carrier molecules with improved characteristics. Although radionuclides such as 32 P, 89 Sr and 131 I, were used from the early days of nuclear medicine in the late 1930s and early 1940s, the inclusion of other particle emitting radionuclides into the nuclear medicine armamentarium was rather late. Only in the early 1980s did the specialized scientific literature start to show the potential for using other beta emitting nuclear reactor produced radionuclides such as 153 Sm, 166 Ho, 165 Dy and 186-188 Re. Bone seeking agents radiolabelled with the above mentioned beta emitting radionuclides demonstrated clear clinical potential in relieving intense bone pain resulting from metastases of the breast, prostate and lung of cancer patients. Therefore, upon the recommendation of a consultants meeting held in Vienna in 1993, the Co-ordinated Research Project (CRP) on Optimization of the Production and quality control of Radiotherapeutic Radionuclides and Radiopharmaceuticals was established in 1994. The CRP aimed at developing and improving existing laboratory protocols for the production of therapeutic radionuclides using existing nuclear research reactors including the corresponding radiolabelling, quality control procedures; and validation in experimental animals. With the participation of ten scientists from IAEA Member States, several laboratory procedures for preparation and quality control were developed, tested and assessed as potential therapeutic radiopharmaceuticals for bone pain palliation. In particular, the CRP optimised the reactor production of 153 Sm and the preparation of the radiopharmaceutical 153 Sm-EDTMP (ethylene diamine tetramethylene phosphonate), as well as radiolabelling techniques and quality control methods for

  17. An Overview on the Role of α -Synuclein in Experimental Models of Parkinson's Disease from Pathogenesis to Therapeutics.

    Science.gov (United States)

    Javed, Hayate; Kamal, Mohammad Amjad; Ojha, Shreesh

    2016-01-01

    Parkinson's disease (PD) is a devastating and progressive movement disorder characterized by symptoms of muscles rigidity, tremor, postural instability and slow physical movements. Biochemically, PD is characterized by lack of dopamine production and its action due to loss of dopaminergic neurons and neuropathologically by the presence of intracytoplasmic inclusions known as Lewy bodies, which mainly consist of presynaptic neuronal protein, α-synuclein (α-syn). It is believed that alteration in α-syn homeostasis leads to increased accumulation and aggregation of α-syn in Lewy body. Based on the important role of α-syn from pathogenesis to therapeutics, the recent researches are mainly focused on deciphering the critical role of α-syn at advanced level. Being a major protein in Lewy body that has a key role in pathogenesis of PD, several model systems including immortalized cell lines (SH-SY5Y), primary neuronal cultures, yeast (saccharomyces cerevisiae), drosophila (fruit flies), nematodes (Caenorhabditis elegans) and rodents are being employed to understand the PD pathogenesis and treatment. In order to study the etiopathogensis and develop novel therapeutic target for α -syn aggregation, majority of investigators rely on toxin (rotenone, 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine, 6-hydroxydopamine, paraquat)-induced animal models of PD as a tool for basic research. Whereas, cell and tissue based models are mostly utilized to elucidate the mechanistic and molecular pathways underlying the α -syn induced toxicity and therapeutic approaches in PD. Gene modified mouse models based on α-syn expression are fascinating for modeling familial PD and toxin induced models provide a suitable approach for sporadic PD. The purpose of this review is to provide a summary and a critical review of the involvement of α-syn in various in vitro and in vivo models of PD based on use of neurotoxins as well as genetic modifications.

  18. Evaluation of scoring models for identifying the need for therapeutic intervention of upper gastrointestinal bleeding: A new prediction score model for Japanese patients.

    Science.gov (United States)

    Iino, Chikara; Mikami, Tatsuya; Igarashi, Takasato; Aihara, Tomoyuki; Ishii, Kentaro; Sakamoto, Jyuichi; Tono, Hiroshi; Fukuda, Shinsaku

    2016-11-01

    Multiple scoring systems have been developed to predict outcomes in patients with upper gastrointestinal bleeding. We determined how well these and a newly established scoring model predict the need for therapeutic intervention, excluding transfusion, in Japanese patients with upper gastrointestinal bleeding. We reviewed data from 212 consecutive patients with upper gastrointestinal bleeding. Patients requiring endoscopic intervention, operation, or interventional radiology were allocated to the therapeutic intervention group. Firstly, we compared areas under the curve for the Glasgow-Blatchford, Clinical Rockall, and AIMS65 scores. Secondly, the scores and factors likely associated with upper gastrointestinal bleeding were analyzed with a logistic regression analysis to form a new scoring model. Thirdly, the new model and the existing model were investigated to evaluate their usefulness. Therapeutic intervention was required in 109 patients (51.4%). The Glasgow-Blatchford score was superior to both the Clinical Rockall and AIMS65 scores for predicting therapeutic intervention need (area under the curve, 0.75 [95% confidence interval, 0.69-0.81] vs 0.53 [0.46-0.61] and 0.52 [0.44-0.60], respectively). Multivariate logistic regression analysis retained seven significant predictors in the model: systolic blood pressure upper gastrointestinal bleeding. © 2016 Japan Gastroenterological Endoscopy Society.

  19. THE QUANTITATIVE MODEL OF THE FINALIZATIONS IN MEN’S COMPETITIVE HANDBALL AND THEIR EFFICIENCY

    Directory of Open Access Journals (Sweden)

    Eftene Alexandru

    2009-10-01

    Full Text Available In the epistemic steps, we approach a competitive performance behavior model build after a quantitativeanalysis of certain data collected from the official International Handball Federation protocols on theperformance of the first four teams of the World Men's Handball Championship - Croatia 2009, duringsemifinals and finals.This model is a part of the integrative (global model of the handball game, which will be graduallyinvestigated during the following research.I have started the construction of this model from the premise that the finalization represents theessence of the game.The components of our model, in a prioritized order: shot at the goal from 9m- 15p; shot at the goalfrom 6m- 12p; shot at the goal from 7m- 12p; fast break shot at the goal - 11,5p; wing shot at the goal - 8,5p;penetration shot at the goal - 7p;

  20. Mathematical models for atmospheric pollutants. Appendix D. Available air quality models. Final report

    International Nuclear Information System (INIS)

    Drake, R.L.; McNaughton, D.J.; Huang, C.

    1979-08-01

    Models that are available for the analysis of airborne pollutants are summarized. In addition, recommendations are given concerning the use of particular models to aid in particular air quality decision making processes. The air quality models are characterized in terms of time and space scales, steady state or time dependent processes, reference frames, reaction mechanisms, treatment of turbulence and topography, and model uncertainty. Using these characteristics, the models are classified in the following manner: simple deterministic models, such as air pollution indices, simple area source models and rollback models; statistical models, such as averaging time models, time series analysis and multivariate analysis; local plume and puff models; box and multibox models; finite difference or grid models; particle models; physical models, such as wind tunnels and liquid flumes; regional models; and global models

  1. Therapeutic and diagnostic nanomaterials

    CERN Document Server

    Devasena T

    2017-01-01

    This brief highlights nanoparticles used in the diagnosis and treatment of prominent diseases and toxic conditions. Ecofriendly methods which are ideal for the synthesis of medicinally valued nanoparticles are explained and the characteristic features of these particles projected. The role of these particles in the therapeutic field, and the induced biological changes in some diseases are discussed. The main focus is on inflammation, oxidative stress and cellular membrane integrity alterations. The effect of nanoparticles on these changes produced by various agents are highlighted using in vitro and in vivo models. The mechanism of nanoparticles in ameliorating the biological changes is supported by relevant images and data. Finally, the brief demonstrates recent developments on the use of nanoparticles in diagnosis or sensing of some biological materials and biologically hazardous environmental materials.

  2. [Therapeutic education didactic techniques].

    Science.gov (United States)

    Valverde, Maite; Vidal, Mercè; Jansa, Margarida

    2012-10-01

    This article includes an introduction to the role of Therapeutic Education for Diabetes treatment according to the recommendations of the American Diabetes Association (ADA), the Diabetes Education Study Group (DESG) of the "European Association for Study of Diabetes (EASD) and the clinical Practice Guidelines (CPG) of the Spanish Ministry of Health. We analyze theoretical models and the differences between teaching vs. learning as well as current trends (including Internet), that can facilitate meaningful learning of people with diabetes and their families and relatives. We analyze the differences, similarities, advantages and disadvantages of individual and group education. Finally, we describe different educational techniques (metaplan, case method, brainstorming, role playing, games, seminars, autobiography, forums, chats,..) applicable to individual, group or virtual education and its application depending on the learning objective.

  3. Developmental origins of metabolic disorders: The need for biomarker candidates and therapeutic targets from adequate preclinical models

    Directory of Open Access Journals (Sweden)

    Antonio Gonzalez-Bulnes

    2016-03-01

    Full Text Available The investigation on obesity and associated disorders have changed from an scenario in which genome drove the phenotype to a dynamic setup in which prenatal and early-postnatal conditions are determinant. However, research in human beings is difficult due to confounding factors (lifestyle and socioeconomic heterogeneity plus ethical issues. Hence, there is currently an intensive effort for developing adequate preclinical models, aiming for an adequate combination of basic studies in rodent models and specific preclinical studies in large animals. The results of these research strategies may increase the identification and development of contrasted biomarkers and therapeutic targets.

  4. Search for the standard model Higgs boson in tau final states

    NARCIS (Netherlands)

    Abazov, V.M.; et al., [Unknown; Ancu, L.S.; de Jong, S.J.; Filthaut, F.; Galea, C.F.; Hegeman, J.G.; Houben, P.; Meijer, M.M.; Svoisky, P.; van den Berg, P.J.; van Leeuwen, W.M.

    2009-01-01

    We present a search for the standard model Higgs boson using hadronically decaying tau leptons, in 1 fb(-1) of data collected with the D0 detector at the Fermilab Tevatron p(p)over-bar collider. We select two final states: tau(+/-) plus missing transverse energy and b jets, and tau(+)tau(-) plus

  5. An Exploratory Study: Assessment of Modeled Dioxin Exposure in Ceramic Art Studios (Final Report, 2008)

    Science.gov (United States)

    EPA announced the availability of the final report, An Exploratory Study: Assessment of Modeled Dioxin Exposure in Ceramic Art Studios. This report investigates the potential dioxin exposure to artists/hobbyists who use ball clay to make pottery and related products. Derm...

  6. Modelling hemoglobin and hemoglobin:haptoglobin complex clearance in a non-rodent species– pharmacokinetic and therapeutic implications

    Directory of Open Access Journals (Sweden)

    Felicitas S Boretti

    2014-10-01

    Full Text Available Preclinical studies suggest that haptoglobin (Hp supplementation could be an effective therapeutic modality during acute or chronic hemolytic diseases. Hp prevents Hb extravasation and neutralizes Hb’s oxidative and NO scavenging activity in the vasculature. Small animal models such as mouse, rat and guinea pig appear to be valuable to provide proof-of-concept for Hb neutralization by Hp in diverse pre-clinical conditions. However, these species differ significantly from human in the clearance of Hb:Hp complexes, which leads to long persistence of circulating Hb:Hp complexes after administration of human plasma derived Hp. Alternative animal models must therefore be explored to guide pre-clinical development of these potential therapeutics. In contrast to rodents, dogs have high Hp plasma concentrations comparable to human. In this study we show that like human macrophages, dog peripheral blood monocyte derived macrophages express a glucocorticoid inducible endocytic clearance pathways with a high specificity for the Hb:Hp complex. Evaluating the Beagle dog as a non-rodent model species we provide the first pharmacokinetic parameter estimates of free Hb and Hb:Hp phenotype complexes. The data reflect a drastically reduced volume of distribution (Vc of the complex compared to free Hb, increased exposures (Cmax and AUC and significantly reduced total body clearance (CL with a terminal half-life (t1/2 of approximately 12 hours. Distribution and clearance was identical for dog and human Hb (± glucocorticoid stimulation and for dimeric and multimeric Hp preparations bound to Hb. Collectively, our study supports the dog as a non-rodent animal model to study pharmacological and pharmacokinetic aspects of Hb clearance systems and apply the model to studying Hp therapeutics.

  7. Inventory of Novel Animal Models Addressing Etiology of Preeclampsia in the Development of New Therapeutic/Intervention Opportunities.

    Science.gov (United States)

    Erlandsson, Lena; Nääv, Åsa; Hennessy, Annemarie; Vaiman, Daniel; Gram, Magnus; Åkerström, Bo; Hansson, Stefan R

    2016-03-01

    Preeclampsia is a pregnancy-related disease afflicting 3-7% of pregnancies worldwide and leads to maternal and infant morbidity and mortality. The disease is of placental origin and is commonly described as a disease of two stages. A variety of preeclampsia animal models have been proposed, but all of them have limitations in fully recapitulating the human disease. Based on the research question at hand, different or multiple models might be suitable. Multiple animal models in combination with in vitro or ex vivo studies on human placenta together offer a synergistic platform to further our understanding of the etiology of preeclampsia and potential therapeutic interventions. The described animal models of preeclampsia divide into four categories (i) spontaneous, (ii) surgically induced, (iii) pharmacologically/substance induced, and (iv) transgenic. This review aims at providing an inventory of novel models addressing etiology of the disease and or therapeutic/intervention opportunities. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  8. Therapeutic Potency of Nanoformulations of siRNAs and shRNAs in Animal Models of Cancers

    Directory of Open Access Journals (Sweden)

    Md. Emranul Karim

    2018-05-01

    Full Text Available RNA Interference (RNAi has brought revolutionary transformations in cancer management in the past two decades. RNAi-based therapeutics including siRNA and shRNA have immense scope to silence the expression of mutant cancer genes specifically in a therapeutic context. Although tremendous progress has been made to establish catalytic RNA as a new class of biologics for cancer management, a lot of extracellular and intracellular barriers still pose a long-lasting challenge on the way to clinical approval. A series of chemically suitable, safe and effective viral and non-viral carriers have emerged to overcome physiological barriers and ensure targeted delivery of RNAi. The newly invented carriers, delivery techniques and gene editing technology made current treatment protocols stronger to fight cancer. This review has provided a platform about the chronicle of siRNA development and challenges of RNAi therapeutics for laboratory to bedside translation focusing on recent advancement in siRNA delivery vehicles with their limitations. Furthermore, an overview of several animal model studies of siRNA- or shRNA-based cancer gene therapy over the past 15 years has been presented, highlighting the roles of genes in multiple cancers, pharmacokinetic parameters and critical evaluation. The review concludes with a future direction for the development of catalytic RNA vehicles and design strategies to make RNAi-based cancer gene therapy more promising to surmount cancer gene delivery challenges.

  9. Comparison of tree types of models for the prediction of final academic achievement

    Directory of Open Access Journals (Sweden)

    Silvana Gasar

    2002-12-01

    Full Text Available For efficient prevention of inappropriate secondary school choices and by that academic failure, school counselors need a tool for the prediction of individual pupil's final academic achievements. Using data mining techniques on pupils' data base and expert modeling, we developed several models for the prediction of final academic achievement in an individual high school educational program. For data mining, we used statistical analyses, clustering and two machine learning methods: developing classification decision trees and hierarchical decision models. Using an expert system shell DEX, an expert system, based on a hierarchical multi-attribute decision model, was developed manually. All the models were validated and evaluated from the viewpoint of their applicability. The predictive accuracy of DEX models and decision trees was equal and very satisfying, as it reached the predictive accuracy of an experienced counselor. With respect on the efficiency and difficulties in developing models, and relatively rapid changing of our education system, we propose that decision trees are used in further development of predictive models.

  10. Utility of a Bayesian Mathematical Model to Predict the Impact of Immunogenicity on Pharmacokinetics of Therapeutic Proteins.

    Science.gov (United States)

    Kathman, Steven; Thway, Theingi M; Zhou, Lei; Lee, Stephanie; Yu, Steven; Ma, Mark; Chirmule, Naren; Jawa, Vibha

    2016-03-01

    The impact of an anti-drug antibody (ADA) response on pharmacokinetic (PK) of a therapeutic protein (TP) requires an in-depth understanding of both PK parameters and ADA characteristics. The ADA and PK bioanalytical assays have technical limitations due to high circulating levels of TP and ADA, respectively, hence, significantly hindering the interpretation of this assessment. The goal of this study was to develop a population-based modeling and simulation approach that can identify a more relevant PK parameter associated with ADA-mediated clearance. The concentration-time data from a single dose PK study using five monoclonal antibodies were modeled using a non-compartmental analysis (NCA), one-compartmental, and two-compartmental Michaelis-Menten kinetic model (MMK). A novel PK parameter termed change in clearance time of the TP (α) derived from the MMK model could predict variations in α much earlier than the time points when ADA could be bioanalytically detectable. The model could also identify subjects that might have been potentially identified as false negative due to interference of TP with ADA detection. While NCA and one-compartment models can estimate loss of exposures, and changes in clearance, the two-compartment model provides this additional ability to predict that loss of exposure by means of α. Modeling data from this study showed that the two-compartment model along with the conventional modeling approaches can help predict the impact of ADA response in the absence of relevant ADA data.

  11. Ectromelia Virus Infections of Mice as a Model to Support the Licensure of Anti-Orthopoxvirus Therapeutics

    Directory of Open Access Journals (Sweden)

    R. Mark Buller

    2010-09-01

    Full Text Available The absence of herd immunity to orthopoxviruses and the concern that variola or monkeypox viruses could be used for bioterroristic activities has stimulated the development of therapeutics and safer prophylactics. One major limitation in this process is the lack of accessible human orthopoxvirus infections for clinical efficacy trials; however, drug licensure can be based on orthopoxvirus animal challenge models as described in the “Animal Efficacy Rule”. One such challenge model uses ectromelia virus, an orthopoxvirus, whose natural host is the mouse and is the etiological agent of mousepox. The genetic similarity of ectromelia virus to variola and monkeypox viruses, the common features of the resulting disease, and the convenience of the mouse as a laboratory animal underscores its utility in the study of orthopoxvirus pathogenesis and in the development of therapeutics and prophylactics. In this review we outline how mousepox has been used as a model for smallpox. We also discuss mousepox in the context of mouse strain, route of infection, infectious dose, disease progression, and recovery from infection.

  12. Therapeutic efficacy of MUC1-specific cytotoxic T lymphocytes and CD137 co-stimulation in a spontaneous breast cancer model.

    Science.gov (United States)

    Mukherjee, Pinku; Tinder, Teresa L; Basu, Gargi D; Pathangey, Latha B; Chen, Lieping; Gendler, Sandra J

    2004-01-01

    To study immunology in breast tumors, we have utilized a mammary gland adenocarcinoma model in which mice develop spontaneous tumors of the mammary gland which are initiated at puberty and express a human tumor antigen, MUC1. MUC1 (CD227) is over-expressed in 90% of human breast cancers and its glycosylation status and pattern of expression in cancer cells is altered. Humoral and cellular responses to MUC1 have been reported in breast cancer patients and therefore, MUC1 is being evaluated as a target for immune intervention. This mouse model of spontaneous breast cancer allows the evaluation of anti-MUC1 immune responses at all stages of the disease. In this report, we review the model as it pertains to a) the development of the tumor, b) MUC1 expression, and the native immune responses against MUC1 as tumors progress, and c) the immune suppressive microenvironment within the developing tumor. Finally, we report our latest findings describing the therapeutic efficacy of adoptively transferred MUC1-specific cytotoxic T lymphocytes (MUC1-CTL) in these mice and discuss ways to increase their effectiveness by agonistic monoclonal antibody against CD137 T cell costimulatory molecule.

  13. Comparing the cardiovascular therapeutic indices of glycopyrronium and tiotropium in an integrated rat pharmacokinetic, pharmacodynamic and safety model

    International Nuclear Information System (INIS)

    Trifilieff, Alexandre; Ethell, Brian T.; Sykes, David A.; Watson, Kenny J.; Collingwood, Steve; Charlton, Steven J.; Kent, Toby C.

    2015-01-01

    Long acting inhaled muscarinic receptor antagonists, such as tiotropium, are widely used as bronchodilator therapy for chronic obstructive pulmonary disease (COPD). Although this class of compounds is generally considered to be safe and well tolerated in COPD patients the cardiovascular safety of tiotropium has recently been questioned. We describe a rat in vivo model that allows the concurrent assessment of muscarinic antagonist potency, bronchodilator efficacy and a potential for side effects, and we use this model to compare tiotropium with NVA237 (glycopyrronium bromide), a recently approved inhaled muscarinic antagonist for COPD. Anaesthetized Brown Norway rats were dosed intratracheally at 1 or 6 h prior to receiving increasing doses of intravenous methacholine. Changes in airway resistance and cardiovascular function were recorded and therapeutic indices were calculated against the ED 50 values for the inhibition of methacholine-induced bronchoconstriction. At both time points studied, greater therapeutic indices for hypotension and bradycardia were observed with glycopyrronium (19.5 and 28.5 fold at 1 h; > 200 fold at 6 h) than with tiotropium (1.5 and 4.2 fold at 1 h; 4.6 and 5.5 fold at 6 h). Pharmacokinetic, protein plasma binding and rat muscarinic receptor binding properties for both compounds were determined and used to generate an integrated model of systemic M 2 muscarinic receptor occupancy, which predicted significantly higher M 2 receptor blockade at ED 50 doses with tiotropium than with glycopyrronium. In our preclinical model there was an improved safety profile for glycopyrronium when compared with tiotropium. - Highlights: • We use an in vivo rat model to study CV safety of inhaled muscarinic antagonists. • We integrate protein and receptor binding and PK of tiotropium and glycopyrrolate. • At ED 50 doses for bronchoprotection we model systemic M 2 receptor occupancy. • Glycopyrrolate demonstrates lower M 2 occupancy at

  14. Validated Models for Radiation Response and Signal Generation in Scintillators: Final Report

    Energy Technology Data Exchange (ETDEWEB)

    Kerisit, Sebastien N.; Gao, Fei; Xie, YuLong; Campbell, Luke W.; Van Ginhoven, Renee M.; Wang, Zhiguo; Prange, Micah P.; Wu, Dangxin

    2014-12-01

    This Final Report presents work carried out at Pacific Northwest National Laboratory (PNNL) under the project entitled “Validated Models for Radiation Response and Signal Generation in Scintillators” (Project number: PL10-Scin-theor-PD2Jf) and led by Drs. Fei Gao and Sebastien N. Kerisit. This project was divided into four tasks: 1) Electronic response functions (ab initio data model) 2) Electron-hole yield, variance, and spatial distribution 3) Ab initio calculations of information carrier properties 4) Transport of electron-hole pairs and scintillation efficiency Detailed information on the results obtained in each of the four tasks is provided in this Final Report. Furthermore, published peer-reviewed articles based on the work carried under this project are included in Appendix. This work was supported by the National Nuclear Security Administration, Office of Nuclear Nonproliferation Research and Development (DNN R&D/NA-22), of the U.S. Department of Energy (DOE).

  15. Therapeutic Effect of Ligustilide-Stimulated Adipose-Derived Stem Cells in a Mouse Thromboembolic Stroke Model.

    Science.gov (United States)

    Chi, Kang; Fu, Ru-Huei; Huang, Yu-Chuen; Chen, Shih-Yin; Lin, Shinn-Zong; Huang, Pi-Chun; Lin, Po-Cheng; Chang, Fu-Kuei; Liu, Shih-Ping

    2016-01-01

    Stroke is a result of cerebral ischemia that triggers a cascade of both physiological and biochemical events. No effective treatment is available for stroke; however, stem cells have the potential to rescue tissue from the effects of stroke. Adipose-derived stem cells (ADSCs) are an abundant source of adult stem cells; therefore, ADSC therapy can be considered as a future strategy for regenerative medicine. However, more research is required to improve the effectiveness of transplanted ADSCs as a treatment for stroke in the mouse stroke model. Ligustilide, isolated from the herb Angelica sinensis, exhibits a protective effect on neurons and inhibits inflammation. We also demonstrated that ligustilide treatment increases the expression levels of homing factors such as SDF-1 and CXCR4. In the present study, we evaluated the therapeutic effects of ADSC transplantation and ligustilide treatment in a mouse thromboembolic stroke model by behavioral tests, including beam walking, locomotor activity, and rotarod analysis. ADSCs pretreated with ligustilide were transplanted into the brains of stroke mice. The results showed that the therapeutic effect of ADSCs pretreated with ligustilide was better than that of ADSCs without ligustilide pretreatment. There was no difference between the recovery of mice treated by ADSC transplantation combined with subcutaneous ligustilide injection and that of mice treated only with ADSCs. The TUNEL assay showed fewer apoptotic cells in the brains of mice transplanted with ADSCs pretreated with ligustilide as well as in those without pretreatment. In summary, pretreatment of ADSCs with ligustilide improves the therapeutic efficacy of ADSC transplantation. The results of this study will help improve stem cell therapies being developed for future clinical applications.

  16. The Novel IκB Kinase β Inhibitor, IMD-0560, Has Potent Therapeutic Efficacy in Ovarian Cancer Xenograft Model Mice.

    Science.gov (United States)

    Sawada, Ikuko; Hashimoto, Kae; Sawada, Kenjiro; Kinose, Yasuto; Nakamura, Koji; Toda, Aska; Nakatsuka, Erika; Yoshimura, Akihiko; Mabuchi, Seiji; Fujikawa, Tomoyuki; Itai, Akiko; Kimura, Tadashi

    2016-05-01

    Aberrant activation of nuclear factor-kappa β (NF-κB) signaling has been correlated with poor outcome among patients with ovarian cancer. Although the therapeutic potential of NF-κB pathway disruption in cancers has been extensively studied, most classical NF-κB inhibitors are poorly selective, exhibit off-target effects, and have failed to be applied in clinical use. IMD-0560, N-[2,5-bis (trifluoromethyl) phenyl]-5-bromo-2-hydroxybenzamide, is a novel low-molecular-weight compound that selectively inhibits the IκB kinase complex and works as an inhibitor of NF-κB signaling. The aim of this study was to assess the therapeutic potential of IMD-0560 against ovarian cancer in vitro and in vivo. NF-κB activity (phosphorylation) was determined in 9 ovarian cancer cell lines and the inhibitory effect of IMD-0560 on NF-κB activation was analyzed by Western blotting. Cell viability, cell cycle, vascular endothelial growth factor (VEGF) expression, and angiogenesis were assessed in vitro to evaluate the effect of IMD-0560 on ovarian cancer cells. In vivo efficacy of IMD-0560 was also investigated using an ovarian cancer xenograft mouse model. The NF-κB signaling pathway was constitutively activated in 8 of 9 ovarian cancer cell lines. IMD-0560 inhibited NF-κB activation and suppressed ovarian cancer cell proliferation by inducing G1 phase arrest. IMD-0560 decreased VEGF secretion from cancer cells and inhibited the tube formation of human umbilical vein endothelial cells. IMD-0560 significantly inhibited peritoneal metastasis and prolonged the survival in an ovarian cancer xenograft mice model. Immunohistochemical staining of excised tumors revealed that IMD-0560 suppressed VEGF expression, tumor angiogenesis, and cancer cell proliferation. IMD-0560 showed promising therapeutic efficacy against ovarian cancer xenograft mice by inducing cell cycle arrest and suppressing VEGF production from cancer cells. IMD-0560 may be a potential future option in regimens for the

  17. ICFD modeling of final settlers - developing consistent and effective simulation model structures

    DEFF Research Database (Denmark)

    Plósz, Benedek G.; Guyonvarch, Estelle; Ramin, Elham

    CFD concept. The case of secondary settling tanks (SSTs) is used to demonstrate the methodological steps using the validated CFD model with the hindered-transientcompression settling velocity model by (10). Factor screening and latin hypercube sampling (LSH) are used to degenerate a 2-D axi-symmetrical CFD...... of (i) assessing different density current sub-models; (ii) implementation of a combined flocculation, hindered, transient and compression settling velocity function; and (iii) assessment of modelling the onset of transient and compression settling. Results suggest that the iCFD model developed...... the feed-layer. These scenarios were inspired by literature (1; 2; 9). As for the D0--iCFD model, values of SSRE obtained are below 1 with an average SSRE=0.206. The simulation model thus can predict the solids distribution inside the tank with a satisfactory accuracy. Averaged relative errors of 8.1 %, 3...

  18. Comparison of therapeutic efficacy and biodistribution of 213Bi- and 211At-labeled monoclonal antibody MX35 in an ovarian cancer model

    DEFF Research Database (Denmark)

    Gustafsson, Anna M E; Bäck, Tom; Elgqvist, Jörgen

    2012-01-01

    The purpose of this study was to compare the therapeutic efficacy and biodistribution of the monoclonal antibody MX35 labeled with either (213)Bi or (211)At, both α-emitters, in an ovarian cancer model.......The purpose of this study was to compare the therapeutic efficacy and biodistribution of the monoclonal antibody MX35 labeled with either (213)Bi or (211)At, both α-emitters, in an ovarian cancer model....

  19. Analysis of Final Energy Demand by Sector in Malaysia using MAED Model

    International Nuclear Information System (INIS)

    Kumar, M.; Muhammed Zulfakar Mohd Zolkaffly; Alawiah Musa

    2011-01-01

    Energy supply security is important in ensuring a long term supply to fulfill the growing energy demand. This paper presents the use of IAEA energy planning tool, Model for Analysis of Energy Demand (MAED) to analyze, simulate and compare final energy demand by five different sectors in Malaysia under some assumptions, bounds and restrictions and the outcome can be used for planning of energy supply in future. (author)

  20. 1993-1994 Final technical report for establishing the SECME Model in the District of Columbia

    Energy Technology Data Exchange (ETDEWEB)

    Vickers, R.G.

    1995-12-31

    This is the final report for a program to establish the SECME Model in the District of Columbia. This program has seen the development of a partnership between the District of Columbia Public Schools, the University of the District of Columbia, the Department of Energy, and SECME. This partnership has demonstrated positive achievement in mathematics and science education and learning in students within the District of Columbia.

  1. 1993-1994 Final technical report for establishing the SECME Model in the District of Columbia

    International Nuclear Information System (INIS)

    Vickers, R.G.

    1995-01-01

    This is the final report for a program to establish the SECME Model in the District of Columbia. This program has seen the development of a partnership between the District of Columbia Public Schools, the University of the District of Columbia, the Department of Energy, and SECME. This partnership has demonstrated positive achievement in mathematics and science education and learning in students within the District of Columbia

  2. Therapeutic effects of microbubble added to combined high-intensity focused ultrasound and chemotherapy in a pancreatic cancer xenograft model

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Mi Hye [Dept. of Radiology, Konkuk University Medical Center, Seoul (Korea, Republic of); Lee, Jae Young; Kim, Bo Ram; Park, Eun Joo; Kim, Hoe Suk; Han, Joon Koo [Dept. of Radiology, Seoul National University Hospital, Seoul (Korea, Republic of); Kim, Hae Ri [Dept. of Pre-Dentistry, Gangneung-Wonju National University College of Dentistry, Gangneung (Korea, Republic of); Choi, Byung Ihn [Dept. of Radiology, Chung-Ang University Hospital, Seoul (Korea, Republic of)

    2016-09-15

    To investigate whether high-intensity focused ultrasound (HIFU) combined with microbubbles enhances the therapeutic effects of chemotherapy. A pancreatic cancer xenograft model was established using BALB/c nude mice and luciferase-expressing human pancreatic cancer cells. Mice were randomly assigned to five groups according to treatment: control (n = 10), gemcitabine alone (GEM; n = 12), HIFU with microbubbles (HIFU + MB, n = 11), combined HIFU and gemcitabine (HIGEM; n = 12), and HIGEM + MB (n = 13). After three weekly treatments, apoptosis rates were evaluated using the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay in two mice per group. Tumor volume and bioluminescence were monitored using high-resolution 3D ultrasound imaging and in vivo bioluminescence imaging for eight weeks in the remaining mice. The HIGEM + MB group showed significantly higher apoptosis rates than the other groups (p < 0.05) and exhibited the slowest tumor growth. From week 5, the tumor-volume-ratio relative to the baseline tumor volume was significantly lower in the HIGEM + MB group than in the control, GEM, and HIFU + MB groups (p < 0.05). Despite visible distinction, the HIGEM and HIGEM + MB groups showed no significant differences. High-intensity focused ultrasound combined with microbubbles enhances the therapeutic effects of gemcitabine chemotherapy in a pancreatic cancer xenograft model.

  3. Therapeutic Effects of Microbubbles Added to Combined High-Intensity Focused Ultrasound and Chemotherapy in a Pancreatic Cancer Xenograft Model

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Mi Hye [Department of Radiology, Konkuk University Medical Center, Seoul 05030 (Korea, Republic of); Lee, Jae Young [Department of Radiology, Seoul National University Hospital, Seoul 03080 (Korea, Republic of); Kim, Hae Ri [Department of Pre-Dentistry, Gangneung-Wonju National University College of Dentistry, Gangneung 25457 (Korea, Republic of); Kim, Bo Ram; Park, Eun-Joo; Kim, Hoe Suk; Han, Joon Koo [Department of Radiology, Seoul National University Hospital, Seoul 03080 (Korea, Republic of); Choi, Byung Ihn [Department of Radiology, Chung-Ang University Hospital, Seoul 06973 (Korea, Republic of)

    2016-11-01

    To investigate whether high-intensity focused ultrasound (HIFU) combined with microbubbles enhances the therapeutic effects of chemotherapy. A pancreatic cancer xenograft model was established using BALB/c nude mice and luciferase-expressing human pancreatic cancer cells. Mice were randomly assigned to five groups according to treatment: control (n = 10), gemcitabine alone (GEM; n = 12), HIFU with microbubbles (HIFU + MB, n = 11), combined HIFU and gemcitabine (HIGEM; n = 12), and HIGEM + MB (n = 13). After three weekly treatments, apoptosis rates were evaluated using the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay in two mice per group. Tumor volume and bioluminescence were monitored using high-resolution 3D ultrasound imaging and in vivo bioluminescence imaging for eight weeks in the remaining mice. The HIGEM + MB group showed significantly higher apoptosis rates than the other groups (p < 0.05) and exhibited the slowest tumor growth. From week 5, the tumor-volume-ratio relative to the baseline tumor volume was significantly lower in the HIGEM + MB group than in the control, GEM, and HIFU + MB groups (p < 0.05). Despite visible distinction, the HIGEM and HIGEM + MB groups showed no significant differences. High-intensity focused ultrasound combined with microbubbles enhances the therapeutic effects of gemcitabine chemotherapy in a pancreatic cancer xenograft model.

  4. Relevance of various animal models of human infections to establish therapeutic equivalence of a generic product of piperacillin/tazobactam.

    Science.gov (United States)

    Agudelo, Maria; Rodriguez, Carlos A; Zuluaga, Andres F; Vesga, Omar

    2015-02-01

    After demonstrating with diverse intravenous antibacterials that pharmaceutical equivalence (PE) does not predict therapeutic equivalence, we tested a single generic product of piperacillin/tazobactam (TZP) in terms of PE, pharmacokinetics and in vitro/vivo pharmacodynamics against several pathogens in neutropenic mouse thigh, lung and brain infection models. A generic product was compared head-to-head against the innovator. PE was evaluated by microbiological assay. Single-dose serum pharmacokinetics were determined in infected mice, and the MIC/MBC were determined by broth microdilution. In vivo experiments were done in a blind fashion. Reproducibility was tested on different days using different infecting organisms and animal models. Neutropenic MPF mice were infected in the thighs with Staphylococcus aureus GRP-0057 or Pseudomonas aeruginosa PA01 and in the lungs or brain with Klebsiella pneumoniae ATCC 10031. Treatment started 2h (thigh and brain) or 14 h (lung) after infection and was administered every 3h over 24h (thigh and lung) or 48 h (brain). Both products exhibited the same MIC/MBC against each strain, yielded overlaid curves in the microbiological assay (P>0.21) and were bioequivalent (IC90 83-117% for AUC test/reference ratio). In vivo, the generic product and innovator were again undistinguishable in all models and against the different bacterial pathogens involved. The relevance of these neutropenic murine models of infection was established by demonstrating their accuracy to predict the biological response following simultaneous treatment with a generic product or the innovator of TZP. Therapeutic equivalence of the generic product was proved in every model and against different pathogens. Copyright © 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

  5. Reservoir architecture modeling: Nonstationary models for quantitative geological characterization. Final report, April 30, 1998

    Energy Technology Data Exchange (ETDEWEB)

    Kerr, D.; Epili, D.; Kelkar, M.; Redner, R.; Reynolds, A.

    1998-12-01

    The study was comprised of four investigations: facies architecture; seismic modeling and interpretation; Markov random field and Boolean models for geologic modeling of facies distribution; and estimation of geological architecture using the Bayesian/maximum entropy approach. This report discusses results from all four investigations. Investigations were performed using data from the E and F units of the Middle Frio Formation, Stratton Field, one of the major reservoir intervals in the Gulf Coast Basin.

  6. A final state interaction model for K and eta decay into three pions

    International Nuclear Information System (INIS)

    Angus, A.G.

    1973-07-01

    The Khuri-Treiman model is adapted in a relativistic formalism with the electromagnetic mass differences of the pions in the final state taken into account to produce new predictions for the relative decay rates and the slope parameters of the four reactions K→3x and the two reactions eta→3x. The pion-pion interaction is investigated in terms of the N/D method and as well as the normal pure pole approximations for the N functions. The Khuri-Treiman equations are solved for the best solutions from both the pure pole and the mixed pole and cut models. (author)

  7. Bone modeling and remodeling: potential as therapeutic targets for the treatment of osteoporosis.

    Science.gov (United States)

    Langdahl, Bente; Ferrari, Serge; Dempster, David W

    2016-12-01

    The adult skeleton is renewed by remodeling throughout life. Bone remodeling is a process where osteoclasts and osteoblasts work sequentially in the same bone remodeling unit. After the attainment of peak bone mass, bone remodeling is balanced and bone mass is stable for one or two decades until age-related bone loss begins. Age-related bone loss is caused by increases in resorptive activity and reduced bone formation. The relative importance of cortical remodeling increases with age as cancellous bone is lost and remodeling activity in both compartments increases. Bone modeling describes the process whereby bones are shaped or reshaped by the independent action of osteoblast and osteoclasts. The activities of osteoblasts and osteoclasts are not necessarily coupled anatomically or temporally. Bone modeling defines skeletal development and growth but continues throughout life. Modeling-based bone formation contributes to the periosteal expansion, just as remodeling-based resorption is responsible for the medullary expansion seen at the long bones with aging. Existing and upcoming treatments affect remodeling as well as modeling. Teriparatide stimulates bone formation, 70% of which is remodeling based and 20-30% is modeling based. The vast majority of modeling represents overflow from remodeling units rather than de novo modeling. Denosumab inhibits bone remodeling but is permissive for modeling at cortex. Odanacatib inhibits bone resorption by inhibiting cathepsin K activity, whereas modeling-based bone formation is stimulated at periosteal surfaces. Inhibition of sclerostin stimulates bone formation and histomorphometric analysis demonstrated that bone formation is predominantly modeling based. The bone-mass response to some osteoporosis treatments in humans certainly suggests that nonremodeling mechanisms contribute to this response and bone modeling may be such a mechanism. To date, this has only been demonstrated for teriparatide, however, it is clear that

  8. Assessing the Therapeutic Environment in Hybrid Models of Treatment: Prisoner Perceptions of Staff

    Science.gov (United States)

    Kubiak, Sheryl Pimlott

    2009-01-01

    Hybrid treatment models within prisons are staffed by both criminal justice and treatment professionals. Because these models may be indicative of future trends, examining the perceptions of prisoners/participants may provide important information. This study examines the perceptions of male and female inmates in three prisons, comparing those in…

  9. Model-Based Optimization of Scaffold Geometry and Operating Conditions of Radial Flow Packed-Bed Bioreactors for Therapeutic Applications

    Directory of Open Access Journals (Sweden)

    Danilo Donato

    2014-01-01

    Full Text Available Radial flow perfusion of cell-seeded hollow cylindrical porous scaffolds may overcome the transport limitations of pure diffusion and direct axial perfusion in the realization of bioengineered substitutes of failing or missing tissues. Little has been reported on the optimization criteria of such bioreactors. A steady-state model was developed, combining convective and dispersive transport of dissolved oxygen with Michaelis-Menten cellular consumption kinetics. Dimensional analysis was used to combine more effectively geometric and operational variables in the dimensionless groups determining bioreactor performance. The effectiveness of cell oxygenation was expressed in terms of non-hypoxic fractional construct volume. The model permits the optimization of the geometry of hollow cylindrical constructs, and direction and magnitude of perfusion flow, to ensure cell oxygenation and culture at controlled oxygen concentration profiles. This may help engineer tissues suitable for therapeutic and drug screening purposes.

  10. Assessment of therapeutic effect of human choriogonadotropin in a chemical cystitis model

    Directory of Open Access Journals (Sweden)

    Serhat Tanik

    2017-05-01

    Full Text Available In this study, female rats induced with chemical cystitis were administered the hormone human choriogonadotropin (HCG, and it was aimed to reveal the usefulness of HCG in the treatment of interstitial cystitis/bladder pain syndrome. The materials for this study were 32 Wistar albino female rats. The study groups were formed as follows: the cystitis group (Group 1, the cystitis + HCG protection group (Group 2, the cystitis + HCG treatment group (Group 3, and the control group (Group 4, with eight rats in each group. In this study, blood and urine samples were taken from the rats, they were euthanized, and their bladders were removed for glutathione, malondialdehyde, tumor necrosis factor alpha, and interferon gamma measurements. It was observed that tissue damage in Group 2 was lower than that in the other two groups. Glutathione levels in Groups 2 and 4 were significantly higher than in Groups 1 and 3 (p = 0.01. Malondialdehyde levels of Groups 2 and 4 were significantly lower than the values in Groups 1 and 3 (p < 0.001. When the cystitis groups were compared in terms of their interferon gamma and tumor necrosis factor alpha levels, the lowest interferon gamma and tumor necrosis factor alpha levels were detected in Group 3. It was found that HCG has positive effects on experimental cystitis in rats. This study revealed that HCG should be researched as a therapeutic agent and formed a step for studies to be carried out on this subject.

  11. Comparative therapeutic effects of velaglucerase alfa and imiglucerase in a Gaucher disease mouse model.

    Directory of Open Access Journals (Sweden)

    You-Hai Xu

    2010-05-01

    Full Text Available Gaucher disease type 1 is caused by the defective activity of the lysosomal enzyme, acid beta-glucosidase (GCase. Regular infusions of purified recombinant GCase are the standard of care for reversing hematologic, hepatic, splenic, and bony manifestations. Here, similar in vitro enzymatic properties, and in vivo pharmacokinetics and pharmacodynamics (PK/PD and therapeutic efficacy of GCase were found with two human GCases, recombinant GCase (CHO cell, imiglucerase, Imig and gene-activated GCase (human fibrosarcoma cells, velaglucerase alfa, Vela, in a Gaucher mouse, D409V/null. About 80+% of either enzyme localized to the liver interstitial cells and <5% was recovered in spleens and lungs after bolus i.v. injections. Glucosylceramide (GC levels and storage cell numbers were reduced in a dose (5, 15 or 60 U/kg/wk dependent manner in livers (60-95% and in spleens ( approximately 10-30%. Compared to Vela, Imig (60 U/kg/wk had lesser effects at reducing hepatic GC (p = 0.0199 by 4 wks; this difference disappeared by 8 wks when nearly WT levels were achieved by Imig. Anti-GCase IgG was detected in GCase treated mice at 60 U/kg/wk, and IgE mediated acute hypersensitivity and death occurred after several injections of 60 U/kg/wk (21% with Vela and 34% with Imig. The responses of GC levels and storage cell numbers in Vela- and Imig-treated Gaucher mice at various doses provide a backdrop for clinical applications and decisions.

  12. Modelling of air quality for Winter and Summer episodes in Switzerland. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Andreani-Aksoyoglu, S.; Keller, J.; Barmpadimos, L.; Oderbolz, D.; Tinguely, M.; Prevot, A. [Paul Scherrer Institute (PSI), Laboratory of Atmospheric Chemistry, Villigen (Switzerland); Alfarra, R. [University of Manchester, Manchester (United Kingdom); Sandradewi, J. [Jisca Sandradewi, Hoexter (Germany)

    2009-05-15

    This final report issued by the General Energy Research Department and its Laboratory of Atmospheric Chemistry at the Paul Scherrer Institute (PSI) reports on the results obtained from the modelling of regional air quality for three episodes, January-February 2006, June 2006 and January 2007. The focus of the calculations is on particulate matter concentrations, as well as on ozone levels in summer. The model results were compared with the aerosol data collected by an Aerosol Mass Spectrometer (AMS), which was operated during all three episodes as well as with the air quality monitoring data from further monitoring programs. The air quality model used in this study is described and the results obtained for various types of locations - rural, city, high-altitude and motorway-near - are presented and discussed. The models used are described.

  13. An overview of animal models for investigating the pathogenesis and therapeutic strategies in acute hepatic failure

    Institute of Scientific and Technical Information of China (English)

    María Jesús Tu(n)ón; Marcelino Alvarez; Jesús M Culebras; Javier González-Gallego

    2009-01-01

    Acute hepatic failure (AHF) is a severe liver injury accompanied by hepatic encephalopathy which causes multiorgan failure with an extremely high mortality rate, even if intensive care is provided. Management of severe AHF continues to be one of the most challenging problems in clinical medicine. Liver transplantation has been shown to be the most effective therapy, but the procedure is limited by shortage of donor organs. Although a number of clinical trials testing different liver assist devices are under way, these systems alone have no significant effect on patient survival and are only regarded as a useful approach to bridge patients with AHF to liver transplantation. As a result, reproducible experimental animal models resembling the clinical conditions are still needed. The three main approaches used to create an animal model for AHF are: surgical procedures, toxic liver injury and infective procedures. Most common models are based on surgical techniques (total/partial hepatectomy, complete/transient devascularization) or the use of hepatotoxic drugs (acetaminophen, galactosamine, thioacetamide, and others), and very few satisfactory viral models are available. We have recently developed a viral model of AHF by meansof the inoculation of rabbits with the virus of rabbit hemorrhagic disease. This model displays biochemical and histological characteristics, and clinical features that resemble those in human AHF. In the present article an overview is given of the most widely used animal models of AHF, and their main advantages and disadvantages are reviewed.

  14. Therapeutic Effects of Monoclonal Antibody against Dengue Virus NS1 in a STAT1 Knockout Mouse Model of Dengue Infection.

    Science.gov (United States)

    Wan, Shu-Wen; Chen, Pei-Wei; Chen, Chin-Yu; Lai, Yen-Chung; Chu, Ya-Ting; Hung, Chia-Yi; Lee, Han; Wu, Hsuan Franziska; Chuang, Yung-Chun; Lin, Jessica; Chang, Chih-Peng; Wang, Shuying; Liu, Ching-Chuan; Ho, Tzong-Shiann; Lin, Chiou-Feng; Lee, Chien-Kuo; Wu-Hsieh, Betty A; Anderson, Robert; Yeh, Trai-Ming; Lin, Yee-Shin

    2017-10-15

    Dengue virus (DENV) is the causative agent of dengue fever, dengue hemorrhagic fever, and dengue shock syndrome and is endemic to tropical and subtropical regions of the world. Our previous studies showed the existence of epitopes in the C-terminal region of DENV nonstructural protein 1 (NS1) which are cross-reactive with host Ags and trigger anti-DENV NS1 Ab-mediated endothelial cell damage and platelet dysfunction. To circumvent these potentially harmful events, we replaced the C-terminal region of DENV NS1 with the corresponding region from Japanese encephalitis virus NS1 to create chimeric DJ NS1 protein. Passive immunization of DENV-infected mice with polyclonal anti-DJ NS1 Abs reduced viral Ag expression at skin inoculation sites and shortened DENV-induced prolonged bleeding time. We also investigated the therapeutic effects of anti-NS1 mAb. One mAb designated 2E8 does not recognize the C-terminal region of DENV NS1 in which host-cross-reactive epitopes reside. Moreover, mAb 2E8 recognizes NS1 of all four DENV serotypes. We also found that mAb 2E8 caused complement-mediated lysis in DENV-infected cells. In mouse model studies, treatment with mAb 2E8 shortened DENV-induced prolonged bleeding time and reduced viral Ag expression in the skin. Importantly, mAb 2E8 provided therapeutic effects against all four serotypes of DENV. We further found that mAb administration to mice as late as 1 d prior to severe bleeding still reduced prolonged bleeding time and hemorrhage. Therefore, administration with a single dose of mAb 2E8 can protect mice against DENV infection and pathological effects, suggesting that NS1-specific mAb may be a therapeutic option against dengue disease. Copyright © 2017 by The American Association of Immunologists, Inc.

  15. Old and new therapeutics for Rheumatoid Arthritis: in vivo models and drug development

    DEFF Research Database (Denmark)

    Sardar, Samra; Andersson, Åsa

    2016-01-01

    Development of novel drugs for treatment of chronic inflammatory diseases is to a large extent dependent on the availability of good experimental in vivo models in order to perform preclinical tests of new drugs and for the identification of novel drug targets. Here, we review a number of existing...... of in vivo models during development of anti-rheumatic drugs; from Methotrexate to various antibody treatments, to novel drugs that are, or have recently been, in clinical trials. For novel drugs, we have explored websites for clinical trials. Although one Rheumatoid Arthritis in vivo model cannot mirror...

  16. Continued development of modeling tools and theory for rf heating. Final report

    International Nuclear Information System (INIS)

    Smithe, D.N.

    1998-01-01

    The work performed during the grant has been reported long before this date, specifically in: (1) the grant's annual performance report for 1991, MRC/WDC-R-277; (2) the published AIP Conference Proceedings number-sign 244, Radio Frequency Power in Plasmas, Charleston, SC 1991, ''Evaluation of Wave Dispersion, Mode-Conversion, and Damping for ECRH with Exact Relativistic Corrections,'' by D.N. Smithe and P.L. Colestock; and (3) an unpublished paper entitled ''Temperature Anisotropy and Rotation Upgrades to the ICRF Modules in SNAP and TRANSP'', presented at the 1992 ICRF Modeling and Theory Workshop, at the Princeton Plasma Physics Laboratory. This final report contains copies of number (1). The specifics of the grant's final months' activities, which to the authors recollection have never been reported to the DOE, are as follows. The original grant, which was to terminate August 15, 1991, was extended without additional funds to October 31, 1992. The primary reason for the extension was to permit attendance at the 1992 ICRF Modeling and Theory Workshop at the Princeton Plasma Physics Laboratory (PPPL), which was finally held August 17--18, 1992, after having been rescheduled several times during the summer of 1992. The body of this report contains copies of the 1991 annual report, which gives detailed discussion of the work accomplished

  17. Meson dynamics beyond the quark model: a study of final state interactions

    International Nuclear Information System (INIS)

    Au, K.L.; Pennington, M.R.; Morgan, D.

    1986-09-01

    A scalar glueball is predicted in the 1 GeV mass region. The present analysis is concerned with experimental evidence for such a state. Recent high statistics results on central dimeson production at the ISR enable the authors to perform an extensive new coupled channel analysis of I = O S-wave ππ and KK-bar final states. This unambiguously reveals three resonances in the 1 GeV region - S 1 (991), S 2 (988) and epsilon(900) - where the naive quark model expects just two. These new features are discussed including how they may be confirmed experimentally and their present interpretation. The S 1 (991) is a plausible candidate for the scalar glueball. Other production reactions are examined (heavy flavour decays and γγ reactions) which lead to the same final states. (author)

  18. Therapeutic Targeting of AXL Receptor Tyrosine Kinase Inhibits Tumor Growth and Intraperitoneal Metastasis in Ovarian Cancer Models

    Directory of Open Access Journals (Sweden)

    Pinar Kanlikilicer

    2017-12-01

    Full Text Available Despite substantial improvements in the treatment strategies, ovarian cancer is still the most lethal gynecological malignancy. Identification of drug treatable therapeutic targets and their safe and effective targeting is critical to improve patient survival in ovarian cancer. AXL receptor tyrosine kinase (RTK has been proposed to be an important therapeutic target for metastatic and advanced-stage human ovarian cancer. We found that AXL-RTK expression is associated with significantly shorter patient survival based on the The Cancer Genome Atlas patient database. To target AXL-RTK, we developed a chemically modified serum nuclease-stable AXL aptamer (AXL-APTAMER, and we evaluated its in vitro and in vivo antitumor activity using in vitro assays as well as two intraperitoneal animal models. AXL-aptamer treatment inhibited the phosphorylation and the activity of AXL, impaired the migration and invasion ability of ovarian cancer cells, and led to the inhibition of tumor growth and number of intraperitoneal metastatic nodules, which was associated with the inhibition of AXL activity and angiogenesis in tumors. When combined with paclitaxel, in vivo systemic (intravenous [i.v.] administration of AXL-aptamer treatment markedly enhanced the antitumor efficacy of paclitaxel in mice. Taken together, our data indicate that AXL-aptamers successfully target in vivo AXL-RTK and inhibit its AXL activity and tumor growth and progression, representing a promising strategy for the treatment of ovarian cancer.

  19. Surface chemistry and size influence the release of model therapeutic nanoparticles from poly(ethylene glycol) hydrogels

    International Nuclear Information System (INIS)

    Hume, Stephanie L.; Jeerage, Kavita M.

    2013-01-01

    Nanoparticles have emerged as promising therapeutic and diagnostic tools, due to their unique physicochemical properties. The specific core and surface chemistries, as well as nanoparticle size, play critical roles in particle transport and interaction with biological tissue. Localized delivery of therapeutics from hydrogels is well established, but these systems generally release molecules with hydrodynamic radii less than ∼5 nm. Here, model nanoparticles with biologically relevant surface chemistries and diameters between 10 and 35 nm are analyzed for their release from well-characterized hydrogels. Functionalized gold nanoparticles or quantum dots were encapsulated in three-dimensional poly(ethylene glycol) hydrogels with varying mesh size. Nanoparticle size, surface chemistry, and hydrogel mesh size all influenced the release of particles from the hydrogel matrix. Size influenced nanoparticle release as expected, with larger particles releasing at a slower rate. However, citrate-stabilized gold nanoparticles were not released from hydrogels. Negatively charged carboxyl or positively charged amine-functionalized quantum dots were released from hydrogels at slower rates than neutrally charged PEGylated nanoparticles of similar size. Transmission electron microscopy images of gold nanoparticles embedded within hydrogel sections demonstrated uniform particle distribution and negligible aggregation, independent of surface chemistry. The nanoparticle-hydrogel interactions observed in this work will aid in the development of localized nanoparticle delivery systems.

  20. Therapeutic effects of remediating autophagy failure in a mouse model of Alzheimer disease by enhancing lysosomal proteolysis.

    Science.gov (United States)

    Yang, Dun-Sheng; Stavrides, Philip; Mohan, Panaiyur S; Kaushik, Susmita; Kumar, Asok; Ohno, Masuo; Schmidt, Stephen D; Wesson, Daniel W; Bandyopadhyay, Urmi; Jiang, Ying; Pawlik, Monika; Peterhoff, Corrinne M; Yang, Austin J; Wilson, Donald A; St George-Hyslop, Peter; Westaway, David; Mathews, Paul M; Levy, Efrat; Cuervo, Ana M; Nixon, Ralph A

    2011-07-01

    The extensive autophagic-lysosomal pathology in Alzheimer disease (AD) brain has revealed a major defect: in the proteolytic clearance of autophagy substrates. Autophagy failure contributes on several levels to AD pathogenesis and has become an important therapeutic target for AD and other neurodegenerative diseases. We recently observed broad therapeutic effects of stimulating autophagic-lysosomal proteolysis in the TgCRND8 mouse model of AD that exhibits defective proteolytic clearance of autophagic substrates, robust intralysosomal amyloid-β peptide (Aβ) accumulation, extracellular β-amyloid deposition and cognitive deficits. By genetically deleting the lysosomal cysteine protease inhibitor, cystatin B (CstB), to selectively restore depressed cathepsin activities, we substantially cleared Aβ, ubiquitinated proteins and other autophagic substrates from autolysosomes/lysosomes and rescued autophagic-lysosomal pathology, as well as reduced total Aβ40/42 levels and extracellular amyloid deposition, highlighting the underappreciated importance of the lysosomal system for Aβ clearance. Most importantly, lysosomal remediation prevented the marked learning and memory deficits in TgCRND8 mice. Our findings underscore the pathogenic significance of autophagic-lysosomal dysfunction in AD and demonstrate the value of reversing this dysfunction as an innovative therapeautic strategy for AD.

  1. Potential therapeutic and protective effect of curcumin against stroke in the male albino stroke-induced model rats.

    Science.gov (United States)

    Zhang, Yuanyuan; Yan, Yi; Cao, Yi; Yang, Yongtao; Zhao, Qing; Jing, Rui; Hu, Jiayi; Bao, Juan

    2017-08-15

    The present study was carried out to understand the therapeutic effect of curcumin (CUR) against stroke in the experimental animal model. The study investigates the healing effect of CUR on mitochondrial dysfunction and inflammation. Male albino, Wistar strain rats were used for the induction of middle cerebral artery occlusion (MCAO), and reperfusion. Enzyme-linked immunosorbent assay (ELISA) was used for the determination of interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) in the brain region. Western blot analysis was used to determine the protein expression levels of Bax, Bcl-2, p53, and Sirt1. The water level was determined in brain region by using standard method. Experimental results indicated that the use of CUR significantly reduced brain edema and water content. IL-6 and TNF-α were significantly reduced in the brain region following use of CUR. Mitochondrial membrane potential (MMP) also reduced significantly after CUR treatment. Protein expression of p53 and Bax were significantly reduced, whereas Bcl-2 and Sirt1 were increased following CUR treatment. Taking all these data together, it is suggested that the use of CUR may be a potential therapeutic agent for the treatment of stroke. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Animal Models of Diabetic Macrovascular Complications: Key Players in the Development of New Therapeutic Approaches

    Directory of Open Access Journals (Sweden)

    Suvi E. Heinonen

    2015-01-01

    Full Text Available Diabetes mellitus is a lifelong, incapacitating metabolic disease associated with chronic macrovascular complications (coronary heart disease, stroke, and peripheral vascular disease and microvascular disorders leading to damage of the kidneys (nephropathy and eyes (retinopathy. Based on the current trends, the rising prevalence of diabetes worldwide will lead to increased cardiovascular morbidity and mortality. Therefore, novel means to prevent and treat these complications are needed. Under the auspices of the IMI (Innovative Medicines Initiative, the SUMMIT (SUrrogate markers for Micro- and Macrovascular hard end points for Innovative diabetes Tools consortium is working on the development of novel animal models that better replicate vascular complications of diabetes and on the characterization of the available models. In the past years, with the high level of genomic information available and more advanced molecular tools, a very large number of models has been created. Selecting the right model for a specific study is not a trivial task and will have an impact on the study results and their interpretation. This review gathers information on the available experimental animal models of diabetic macrovascular complications and evaluates their pros and cons for research purposes as well as for drug development.

  3. Investigating the empirical support for therapeutic targets proposed by the temporal experience of pleasure model in schizophrenia: A systematic review.

    Science.gov (United States)

    Edwards, Clementine J; Cella, Matteo; Tarrier, Nicholas; Wykes, Til

    2015-10-01

    Anhedonia and amotivation are substantial predictors of poor functional outcomes in people with schizophrenia and often present a formidable barrier to returning to work or building relationships. The Temporal Experience of Pleasure Model proposes constructs which should be considered therapeutic targets for these symptoms in schizophrenia e.g. anticipatory pleasure, memory, executive functions, motivation and behaviours related to the activity. Recent reviews have highlighted the need for a clear evidence base to drive the development of targeted interventions. To review systematically the empirical evidence for each TEP model component and propose evidence-based therapeutic targets for anhedonia and amotivation in schizophrenia. Following PRISMA guidelines, PubMed and PsycInfo were searched using the terms "schizophrenia" and "anhedonia". Studies were included if they measured anhedonia and participants had a diagnosis of schizophrenia. The methodology, measures and main findings from each study were extracted and critically summarised for each TEP model construct. 80 independent studies were reviewed and executive functions, emotional memory and the translation of motivation into actions are highlighted as key deficits with a strong evidence base in people with schizophrenia. However, there are many relationships that are unclear because the empirical work is limited by over-general tasks and measures. Promising methods for research which have more ecological validity include experience sampling and behavioural tasks assessing motivation. Specific adaptations to Cognitive Remediation Therapy, Cognitive Behavioural Therapy and the utilisation of mobile technology to enhance representations and emotional memory are recommended for future development. Copyright © 2015. Published by Elsevier B.V.

  4. The Dual Rounding Model: Forging Therapeutic Alliances 
in Oncology and Palliative Care.

    Science.gov (United States)

    Baxley, Carey E

    2016-04-01

    Inpatients with solid tumors at Duke University Hospital in Durham, NC, are cared for in a dynamic integrated care model that incorporates medical oncology and palliative care. This has profound implications for patients, their loved ones, medical and surgical staff, and oncology nurses. As a nurse with less than three years of experience, my participation in a setting that uses the Dual Rounding Model has accelerated my professional and personal development. During a typical shift, I am an oncology nurse, a palliative care nurse, and a hospice nurse.
.

  5. Vascular risk factors and Alzheimer’s disease. Therapeutic approaches in mouse models

    NARCIS (Netherlands)

    Wiesmann, M.

    2017-01-01

    The first aim of this thesis was to elucidate the impact of major vascular risk factors like hypertension, apoE4 and stroke during the very early phase of Alzheimer’s disease (AD) using several mice models. Hypertension has proven to be associated with cerebrovascular impairment already at young age

  6. An experimental Toxoplasma gondii dose response challenge model to study therapeutic or vaccine efficacy in cats

    NARCIS (Netherlands)

    Cornelissen, J.B.W.J.; Giessen, van der J.W.B.; Takumi, K.; Teunis, P.F.M.; Wisselink, H.J.

    2014-01-01

    High numbers of Toxoplasma gondii oocysts in the environment are a risk factor to humans. The environmental contamination might be reduced by vaccinating the definitive host, cats. An experimental challenge model is necessary to quantitatively assess the efficacy of a vaccine or drug treatment.

  7. Final-year diagnostic radiography students' perception of role models within the profession.

    Science.gov (United States)

    Conway, Alinya; Lewis, Sarah; Robinson, John

    2008-01-01

    Within a clinical education setting, the value of role models and prescribed mentors can be seen as an important influence in shaping the student's future as a diagnostic radiographer. A study was undertaken to create a new understanding of how diagnostic radiography students perceive role models and professional behavior in the workforce. The study aimed to determine the impact of clinical education in determining modeling expectations, role model identification and attributes, and the integration of academic education and "hands-on" clinical practice in preparing diagnostic radiography students to enter the workplace. Thirteen final-year (third-year) diagnostic radiography students completed an hour-long interview regarding their experiences and perceptions of role models while on clinical placement. The key concepts that emerged illustrated that students gravitate toward radiographers who enjoy sharing practical experiences with students and are good communicators. Unique to diagnostic radiography, students made distinctions about the presence of role models in private versus public service delivery. This study gives insight to clinical educators in diagnostic radiography and wider allied health into how students perceive role models, interact with preceptors, and combine real-life experiences with formal learning.

  8. ADVANCED BIOMASS REBURNING FOR HIGH EFFICIENCY NOx CONTROL AND BIOMASS REBURNING - MODELING/ENGINEERING STUDIES JOINT FINAL REPORT; FINAL

    International Nuclear Information System (INIS)

    Vladimir M Zamansky; Mark S. Sheldon; Vitali V. Lissianski; Peter M. Maly; David K. Moyeda; Antonio Marquez; W. Randall Seeker

    2000-01-01

    This report presents results of studies under a Phase II SBIR program funded by the U. S. Department of Agriculture, and a closely coordinated project sponsored by the DOE National Energy Technology Laboratory (NETL, formerly FETC). The overall Phase II objective of the SBIR project is to experimentally optimize the biomass reburning technologies and conduct engineering design studies needed for process demonstration at full scale. The DOE project addresses supporting issues for the process design including modeling activities, economic studies of biomass handling, and experimental evaluation of slagging and fouling. The performance of biomass has been examined in a 300 kW (1 x 10(sup 6) Btu/hr) Boiler Simulator Facility under different experimental conditions. Fuels under investigation include furniture waste, willow wood and walnut shells. Tests showed that furniture pellets and walnut shells provided similar NO(sub x) control as that of natural gas in basic reburning at low heat inputs. Maximum NO(sub x) reduction achieved with walnut shell and furniture pellets was 65% and 58% respectively. Willow wood provided a maximum NO(sub x) reduction of 50% and was no better than natural gas at any condition tested. The efficiency of biomass increases when N-agent is injected into reburning and/or burnout zones, or along with OFA (Advanced Reburning). Co-injection of Na(sub 2)CO(sub 3) with N-agent further increases efficiency of NO(sub x) reduction. Maximum NO(sub x) reduction achieved with furniture pellets and willow wood in Advanced Reburning was 83% and 78% respectively. All combustion experiments of the Phase II project have been completed. All objectives of the experimental tasks were successfully met. The kinetic model of biomass reburning has been developed. Model agrees with experimental data for a wide range of initial conditions and thus correctly represents main features of the reburning process. Modeling suggests that the most important factors that provide

  9. Aespoe Pillar Stability Experiment. Final coupled 3D thermo-mechanical modeling. Preliminary particle mechanical modeling

    International Nuclear Information System (INIS)

    Wanne, Toivo; Johansson, Erik; Potyondy, David

    2004-02-01

    SKB is planning to perform a large-scale pillar stability experiment called APSE (Aespoe Pillar Stability Experiment) at Aespoe HRL. The study is focused on understanding and control of progressive rock failure in hard crystalline rock and damage caused by high stresses. The elastic thermo-mechanical modeling was carried out in three dimensions because of the complex test geometry and in-situ stress tensor by using a finite-difference modeling software FLAC3D. Cracking and damage formation were modeled in the area of interest (pillar between two large scale holes) in two dimensions by using the Particle Flow Code (PFC), which is based on particle mechanics. FLAC and PFC were coupled to minimize the computer resources and the computing time. According to the modeling the initial temperature rises from 15 deg C to about 65 deg C in the pillar area during the heating period of 120 days. The rising temperature due to thermal expansion induces stresses in the pillar area and after 120 days heating the stresses have increased about 33% from the excavation induced maximum stress of 150 MPa to 200 MPa in the end of the heating period. The results from FLAC3D model showed that only regions where the crack initiation stress has exceeded were identified and they extended to about two meters down the hole wall. These could be considered the areas where damage may occur during the in-situ test. When the other hole is pressurized with a 0.8 MPa confining pressure it yields that 5 MPa more stress is needed to damage the rock than without confining pressure. This makes the damaged area in some degree smaller. High compressive stresses in addition to some tensile stresses might induce some AE (acoustic emission) activity in the upper part of the hole from the very beginning of the test and are thus potential areas where AE activities may be detected. Monitoring like acoustic emissions will be measured during the test execution. The 2D coupled PFC-FLAC modeling indicated that

  10. Aespoe Pillar Stability Experiment. Final coupled 3D thermo-mechanical modeling. Preliminary particle mechanical modeling

    Energy Technology Data Exchange (ETDEWEB)

    Wanne, Toivo; Johansson, Erik; Potyondy, David [Saanio and Riekkola Oy, Helsinki (Finland)

    2004-02-01

    SKB is planning to perform a large-scale pillar stability experiment called APSE (Aespoe Pillar Stability Experiment) at Aespoe HRL. The study is focused on understanding and control of progressive rock failure in hard crystalline rock and damage caused by high stresses. The elastic thermo-mechanical modeling was carried out in three dimensions because of the complex test geometry and in-situ stress tensor by using a finite-difference modeling software FLAC3D. Cracking and damage formation were modeled in the area of interest (pillar between two large scale holes) in two dimensions by using the Particle Flow Code (PFC), which is based on particle mechanics. FLAC and PFC were coupled to minimize the computer resources and the computing time. According to the modeling the initial temperature rises from 15 deg C to about 65 deg C in the pillar area during the heating period of 120 days. The rising temperature due to thermal expansion induces stresses in the pillar area and after 120 days heating the stresses have increased about 33% from the excavation induced maximum stress of 150 MPa to 200 MPa in the end of the heating period. The results from FLAC3D model showed that only regions where the crack initiation stress has exceeded were identified and they extended to about two meters down the hole wall. These could be considered the areas where damage may occur during the in-situ test. When the other hole is pressurized with a 0.8 MPa confining pressure it yields that 5 MPa more stress is needed to damage the rock than without confining pressure. This makes the damaged area in some degree smaller. High compressive stresses in addition to some tensile stresses might induce some AE (acoustic emission) activity in the upper part of the hole from the very beginning of the test and are thus potential areas where AE activities may be detected. Monitoring like acoustic emissions will be measured during the test execution. The 2D coupled PFC-FLAC modeling indicated that

  11. Molecular Modeling of Estrogen Receptor Alpha Mutated Breast Cancer to Guide New Therapeutic Strategies

    Science.gov (United States)

    2017-10-01

    Care and Use of Laboratory Animals in DOD Programs" (c) Animal Welfare Regulations (CFR Title 9, Chapter 1, Subchapter A, Parts 1-3) In...vivo work, the animal protocol has been approved (see appendix) and we have received approval to use the cell lines and xenograft model, HCI-013EI...Report Significant changes in use or care of human subjects, vertebrate animals , biohazards, and/or select agents Nothing to Report Significant changes

  12. Comparing the cardiovascular therapeutic indices of glycopyrronium and tiotropium in an integrated rat pharmacokinetic, pharmacodynamic and safety model

    Energy Technology Data Exchange (ETDEWEB)

    Trifilieff, Alexandre; Ethell, Brian T. [Respiratory Disease Area, Novartis Institutes for Biomedical Research, Wimblehurst Road, Horsham, West Sussex RH12 5AB (United Kingdom); Sykes, David A. [Respiratory Disease Area, Novartis Institutes for Biomedical Research, Wimblehurst Road, Horsham, West Sussex RH12 5AB (United Kingdom); School of Life Sciences, Queen' s Medical Centre, University of Nottingham, Nottingham, NG7 2UH (United Kingdom); Watson, Kenny J.; Collingwood, Steve [Respiratory Disease Area, Novartis Institutes for Biomedical Research, Wimblehurst Road, Horsham, West Sussex RH12 5AB (United Kingdom); Charlton, Steven J. [Respiratory Disease Area, Novartis Institutes for Biomedical Research, Wimblehurst Road, Horsham, West Sussex RH12 5AB (United Kingdom); School of Life Sciences, Queen' s Medical Centre, University of Nottingham, Nottingham, NG7 2UH (United Kingdom); Kent, Toby C., E-mail: tobykent@me.com [Respiratory Disease Area, Novartis Institutes for Biomedical Research, Wimblehurst Road, Horsham, West Sussex RH12 5AB (United Kingdom)

    2015-08-15

    Long acting inhaled muscarinic receptor antagonists, such as tiotropium, are widely used as bronchodilator therapy for chronic obstructive pulmonary disease (COPD). Although this class of compounds is generally considered to be safe and well tolerated in COPD patients the cardiovascular safety of tiotropium has recently been questioned. We describe a rat in vivo model that allows the concurrent assessment of muscarinic antagonist potency, bronchodilator efficacy and a potential for side effects, and we use this model to compare tiotropium with NVA237 (glycopyrronium bromide), a recently approved inhaled muscarinic antagonist for COPD. Anaesthetized Brown Norway rats were dosed intratracheally at 1 or 6 h prior to receiving increasing doses of intravenous methacholine. Changes in airway resistance and cardiovascular function were recorded and therapeutic indices were calculated against the ED{sub 50} values for the inhibition of methacholine-induced bronchoconstriction. At both time points studied, greater therapeutic indices for hypotension and bradycardia were observed with glycopyrronium (19.5 and 28.5 fold at 1 h; > 200 fold at 6 h) than with tiotropium (1.5 and 4.2 fold at 1 h; 4.6 and 5.5 fold at 6 h). Pharmacokinetic, protein plasma binding and rat muscarinic receptor binding properties for both compounds were determined and used to generate an integrated model of systemic M{sub 2} muscarinic receptor occupancy, which predicted significantly higher M{sub 2} receptor blockade at ED{sub 50} doses with tiotropium than with glycopyrronium. In our preclinical model there was an improved safety profile for glycopyrronium when compared with tiotropium. - Highlights: • We use an in vivo rat model to study CV safety of inhaled muscarinic antagonists. • We integrate protein and receptor binding and PK of tiotropium and glycopyrrolate. • At ED{sub 50} doses for bronchoprotection we model systemic M{sub 2} receptor occupancy. • Glycopyrrolate demonstrates lower M

  13. Modelling Fanconi anemia pathogenesis and therapeutics using integration-free patient-derived iPSCs.

    Science.gov (United States)

    Liu, Guang-Hui; Suzuki, Keiichiro; Li, Mo; Qu, Jing; Montserrat, Nuria; Tarantino, Carolina; Gu, Ying; Yi, Fei; Xu, Xiuling; Zhang, Weiqi; Ruiz, Sergio; Plongthongkum, Nongluk; Zhang, Kun; Masuda, Shigeo; Nivet, Emmanuel; Tsunekawa, Yuji; Soligalla, Rupa Devi; Goebl, April; Aizawa, Emi; Kim, Na Young; Kim, Jessica; Dubova, Ilir; Li, Ying; Ren, Ruotong; Benner, Chris; Del Sol, Antonio; Bueren, Juan; Trujillo, Juan Pablo; Surralles, Jordi; Cappelli, Enrico; Dufour, Carlo; Esteban, Concepcion Rodriguez; Belmonte, Juan Carlos Izpisua

    2014-07-07

    Fanconi anaemia (FA) is a recessive disorder characterized by genomic instability, congenital abnormalities, cancer predisposition and bone marrow (BM) failure. However, the pathogenesis of FA is not fully understood partly due to the limitations of current disease models. Here, we derive integration free-induced pluripotent stem cells (iPSCs) from an FA patient without genetic complementation and report in situ gene correction in FA-iPSCs as well as the generation of isogenic FANCA-deficient human embryonic stem cell (ESC) lines. FA cellular phenotypes are recapitulated in iPSCs/ESCs and their adult stem/progenitor cell derivatives. By using isogenic pathogenic mutation-free controls as well as cellular and genomic tools, our model serves to facilitate the discovery of novel disease features. We validate our model as a drug-screening platform by identifying several compounds that improve hematopoietic differentiation of FA-iPSCs. These compounds are also able to rescue the hematopoietic phenotype of FA patient BM cells.

  14. Modeling silicon diode energy response factors for use in therapeutic photon beams.

    Science.gov (United States)

    Eklund, Karin; Ahnesjö, Anders

    2009-10-21

    Silicon diodes have good spatial resolution, which makes them advantageous over ionization chambers for dosimetry in fields with high dose gradients. However, silicon diodes overrespond to low-energy photons, that are more abundant in scatter which increase with large fields and larger depths. We present a cavity-theory-based model for a general response function for silicon detectors at arbitrary positions within photon fields. The model uses photon and electron spectra calculated from fluence pencil kernels. The incident photons are treated according to their energy through a bipartition of the primary beam photon spectrum into low- and high-energy components. Primary electrons from the high-energy component are treated according to Spencer-Attix cavity theory. Low-energy primary photons together with all scattered photons are treated according to large cavity theory supplemented with an energy-dependent factor K(E) to compensate for energy variations in the electron equilibrium. The depth variation of the response for an unshielded silicon detector has been calculated for 5 x 5 cm(2), 10 x 10 cm(2) and 20 x 20 cm(2) fields in 6 and 15 MV beams and compared with measurements showing that our model calculates response factors with deviations less than 0.6%. An alternative method is also proposed, where we show that one can use a correlation with the scatter factor to determine the detector response of silicon diodes with an error of less than 3% in 6 MV and 15 MV photon beams.

  15. Modeling Fanconi Anemia pathogenesis and therapeutics using integration-free patient-derived iPSCs

    Science.gov (United States)

    Montserrat, Nuria; Tarantino, Carolina; Gu, Ying; Yi, Fei; Xu, Xiuling; Zhang, Weiqi; Ruiz, Sergio; Plongthongkum, Nongluk; Zhang, Kun; Masuda, Shigeo; Nivet, Emmanuel; Tsunekawa, Yuji; Soligalla, Rupa Devi; Goebl, April; Aizawa, Emi; Kim, Na Young; Kim, Jessica; Dubova, Ilir; Li, Ying; Ren, Ruotong; Benner, Chris; del Sol, Antonio; Bueren, Juan; Trujillo, Juan Pablo; Surralles, Jordi; Cappelli, Enrico; Dufour, Carlo; Esteban, Concepcion Rodriguez; Belmonte, Juan Carlos Izpisua

    2014-01-01

    Fanconi Anemia (FA) is a recessive disorder characterized by genomic instability, congenital abnormalities, cancer predisposition and bone marrow failure. However, the pathogenesis of FA is not fully understood partly due to the limitations of current disease models. Here, we derive integration-free induced pluripotent stem cells (iPSCs) from an FA patient without genetic complementation and report in situ gene correction in FA-iPSCs as well as the generation of isogenic FANCA deficient human embryonic stem cell (ESC) lines. FA cellular phenotypes are recapitulated in iPSCs/ESCs and their adult stem/progenitor cell derivatives. By using isogenic pathogenic mutation-free controls as well as cellular and genomic tools, our model serves to facilitate the discovery of novel disease features. We validate our model as a drug-screening platform by identifying several compounds that improve hematopoietic differentiation of FA-iPSCs. These compounds are also able to rescue the hematopoietic phenotype of FA-patient bone marrow cells. PMID:24999918

  16. Modeling silicon diode energy response factors for use in therapeutic photon beams

    International Nuclear Information System (INIS)

    Eklund, Karin; Ahnesjoe, Anders

    2009-01-01

    Silicon diodes have good spatial resolution, which makes them advantageous over ionization chambers for dosimetry in fields with high dose gradients. However, silicon diodes overrespond to low-energy photons, that are more abundant in scatter which increase with large fields and larger depths. We present a cavity-theory-based model for a general response function for silicon detectors at arbitrary positions within photon fields. The model uses photon and electron spectra calculated from fluence pencil kernels. The incident photons are treated according to their energy through a bipartition of the primary beam photon spectrum into low- and high-energy components. Primary electrons from the high-energy component are treated according to Spencer-Attix cavity theory. Low-energy primary photons together with all scattered photons are treated according to large cavity theory supplemented with an energy-dependent factor K(E) to compensate for energy variations in the electron equilibrium. The depth variation of the response for an unshielded silicon detector has been calculated for 5 x 5 cm 2 , 10 x 10 cm 2 and 20 x 20 cm 2 fields in 6 and 15 MV beams and compared with measurements showing that our model calculates response factors with deviations less than 0.6%. An alternative method is also proposed, where we show that one can use a correlation with the scatter factor to determine the detector response of silicon diodes with an error of less than 3% in 6 MV and 15 MV photon beams.

  17. Mathematic model of regional economy development by the final result of labor resources

    Science.gov (United States)

    Zaitseva, Irina; Malafeev, Oleg; Strekopytov, Sergei; Bondarenko, Galina; Lovyannikov, Denis

    2018-04-01

    This article presents the mathematic model of regional economy development based on the result of labor resources. The solution of a region development-planning problem is considered for the period of long-lasting planning taking into account the beginning and the end of the planned period. The challenge is to find the distribution of investments in the main and additional branches of the regional economy, which will provide simultaneous transaction of all major sectors of the regional economy from the given condition to the predetermined final state.

  18. Final technical report for DE-SC00012633 AToM (Advanced Tokamak Modeling)

    Energy Technology Data Exchange (ETDEWEB)

    Holland, Christopher [Univ. of California, San Diego, CA (United States); Orlov, Dmitri [Univ. of California, San Diego, CA (United States); Izzo, Valerie [Univ. of California, San Diego, CA (United States)

    2018-02-05

    This final report for the AToM project documents contributions from University of California, San Diego researchers over the period of 9/1/2014 – 8/31/2017. The primary focus of these efforts was on performing validation studies of core tokamak transport models using the OMFIT framework, including development of OMFIT workflow scripts. Additional work was performed to develop tools for use of the nonlinear magnetohydrodynamics code NIMROD in OMFIT, and its use in the study of runaway electron dynamics in tokamak disruptions.

  19. Windfield and trajectory models for tornado-propelled objects. Final report

    International Nuclear Information System (INIS)

    Redmann, G.H.; Radbill, J.R.; Marte, J.E.; Dergarabedian, P.; Fendell, F.E.

    1983-03-01

    This is the final report of a three-phased research project to develop a six-degree-of-freedom mathematical model to predict the trajectories of tornado-propelled objects. The model is based on the meteorological, aerodynamic, and dynamic processes that govern the trajectories of missiles in a tornadic windfield. The aerodynamic coefficients for the postulated missiles were obtained from full-scale wind tunnel tests on a 12-inch pipe and car and from drop tests. Rocket sled tests were run whereby the 12-inch pipe and car were injected into a worst-case tornado windfield in order to verify the trajectory model. To simplify and facilitate the use of the trajectory model for design applications without having to run the computer program, this report gives the trajectory data for NRC-postulated missiles in tables based on given variables of initial conditions of injection and tornado windfield. Complete descriptions of the tornado windfield and trajectory models are presented. The trajectory model computer program is also included for those desiring to perform trajectory or sensitivity analyses beyond those included in the report or for those wishing to examine other missiles and use other variables

  20. A highly invasive human glioblastoma pre-clinical model for testing therapeutics

    Directory of Open Access Journals (Sweden)

    Cao Brian

    2008-12-01

    Full Text Available Abstract Animal models greatly facilitate understanding of cancer and importantly, serve pre-clinically for evaluating potential anti-cancer therapies. We developed an invasive orthotopic human glioblastoma multiforme (GBM mouse model that enables real-time tumor ultrasound imaging and pre-clinical evaluation of anti-neoplastic drugs such as 17-(allylamino-17-demethoxy geldanamycin (17AAG. Clinically, GBM metastasis rarely happen, but unexpectedly most human GBM tumor cell lines intrinsically possess metastatic potential. We used an experimental lung metastasis assay (ELM to enrich for metastatic cells and three of four commonly used GBM lines were highly metastatic after repeated ELM selection (M2. These GBM-M2 lines grew more aggressively orthotopically and all showed dramatic multifold increases in IL6, IL8, MCP-1 and GM-CSF expression, cytokines and factors that are associated with GBM and poor prognosis. DBM2 cells, which were derived from the DBTRG-05MG cell line were used to test the efficacy of 17AAG for treatment of intracranial tumors. The DMB2 orthotopic xenografts form highly invasive tumors with areas of central necrosis, vascular hyperplasia and intracranial dissemination. In addition, the orthotopic tumors caused osteolysis and the skull opening correlated to the tumor size, permitting the use of real-time ultrasound imaging to evaluate antitumor drug activity. We show that 17AAG significantly inhibits DBM2 tumor growth with significant drug responses in subcutaneous, lung and orthotopic tumor locations. This model has multiple unique features for investigating the pathobiology of intracranial tumor growth and for monitoring systemic and intracranial responses to antitumor agents.

  1. Canine Models of Duchenne Muscular Dystrophy and Their Use in Therapeutic Strategies

    Science.gov (United States)

    Kornegay, Joe N.; Bogan, Janet R.; Bogan, Daniel J.; Childers, Martin K.; Li, Juan; Nghiem, Peter; Detwiler, David A.; Larsen, C. Aaron; Grange, Robert W.; Bhavaraju-Sanka, Ratna K.; Tou, Sandra; Keene, Bruce P.; Howard, James F.; Wang, Jiahui; Fan, Zheng; Schatzberg, Scott J.; Styner, Martin A.; Flanigan, Kevin M.; Xiao, Xiao; Hoffman, Eric P.

    2013-01-01

    Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder in which the loss of dystrophin causes progressive degeneration of skeletal and cardiac muscle. Potential therapies that carry substantial risk, such as gene and cell-based approaches, must first be tested in animal models, notably the mdx mouse and several dystrophin-deficient breeds of dogs, including golden retriever muscular dystrophy (GRMD). Affected dogs have a more severe phenotype, in keeping with that of DMD, so may better predict disease pathogenesis and treatment efficacy. We and others have developed various phenotypic tests to characterize disease progression in the GRMD model. These biomarkers range from measures of strength and joint contractures to magnetic resonance imaging. Some of these tests are routinely used in clinical veterinary practice, while others require specialized equipment and expertise. By comparing serial measurements from treated and untreated groups, one can document improvement or delayed progression of disease. Potential treatments for DMD may be broadly categorized as molecular, cellular, or pharmacologic. The GRMD model has increasingly been used to assess efficacy of a range of these therapies. While some of these studies have largely provided general proof-of-concept for the treatment under study, others have demonstrated efficacy using the biomarkers discussed. Importantly, just as symptoms in DMD vary among patients, GRMD dogs display remarkable phenotypic variation. While confounding statistical analysis in preclinical trials, this variation offers insight regarding the role that modifier genes play in disease pathogenesis. By correlating functional and mRNA profiling results, gene targets for therapy development can be identified. PMID:22218699

  2. Stargardt disease: clinical features, molecular genetics, animal models and therapeutic options

    Science.gov (United States)

    Tanna, Preena; Strauss, Rupert W; Fujinami, Kaoru; Michaelides, Michel

    2017-01-01

    Stargardt disease (STGD1; MIM 248200) is the most prevalent inherited macular dystrophy and is associated with disease-causing sequence variants in the gene ABCA4. Significant advances have been made over the last 10 years in our understanding of both the clinical and molecular features of STGD1, and also the underlying pathophysiology, which has culminated in ongoing and planned human clinical trials of novel therapies. The aims of this review are to describe the detailed phenotypic and genotypic characteristics of the disease, conventional and novel imaging findings, current knowledge of animal models and pathogenesis, and the multiple avenues of intervention being explored. PMID:27491360

  3. Therapeutic effect of an injectable sustained-release sinomenine hydrochloride and sodium hyaluronate compound in a rabbit model of osteoarthritis.

    Science.gov (United States)

    Liu, Wen-Guang; Ling, Pei-Xue; Lin, Xiu-Kun; Chen, Jian-Ying; Wang, Shao-Jin; Li, Peng; Wu, Xiao-Juan; Zhao, Dong-Mei; Liu, Sheng-Hou

    2012-07-01

    While intra-articular injection of sinomenine hydrochloride has a therapeutic effect on osteoarthritis, it has a short half-life, and is thermolabile and photolabile. The aim of this research was to evaluate the sustained-release of sinomenine hydrochloride from an injectable sinomenine hydrochloride and sodium hyaluronate compound (CSSSI) and its therapeutic effect in a rabbit model of osteoarthritis following intra-articular injection. An injectable compound consisting of 1% sodium hyaluronate and 2.5% sinomenine hydrochloride was prepared and kept as the experiment group, and 2.5% sinomenine hydrochloride was prepared and kept as the control group. The cumulative mass release was measured at different time points in each group in vitro. Sixty-five male Zelanian rabbits were randomly divided into five groups: 15 (30 knees) each for the control, sodium hyaluronate, sinomenine hydrochloride, and CSSSI groups respectively, and five (10 knees) for the modeling group. Papain was injected into both knees of each rabbit for model establishment. Subsequently, 0.2 ml of the corresponding drugs was injected into the articular cavities of the remaining experiment groups, while the control group was treated with 0.2 ml normal saline. All groups were treated once a week for 4 weeks. Seven days after the last treatment, knees were anatomized to perform pathological observations and Mankin's evaluation of the synovium. Four groups were compared using the SPSS 13.0 software package. In the in vitro sustained-release experiments, 90% of the drug was released in the experiment group 360 minutes following the injection. Comparison of the Mankin's evaluations of the four groups illustrated statistical discrepancies (P sodium hyaluronate/sinomenine hydrochloride groups, statistical significance was uniformly obtained. Moreover, sodium hyaluronate and sinomenine hydrochloride treatments showed significant improvement over the modeling control (P sodium hyaluronate vs. sinomenine

  4. Myotubular myopathy and the neuromuscular junction: a novel therapeutic approach from mouse models

    Directory of Open Access Journals (Sweden)

    James J. Dowling

    2012-11-01

    Myotubular myopathy (MTM is a severe congenital muscle disease characterized by profound weakness, early respiratory failure and premature lethality. MTM is defined by muscle biopsy findings that include centralized nuclei and disorganization of perinuclear organelles. No treatments currently exist for MTM. We hypothesized that aberrant neuromuscular junction (NMJ transmission is an important and potentially treatable aspect of the disease pathogenesis. We tested this hypothesis in two murine models of MTM. In both models we uncovered evidence of a disorder of NMJ transmission: fatigable weakness, improved strength with neostigmine, and electrodecrement with repetitive nerve stimulation. Histopathological analysis revealed abnormalities in the organization, appearance and size of individual NMJs, abnormalities that correlated with changes in acetylcholine receptor gene expression and subcellular localization. We additionally determined the ability of pyridostigmine, an acetylcholinesterase inhibitor, to ameliorate aspects of the behavioral phenotype related to NMJ dysfunction. Pyridostigmine treatment resulted in significant improvement in fatigable weakness and treadmill endurance. In all, these results describe a newly identified pathological abnormality in MTM, and uncover a potential disease-modifying therapy for this devastating disorder.

  5. Therapeutic effects of neurotrophic factors in experimental spinal cord injury models

    Directory of Open Access Journals (Sweden)

    Enomoto M

    2016-03-01

    Full Text Available Mitsuhiro Enomoto1,21Department of Orthopaedic and Spinal Surgery, Graduate School, 2Hyperbaric Medical Center, Tokyo Medical and Dental University, Tokyo, JapanAbstract: Neurotrophic factors (NFs play important roles in regenerative medicine approaches to mitigate primary and secondary damage after spinal cord injury (SCI because their receptors are still present in the injured spinal cord even though the expression of the NFs themselves is decreased. Several reports have shown that NF administration increases regenerative signaling after SCI, particularly by stimulating axonal growth. However, few NFs cross the blood–brain barrier, and most of them show low stability and limited diffusion within the central nervous system. To overcome this problem, transplantation strategies using genetically modified NF-secreting Schwann cells, neural and glial progenitor cells, and mesenchymal stem cells have been applied to animal models of SCI. In particular, multifunctional NFs that bind to TrkB, TrkC, and p75NTR receptors have been discovered in the last decade and utilized in preclinical cell therapies for spinal cord repair. To achieve functional recovery after SCI, it is important to consider the different effects of each NF on axonal regeneration, and strategies should be established to specifically harness the multifunctional properties of NFs. This review provides an overview of multifunctional NFs combined with cell therapy in experimental SCI models and a proposal to implement their use as a clinically viable therapy.Keywords: spinal cord injury, neurotrophic factor, multineurotrophin, regeneration, cell transplantation

  6. Therapeutic benefits of a component of coffee in a rat model of Alzheimer's disease.

    Science.gov (United States)

    Basurto-Islas, Gustavo; Blanchard, Julie; Tung, Yunn Chyn; Fernandez, Jose R; Voronkov, Michael; Stock, Maxwell; Zhang, Sherry; Stock, Jeffry B; Iqbal, Khalid

    2014-12-01

    A minor component of coffee unrelated to caffeine, eicosanoyl-5-hydroxytryptamide (EHT), provides protection in a rat model for Alzheimer's disease (AD). In this model, viral expression of the phosphoprotein phosphatase 2A (PP2A) endogenous inhibitor, the I2(PP2A), or SET protein in the brains of rats leads to several characteristic features of AD including cognitive impairment, tau hyperphosphorylation, and elevated levels of cytoplasmic amyloid-β protein. Dietary supplementation with EHT for 6-12 months resulted in substantial amelioration of all these defects. The beneficial effects of EHT could be associated with its ability to increase PP2A activity by inhibiting the demethylation of its catalytic subunit PP2Ac. These findings raise the possibility that EHT may make a substantial contribution to the apparent neuroprotective benefits associated with coffee consumption as evidenced by numerous epidemiologic studies indicating that coffee drinkers have substantially lowered risk of developing AD. Copyright © 2014 Elsevier Inc. All rights reserved.

  7. Pulsed magnetic field enhances therapeutic efficiency of mesenchymal stem cells in chronic neuropathic pain model.

    Science.gov (United States)

    Mert, Tufan; Kurt, Akif Hakan; Altun, İdiris; Celik, Ahmet; Baran, Furkan; Gunay, Ismail

    2017-05-01

    Cell-based or magnetic field therapies as alternative approaches to pain management have been tested in several experimental pain models. The aim of this study therefore was to investigate the actions of the cell-based therapy (adipose tissue derived mesenchymal stem cells; ADMSC) or pulsed magnetic field (PMF) therapy and magneto-cell therapy (combination of ADMSC and PMF) in chronic constriction nerve injury model (CCI). The actions of individual ADMSC (route dependent [systemic or local], time-dependent [a day or a week after surgery]), or PMF and their combination (magneto-cell) therapies on hyperalgesia and allodynia were investigated by using thermal plantar test and a dynamic plantar aesthesiometer, respectively. In addition, various cytokine levels (IL-1β, IL-6, and IL-10) of rat sciatic nerve after CCI were analyzed. Following the CCI, both latency and threshold significantly decreased. ADMSC or PMF significantly increased latencies and thresholds. The combination of ADMSC with PMF even more significantly increased latency and threshold when compared with ADMSC alone. However, ADMSC-induced decrease in pro-inflammatory or increase in anti-inflammatory cytokines levels were partially prevented by PMF treatments. Present findings may suggest that both cell-based and magnetic therapies can effectively attenuate chronic neuropathic pain symptoms. Combined magneto-cell therapy may also efficiently reverse neuropathic signs. Bioelectromagnetics. 38:255-264, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  8. Stargardt disease: clinical features, molecular genetics, animal models and therapeutic options.

    Science.gov (United States)

    Tanna, Preena; Strauss, Rupert W; Fujinami, Kaoru; Michaelides, Michel

    2017-01-01

    Stargardt disease (STGD1; MIM 248200) is the most prevalent inherited macular dystrophy and is associated with disease-causing sequence variants in the gene ABCA4 Significant advances have been made over the last 10 years in our understanding of both the clinical and molecular features of STGD1, and also the underlying pathophysiology, which has culminated in ongoing and planned human clinical trials of novel therapies. The aims of this review are to describe the detailed phenotypic and genotypic characteristics of the disease, conventional and novel imaging findings, current knowledge of animal models and pathogenesis, and the multiple avenues of intervention being explored. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  9. The pathogenomics of McArdle disease--genes, enzymes, models, and therapeutic implications.

    Science.gov (United States)

    Nogales-Gadea, Gisela; Santalla, Alfredo; Brull, Astrid; de Luna, Noemi; Lucia, Alejandro; Pinós, Tomàs

    2015-03-01

    Numerous biomedical advances have been made since Carl and Gerty Cori discovered the enzyme phosphorylase in the 1940s and the Scottish physician Brian McArdle reported in 1951 a previously 'undescribed disorder characterized by a gross failure of the breakdown in muscle of glycogen'. Today we know that this disorder, commonly known as 'McArdle disease', is caused by inherited deficiency of the muscle isoform of glycogen phosphorylase (GP). Here we review the main aspects of the 'pathogenomics' of this disease including, among others: the spectrum of mutations in the gene (PYGM) encoding muscle GP; the interplay between the different tissue GP isoforms in cellular cultures and in patients; what can we learn from naturally occurring and recently laboratory-generated animal models of the disease; and potential therapies.

  10. Model-based therapeutic correction of hypothalamic-pituitary-adrenal axis dysfunction.

    Directory of Open Access Journals (Sweden)

    Amos Ben-Zvi

    2009-01-01

    Full Text Available The hypothalamic-pituitary-adrenal (HPA axis is a major system maintaining body homeostasis by regulating the neuroendocrine and sympathetic nervous systems as well modulating immune function. Recent work has shown that the complex dynamics of this system accommodate several stable steady states, one of which corresponds to the hypocortisol state observed in patients with chronic fatigue syndrome (CFS. At present these dynamics are not formally considered in the development of treatment strategies. Here we use model-based predictive control (MPC methodology to estimate robust treatment courses for displacing the HPA axis from an abnormal hypocortisol steady state back to a healthy cortisol level. This approach was applied to a recent model of HPA axis dynamics incorporating glucocorticoid receptor kinetics. A candidate treatment that displays robust properties in the face of significant biological variability and measurement uncertainty requires that cortisol be further suppressed for a short period until adrenocorticotropic hormone levels exceed 30% of baseline. Treatment may then be discontinued, and the HPA axis will naturally progress to a stable attractor defined by normal hormone levels. Suppression of biologically available cortisol may be achieved through the use of binding proteins such as CBG and certain metabolizing enzymes, thus offering possible avenues for deployment in a clinical setting. Treatment strategies can therefore be designed that maximally exploit system dynamics to provide a robust response to treatment and ensure a positive outcome over a wide range of conditions. Perhaps most importantly, a treatment course involving further reduction in cortisol, even transient, is quite counterintuitive and challenges the conventional strategy of supplementing cortisol levels, an approach based on steady-state reasoning.

  11. Final Thesis Models in European Teacher Education and Their Orientation towards the Academy and the Teaching Profession

    Science.gov (United States)

    Råde, Anders

    2014-01-01

    This study concerns different final thesis models in the research on teacher education in Europe and their orientation towards the academy and the teaching profession. In scientific journals, 33 articles support the occurrence of three models: the portfolio model, with a mainly teaching-professional orientation; the thesis model, with a mainly…

  12. Tests of the Standard Model with Multi boson final states at the ATLAS Detector

    CERN Document Server

    Gonella, Giulia; The ATLAS collaboration

    2018-01-01

    Measurements of the cross sections of the production of pairs of electroweak gauge bosons at the LHC constitute stringent tests of the electroweak sector of the Standard Model and provide a model- independent means to search for new physics at the TeV scale. The ATLAS collaboration has performed detailed measurements of integrated and differential cross sections of the production of heavy di-boson pairs in fully-leptonic and semi-leptonic final states at centre-of-mass energies of 13 TeV. The results are compared to predictions and provide constraints on new physics, by setting limits on anomalous triple gauge couplings. Some analyses in this area will be reviewed and their main results summarised.

  13. Optimization and validation of an existing, surgical and robust dry eye rat model for the evaluation of therapeutic compounds.

    Science.gov (United States)

    Joossen, Cedric; Lanckacker, Ellen; Zakaria, Nadia; Koppen, Carina; Joossens, Jurgen; Cools, Nathalie; De Meester, Ingrid; Lambeir, Anne-Marie; Delputte, Peter; Maes, Louis; Cos, Paul

    2016-05-01

    The aim of this research was to optimize and validate an animal model for dry eye, adopting clinically relevant evaluation parameters. Dry eye was induced in female Wistar rats by surgical removal of the exorbital lacrimal gland. The clinical manifestations of dry eye were evaluated by tear volume measurements, corneal fluorescein staining, cytokine measurements in tear fluid, MMP-9 mRNA expression and CD3(+) cell infiltration in the conjunctiva. The animal model was validated by treatment with Restasis(®) (4 weeks) and commercial dexamethasone eye drops (2 weeks). Removal of the exorbital lacrimal gland resulted in 50% decrease in tear volume and a gradual increase in corneal fluorescein staining. Elevated levels of TNF-α and IL-1α have been registered in tear fluid together with an increase in CD3(+) cells in the palpebral conjunctiva when compared to control animals. Additionally, an increase in MMP-9 mRNA expression was recorded in conjunctival tissue. Reference treatment with Restasis(®) and dexamethasone eye drops had a positive effect on all evaluation parameters, except on tear volume. This rat dry eye model was validated extensively and judged appropriate for the evaluation of novel compounds and therapeutic preparations for dry eye disease. Copyright © 2016 Elsevier Ltd. All rights reserved.

  14. Animal models of arrhythmogenic right ventricular cardiomyopathy: what have we learned and where do we go? Insight for therapeutics.

    Science.gov (United States)

    Padrón-Barthe, Laura; Domínguez, Fernando; Garcia-Pavia, Pablo; Lara-Pezzi, Enrique

    2017-09-01

    Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare genetically-determined cardiac heart muscle disorder characterized by fibro-fatty replacement of the myocardium that results in heart failure and sudden cardiac death (SCD), predominantly in young males. The disease is often caused by mutations in genes encoding proteins of the desmosomal complex, with a significant minority caused by mutations in non-desmosomal proteins. Existing treatment options are based on SCD prevention with the implantable cardioverter defibrillator, antiarrhythmic drugs, and anti-heart failure medication. Heart transplantation may also be required and there is currently no cure. Several genetically modified animal models have been developed to characterize the disease, assess its progression, and determine the influence of potential environmental factors. These models have also been very valuable for translational therapeutic approaches, to screen new treatment options that prevent and/or reverse the disease. Here, we review the available ARVC animal models reported to date, highlighting the most important pathophysiological findings and discussing the effect of treatments tested so far in this setting. We also describe gaps in our knowledge of the disease, with the goal of stimulating research and improving patient outcomes.

  15. A novel murine model for evaluating bovine papillomavirus prophylactics/therapeutics for equine sarcoid-like tumours.

    Science.gov (United States)

    Bogaert, Lies; Woodham, Andrew W; Da Silva, Diane M; Martens, Ann; Meyer, Evelyne; Kast, W Martin

    2015-09-01

    Equine sarcoids are highly recurrent bovine papillomavirus (BPV)-induced fibroblastic neoplasms that are the most common skin tumours in horses. In order to facilitate the study of potential equine sarcoid prophylactics or therapeutics, which can be a slow and costly process in equines, a murine model for BPV-1 protein-expressing equine sarcoid-like tumours was developed in mice through stable transfection of BPV-1 E5 and E6 in a murine fibroblast tumour cell line (K-BALB). Like equine sarcoids, these murine tumour cells (BPV-KB) were of fibroblast origin, were tumorigenic and expressed BPV-1 proteins. As an initial investigation of the preclinical potential of this tumour model for equine sarcoids prophylactics, mice were immunized with BPV-1 E5E6 Venezuelan equine encephalitis virus replicon particles, prior to BPV-KB challenge, which resulted in an increased tumour-free period compared with controls, indicating that the BPV-KB murine model may be a valuable preclinical alternative to equine clinical trials.

  16. Curcumin's Neuroprotective Efficacy in Drosophila Model of Idiopathic Parkinson's Disease Is Phase Specific: Implication of its Therapeutic Effectiveness

    Science.gov (United States)

    Phom, Limamanen; Achumi, Bovito; Alone, Debasmita P.; Muralidhara

    2014-01-01

    Abstract Selective degeneration of dopaminergic neurons in the substantia nigra underlies the basic motor impairments of Parkinson's disease (PD). Curcumin has been used for centuries in traditional medicines in India. Our aim is to understand the efficacy of genotropic drug curcumin as a neuroprotective agent in PD. Analysis of different developmental stages in model organisms revealed that they are characterized by different patterns of gene expression which is similar to that of developmental stages of human. Genotropic drugs would be effective only during those life cycle stages for which their target molecules are available. Hence there exists a possibility that targets of genotropic compounds such as curcumin may not be present in all life stages. However, no reports are available in PD models illustrating the efficacy of curcumin in later phases of adult life. This is important because this is the period during which late-onset disorders such as idiopathic PD set in. To understand this paradigm, we tested the protective efficacy of curcumin in different growth stages (early, late health stage, and transition phase) in adult Drosophila flies. Results showed that it can rescue the motor defects during early stages of life but is ineffective at later phases. This observation was substantiated with the finding that curcumin treatment could replenish depleted brain dopamine levels in the PD model only during early stages of life cycle, clearly suggesting its limitation as a therapeutic agent in late-onset neurodegenerative disorders such as PD. PMID:25238331

  17. Investigation of modern methods of probalistic sensitivity analysis of final repository performance assessment models (MOSEL)

    International Nuclear Information System (INIS)

    Spiessl, Sabine; Becker, Dirk-Alexander

    2017-06-01

    Sensitivity analysis is a mathematical means for analysing the sensitivities of a computational model to variations of its input parameters. Thus, it is a tool for managing parameter uncertainties. It is often performed probabilistically as global sensitivity analysis, running the model a large number of times with different parameter value combinations. Going along with the increase of computer capabilities, global sensitivity analysis has been a field of mathematical research for some decades. In the field of final repository modelling, probabilistic analysis is regarded a key element of a modern safety case. An appropriate uncertainty and sensitivity analysis can help identify parameters that need further dedicated research to reduce the overall uncertainty, generally leads to better system understanding and can thus contribute to building confidence in the models. The purpose of the project described here was to systematically investigate different numerical and graphical techniques of sensitivity analysis with typical repository models, which produce a distinctly right-skewed and tailed output distribution and can exhibit a highly nonlinear, non-monotonic or even non-continuous behaviour. For the investigations presented here, three test models were defined that describe generic, but typical repository systems. A number of numerical and graphical sensitivity analysis methods were selected for investigation and, in part, modified or adapted. Different sampling methods were applied to produce various parameter samples of different sizes and many individual runs with the test models were performed. The results were evaluated with the different methods of sensitivity analysis. On this basis the methods were compared and assessed. This report gives an overview of the background and the applied methods. The results obtained for three typical test models are presented and explained; conclusions in view of practical applications are drawn. At the end, a recommendation

  18. Investigation of modern methods of probalistic sensitivity analysis of final repository performance assessment models (MOSEL)

    Energy Technology Data Exchange (ETDEWEB)

    Spiessl, Sabine; Becker, Dirk-Alexander

    2017-06-15

    Sensitivity analysis is a mathematical means for analysing the sensitivities of a computational model to variations of its input parameters. Thus, it is a tool for managing parameter uncertainties. It is often performed probabilistically as global sensitivity analysis, running the model a large number of times with different parameter value combinations. Going along with the increase of computer capabilities, global sensitivity analysis has been a field of mathematical research for some decades. In the field of final repository modelling, probabilistic analysis is regarded a key element of a modern safety case. An appropriate uncertainty and sensitivity analysis can help identify parameters that need further dedicated research to reduce the overall uncertainty, generally leads to better system understanding and can thus contribute to building confidence in the models. The purpose of the project described here was to systematically investigate different numerical and graphical techniques of sensitivity analysis with typical repository models, which produce a distinctly right-skewed and tailed output distribution and can exhibit a highly nonlinear, non-monotonic or even non-continuous behaviour. For the investigations presented here, three test models were defined that describe generic, but typical repository systems. A number of numerical and graphical sensitivity analysis methods were selected for investigation and, in part, modified or adapted. Different sampling methods were applied to produce various parameter samples of different sizes and many individual runs with the test models were performed. The results were evaluated with the different methods of sensitivity analysis. On this basis the methods were compared and assessed. This report gives an overview of the background and the applied methods. The results obtained for three typical test models are presented and explained; conclusions in view of practical applications are drawn. At the end, a recommendation

  19. Therapeutic effect of androgen therapy in a mouse model of aplastic anemia produced by short telomeres.

    Science.gov (United States)

    Bär, Christian; Huber, Nicolas; Beier, Fabian; Blasco, Maria A

    2015-10-01

    Aplastic anemia is a rare but life-threatening disorder characterized by cytopenia in at least two of the three blood lineages. A frequent feature of patients with aplastic anemia is that they have shorter telomeres than those of age-matched controls. Testosterone has been used for over half a century in the treatment of aplastic anemia. However, although remissions are frequent following hormone therapy, the molecular mechanism underlying the response to treatment has remained unknown. Here we explored the possibility that the recently described regulation of telomerase activity by sex hormones may be the mechanism responsible. To this end, we used a mouse model of aplastic anemia induced by short telomeres in the bone marrow compartment. We found that testosterone therapy results in telomerase up-regulation, improved blood counts, and a significant extension of life-span of these mice. Importantly, longitudinal follow-up studies revealed longer telomeres in peripheral blood in mice subjected to hormone treatment. Our results demonstrate that testosterone-mediated telomerase activation can attenuate or reverse aplastic anemia disease progression associated with the presence of short telomeres. Copyright© Ferrata Storti Foundation.

  20. In vitro modeling of skin dose and monitoring of DCA following therapeutic intervention

    International Nuclear Information System (INIS)

    Balajee, Adayabalam S.; Dainiak, Nicholas

    2016-01-01

    Human skin is the largest organ of the body accounting for approximately 16% of the total bodyweight. Skin is readily exposed to ionizing radiation during either accidental or intentional exposure such as radiotherapy or other medical procedures because it constitutes the interface between environment and internal organs. Estimation of accurate entrance skin dose and maximum absorbed dose (MAD) is crucial to prevent serious skin injuries. Cutaneous Radiation Syndrome (CRS) is defined by a number of pathological changes manifested in the skin and severity of these changes depend on Liner Energy Transfer (LET), dose, dose-rate, geometry of exposure and volume of body part exposed. In most of the radiological accident scenarios, reconstructive dosimetry in the skin has been performed using physical (thermoluminescence and optical stimulated luminescence), biological (cytogenetics) and computational methods/models to manage radiation exposed victims.Results of the cytogenetic testing performed at the CBL on a few patients will be discussed to illustrate the potential use of DCA and other cytogenetic techniques such as micronuclei and multicolor FISH in monitoring the health of radiotherapy patients

  1. Modelling the induction of cell death and chromosome damage by therapeutic protons

    CERN Document Server

    Carante, M P

    2015-01-01

    A two-parameter biophysical model cal led BIANCA (BIophysical ANalysis of Cell death and chromosome Aberrations), which assumes a pivotal role for DNA cluster damage and for “lethal” chromosome aberrations, was applied to calculate cell death and chromosome aberrations for normal and radio-resistant cells along a 62-MeV eye melanoma proton beam. The yield of DNA “Cluster Lesions” and the probability for a chromosome fragment of not being rejoined with any partne r were adjustable parameters. In line with other works, the beam effectiveness at inducing both biological endpoints was found to increase with increasing depth, and high levels of damage were found also beyond the dose fall-off, due to the higher biological effectiveness of low-energy protons. This implies that assuming a constant RBE along the whole SOBP, as is currently done in clinical practice, may be sub-optimal, also implying a possible underestimation of normal tissue damage. Furthermore, the calculations suggested that fo...

  2. Therapeutic Potential of Tolerogenic Dendritic Cells in IBD: From Animal Models to Clinical Application

    Directory of Open Access Journals (Sweden)

    Raquel Cabezón

    2013-01-01

    Full Text Available The gut mucosa undergoes continuous antigenic exposure from food antigens, commensal flora derived ligands, and pathogens. This constant stimulation results in controlled inflammatory responses that are effectively suppressed by multiple factors. This tight regulation, necessary to maintain intestinal homeostasis, is affected during inflammatory bowel diseases (IBD resulting in altered immune responses to harmless microorganisms. Dendritic cells (DCs are sentinels of immunity, located in peripheral and lymphoid tissues, which are essential for homeostasis of T cell-dependent immune responses. The expression of a particular set of pathogen recognition receptors allows DCs to initiate immune responses. However, in the absence of danger signals, different DC subsets can induce active tolerance by inducing regulatory T cells (Treg, inhibiting inflammatory T helper cell responses, or both. Interestingly, several protocols to generate clinical grade tolerogenic DC (tol-DCs in vitro have been described, opening the possibility to restore the intestinal homeostasis to bacterial flora by cellular therapy. In this review, we discuss different DC subsets and their role in IBD. Additionally, we will review preclinical studies performed in animal models while describing recent characterization of tol-DCs from Crohn’s disease patients for clinical application.

  3. Therapeutically Targeting the Inflammasome Product in a Chimeric Model of Endometriosis-Related Surgical Adhesions.

    Science.gov (United States)

    Stocks, Meredith M; Crispens, Marta A; Ding, Tianbing; Mokshagundam, Shilpa; Bruner-Tran, Kaylon L; Osteen, Kevin G

    2017-08-01

    Development of adhesions commonly occurs in association with surgery for endometriosis. Even in the absence of surgery, women with endometriosis appear to be at an enhanced risk of developing adhesions. In the current study, we utilized a chimeric mouse model of experimental endometriosis in order to examine the role of inflammasome activation in the development of postsurgical adhesions. Mice were randomized to receive peritoneal injections of human endometrial tissue fragments or endometrial tissue conditioned media (CM) from women with or without endometriosis 16 hours after ovariectomy and placement of an estradiol-releasing silastic capsule. A subset of mice receiving CM was also treated with interleukin (IL) 1 receptor antagonist (IL-1ra). Our studies demonstrate that peritoneal injection of endometrial tissue fragments near the time of surgery resulted in extensive adhesive disease regardless of tissue origin. However, adhesion scores were significantly higher in mice receiving CM from tissues acquired from patients with endometriosis compared to control tissue CM ( P = .0001). Cytokine bead array analysis of endometrial CM revealed enhanced expression of IL-1β from patients with endometriosis compared to controls ( P endometriosis as a potential causal factor in their increased susceptibility of developing postsurgical adhesions. Thus, targeting inflammasome activation may be an effective strategy for the prevention of surgical adhesions in patients with endometriosis.

  4. Adipose-derived Stem Cells Stimulated with n-Butylidenephthalide Exhibit Therapeutic Effects in a Mouse Model of Parkinson's Disease.

    Science.gov (United States)

    Chi, Kang; Fu, Ru-Huei; Huang, Yu-Chuen; Chen, Shih-Yin; Hsu, Ching-Ju; Lin, Shinn-Zong; Tu, Chi-Tang; Chang, Li-Hsun; Wu, Ping-An; Liu, Shih-Ping

    2018-03-01

    Parkinson's disease (PD) causes motor dysfunction and dopaminergic cell death. Drug treatments can effectively reduce symptoms but often cause unwanted side effects. Stem cell therapies using cell replacement or indirect beneficial secretomes have recently emerged as potential therapeutic strategies. Although various types of stem cells have been proposed as possible candidates, adipose-derived stem cells (ADSCs) are easily obtainable, more abundant, less ethically disputed, and able to differentiate into multiple cell lineages. However, treatment of PD using adult stem cells is known to be less efficacious than neuron or embryonic stem cell transplantation. Therefore, improved therapies are urgently needed. n-Butylidenephthalide (BP), which is extracted from Angelica sinensis, has been shown to have anti-inflammatory and neuroprotective effects. Indeed, we previously demonstrated that BP treatment of ADSCs enhances the expression of neurogenesis and homing factors such as nuclear receptor related 1 protein, stromal-derived factor 1, and brain-derived neurotrophic factor. In the present study, we examined the ability of BP-pretreated ADSC transplantation to improve PD motor symptoms and protect dopamine neurons in a mouse model of PD. We evaluated the results using neuronal behavior tests such as beam walking, rotarod, and locomotor activity tests. ADSCs with or without BP pretreatment were transplanted into the striatum. Our findings demonstrated that ADSC transplantation improved motor abilities with varied efficacies and that BP stimulation improved the therapeutic effects of transplantation. Dopaminergic cell numbers returned to normal in ADSC-transplanted mice after 22 d. In summary, stimulating ADSCs with BP improved PD recovery efficiency. Thus, our results provide important new strategies to improve stem cell therapies for neurodegenerative diseases in future studies.

  5. Plantar pressure relief under the metatarsal heads: therapeutic insole design using three-dimensional finite element model of the foot.

    Science.gov (United States)

    Chen, Wen-Ming; Lee, Sung-Jae; Lee, Peter Vee Sin

    2015-02-26

    Therapeutic footwear with specially-made insoles is often used in people with diabetes and rheumatoid arthritis to relieve ulcer risks and pain due to high pressures from areas beneath bony prominences of the foot, in particular to the metatarsal heads (MTHs). In a three-dimensional finite element study of the foot and footwear with sensitivity analysis, effects of geometrical variations of a therapeutic insole, in terms of insole thicknesses and metatarsal pad (MP) placements, on local peak plantar pressure under MTHs and stress/strain states within various forefoot tissues, were determined. A validated musculoskeletal finite element model of the human foot was employed. Analyses were performed in a simulated muscle-demanding instant in gait. For many design combinations, increasing insole thicknesses consistently reduce peak pressures and internal tissue strain under MTHs, but the effects reach a plateau when insole becomes very thick (e.g., a value of 12.7mm or greater). Altering MP placements, however, showed a proximally- and a distally-placed MP could result in reverse effects on MTH pressure-relief. The unsuccessful outcome due to a distally-placed MP may attribute to the way it interacts with plantar tissue (e.g., plantar fascia) adjacent to the MTH. A uniform pattern of tissue compression under metatarsal shaft is necessary for a most favorable pressure-relief under MTHs. The designated functions of an insole design can best be achieved when the insole is very thick, and when the MP can achieve a uniform tissue compression pattern adjacent to the MTH. Copyright © 2015 Elsevier Ltd. All rights reserved.

  6. Therapeutic effects of FuZhiSan on Alzheimer's disease rat model:evaluation with PET imaging

    International Nuclear Information System (INIS)

    Guo Zhe; Zhang Jinming; Yao Shulin; Feng Huiru; Li Xuling; Yin Dayi; Tian Jiahe

    2010-01-01

    Objective: To assess the feasibility of using PET molecular imaging to evaluate the therapeutic effects of traditional Chinese medicine FuZhiSan (FZS) on the model of aging Alzheimer's disease (AD) rats. Methods: Twenty aged AD rats (Sparague-Dawley rats,male) were randomly divided into FZS treated group (n = 10) and control group (n = 10). Another 10 healthy adult rats were as blank controls. Morris water maze record system was used for cognitive function assessment. Before and after FZS treatment 18 F-fluorodeoxyglucose (FDG) and 11 C-2- [4'-(methylamino) phenyl] benzothiazol-6-ol (PIB) PET imaging was undertaken. After post-treatment imaging procedures the brain tissues of all animals were taken for histochemical study, such as staining with HE, congo red, amyloid β (Aβ) immunofluorescence, 5-bromo-2-deoxyuridine (BrdU) immunofluorescence and NeuN immunofluorescence. Paired t-test was performed with SPSS 13.0 software for the data analysis. Results: The cognitive dysfunction of aging AD rats was improved after FZS treatment. The escape latency in FZS treated group was significantly shorter than that of control group ((32.5 ±10.8) s vs (102.6±8.8) s, t =15.7987, P=0. 0001). Diffuse neuronal loss and Aβ deposition were detected in the hippocampus and cortex in the aged AD rats. The imaging data showed that brain glucose metabolism was amended in FZS treated group while the abatement of amyloid deposition was not significant. Immunofluorescence results indicated that the neuronal proliferation was more remarkable in FZS treated group. Conclusions: It may be feasible to use PET imaging as a method to evaluate the therapeutic effect in AD rats. FZS may ameliorate memory dysfunction of aged AD rats. Its mechanism may be partly contributed to the enhancement of the neuronal proliferation and survival. (authors)

  7. In vivo effects of traditional Ayurvedic formulations in Drosophila melanogaster model relate with therapeutic applications.

    Directory of Open Access Journals (Sweden)

    Vibha Dwivedi

    Full Text Available Ayurveda represents the traditional medicine system of India. Since mechanistic details of therapy in terms of current biology are not available in Ayurvedic literature, modern scientific studies are necessary to understand its major concepts and procedures. It is necessary to examine effects of the whole Ayurvedic formulations rather than their "active" components as is done in most current studies.We tested two different categories of formulations, a Rasayana (Amalaki Rasayana or AR, an herbal derivative and a Bhasma (Rasa-Sindoor or RS, an organo-metallic derivative of mercury, for effects on longevity, development, fecundity, stress-tolerance, and heterogeneous nuclear ribonucleoprotein (hnRNP levels of Drosophila melanogaster using at least 200 larvae or flies for each assay.A 0.5% (weight/volume supplement of AR or RS affected life-history and other physiological traits in distinct ways. While the size of salivary glands, hnRNP levels in larval tissues, and thermotolerance of larvae/adult flies improved significantly following feeding either of the two formulations, the median life span and starvation resistance improved only with AR. Feeding on AR or RS supplemented food improved fecundity differently. Feeding of larvae and adults with AR increased the fecundity while the same with RS had opposite effect. On the contrary, feeding larvae on normal food and adults on AR supplement had no effect on fecundity but a comparable regime of feeding on RS-supplemented food improved fecundity. RS feeding did not cause heavy metal toxicity.The present study with two Ayurvedic formulations reveals formulation-specific effects on several parameters of the fly's life, which seem to generally agree with their recommended human usages in Ayurvedic practices. Thus, Drosophila, with its very rich genetic tools and well-worked-out developmental pathways promises to be a very good model for examining the cellular and molecular bases of the effects of

  8. Targeting therapeutics to the glomerulus with nanoparticles.

    Science.gov (United States)

    Zuckerman, Jonathan E; Davis, Mark E

    2013-11-01

    Nanoparticles are an enabling technology for the creation of tissue-/cell-specific therapeutics that have been investigated extensively as targeted therapeutics for cancer. The kidney, specifically the glomerulus, is another accessible site for nanoparticle delivery that has been relatively overlooked as a target organ. Given the medical need for the development of more potent, kidney-targeted therapies, the use of nanoparticle-based therapeutics may be one such solution to this problem. Here, we review the literature on nanoparticle targeting of the glomerulus. Specifically, we provide a broad overview of nanoparticle-based therapeutics and how the unique structural characteristics of the glomerulus allow for selective, nanoparticle targeting of this area of the kidney. We then summarize literature examples of nanoparticle delivery to the glomerulus and elaborate on the appropriate nanoparticle design criteria for glomerular targeting. Finally, we discuss the behavior of nanoparticles in animal models of diseased glomeruli and review examples of nanoparticle therapeutic approaches that have shown promise in animal models of glomerulonephritic disease. Copyright © 2013 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

  9. 78 FR 70598 - Submission for Review: Request for External Review (3206-NEW); Model Notice of Final Internal...

    Science.gov (United States)

    2013-11-26

    ... notice to enrollees about the result of any final internal adverse benefit determination, their external... OFFICE OF PERSONNEL MANAGEMENT Submission for Review: Request for External Review (3206-NEW); Model Notice of Final Internal Adverse Benefit Determination and Case Intake Form AGENCY: U.S. Office of...

  10. A comparison of the COG and MCNP codes in computational neutron capture therapy modeling, Part II: gadolinium neutron capture therapy models and therapeutic effects.

    Science.gov (United States)

    Wangerin, K; Culbertson, C N; Jevremovic, T

    2005-08-01

    The goal of this study was to evaluate the COG Monte Carlo radiation transport code, developed and tested by Lawrence Livermore National Laboratory, for gadolinium neutron capture therapy (GdNCT) related modeling. The validity of COG NCT model has been established for this model, and here the calculation was extended to analyze the effect of various gadolinium concentrations on dose distribution and cell-kill effect of the GdNCT modality and to determine the optimum therapeutic conditions for treating brain cancers. The computational results were compared with the widely used MCNP code. The differences between the COG and MCNP predictions were generally small and suggest that the COG code can be applied to similar research problems in NCT. Results for this study also showed that a concentration of 100 ppm gadolinium in the tumor was most beneficial when using an epithermal neutron beam.

  11. Study of GMSB models with photon final states using the ATLAS detector

    Energy Technology Data Exchange (ETDEWEB)

    Terwort, Mark

    2009-11-30

    Models with gauge mediated supersymmetry breaking (GMSB) provide a possible mechanism to mediate supersymmetry breaking to the electroweak scale. In these models the lightest-supersymmetric particle is the gravitino, while the next-to-lightest supersymmetric particle is either the lightest neutralino or a slepton. In the former case final states with large missing transverse energy from the gravitinos, multiple jets and two hard photons are expected in pp-collisions at the LHC. Depending on the lifetime of the neutralino the photons might not point back to the interaction vertex, which requires dedicated search strategies. Additionally, this feature can be used to measure the neutralino lifetime using either the timing information from the electromagnetic calorimeter or the reconstructed photon direction. Together with the measurements of kinematic endpoints in invariant mass distributions, the lifetime can be used as input for fits of the GMSB model and for the determination of the underlying parameters. The signal selection and the discovery potential for GMSB models with photons in the nal state are discussed using simulated data of the ATLAS detector. In addition, the measurement of supersymmetric particle masses and of the neutralino lifetime as well as the results of the global GMSB fits are presented. (orig.)

  12. Therapeutic Nanodevices

    Science.gov (United States)

    Lee, Stephen; Ruegsegger, Mark; Barnes, Philip; Smith, Bryan; Ferrari, Mauro

    Therapeutic nanotechnology offers minimally invasive therapies with high densities of function concentrated in small volumes, features that may reduce patient morbidity and mortality. Unlike other areas of nanotechnology, novel physical properties associated with nanoscale dimensionality are not the raison d'être of therapeutic nanotechnology, whereas the aggregation of multiple biochemical (or comparably precise) functions into controlled nanoarchitectures is. Multifunctionality is a hallmark of emerging nanotherapeutic devices, and multifunctionality can allow nanotherapeutic devices to perform multistep work processes, with each functional component contributing to one or more nanodevice subroutine such that, in aggregate, subroutines sum to a cogent work process. Cannonical nanotherapeutic subroutines include tethering (targeting) to sites of disease, dispensing measured doses of drug (or bioactive compound), detection of residual disease after therapy and communication with an external clinician/operator. Emerging nanotherapeutics thus blur the boundaries between medical devices and traditional pharmaceuticals. Assembly of therapeutic nanodevices generally exploits either (bio)material self-assembly properties or chemoselective bioconjugation techniques, or both. Given the complexity, composition, and the necessity for their tight chemical and structural definition inherent in the nature of nanotherapeutics, their cost of goods (COGs) might exceed that of (already expensive) biologics. Early therapeutic nanodevices will likely be applied to disease states which exhibit significant unmet patient need (cancer and cardiovascular disease), while application to other disease states well-served by conventional therapy may await perfection of nanotherapeutic design and assembly protocols.

  13. Measuring oxygen tension modulation, induced by a new pre-radiotherapy therapeutic, in a mammary window chamber mouse model

    Science.gov (United States)

    Schafer, Rachel; Gmitro, Arthur F.

    2015-03-01

    Tumor regions under hypoxic or low oxygen conditions respond less effectively to many treatment strategies, including radiation therapy. A novel investigational therapeutic, NVX-108 (NuvOx Pharma), has been developed to increase delivery of oxygen through the use of a nano-emulsion of dodecofluoropentane. By raising pO2 levels prior to delivering radiation, treatment efficacy may be improved. To aid in evaluating the novel drug, oxygen tension was quantitatively measured, spatially and temporally, to record the effect of administrating NVX-108 in an orthotopic mammary window chamber mouse model of breast cancer. The oxygen tension was measured through the use of an oxygen-sensitive coating, comprised of phosphorescent platinum porphyrin dye embedded in a polystyrene matrix. The coating, applied to the surface of the coverslip of the window chamber through spin coating, is placed in contact with the mammary fat pad to record the oxygenation status of the surface tissue layer. Prior to implantation of the window chamber, a tumor is grown in the SCID mouse model by injection of MCF-7 cells into the mammary fat pad. Two-dimensional spatial distributions of the pO2 levels were obtained through conversion of measured maps of phosphorescent lifetime. The resulting information on the spatial and temporal variation of the induced oxygen modulation could provide valuable insight into the optimal timing between administration of NVX-108 and radiation treatment to provide the most effective treatment outcome.

  14. Regulatory T Cell Induced by Poria cocos Bark Exert Therapeutic Effects in Murine Models of Atopic Dermatitis and Food Allergy

    Directory of Open Access Journals (Sweden)

    Min-Jung Bae

    2016-01-01

    Full Text Available The prevalence of allergic disorders including atopic dermatitis (AD and food allergy (FA has increased dramatically in pediatric populations, but there is no effective drug available for their management. Therefore, trials are required for the development of safe therapeutic agents such as herbal medicines. We determined whether orally administered Poria cocos bark (PCB extract could exert immunosuppressive effects on allergic and inflammatory symptoms of AD and FA. For both AD, which was induced using house dust mite extract, and FA, which was induced by exposure to ovalbumin, model mice were orally treated with PCB extract for 62 days and 18 days, respectively. We also investigated the inductive effect of PCB extract on the generation and maintenance of Foxp3+CD4+ regulatory T cells (Tregs. The symptoms of AD and FA were ameliorated by the administration of PCB extract. Furthermore, PCB extract inhibited the Th2-related cytokines and increased the population of Foxp3+CD4+ Tregs in both AD and FA models. In ex vivo experiments, PCB extract promoted the functional differentiation of Foxp3+CD4+ Tregs, which is dependent on aryl hydrocarbon receptor activation. Thus, PCB extract has potential as an oral immune suppressor for the treatment of AD and FA through the generation of Tregs.

  15. Therapeutic Efficacy of Topically Applied Antioxidant Medicinal Plant Extracts in a Mouse Model of Experimental Dry Eye.

    Science.gov (United States)

    Choi, Won; Lee, Jee Bum; Cui, Lian; Li, Ying; Li, Zhengri; Choi, Ji Suk; Lee, Hyo Seok; Yoon, Kyung Chul

    2016-01-01

    Purpose. To investigate the therapeutic effects of topical administration of antioxidant medicinal plant extracts in a mouse model of experimental dry eye (EDE). Methods. Eye drops containing balanced salt solution (BSS) or 0.001%, 0.01%, and 0.1% extracts were applied for the treatment of EDE. Tear volume, tear film break-up time (BUT), and corneal fluorescein staining scores were measured 10 days after desiccating stress. In addition, we evaluated the levels of interleukin- (IL-) 1β, tumor necrosis factor- (TNF-) α, IL-6, interferon- (IFN-) γ, and IFN-γ associated chemokines, percentage of CD4+C-X-C chemokine receptor type 3 positive (CXCR3+) T cells, goblet cell density, number of 4-hydroxy-2-nonenal (4-HNE) positive cells, and extracellular reactive oxygen species (ROS) production. Results. Compared to the EDE and BSS control groups, the mice treated with topical application of the 0.1% extract showed significant improvements in all clinical parameters, IL-1β, IL-6, TNF-α, and IFN-γ levels, percentage of CD4+CXCR3+ T cells, goblet cell density, number of 4-HNE-positive cells, and extracellular ROS production (P model mice.

  16. From Chemotherapy to Combined Targeted Therapeutics: In Vitro and in Vivo Models to Decipher Intra-tumor Heterogeneity

    Directory of Open Access Journals (Sweden)

    Guido Gambara

    2018-02-01

    Full Text Available Recent advances in next-generation sequencing and other omics technologies capable to map cell fate provide increasing evidence on the crucial role of intra-tumor heterogeneity (ITH for cancer progression. The different facets of ITH, from genomic to microenvironmental heterogeneity and the hierarchical cellular architecture originating from the cancer stem cell compartment, contribute to the range of tumor phenotypes. Decoding these complex data resulting from the analysis of tumor tissue complexity poses a challenge for developing novel therapeutic strategies that can counteract tumor evolution and cellular plasticity. To achieve this aim, the development of in vitro and in vivo cancer models that resemble the complexity of ITH is crucial in understanding the interplay of cells and their (microenvironment and, consequently, in testing the efficacy of new targeted treatments and novel strategies of tailoring combinations of treatments to the individual composition of the tumor. This challenging approach may be an important cornerstone in overcoming the development of pharmaco-resistances during multiple lines of treatment. In this paper, we report the latest advances in patient-derived 3D (PD3D cell cultures and patient-derived tumor xenografts (PDX as in vitro and in vivo models that can retain the genetic and phenotypic heterogeneity of the tumor tissue.

  17. Serial micro-CT assessment of the therapeutic effects of rosiglitazone in a bleomycin-induced lung fibrosis mouse model

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Eun Jung; Jin, Gong Yong; Bok, Se Mi; Han, Young Min; Lee, Young Sun; Jung, Myung Ja; Kwon, Keun Sang [Research Institute of Clinical Medicine of Chonbuk National University, Biomedical Research Institute of Chonbuk National University Hospital, Institute for Medical Sciences, Jeonju (Korea, Republic of)

    2014-08-15

    The aim of this study was to assess the therapeutic effects of rosiglitazone with serial micro-CT findings before and after rosiglitazone administration in a lung fibrosis mouse model induced with bleomycin. We instilled the bleomycin solution directly into the trachea in twenty mice (female, C57BL/6 mice). After the instillation with bleomycin, mice were closely observed for 3 weeks and then all mice were scanned using micro-CT without sacrifice. At 3 weeks, the mice were treated with rosiglitazone on days 21 to 27 if they had abnormal CT findings (n = 9, 45%). For the mice treated with rosiglitazone, we performed micro-CT with mouse sacrifice 2 weeks after the rosiglitazone treatment completion. We assessed the abnormal CT findings (ground glass attenuation, consolidation, bronchiectasis, reticular opacity, and honeycombing) using a five-point scale at 3 and 6 weeks using Wilcoxon-signed ranked test. The micro-CT findings were correlated with the histopathologic results. One out of nine (11.1%) mice improved completely. In terms of consolidation, all mice (100%) showed marked decrease from 3.1 ± 1.4 at 3 weeks to 0.9 ± 0.9 at 6 weeks (p = 0.006). At 6 weeks, mild bronchiectasis (n = 6, 66.7%), mild reticular opacity (n 7, 77.8%) and mild honeycomb patterns (n = 3, 33.3%) appeared. A serial micro-CT enables the evaluation of drug effects in a lung fibrosis mouse model.

  18. A new glucocerebrosidase-deficient neuronal cell model provides a tool to probe pathophysiology and therapeutics for Gaucher disease.

    Science.gov (United States)

    Westbroek, Wendy; Nguyen, Matthew; Siebert, Marina; Lindstrom, Taylor; Burnett, Robert A; Aflaki, Elma; Jung, Olive; Tamargo, Rafael; Rodriguez-Gil, Jorge L; Acosta, Walter; Hendrix, An; Behre, Bahafta; Tayebi, Nahid; Fujiwara, Hideji; Sidhu, Rohini; Renvoise, Benoit; Ginns, Edward I; Dutra, Amalia; Pak, Evgenia; Cramer, Carole; Ory, Daniel S; Pavan, William J; Sidransky, Ellen

    2016-07-01

    Glucocerebrosidase is a lysosomal hydrolase involved in the breakdown of glucosylceramide. Gaucher disease, a recessive lysosomal storage disorder, is caused by mutations in the gene GBA1 Dysfunctional glucocerebrosidase leads to accumulation of glucosylceramide and glycosylsphingosine in various cell types and organs. Mutations in GBA1 are also a common genetic risk factor for Parkinson disease and related synucleinopathies. In recent years, research on the pathophysiology of Gaucher disease, the molecular link between Gaucher and Parkinson disease, and novel therapeutics, have accelerated the need for relevant cell models with GBA1 mutations. Although induced pluripotent stem cells, primary rodent neurons, and transfected neuroblastoma cell lines have been used to study the effect of glucocerebrosidase deficiency on neuronal function, these models have limitations because of challenges in culturing and propagating the cells, low yield, and the introduction of exogenous mutant GBA1 To address some of these difficulties, we established a high yield, easy-to-culture mouse neuronal cell model with nearly complete glucocerebrosidase deficiency representative of Gaucher disease. We successfully immortalized cortical neurons from embryonic null allele gba(-/-) mice and the control littermate (gba(+/+)) by infecting differentiated primary cortical neurons in culture with an EF1α-SV40T lentivirus. Immortalized gba(-/-) neurons lack glucocerebrosidase protein and enzyme activity, and exhibit a dramatic increase in glucosylceramide and glucosylsphingosine accumulation, enlarged lysosomes, and an impaired ATP-dependent calcium-influx response; these phenotypical characteristics were absent in gba(+/+) neurons. This null allele gba(-/-) mouse neuronal model provides a much-needed tool to study the pathophysiology of Gaucher disease and to evaluate new therapies. © 2016. Published by The Company of Biologists Ltd.

  19. A new glucocerebrosidase-deficient neuronal cell model provides a tool to probe pathophysiology and therapeutics for Gaucher disease

    Directory of Open Access Journals (Sweden)

    Wendy Westbroek

    2016-07-01

    Full Text Available Glucocerebrosidase is a lysosomal hydrolase involved in the breakdown of glucosylceramide. Gaucher disease, a recessive lysosomal storage disorder, is caused by mutations in the gene GBA1. Dysfunctional glucocerebrosidase leads to accumulation of glucosylceramide and glycosylsphingosine in various cell types and organs. Mutations in GBA1 are also a common genetic risk factor for Parkinson disease and related synucleinopathies. In recent years, research on the pathophysiology of Gaucher disease, the molecular link between Gaucher and Parkinson disease, and novel therapeutics, have accelerated the need for relevant cell models with GBA1 mutations. Although induced pluripotent stem cells, primary rodent neurons, and transfected neuroblastoma cell lines have been used to study the effect of glucocerebrosidase deficiency on neuronal function, these models have limitations because of challenges in culturing and propagating the cells, low yield, and the introduction of exogenous mutant GBA1. To address some of these difficulties, we established a high yield, easy-to-culture mouse neuronal cell model with nearly complete glucocerebrosidase deficiency representative of Gaucher disease. We successfully immortalized cortical neurons from embryonic null allele gba−/− mice and the control littermate (gba+/+ by infecting differentiated primary cortical neurons in culture with an EF1α-SV40T lentivirus. Immortalized gba−/− neurons lack glucocerebrosidase protein and enzyme activity, and exhibit a dramatic increase in glucosylceramide and glucosylsphingosine accumulation, enlarged lysosomes, and an impaired ATP-dependent calcium-influx response; these phenotypical characteristics were absent in gba+/+ neurons. This null allele gba−/− mouse neuronal model provides a much-needed tool to study the pathophysiology of Gaucher disease and to evaluate new therapies.

  20. Cowichan Valley energy mapping and modelling. Report 6 - Findings and recommendations. Final report. [Vancouver Island, Canada

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2012-06-15

    This report is the final report in a series of six reports detailing the findings from the Cowichan Valley Energy Mapping and Modelling project that was carried out from April of 2011 to March of 2012 by Ea Energy Analyses in conjunction with Geographic Resource Analysis and Science (GRAS). The driving force behind the Integrated Energy Mapping and Analysis project was the identification and analysis of a suite of pathways that the Cowichan Valley Regional District (CVRD) can utilise to increase its energy resilience, as well as reduce energy consumption and GHG emissions, with a primary focus on the residential sector. Mapping and analysis undertaken will support provincial energy and GHG reduction targets, and the suite of pathways outlined will address a CVRD internal target that calls for 75% of the region's energy within the residential sector to come from locally sourced renewables by 2050. The target has been developed as a mechanism to meet resilience and climate action target. The maps and findings produced are to be integrated as part of a regional policy framework currently under development. The present report is the final report and presents a summary of the findings of project tasks 1-5 and provides a set of recommendations to the CVRD based on the work done and with an eye towards the next steps in the energy planning process of the CVRD. (LN)

  1. Uncertainty and Variability in Physiologically-Based Pharmacokinetic (PBPK) Models: Key Issues and Case Studies (Final Report)

    Science.gov (United States)

    EPA announced the availability of the final report, Uncertainty and Variability in Physiologically-Based Pharmacokinetic (PBPK) Models: Key Issues and Case Studies. This report summarizes some of the recent progress in characterizing uncertainty and variability in physi...

  2. Towards the final BSA modeling for the accelerator-driven BNCT facility at INFN LNL

    Energy Technology Data Exchange (ETDEWEB)

    Ceballos, C. [Centro de Aplicaciones Tecnlogicas y Desarrollo Nuclear, 5ta y30, Miramar, Playa, Ciudad Habana (Cuba); Esposito, J., E-mail: juan.esposito@lnl.infn.it [INFN, Laboratori Nazionali di Legnaro (LNL), via dell' Universita, 2, I-35020 Legnaro (PD) (Italy); Agosteo, S. [Politecnico di Milano, Dipartimento di Energia, Piazza Leonardo da Vinci 32, 20133 Milano (Italy)] [INFN, Sezione di Milano, via Celoria 16, 20133 Milano (Italy); Colautti, P.; Conte, V.; Moro, D. [INFN, Laboratori Nazionali di Legnaro (LNL), via dell' Universita, 2, I-35020 Legnaro (PD) (Italy); Pola, A. [Politecnico di Milano, Dipartimento di Energia, Piazza Leonardo da Vinci 32, 20133 Milano (Italy)] [INFN, Sezione di Milano, via Celoria 16, 20133 Milano (Italy)

    2011-12-15

    Some remarkable advances have been made in the last years on the SPES-BNCT project of the Istituto Nazionale di Fisica Nucleare (INFN) towards the development of the accelerator-driven thermal neutron beam facility at the Legnaro National Laboratories (LNL), aimed at the BNCT experimental treatment of extended skin melanoma. The compact neutron source will be produced via the {sup 9}Be(p,xn) reactions using the 5 MeV, 30 mA beam driven by the RFQ accelerator, whose modules construction has been recently completed, into a thick beryllium target prototype already available. The Beam Shaping Assembly (BSA) final modeling, using both neutron converter and the new, detailed, Be(p,xn) neutron yield spectra at 5 MeV energy recently measured at the CN Van de Graaff accelerator at LNL, is summarized here.

  3. Modeling of integrated environmental control systems for coal-fired power plants. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Rubin, E.S.; Salmento, J.S.; Frey, H.C.; Abu-Baker, A.; Berkenpas, M.

    1991-05-01

    The Integrated Environmental Control Model (IECM) was designed to permit the systematic evaluation of environmental control options for pulverized coal-fired (PC) power plants. Of special interest was the ability to compare the performance and cost of advanced pollution control systems to ``conventional`` technologies for the control of particulate, SO{sub 2} and NO{sub x}. Of importance also was the ability to consider pre-combustion, combustion and post-combustion control methods employed alone or in combination to meet tough air pollution emission standards. Finally, the ability to conduct probabilistic analyses is a unique capability of the IECM. Key results are characterized as distribution functions rather than as single deterministic values. (VC)

  4. Therapeutic Effects of Transplantation of As-MiR-937-Expressing Mesenchymal Stem Cells in Murine Model of Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Zhen Liu

    2015-08-01

    Full Text Available Background/Aims: Alzheimer's disease (AD is one of the most common dementias among aged people, and is clinically characterized by progressive memory loss, behavioral and learning dysfunction and cognitive deficits. So far, this is no cure for AD. A therapeutic effect of transplantation of mesenchymal stem cells (MSCs into murine model of AD has been reported, but remains to be further improved. Brn-4 is a transcription factor that plays a critical role in neuronal development, whereas the effects of Brn-4 overexpression in transplanted MSCs on AD are unknown. Methods: MSCs were isolated from mouse bone marrow and induced to overexpress antisense of miRNA-937 (as-miR-937 through adeno-associated virus (AAV-mediated transduction, and purified by flow cytometry based on expression of a GFP co-transgene in the cells. The Brn-4 levels in mouse MSCs were examined in miR-937-modified MSCs by RT-qPCR and by Western blot. These miR-937-modified MSCs were then transplanted into an APP/PS1 transgenic AD model in mice. The effects of saline control, MSCs and asmiR-937 MSCs on AD mice were examined by deposition of amyloid-beta peptide aggregates (Aβ, social recognition test (SR, Plus-Maze Discriminative Avoidance Task (PM-DAT and the levels of Brain-derived neurotrophic factor (BDNF in the mouse brain. Results: MSCs expressed high levels of Brn-4 transcripts but low levels of Brn-4 protein. Poor protein vs mRNA levels of Brn-4 in MSCs appeared to result from the presence of high levels of miR-937 in MSCs. miR-937 inhibited translation of Brn-4 mRNA through binding to the 3'-UTR of the Brn-4 mRNA in MSCs. Expression of as-miR-937 significantly increased Brn-4 protein levels in MSCs. Transplantation of as-miR-937-expressing MSCs significantly reduced the deposition of Aβ, increased the levels of BDNF, and significantly improved the appearance in SR and PM-DAT in AD mice. Conclusion: Overexpression of as-miR-937 in MSCs may substantially improve the

  5. Final Report. Fumex-III. Improvement of Models Used for Fuel Behaviour Simulation

    International Nuclear Information System (INIS)

    Kulacsy, Katalin

    2013-01-01

    The FUMEX-III coordinated research programme organised by the IAEA was the first FUMEX exercise in which AEKI (Hungarian Academy of Sciences KFKI Atomic Energy Research Institute) took part with the partial support of Paks NPP. The aim of the participation was to test the code FUROM developed at AEKI against not only measurements but also other fuel behaviour simulation codes, to share and discuss modelling experience and issues, and to establish acquaintance with fuel modellers in other countries. Among the numerous cases proposed for the programme, AEKI chose to simulate normal operation up to high burn-up and ramp tests, with special interest in VVER rods and PWR rods with annular pellets. The US PWR 16x16, the SPC RE GINNA, the Kola3-MIR, the IFA-519.9 cases and the AREVA idealised rod were thus selected. The present Final Report gives a short description of the FUROM models relevant to the selected cases, presents the results for the 5 cases and summarises the conclusions of the FUMEX-III programme. The input parameters used for the simulations can be found in the Appendix at the end of the Report. Observations concerning the IFPE datasets are collected for each dataset in their respective Sections for possible use in the IFPE database. (author)

  6. Evaluation of disease and viral biomarkers as triggers for therapeutic intervention in respiratory mousepox - an animal model of smallpox.

    Science.gov (United States)

    Parker, Scott; Chen, Nanhai G; Foster, Scott; Hartzler, Hollyce; Hembrador, Ed; Hruby, Dennis; Jordan, Robert; Lanier, Randall; Painter, George; Painter, Wesley; Sagartz, John E; Schriewer, Jill; Mark Buller, R

    2012-04-01

    The human population is currently faced with the potential use of natural or recombinant variola and monkeypox viruses as biological weapons. Furthermore, the emergence of human monkeypox in Africa and its expanding environs poses a significant natural threat. Such occurrences would require therapeutic and prophylactic intervention with antivirals to minimize morbidity and mortality of exposed populations. Two orally-bioavailable antivirals are currently in clinical trials; namely CMX001, an ether-lipid analog of cidofovir with activity at the DNA replication stage and ST-246, a novel viral egress inhibitor. Both of these drugs have previously been evaluated in the ectromelia/mousepox system; however, the trigger for intervention was not linked to a disease biomarker or a specific marker of virus replication. In this study we used lethal, intranasal, ectromelia virus infections of C57BL/6 and hairless SKH1 mice to model human disease and evaluate exanthematous rash (rash) as an indicator to initiate antiviral treatment. We show that significant protection can be provided to C57BL/6 mice by CMX001 or ST-246 when therapy is initiated on day 6 post infection or earlier. We also show that significant protection can be provided to SKH1 mice treated with CMX001 at day 3 post infection or earlier, but this is four or more days before detection of rash (ST-246 not tested). Although in this model rash could not be used as a treatment trigger, viral DNA was detected in blood by day 4 post infection and in the oropharyngeal secretions (saliva) by day 2-3 post infection - thus providing robust and specific markers of virus replication for therapy initiation. These findings are discussed in the context of current respiratory challenge animal models in use for the evaluation of poxvirus antivirals. Copyright © 2012 Elsevier B.V. All rights reserved.

  7. Therapeutic advantage of pro-electrophilic drugs to activate the Nrf2/ARE pathway in Alzheimer's disease models.

    Science.gov (United States)

    Lipton, Stuart A; Rezaie, Tayebeh; Nutter, Anthony; Lopez, Kevin M; Parker, James; Kosaka, Kunio; Satoh, Takumi; McKercher, Scott R; Masliah, Eliezer; Nakanishi, Nobuki

    2016-12-01

    Alzheimer's disease (AD) is characterized by synaptic and neuronal loss, which occurs at least partially through oxidative stress induced by oligomeric amyloid-β (Aβ)-peptide. Carnosic acid (CA), a chemical found in rosemary and sage, is a pro-electrophilic compound that is converted to its active form by oxidative stress. The active form stimulates the Keap1/Nrf2 transcriptional pathway and thus production of phase 2 antioxidant enzymes. We used both in vitro and in vivo models. For in vitro studies, we evaluated protective effects of CA on primary neurons exposed to oligomeric Aβ. For in vivo studies, we used two transgenic mouse models of AD, human amyloid precursor protein (hAPP)-J20 mice and triple transgenic (3xTg AD) mice. We treated these mice trans-nasally with CA twice weekly for 3 months. Subsequently, we performed neurobehavioral tests and quantitative immunohistochemistry to assess effects on AD-related phenotypes, including learning and memory, and synaptic damage. In vitro, CA reduced dendritic spine loss in rat neurons exposed to oligomeric Aβ. In vivo, CA treatment of hAPP-J20 mice improved learning and memory in the Morris water maze test. Histologically, CA increased dendritic and synaptic markers, and decreased astrogliosis, Aβ plaque number, and phospho-tau staining in the hippocampus. We conclude that CA exhibits therapeutic benefits in rodent AD models and since the FDA has placed CA on the 'generally regarded as safe' (GRAS) list, thus obviating the need for safety studies, human clinical trials will be greatly expedited.

  8. A natural human IgM that binds to gangliosides is therapeutic in murine models of amyotrophic lateral sclerosis

    Directory of Open Access Journals (Sweden)

    Xiaohua Xu

    2015-08-01

    Full Text Available Amyotrophic lateral sclerosis (ALS is a devastating, fatal neurological disease that primarily affects spinal cord anterior horn cells and their axons for which there is no treatment. Here we report the use of a recombinant natural human IgM that binds to the surface of neurons and supports neurite extension, rHIgM12, as a therapeutic strategy in murine models of human ALS. A single 200 µg intraperitoneal dose of rHIgM12 increases survival in two independent genetic-based mutant SOD1 mouse strains (SOD1G86R and SOD1G93A by 8 and 10 days, delays the onset of neurological deficits by 16 days, delays the onset of weight loss by 5 days, and preserves spinal cord axons and anterior horn neurons. Immuno-overlay of thin layer chromatography and surface plasmon resonance show that rHIgM12 binds with high affinity to the complex gangliosides GD1a and GT1b. Addition of rHIgM12 to neurons in culture increases α-tubulin tyrosination levels, suggesting an alteration of microtubule dynamics. We previously reported that a single peripheral dose of rHIgM12 preserved neurological function in a murine model of demyelination with axon loss. Because rHIgM12 improves three different models of neurological disease, we propose that the IgM might act late in the cascade of neuronal stress and/or death by a broad mechanism.

  9. DECOVALEX III PROJECT. Modelling of FEBEX In-Situ Test. Task1 Final Report

    Energy Technology Data Exchange (ETDEWEB)

    Alonso, E.E.; Alcoverro, J. [Univ. Politecnica de Catalunya, Barcelona (Spain)] (comps.)

    2005-02-15

    Task 1 of DECOVALEX III was conceived as a benchmark exercise supported by all field and laboratory data generated during the performance of the FEBEX experiment designed to study thermo-hydro-mechanical and thermo-hydro-geochemical processes of the buffer and rock in the near field. The task was defined as a series of three successive blind prediction exercises (Parts A, B and C), which cover the behaviour of both the rock and bentonite barrier. Research teams participating in the FEBEX task were given, for each of the three parts, a set of field and laboratory data theoretically sufficient to generate a proper model and were asked to submit predictions, at given locations and time, for some of the measured variables. The merits and limitations of different modeling approaches were therefore established. The teams could perform additional calculations, once the actual 'solution' was disclosed. Final calculations represented the best approximation that a given team could provide, always within the general time constraints imposed by the General DECOVALEX III Organization. This report presents the works performed for Task 1. It contains the case definitions and evaluations of modelling results for Part A, B and C, and the overall evaluation of the works performed. The report is completed by a CD-ROM containing a set of final reports provided by the modeling teams participating in each of the three parts defined. These reports provide the necessary details to better understand the nature of the blind or final predictions included in this report. The report closes with a set of conclusions, which provides a summary of the main findings and highlights the lessons learned, some of which were summarized below. The best predictions of the water inflow into the excavated tunnel are found when the hydro geological model is properly calibrated on the basis of other known flow measurements in the same area. The particular idealization of the rock mass (equivalent

  10. DECOVALEX III PROJECT. Modelling of FEBEX In-Situ Test. Task1 Final Report

    International Nuclear Information System (INIS)

    Alonso, E.E.; Alcoverro, J.

    2005-02-01

    Task 1 of DECOVALEX III was conceived as a benchmark exercise supported by all field and laboratory data generated during the performance of the FEBEX experiment designed to study thermo-hydro-mechanical and thermo-hydro-geochemical processes of the buffer and rock in the near field. The task was defined as a series of three successive blind prediction exercises (Parts A, B and C), which cover the behaviour of both the rock and bentonite barrier. Research teams participating in the FEBEX task were given, for each of the three parts, a set of field and laboratory data theoretically sufficient to generate a proper model and were asked to submit predictions, at given locations and time, for some of the measured variables. The merits and limitations of different modeling approaches were therefore established. The teams could perform additional calculations, once the actual 'solution' was disclosed. Final calculations represented the best approximation that a given team could provide, always within the general time constraints imposed by the General DECOVALEX III Organization. This report presents the works performed for Task 1. It contains the case definitions and evaluations of modelling results for Part A, B and C, and the overall evaluation of the works performed. The report is completed by a CD-ROM containing a set of final reports provided by the modeling teams participating in each of the three parts defined. These reports provide the necessary details to better understand the nature of the blind or final predictions included in this report. The report closes with a set of conclusions, which provides a summary of the main findings and highlights the lessons learned, some of which were summarized below. The best predictions of the water inflow into the excavated tunnel are found when the hydro geological model is properly calibrated on the basis of other known flow measurements in the same area. The particular idealization of the rock mass (equivalent porous media

  11. Final Report: Optimal Model Complexity in Geological Carbon Sequestration: A Response Surface Uncertainty Analysis

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Ye [Univ. of Wyoming, Laramie, WY (United States)

    2018-01-17

    equivalency, all the stratigraphic models were successfully upscaled from the reference heterogeneous model for bulk flow and transport predictions (Zhang & Zhang, 2015). GCS simulation was then simulated with all models, yielding insights into the level of parameterization complexity that is needed for the accurate simulation of reservoir pore pressure, CO2 storage, leakage, footprint, and dissolution over both short (i.e., injection) and longer (monitoring) time scales. Important uncertainty parameters that impact these key performance metrics were identified for the stratigraphic models as well as for the heterogeneous model, leading to the development of reduced/simplified models at lower characterization cost that can be used for the reservoir uncertainty analysis. All the CO2 modeling was conducted using PFLOTRAN – a massively parallel, multiphase, multi-component, and reactive transport simulator developed by a multi-laboratory DOE/SciDAC (Scientific Discovery through Advanced Computing) project (Zhang et al., 2017, in review). Within the uncertainty analysis framework, increasing reservoir depth were investigated to explore its effect on the uncertainty outcomes and the potential for developing gravity-stable injection with increased storage security (Dai et al., 20126; Dai et al., 2017, in review). Finally, to accurately model CO2 fluid-rock reactions and resulting long-term storage as secondary carbonate minerals, a modified kinetic rate law for general mineral dissolution and precipitation was proposed and verified that is invariant to a scale transformation of the mineral formula weight. This new formulation will lead to more accurate assessment of mineral storage over geologic time scales (Lichtner, 2016).

  12. The Impact of CRISPR/Cas9 Technology on Cardiac Research: From Disease Modelling to Therapeutic Approaches

    Science.gov (United States)

    Pramstaller, Peter P.; Hicks, Andrew A.; Rossini, Alessandra

    2017-01-01

    Genome-editing technology has emerged as a powerful method that enables the generation of genetically modified cells and organisms necessary to elucidate gene function and mechanisms of human diseases. The clustered regularly interspaced short palindromic repeats- (CRISPR-) associated 9 (Cas9) system has rapidly become one of the most popular approaches for genome editing in basic biomedical research over recent years because of its simplicity and adaptability. CRISPR/Cas9 genome editing has been used to correct DNA mutations ranging from a single base pair to large deletions in both in vitro and in vivo model systems. CRISPR/Cas9 has been used to increase the understanding of many aspects of cardiovascular disorders, including lipid metabolism, electrophysiology and genetic inheritance. The CRISPR/Cas9 technology has been proven to be effective in creating gene knockout (KO) or knockin in human cells and is particularly useful for editing induced pluripotent stem cells (iPSCs). Despite these progresses, some biological, technical, and ethical issues are limiting the therapeutic potential of genome editing in cardiovascular diseases. This review will focus on various applications of CRISPR/Cas9 genome editing in the cardiovascular field, for both disease research and the prospect of in vivo genome-editing therapies in the future. PMID:29434642

  13. mRNA and microRNA transcriptomics analyses in a murine model of dystrophin loss and therapeutic restoration

    Directory of Open Access Journals (Sweden)

    Thomas C. Roberts

    2016-03-01

    Full Text Available Duchenne muscular dystrophy (DMD is a pediatric, X-linked, progressive muscle-wasting disorder caused by loss of function mutations affecting the gene encoding the dystrophin protein. While the primary genetic insult in DMD is well described, many details of the molecular and cellular pathologies that follow dystrophin loss are incompletely understood. To investigate gene expression in dystrophic muscle we have applied mRNA and microRNA (miRNA microarray technology to the mdx mouse model of DMD. This study was designed to generate a complete description of gene expression changes associated with dystrophic pathology and the response to an experimental therapy which restores dystrophin protein function. These datasets have enabled (1 the determination of gene expression changes associated with dystrophic pathology, (2 identification of differentially expressed genes that are restored towards wild-type levels after therapeutic dystrophin rescue, (3 investigation of the correlation between mRNA and protein expression (determined by parallel mass spectrometry proteomics analysis, and (4 prediction of pathology associated miRNA-target interactions. Here we describe in detail how the data were generated including the basic analysis as contained in the manuscript published in Human Molecular Genetics with PMID 26385637. The data have been deposited in the Gene Expression Omnibus (GEO with the accession number GSE64420.

  14. Prevention and Therapeutic Effects and Mechanisms of Tanshinone IIA Sodium Sulfonate on Acute Liver Injury Mice Model

    Directory of Open Access Journals (Sweden)

    Lunjie Lu

    2016-01-01

    Full Text Available Tanshinone IIA sodium sulfonate (TSS is a water-soluble derivative of tanshinone IIA, which is the main pharmacologically active component of Salvia miltiorrhiza. This study aimed to verify the preventive and therapeutic effects of TSS and its combined therapeutic effects with magnesium isoglycyrrhizinate (MI in D-galactosamine- (D-Gal- induced acute liver injury (ALI in mice. The potential regulatory mechanisms of TSS on ALI were also examined. Our results may provide a basis for the development of novel therapeutics for ALI.

  15. Therapeutic risk management of the suicidal patient: safety planning.

    Science.gov (United States)

    Matarazzo, Bridget B; Homaifar, Beeta Y; Wortzel, Hal S

    2014-05-01

    This column is the fourth in a series describing a model for therapeutic risk management of the suicidal patient. Previous columns presented an overview of the therapeutic risk management model, provided recommendations for how to augment risk assessment using structured assessments, and discussed the importance of risk stratification in terms of both severity and temporality. This final column in the series discusses the safety planning intervention as a critical component of therapeutic risk management of suicide risk. We first present concerns related to the relatively common practice of using no-suicide contracts to manage risk. We then present the safety planning intervention as an alternative approach and provide recommendations for how to use this innovative strategy to therapeutically mitigate risk in the suicidal patient.

  16. Software package r3t. Model for transport and retention in porous media. Final report

    International Nuclear Information System (INIS)

    Fein, E.

    2004-01-01

    In long-termsafety analyses for final repositories for hazardous wastes in deep geological formations the impact to the biosphere due to potential release of hazardous materials is assessed for relevant scenarios. The model for migration of wastes from repositories to men is divided into three almost independent parts: the near field, the geosphere, and the biosphere. With the development of r 3 t the feasibility to model the pollutant transport through the geosphere for porous or equivalent porous media in large, three-dimensional, and complex regions is established. Furthermore one has at present the ability to consider all relevant retention and interaction effects which are important for long-term safety analyses. These are equilibrium sorption, kinetically controlled sorption, diffusion into immobile pore waters, and precipitation. The processes of complexing, colloidal transport and matrix diffusion may be considered at least approximately by skilful choice of parameters. Speciation is not part of the very recently developed computer code r 3 t. With r 3 t it is possible to assess the potential dilution and the barrier impact of the overburden close to reality

  17. Use on non-conjugate prior distributions in compound failure models. Final technical report

    International Nuclear Information System (INIS)

    Shultis, J.K.; Johnson, D.E.; Milliken, G.A.; Eckhoff, N.D.

    1981-12-01

    Several theoretical and computational techniques are presented for compound failure models in which the failure rate or failure probability for a class of components is considered to be a random variable. Both the failure-on-demand and failure-rate situation are considered. Ten different prior families are presented for describing the variation or uncertainty of the failure parameter. Methods considered for estimating values for the prior parameters from a given set of failure data are (1) matching data moments to those of the prior distribution, (2) matching data moments to those of the compound marginal distribution, and (3) the marginal maximum likelihood method. Numerical methods for computing the parameter estimators for all ten prior families are presented, as well as methods for obtaining estimates of the variances and covariance of the parameter estimators, it is shown that various confidence, probability, and tolerance intervals can be evaluated. Finally, to test the resulting failure models against the given failure data, generalized chi-squage and Kolmogorov-Smirnov goodness-of-fit tests are proposed together with a test to eliminate outliers from the failure data. Computer codes based on the results presented here have been prepared and are presented in a companion report

  18. Revisit the modeling of the Saturnian ring atmosphere and ionosphere from the "Cassini Grand Finale" results

    Science.gov (United States)

    Tseng, W. L.; Johnson, R. E.; Tucker, O. J.; Perry, M. E.; Ip, W. H.

    2017-12-01

    During the Cassini Grand Finale mission, this spacecraft, for the first time, has done the in-situ measurements of Saturn's upper atmosphere and its rings and provides critical information for understanding the coupling dynamics between the main rings and the Saturnian system. The ring atmosphere is the source of neutrals (i.e., O2, H2, H; Tseng et al., 2010; 2013a), which is primarily generated by photolytic decomposition of water ice (Johnson et al., 2006), and plasma (i.e., O2+ and H2+; Tseng et al., 2011) in the Saturnian magnetosphere. In addition, the main rings have strong interaction with Saturn's atmosphere and ionosphere (i.e., a source of oxygen into Saturn's upper atmosphere and/or the "ring rain" in O'Donoghue et al., 2013). Furthermore, the near-ring plasma environment is complicated by the neutrals from both the seasonally dependent ring atmosphere and Enceladus torus (Tseng et al., 2013b), and, possibly, from small grains from the main and tenuous F and G rings (Johnson et al.2017). The data now coming from Cassini Grand Finale mission already shed light on the dominant physics and chemistry in this region of Saturn's magnetosphere, for example, the presence of carbonaceous material from meteorite impacts in the main rings and each gas species have similar distribution in the ring atmosphere. We will revisit the details in our ring atmosphere/ionosphere model to study, such as the source mechanism for the organic material and the neutral-grain-plasma interaction processes.

  19. Final Technical Report: "Representing Endogenous Technological Change in Climate Policy Models: General Equilibrium Approaches"

    Energy Technology Data Exchange (ETDEWEB)

    Ian Sue Wing

    2006-04-18

    The research supported by this award pursued three lines of inquiry: (1) The construction of dynamic general equilibrium models to simulate the accumulation and substitution of knowledge, which has resulted in the preparation and submission of several papers: (a) A submitted pedagogic paper which clarifies the structure and operation of computable general equilibrium (CGE) models (C.2), and a review article in press which develops a taxonomy for understanding the representation of technical change in economic and engineering models for climate policy analysis (B.3). (b) A paper which models knowledge directly as a homogeneous factor, and demonstrates that inter-sectoral reallocation of knowledge is the key margin of adjustment which enables induced technical change to lower the costs of climate policy (C.1). (c) An empirical paper which estimates the contribution of embodied knowledge to aggregate energy intensity in the U.S. (C.3), followed by a companion article which embeds these results within a CGE model to understand the degree to which autonomous energy efficiency improvement (AEEI) is attributable to technical change as opposed to sub-sectoral shifts in industrial composition (C.4) (d) Finally, ongoing theoretical work to characterize the precursors and implications of the response of innovation to emission limits (E.2). (2) Data development and simulation modeling to understand how the characteristics of discrete energy supply technologies determine their succession in response to emission limits when they are embedded within a general equilibrium framework. This work has produced two peer-reviewed articles which are currently in press (B.1 and B.2). (3) Empirical investigation of trade as an avenue for the transmission of technological change to developing countries, and its implications for leakage, which has resulted in an econometric study which is being revised for submission to a journal (E.1). As work commenced on this topic, the U.S. withdrawal

  20. Final report of the TRUE Block Scale project. 3. Modelling of flow and transport

    Energy Technology Data Exchange (ETDEWEB)

    Poteri, Antti [VTT Processes, Helsinki (Finland); Billaux, Daniel [Itasca Consultants SA, Ecully (France); Dershowitz, William [Golder Associates Inc., Redmond, WA (United States); Gomez-Hernandez, J. Jaime [Univ. Politecnica de Valencia (Spain). Dept. of Hydrahulic and Environmental Engineering; Cvetkovic, Vladimir [Royal Inst. of Tech., Stockholm (Sweden). Div. of Water Resources Engineering; Hautojaervi, Aimo [Posiva Oy, Olkiluoto (Finland); Holton, David [Serco Assurance, Harwell (United Kingdom); Medina, Agustin [UPC, Barcelona (Spain); Winberg, Anders (ed.) [Conterra AB, Uppsala (Sweden)

    2002-12-01

    included, and if and how heterogeneity in retention parameters was accounted for. The integration of the modelling performed emphasised assessment the relative roles of advection, diffusion and sorption. The evaluation results showed similar retention characteristics for the three tested flow paths, which in turn were found to be similar to those seen in the flow paths tested by the TRUE-1 experiment. The evaluation modelling showed that the most consistent interpretation of the performed tests is obtained when diffusional mass transfer and sorption in immobile zones is included. It was also noted that no additional phenomena/processes (apart from surface sorption) were required to explain the observed in situ retention. It was further found not possible to fully discriminate the relative importance of potentially available immobile zones along the flow paths using available data. It was finally observed that heterogeneity in retention properties calls for additional analysis of 'effective' retention parameters in order to improve understanding and interpretation of in situ retention parameters.

  1. Final report of the TRUE Block Scale project. 3. Modelling of flow and transport

    International Nuclear Information System (INIS)

    Poteri, Antti; Billaux, Daniel; Dershowitz, William; Gomez-Hernandez, J. Jaime; Holton, David; Medina, Agustin; Winberg, Anders

    2002-12-01

    , and if and how heterogeneity in retention parameters was accounted for. The integration of the modelling performed emphasised assessment the relative roles of advection, diffusion and sorption. The evaluation results showed similar retention characteristics for the three tested flow paths, which in turn were found to be similar to those seen in the flow paths tested by the TRUE-1 experiment. The evaluation modelling showed that the most consistent interpretation of the performed tests is obtained when diffusional mass transfer and sorption in immobile zones is included. It was also noted that no additional phenomena/processes (apart from surface sorption) were required to explain the observed in situ retention. It was further found not possible to fully discriminate the relative importance of potentially available immobile zones along the flow paths using available data. It was finally observed that heterogeneity in retention properties calls for additional analysis of 'effective' retention parameters in order to improve understanding and interpretation of in situ retention parameters

  2. Therapeutic ultrasound

    International Nuclear Information System (INIS)

    Crum, Lawrence A

    2004-01-01

    The use of ultrasound in medicine is now quite commonplace, especially with the recent introduction of small, portable and relatively inexpensive, hand-held diagnostic imaging devices. Moreover, ultrasound has expanded beyond the imaging realm, with methods and applications extending to novel therapeutic and surgical uses. These applications broadly include: tissue ablation, acoustocautery, lipoplasty, site-specific and ultrasound mediated drug activity, extracorporeal lithotripsy, and the enhancement of natural physiological functions such as wound healing and tissue regeneration. A particularly attractive aspect of this technology is that diagnostic and therapeutic systems can be combined to produce totally non-invasive, imageguided therapy. This general lecture will review a number of these exciting new applications of ultrasound and address some of the basic scientific questions and future challenges in developing these methods and technologies for general use in our society. We shall particularly emphasize the use of High Intensity Focused Ultrasound (HIFU) in the treatment of benign and malignant tumors as well as the introduction of acoustic hemostasis, especially in organs which are difficult to treat using conventional medical and surgical techniques. (amum lecture)

  3. Neural induction with neurogenin 1 enhances the therapeutic potential of mesenchymal stem cells in an amyotrophic lateral sclerosis mouse model.

    Science.gov (United States)

    Chan-Il, Choi; Young-Don, Lee; Heejaung, Kim; Kim, Seung Hyun; Suh-Kim, Haeyoung; Kim, Sung-Soo

    2013-01-01

    Amyotrophic lateral sclerosis (ALS) is characterized by progressive dysfunction and degeneration of motor neurons in the central nervous system (CNS). In the absence of effective drug treatments for ALS, stem cell treatment has emerged as a candidate therapy for this disease. To date, however, there is no consensus protocol that stipulates stem cell types, transplantation timing, or frequency. Using an ALS mouse model carrying a high copy number of a mutant human superoxide dismutase-1 (SOD1)(G93A) transgene, we investigated the effect of neural induction on the innate therapeutic potential of mesenchymal stem cells (MSCs) in relation to preclinical transplantation parameters. In our study, the expression of monocyte chemoattractant protein-1 (MCP-1) was elevated in the ALS mouse spinal cord. Neural induction of MSCs with neurogenin 1 (Ngn1) upregulated the expression level of the MCP-1 receptor, CCR2, and enhanced the migration activity toward MCP-1 in vitro. Ngn1-expressing MSCs (MSCs-Ngn1) showed a corresponding increase in tropism to the CNS after systemic transplantation in ALS mice. Notably, MSCs-Ngn1 delayed disease onset if transplanted during preonset ages,whereas unprocessed MSCs failed to do so. If transplanted near the onset ages, a single treatment with MSCs-Ngn1 was sufficient to enhance motor functions during the symptomatic period (15–17 weeks), whereas unprocessed MSCs required repeated transplantation to achieve similar levels of motor function improvement. Our data indicate that systemically transplanted MSCs-Ngn1 can migrate to the CNS and exert beneficial effects on host neural cells for an extended period of time through paracrine functions, suggesting a potential benefit of neural induction of transplanted MSCs in long-term treatment of ALS.

  4. Thrombospondin-1 type 1 repeats in a model of inflammatory bowel disease: transcript profile and therapeutic effects.

    Directory of Open Access Journals (Sweden)

    Zenaida P Lopez-Dee

    Full Text Available Thrombospondin-1 (TSP-1 is a matricellular protein with regulatory functions in inflammation and cancer. The type 1 repeats (TSR domains of TSP-1 have been shown to interact with a wide range of proteins that result in the anti-angiogenic and anti-tumor properties of TSP-1. To ascertain possible functions and evaluate potential therapeutic effects of TSRs in inflammatory bowel disease, we conducted clinical, histological and microarray analyses on a mouse model of induced colitis. We used dextran sulfate sodium (DSS to induce colitis in wild-type (WT mice for 7 days. Simultaneously, mice were injected with either saline or one form of TSP-1 derived recombinant proteins, containing either (1 the three type 1 repeats of the TSP-1 (3TSR, (2 the second type 1 repeat (TSR2, or (3 TSR2 with the RFK sequence (TSR2+RFK. Total RNA isolated from the mice colons were processed and hybridized to mouse arrays. Array data were validated by real-time qPCR and immunohistochemistry. Histological and disease indices reveal that the mice treated with the TSRs show different patterns of leukocytic infiltration and that 3TSR treatment was the most effective in decreasing inflammation in DSS-induced colitis. Transcriptional profiling revealed differentially expressed (DE genes, with the 3TSR-treated mice showing the least deviation from the WT-water controls. In conclusion, this study shows that 3TSR treatment is effective in attenuating the inflammatory response to DSS injury. In addition, the transcriptomics work unveils novel genetic data that suggest beneficial application of the TSR domains in inflammatory bowel disease.

  5. FINAL REPORT:Observation and Simulations of Transport of Molecules and Ions Across Model Membranes

    Energy Technology Data Exchange (ETDEWEB)

    MURAD, SOHAIL [University of Illinois at Chicago; JAMESON, CYNTHIA J [University of Illinois at Chicago

    2013-10-22

    During the this new grant we developed a robust methodology for investigating a wide range of properties of phospho-lipid bilayers. The approach developed is unique because despite using periodic boundary conditions, we can simulate an entire experiment or process in detail. For example, we can follow the entire permeation process in a lipid-membrane. This includes transport from the bulk aqueous phase to the lipid surface; permeation into the lipid; transport inside the lipid; and transport out of the lipid to the bulk aqueous phase again. We studied the transport of small gases in both the lipid itself and in model protein channels. In addition, we have examined the transport of nanocrystals through the lipid membrane, with the main goal of understanding the mechanical behavior of lipids under stress including water and ion leakage and lipid flip flop. Finally we have also examined in detail the deformation of lipids when under the influence of external fields, both mechanical and electrostatic (currently in progress). The important observations and conclusions from our studies are described in the main text of the report

  6. Development of generalised model for grate combustion of biomass. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Rosendahl, L.

    2007-02-15

    This project has been divided into two main parts, one of which has focused on modelling and one on designing and constructing a grate fired biomass test rig. The modelling effort has been defined due to a need for improved knowledge of the transport and conversion processes within the bed layer for two reasons: 1) to improve emission understanding and reduction measures and 2) to improve boundary conditions for CFD-based furnace modelling. The selected approach has been based on a diffusion coefficient formulation, where conservation equations for the concentration of fuel are solved in a spatially resolved grid, much in the same manner as in a finite volume CFD code. Within this porous layer of fuel, gas flows according to the Ergun equation. The diffusion coefficient links the properties of the fuel to the grate type and vibration mode, and is determined for each combination of fuel, grate and vibration mode. In this work, 3 grates have been tested as well as 4) types of fuel, drinking straw, wood beads, straw pellets and wood pellets. Although much useful information and knowledge has been obtained on transport processes in fuel layers, the model has proved to be less than perfect, and the recommendation is not to continue along this path. New visual data on the motion of straw on vibrating grates indicate that a diffusion governed motion does not very well represent the transport. Furthermore, it is very difficult to obtain the diffusion coefficient in other places than the surface layer of the grate, and it is not likely that this is representative for the motion within the layer. Finally, as the model complexity grows, model turnover time increases to a level where it is comparable to that of the full furnace model. In order to proceed and address the goals of the first paragraph, it is recommended to return to either a walking column approach or even some other, relatively simple method of prediction, and combine this with a form of randomness, to mimic the

  7. Site-conditions map for Portugal based on VS measurements: methodology and final model

    Science.gov (United States)

    Vilanova, Susana; Narciso, João; Carvalho, João; Lopes, Isabel; Quinta Ferreira, Mario; Moura, Rui; Borges, José; Nemser, Eliza; Pinto, carlos

    2017-04-01

    In this paper we present a statistically significant site-condition model for Portugal based on shear-wave velocity (VS) data and surface geology. We also evaluate the performance of commonly used Vs30 proxies based on exogenous data and analyze the implications of using those proxies for calculating site amplification in seismic hazard assessment. The dataset contains 161 Vs profiles acquired in Portugal in the context of research projects, technical reports, academic thesis and academic papers. The methodologies involved in characterizing the Vs structure at the sites in the database include seismic refraction, multichannel analysis of seismic waves and refraction microtremor. Invasive measurements were performed in selected locations in order to compare the Vs profiles obtained from both invasive and non-invasive techniques. In general there was good agreement in the subsurface structure of Vs30 obtained from the different methodologies. The database flat-file includes information on Vs30, surface geology at 1:50.000 and 1:500.000 scales, elevation and topographic slope and based on SRTM30 topographic dataset. The procedure used to develop the site-conditions map is based on a three-step process that includes defining a preliminary set of geological units based on the literature, performing statistical tests to assess whether or not the differences in the distributions of Vs30 are statistically significant, and merging of the geological units accordingly. The dataset was, to some extent, affected by clustering and/or preferential sampling and therefore a declustering algorithm was applied. The final model includes three geological units: 1) Igneous, metamorphic and old (Paleogene and Mesozoic) sedimentary rocks; 2) Neogene and Pleistocene formations, and 3) Holocene formations. The evaluation of proxies indicates that although geological analogues and topographic slope are in general unbiased, the latter shows significant bias for particular geological units and

  8. A theoretical model for prescription of the patient-specific therapeutic activity for radioiodine therapy of Graves' disease

    International Nuclear Information System (INIS)

    Di Martino, F.; Traino, A.C.; Lazzeri, M.; Brill, A.B.; Stabin, M.G.

    2002-01-01

    A fundamental function of the thyroid is to extract iodine from the blood, synthesize it into thyroid hormones, and release it into the circulation under feedback control by pituitary-secreted hormones. This capability of the thyroid, termed as functionality, can in principle be related to the severity of hyperthyroidism in individual patients. In this paper the uptake and release of 131 I by the thyroid following the administration of 131 I therapy for Graves' disease has been theoretically studied. The kinetics of iodine in the thyroid and blood have been evaluated using a two-compartment model. This simplified model appears to be adequate for dosimetry purposes and allows one to correlate levels of increased thyroid functionality (hyperthyroidism) with clinically measurable kinetic parameters. An expression has been derived for the rate of change of thyroid mass following therapy; this has the same form as an empirical relationship described in an earlier work. A method is presented for calculation of the amount of radioiodine activity to be administered to individual patients in order to achieve the desired final functionality of the gland. The activity to be administered is based on measurements of 131 I kinetics after the administration of a 'low-activity' (1850 kBq) tracer for treatment planning. (author)

  9. 4-1BB Aptamer-Based Immunomodulation Enhances the Therapeutic Index of Radiation Therapy in Murine Tumor Models

    Energy Technology Data Exchange (ETDEWEB)

    Benaduce, Ana Paula; Brenneman, Randall; Schrand, Brett; Pollack, Alan; Gilboa, Eli; Ishkanian, Adrian, E-mail: aishkanian@med.miami.edu

    2016-10-01

    Purpose: To report a novel strategy using oligonucleotide aptamers to 4-1BB as an alternate method for costimulation, and show that combinatorial therapy with radiation improves the therapeutic ratio over equivalent monoclonal antibodies. Methods and Materials: Subcutaneous 4T1 (mouse mammary carcinoma) tumors were established (approximately 100 mm{sup 3}), and a radiation therapy (RT) dose/fractionation schedule that optimally synergizes with 4-1BB monoclonal antibody (mAb) was identified. Comparable tumor control and animal survival was observed when either 4-1BB antibody or aptamer were combined with RT using models of breast cancer and melanoma (4T1 and B16-F10). Off-target CD8{sup +} T-cell toxicity was evaluated by quantification of CD8{sup +} T cells in livers and spleens of treated animals. Results: When combined with 4-1BB mAb, significant differences in tumor control were observed by varying RT dose and fractionation schedules. Optimal synergy between RT and 4-1BB mAb was observed at 5 Gy × 6. Testing 4-1BB mAb and aptamer independently using the optimal RT (5 Gy × 6 for 4T1/Balb/c and 12 Gy × 1 for B16/C57BL6J mouse models) revealed equivalent tumor control using 4-1BB aptamer and 4-1BB mAb. 4-1BB mAb, but not 4-1BB aptamer-treated animals, exhibited increased lymphocytic liver infiltrates and increased splenic and liver CD8{sup +} T cells. Conclusions: Radiation therapy synergizes with 4-1BB mAb, and this effect is dependent on RT dose and fractionation. Tumor control by 4-1BB aptamer is equivalent to 4-1BB mAb when combined with optimal RT dose, without eliciting off-target liver and spleen CD8{sup +} expansion. 4-1BB aptamer-based costimulation affords a comparable and less toxic strategy to augment RT-mediated tumor control.

  10. Efeitos do ultrassom terapêutico em modelo experimental de ciatalgia Therapeutic ultrasound effects in a sciatica experimental model

    Directory of Open Access Journals (Sweden)

    Adriano Policam Ciena

    2009-12-01

    Full Text Available A ciática possui grande prevalência geral e seu tratamento tende a resolver as causas de compressão nervosa. A fisioterapia objetiva reduzir os sintomas causados pela compressão. O presente estudo teve como objetivo avaliar a eficácia do ultrassom terapêutico sobre a dor, em animais submetidos a modelo experimental de ciatalgia. Foram usados 18 ratos neste estudo, divididos em três grupos: GS (n = 4, submetido a modelo de ciatalgia e tratados com ultrassom desligado; GUP (n = 7, submetido à ciatalgia e tratados com ultrassom pulsado 2W/cm² (SATP; 0,4 - SATA; e grupo GUC (n = 7, submetido à ciática e ultrassom contínuo (0,4W/cm². O nervo ciático do membro posterior direito foi exposto à compressão com fio categute em quatro pontos. No 3º dia pós-operatório (PO, iniciou-se tratamento indireto por quatro dias. No 9º dia PO, o tratamento direto começou sobre a área do procedimento cirúrgico, por cinco dias consecutivos. O tempo de elevação da pata, durante a marcha, foi avaliado antes e após a ciatalgia, no 3º, 6º, 9º e 13º PO. Os resultados demonstraram que a aplicação do ultrassom reduziu a dor com ambos os tratamentos efetivos e tendeu a ser mais eficaz na forma pulsada.The sciatica possesses great general population prevalence, and its treatment tends to solve the nervous compression causes. Physiotherapy aims to reduce the symptoms caused by compression. This study aimed to evaluate the effectiveness of therapeutic ultrasound on pain in animals subjected to sciatica experimental model. Eighteen rats were used and they were divided in 3 groups: group SG (n=4 submitted to the sciatica and treated with the ultrasound off, group PUG (n=7 submitted to the sciatica and treated with pulsed ultrasound 2 W/cm² (SATP; 0,4 - SATA and group CUG (n=7 submitted to the sciatica and treated with continuous ultrasound (0,4 W/cm². The sciatic nerve of the posterior right limb was exposed to the compression with Catgut wire in 4

  11. Using pharmacokinetic-pharmacodynamic modelling as a tool for prediction of therapeutic effective plasma levels of antipsychotics

    DEFF Research Database (Denmark)

    Olsen, Christina Kurre; Brennum, Lise Tøttrup; Kreilgaard, Mads

    2008-01-01

    response behaviour correlates well with the relationship between human dopamine D2 receptor occupancy and clinical effect. The aim of the present study was to evaluate how pharmacokinetic/pharmacodynamic (PK/PD) predictions of therapeutic effective steady-state plasma levels by means of conditioned...... the rat dopamine D2 receptor occupancy levels providing 50% response in the conditioned avoidance response test and the dopamine D2 receptor occupancy levels reported from responding schizophrenic patients treated with antipsychotics. Predictions of therapeutically effective steady-state levels...... for sertindole (+dehydrosertindole) and olanzapine were 3-4-fold too high whereas for haloperidol, clozapine and risperidone the predicted steady-state EC50 in conditioned avoidance responding rats correlated well with the therapeutically effective plasma levels observed in patients. Accordingly, the proposed PK...

  12. Medicare Program; Advancing Care Coordination Through Episode Payment Models (EPMs); Cardiac Rehabilitation Incentive Payment Model; and Changes to the Comprehensive Care for Joint Replacement Model (CJR). Final rule.

    Science.gov (United States)

    2017-01-03

    This final rule implements three new Medicare Parts A and B episode payment models, a Cardiac Rehabilitation (CR) Incentive Payment model and modifications to the existing Comprehensive Care for Joint Replacement model under section 1115A of the Social Security Act. Acute care hospitals in certain selected geographic areas will participate in retrospective episode payment models targeting care for Medicare fee-forservice beneficiaries receiving services during acute myocardial infarction, coronary artery bypass graft, and surgical hip/femur fracture treatment episodes. All related care within 90 days of hospital discharge will be included in the episode of care. We believe these models will further our goals of improving the efficiency and quality of care for Medicare beneficiaries receiving care for these common clinical conditions and procedures.

  13. Aespoe Pillar Stability Experiment. Final 2D coupled thermo-mechanical modelling

    Energy Technology Data Exchange (ETDEWEB)

    Fredriksson, Anders; Staub, Isabelle; Outters, Nils [Golder Associates AB, Uppsala (Sweden)

    2004-02-01

    A site scale Pillar Stability Experiment is planned in the Aespoe Hard Rock Laboratory. One of the experiment's aims is to demonstrate the possibilities of predicting spalling in the fractured rock mass. In order to investigate the probability and conditions for spalling in the pillar 'prior to experiment' numerical simulations have been undertaken. This report presents the results obtained from 2D coupled thermo-mechanical numerical simulations that have been done with the Finite Element based programme JobFem. The 2D numerical simulations were conducted at two different depth levels, 0.5 and 1.5 m below tunnel floor. The in situ stresses have been confirmed with convergence measurements during the excavation of the tunnel. After updating the mechanical and thermal properties of the rock mass the final simulations have been undertaken. According to the modelling results the temperature in the pillar will increase from the initial 15.2 deg up to 58 deg after 120 days of heating. Based on these numerical simulations and on the thermal induced stresses the total stresses are expected to exceed 210 MPa at the border of the pillar for the level at 0.5 m below tunnel floor and might reach 180-182 MPa for the level at 1.5 m below tunnel floor. The stresses are slightly higher at the border of the confined hole. Upon these results and according to the rock mechanical properties the Crack Initiation Stress is exceeded at the border of the pillar already after the excavation phase. These results also illustrate that the Crack Damage Stress is exceeded only for the level at 0.5 m below tunnel floor and after at least 80 days of heating. The interpretation of the results shows that the required level of stress for spalling can be reached in the pillar.

  14. An assessment of the utilization of the preclinical rodent model literature in clinical trials of putative therapeutics for the treatment of alcohol use disorders.

    Science.gov (United States)

    Barajaz, Ashley M; Kliethermes, Christopher L

    2017-12-01

    Rodent models of Alcohol Use Disorders (AUD) are used extensively by preclinical researchers to develop new therapeutics for the treatment of AUD. Although these models play an important role in the development of novel, targeted therapeutics, their role in bringing therapeutics to clinical trials is unclear, as off-label use of existing medications not approved for the treatment of AUD is commonly seen in the clinic and clinical trials. In the current study, we used the Clinicaltrials.gov database to obtain a list of drugs that have been tested for efficacy in a clinical trial between 1997 and 2017. We then conducted a set of literature searches to determine which of the 98 unique drugs we identified had shown efficacy in a rodent model of an AUD prior to being tested in a clinical trial. We found that slightly less than half of the drugs tested in clinical trials (48%) had shown prior efficacy in any rodent model of an AUD, while the remaining 52% of drugs were used off-label, or in some cases, following non-published studies. This study raises the question of how clinical researchers incorporate results from preclinical studies in the decision to bring a drug to a clinical trial. Our results underscore the need for ongoing communication among preclinical and clinical researchers. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Usage of model BH6012 two dimensional bone densimeter in the therapeutic effect observation of traditional chinese medicine cured osteoporosis

    International Nuclear Information System (INIS)

    Sun Jiaxiang; Tang Yahang; Gao Weiling; Chen Hengliang; Pang Jingshun

    1998-01-01

    Osteoporosis (OP) is a disease characterized by reduced bone mineral, lowered density, weakened strength, etc. A great deal of the illness appeared in the old people, especially old women. The article will deal mainly with two questions: traditional chinese medicine care OP and the usage of two dimensional bone densimeter in the therapeutic effect observation

  16. Utilizing native fluorescence imaging, modeling and simulation to examine pharmacokinetics and therapeutic regimen of a novel anticancer prodrug

    International Nuclear Information System (INIS)

    Wang, Jing-Hung; Endsley, Aaron N.; Green, Carol E.; Matin, A. C.

    2016-01-01

    Success of cancer prodrugs relying on a foreign gene requires specific delivery of the gene to the cancer, and improvements such as higher level gene transfer and expression. Attaining these objectives will be facilitated in preclinical studies using our newly discovered CNOB-GDEPT, consisting of the produrg: 6-chloro-9-nitro-5-oxo-5H-benzo-(a)-phenoxazine (CNOB) and its activating enzyme ChrR6, which generates the cytotoxic product 9-amino-6-chloro-5H-benzo[a]phenoxazine-5-one (MCHB). MCHB is fluorescent and can be noninvasively imaged in mice, and here we investigated whether MCHB fluorescence quantitatively reflects its concentration, as this would enhance its reporter value in further development of the CNOB-GDEPT therapeutic regimen. PK parameters were estimated and used to predict more effective CNOB administration schedules. CNOB (3.3 mg/kg) was injected iv in mice implanted with humanized ChrR6 (HChrR6)-expressing 4T1 tumors. Fluorescence was imaged in live mice using IVIS Spectrum, and quantified by Living Image 3.2 software. MCHB and CNOB were quantified also by LC/MS/MS analysis. We used non-compartmental model to estimate PK parameters. Phoenix WinNonlin software was used for simulations to predict a more effective CNOB dosage regimen. CNOB administration significantly prolonged mice survival. MCHB fluorescence quantitatively reflected its exposure levels to the tumor and the plasma, as verified by LC/MS/MS analysis at various time points, including at a low concentration of 2 ng/g tumor. The LC/MS/MS data were used to estimate peak plasma concentrations, exposure (AUC 0-24 ), volume of distribution, clearance and half-life in plasma and the tumor. Simulations suggested that the CNOB-GDEPT can be a successful therapy without large increases in the prodrug dosage. MCHB fluorescence quantifies this drug, and CNOB can be effective at relatively low doses. MCHB fluorescence characteristics will expedite further development of CNOB-GDEPT by, for example

  17. The TREAT-NMD advisory committee for therapeutics (TACT): an innovative de-risking model to foster orphan drug development.

    Science.gov (United States)

    Heslop, Emma; Csimma, Cristina; Straub, Volker; McCall, John; Nagaraju, Kanneboyina; Wagner, Kathryn R; Caizergues, Didier; Korinthenberg, Rudolf; Flanigan, Kevin M; Kaufmann, Petra; McNeil, Elizabeth; Mendell, Jerry; Hesterlee, Sharon; Wells, Dominic J; Bushby, Kate

    2015-04-23

    Despite multiple publications on potential therapies for neuromuscular diseases (NMD) in cell and animal models only a handful reach clinical trials. The ability to prioritise drug development according to objective criteria is particularly critical in rare diseases with large unmet needs and a limited numbers of patients who can be enrolled into clinical trials. TREAT-NMD Advisory Committee for Therapeutics (TACT) was established to provide independent and objective guidance on the preclinical and development pathway of potential therapies (whether novel or repurposed) for NMD.We present our experience in the establishment and operation of the TACT. TACT provides a unique resource of recognized experts from multiple disciplines. The goal of each TACT review is to help the sponsor to position the candidate compound along a realistic and well-informed plan to clinical trials, and eventual registration. The reviews and subsequent recommendations are focused on generating meaningful and rigorous data that can enable clear go/no-go decisions and facilitate longer term funding or partnering opportunities. The review process thereby acts to comment on viability, de-risking the process of proceeding on a development programme.To date TACT has held 10 review meeting and reviewed 29 program applications in several rare neuromuscular diseases: Of the 29 programs reviewed, 19 were from industry and 10 were from academia; 15 were for novel compounds and 14 were for repurposed drugs; 16 were small molecules and 13 were biologics; 14 were preclinical stage applications and 15 were clinical stage applications. 3 had received Orphan drug designation from European Medicines Agency and 3 from Food and Drug Administration. A number of recurrent themes emerged over the course of the reviews and we found that applicants frequently require advice and education on issues concerned with preclinical standard operating procedures, interactions with regulatory agencies, formulation

  18. Feasibility of a Miniature Esophageal Heat Exchange Device for Rapid Therapeutic Cooling in Newborns: Preliminary Investigations in a Piglet Model.

    Science.gov (United States)

    Dingley, John; Okano, Satomi; Planas, Silvia; Chakkarapani, Elavazhagan

    2018-03-01

    Therapeutic hypothermia (TH) after neonatal encephalopathy, commonly provided by 72 hours of whole-body cooling using a wrap, limits parents' physical contact with their infants affecting bonding and may not be suitable for encephalopathic preterm infants with fragile skin. Alternative cooling methods are unavailable for this population. We investigated in a neonatal pig model the feasibility of achieving a 3.5°C reduction in rectal temperature (T rectal ) similar to clinical TH protocols from 38.5°C (normothermia for pigs) to a target of 35°C ± 0.2°C, using a novel neonatal esophageal heat exchanger (NEHE), compared its efficacy to passive cooling, and investigated its ability to maintain target T rectal . Ventilated and anesthetized Landrace/Large white newborn pigs had the NEHE inserted. Water at adjustable temperatures and rates flowed down a central tube, returning up a surrounding distensible blind ending latex tube in a continuous loop. An initial experiment guided four subsequent cycles of passive cooling (30 minutes), rewarming to 38.5°C, active esophageal cooling to 35°C ± 0.2°C, active maintenance of target T rectal (30 minutes), and rewarming. We compared surface, rectal temperature, and hemodynamic changes among passive, active, and maintenance phases, and esophageal histopathology against control. Compared with passive cooling, esophageal cooling achieved target T rectal significantly earlier (71.3 minutes vs. 17.25 minutes, p = 0.003) with significantly greater rates of reduction in rectal (p = 0.0002) and surface (p = 0.005) temperatures and heart rate (p = 0.04). A water temperature of 39.1°C-40.2°C at a flow of 108-120 mL/min maintained T rectal around 35°C ± 0.2°C. The higher peak heart rate and blood pressure within 8 minutes of the maintenance phase (p = 0.04) subsequently stabilized. Histopathology showed congestion, edema, and neutrophil infiltration with increasing cycles. Esophageal cooling is

  19. Modelling of capital requirements in the energy sector: capital market access. Final memorandum

    Energy Technology Data Exchange (ETDEWEB)

    1978-04-01

    Formal modelling techniques for analyzing the capital requirements of energy industries have been performed at DOE. A survey has been undertaken of a number of models which forecast energy-sector capital requirements or which detail the interactions of the energy sector and the economy. Models are identified which can be useful as prototypes for some portion of DOE's modelling needs. The models are examined to determine any useful data bases which could serve as inputs to an original DOE model. A selected group of models are examined which can comply with the stated capabilities. The data sources being used by these models are covered and a catalog of the relevant data bases is provided. The models covered are: capital markets and capital availability models (Fossil 1, Bankers Trust Co., DRI Macro Model); models of physical capital requirements (Bechtel Supply Planning Model, ICF Oil and Gas Model and Coal Model, Stanford Research Institute National Energy Model); macroeconomic forecasting models with input-output analysis capabilities (Wharton Annual Long-Term Forecasting Model, Brookhaven/University of Illinois Model, Hudson-Jorgenson/Brookhaven Model); utility models (MIT Regional Electricity Model-Baughman Joskow, Teknekron Electric Utility Simulation Model); and others (DRI Energy Model, DRI/Zimmerman Coal Model, and Oak Ridge Residential Energy Use Model).

  20. Final Report

    Energy Technology Data Exchange (ETDEWEB)

    Stinis, Panos [Pacific Northwest National Lab. (PNNL), Richland, WA (United States)

    2016-08-07

    This is the final report for the work conducted at the University of Minnesota (during the period 12/01/12-09/18/14) by PI Panos Stinis as part of the "Collaboratory on Mathematics for Mesoscopic Modeling of Materials" (CM4). CM4 is a multi-institution DOE-funded project whose aim is to conduct basic and applied research in the emerging field of mesoscopic modeling of materials.

  1. Final Report - Spacially-Resolved Diagnostics and Modeling of Micro-Discharges

    International Nuclear Information System (INIS)

    Donnelly, Vincent M.; Economou, Demetre J.

    2012-01-01

    predictions. Finally, laser scattering experiments were performed at pressures of 100s of Torr in argon or nitrogen. Laser Thomson Scattering (LTS) and Rotational Raman Scattering were employed in a novel, backscattering, confocal configuration. LTS allows direct and simultaneous measurement of both electron density (ne) and electron temperature (Te). For 50 mA current and over the pressure range of 300-700 Torr, LTS yielded Te = 0.9 ± 0.3 eV and ne = (6 ± 3) 1013 cm-3, in reasonable agreement with the predictions of a mathematical model. Rotational Raman spectroscopy (RRS) was employed for absolute calibration of the LTS signal. RRS was also applied to measure the 3D gas temperature (Tg) in nitrogen DC microdischarges. In addition, diode laser absorption spectroscopy was employed to measure the density of argon metastables (1s5 in Paschen notations) in argon microdischarges. The gas temperature, extracted from the width of the absorption profile, was compared with Tg values obtained by optical emission spectroscopy.

  2. CFD modelling of axial mixing in the intermediate and final rinses of cleaning-in-place procedures of straight pipes

    DEFF Research Database (Denmark)

    Yang, Jifeng; Jensen, Bo Boye Busk; Nordkvist, Mikkel

    2018-01-01

    The intermediate and final rinses of straight pipes, in which water replaces a cleaning agent of similar density and viscosity, are modelled using Computational Fluid Dynamic (CFD) methods. It is anticipated that the displacement process is achieved by convective and diffusive transport. The simu...

  3. Mirtazapine has a therapeutic potency in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mice model of Parkinson's disease.

    Science.gov (United States)

    Kadoguchi, Naoto; Okabe, Shinji; Yamamura, Yukio; Shono, Misaki; Fukano, Tatsuya; Tanabe, Akie; Yokoyama, Hironori; Kasahara, Jiro

    2014-06-25

    Mirtazapine, a noradrenergic and specific serotonergic antidepressant (NaSSA), shows multiple pharmacological actions such as inhibiting presynaptic α2 noradrenaline receptor (NAR) and selectively activating 5-hydroxytriptamine (5-HT) 1A receptor (5-HT1AR). Mirtazapine was also reported to increase dopamine release in the cortical neurons with 5-HT dependent manner. To examine whether mirtazapine has a therapeutic potency in Parkinson's disease (PD), we examined this compound in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice model of PD. Male C57BL/6 mice were subjected to MPTP treatment to establish a PD model. Mirtazapine was administered once a day for 3 days after MPTP treatment. MPTP-induced motor dysfunction, assessed by beam-walking and rota-rod tests, was significantly improved by administration of mirtazapine. Biochemical examinations by high performance liquid chromatography and western blot analysis suggested mirtazapine facilitated utilization of dopamine by increasing turnover and protein expression of transporters, without affecting on neurodegenerative process by MPTP. These therapeutic effects of mirtazapine were reduced by administration of WAY100635, an inhibitor for 5HT1AR, or of clonidine, a selective agonist for α2-NAR, or of prazosin, an inhibitor for α1-NAR, respectively. Our results showed mirtazapine had a therapeutic potency against PD in a mouse model. Because PD patients sometimes show depression together, it will be a useful drug for a future PD treatment.

  4. Mirtazapine has a therapeutic potency in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mice model of Parkinson’s disease

    Science.gov (United States)

    2014-01-01

    Background Mirtazapine, a noradrenergic and specific serotonergic antidepressant (NaSSA), shows multiple pharmacological actions such as inhibiting presynaptic α2 noradrenaline receptor (NAR) and selectively activating 5-hydroxytriptamine (5-HT) 1A receptor (5-HT1AR). Mirtazapine was also reported to increase dopamine release in the cortical neurons with 5-HT dependent manner. To examine whether mirtazapine has a therapeutic potency in Parkinson’s disease (PD), we examined this compound in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice model of PD. Results Male C57BL/6 mice were subjected to MPTP treatment to establish a PD model. Mirtazapine was administered once a day for 3 days after MPTP treatment. MPTP-induced motor dysfunction, assessed by beam-walking and rota-rod tests, was significantly improved by administration of mirtazapine. Biochemical examinations by high performance liquid chromatography and western blot analysis suggested mirtazapine facilitated utilization of dopamine by increasing turnover and protein expression of transporters, without affecting on neurodegenerative process by MPTP. These therapeutic effects of mirtazapine were reduced by administration of WAY100635, an inhibitor for 5HT1AR, or of clonidine, a selective agonist for α2-NAR, or of prazosin, an inhibitor for α1-NAR, respectively. Conclusion Our results showed mirtazapine had a therapeutic potency against PD in a mouse model. Because PD patients sometimes show depression together, it will be a useful drug for a future PD treatment. PMID:24965042

  5. Development and Pre-Clinical Evaluation of Recombinant Human Myelin Basic Protein Nano Therapeutic Vaccine in Experimental Autoimmune Encephalomyelitis Mice Animal Model

    Science.gov (United States)

    Al-Ghobashy, Medhat A.; Elmeshad, Aliaa N.; Abdelsalam, Rania M.; Nooh, Mohammed M.; Al-Shorbagy, Muhammad; Laible, Götz

    2017-04-01

    Recombinant human myelin basic protein (rhMBP) was previously produced in the milk of transgenic cows. Differences in molecular recognition of either hMBP or rhMBP by surface-immobilized anti-hMBP antibodies were demonstrated. This indicated differences in immunological response between rhMBP and hMBP. Here, the activity of free and controlled release rhMBP poly(ɛ-caprolactone) nanoparticles (NPs), as a therapeutic vaccine against multiple sclerosis (MS) was demonstrated in experimental autoimmune encephalomyelitis (EAE) animal model. Following optimization of nanoformulation, discrete spherical, rough-surfaced rhMBP NPs with high entrapment efficiency and controlled release pattern were obtained. Results indicated that rhMBP was loaded into and electrostatically adsorbed onto the surface of NPs. Subcutaneous administration of free or rhMBP NPs before EAE-induction reduced the average behavioral score in EAE mice and showed only mild histological alterations and preservation of myelin sheath, with rhMBP NPs showing increased protection. Moreover, analysis of inflammatory cytokines (IFN-γ and IL-10) in mice brains revealed that pretreatment with free or rhMBP NPs significantly protected against induced inflammation. In conclusion: i) rhMBP ameliorated EAE symptoms in EAE animal model, ii) nanoformulation significantly enhanced efficacy of rhMBP as a therapeutic vaccine and iii) clinical investigations are required to demonstrate the activity of rhMBP NPs as a therapeutic vaccine for MS.

  6. The pig as a model for therapeutic human anti-cancer vaccine development, elucidating the T-cell reactivity against IDO and RhoC

    DEFF Research Database (Denmark)

    Overgaard, Nana Haahr; Frøsig, Thomas Mørch; Welner, Simon

    is important. Previous development of therapeutic cancer vaccines has largely been based on studies in mice and the majority of these candidate vaccines failed to establish therapeutic responses in subsequent human clinical trials. Since the porcine immunome is more closely related to the human counterpart, we...... here introduce pigs as a superior large animal model for human cancer vaccine development via the use of our unique technology for swine leukocyte antigen (SLA) production. IDO and RhoC, both known to be important in human cancer development and progression, were used as vaccine targets. Pigs were......, and peptide-SLA complex stability measurements revealed 89 stable (t½ ≥ 0.5 hour) complexes. Vaccine-induced peptide-specific CTL responses were monitored using IFN-γ release as a read out. We found responses to IDO- and RhoC-derived peptides across all groups; surprisingly non-stably binding peptides also...

  7. Prediction of a Therapeutic Dose for Buagafuran, a Potent Anxiolytic Agent by Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling Starting from Pharmacokinetics in Rats and Human

    Directory of Open Access Journals (Sweden)

    Fen Yang

    2017-10-01

    Full Text Available Physiologically based pharmacokinetic (PBPK/pharmacodynamic (PD models can contribute to animal-to-human extrapolation and therapeutic dose predictions. Buagafuran is a novel anxiolytic agent and phase I clinical trials of buagafuran have been completed. In this paper, a potentially effective dose for buagafuran of 30 mg t.i.d. in human was estimated based on the human brain concentration predicted by a PBPK/PD modeling. The software GastroPlusTM was used to build the PBPK/PD model for buagafuran in rat which related the brain tissue concentrations of buagafuran and the times of animals entering the open arms in the pharmacological model of elevated plus-maze. Buagafuran concentrations in human plasma were fitted and brain tissue concentrations were predicted by using a human PBPK model in which the predicted plasma profiles were in good agreement with observations. The results provided supportive data for the rational use of buagafuran in clinic.

  8. Probabilistic modelling of the damage of geological barriers of the nuclear waste deep storage - ENDOSTON project, final report

    International Nuclear Information System (INIS)

    2010-01-01

    As the corrosion of metallic casings of radioactive waste storage packages releases hydrogen under pressure, and as the overpressure disturbs the stress fields, the authors report the development of methodologies and numerical simulation tools aimed at a better understanding of the mechanisms of development and propagation of crack networks in the geological barrier due to this overpressure. They present a probabilistic model of the formation of crack networks in rocks, with the probabilistic post-processing of a finite element calculation. They describe the modelling of crack propagation and damage in quasi-brittle materials. They present the ENDO-HETEROGENE model for the formation and propagation of cracks in heterogeneous media, describe the integration of the model into the Aster code, and report the model validation (calculation of the stress intensity factor, grid dependence). They finally report a test case of the ENDO-HETEROGENE model

  9. Analyses, algorithms, and computations for models of high-temperature superconductivity. Final report

    International Nuclear Information System (INIS)

    Du, Q.

    1997-01-01

    Under the sponsorship of the Department of Energy, the authors have achieved significant progress in the modeling, analysis, and computation of superconducting phenomena. The work so far has focused on mezoscale models as typified by the celebrated Ginzburg-Landau equations; these models are intermediate between the microscopic models (that can be used to understand the basic structure of superconductors and of the atomic and sub-atomic behavior of these materials) and the macroscale, or homogenized, models (that can be of use for the design of devices). The models they have considered include a time dependent Ginzburg-Landau model, a variable thickness thin film model, models for high values of the Ginzburg-landau parameter, models that account for normal inclusions and fluctuations and Josephson effects, and the anisotropic ginzburg-Landau and Lawrence-Doniach models for layered superconductors, including those with high critical temperatures. In each case, they have developed or refined the models, derived rigorous mathematical results that enhance the state of understanding of the models and their solutions, and developed, analyzed, and implemented finite element algorithms for the approximate solution of the model equations

  10. Analyses, algorithms, and computations for models of high-temperature superconductivity. Final technical report

    International Nuclear Information System (INIS)

    Gunzburger, M.D.; Peterson, J.S.

    1998-01-01

    Under the sponsorship of the Department of Energy, the authors have achieved significant progress in the modeling, analysis, and computation of superconducting phenomena. Their work has focused on mezoscale models as typified by the celebrated ginzburg-Landau equations; these models are intermediate between the microscopic models (that can be used to understand the basic structure of superconductors and of the atomic and sub-atomic behavior of these materials) and the macroscale, or homogenized, models (that can be of use for the design of devices). The models the authors have considered include a time dependent Ginzburg-Landau model, a variable thickness thin film model, models for high values of the Ginzburg-Landau parameter, models that account for normal inclusions and fluctuations and Josephson effects, and the anisotropic Ginzburg-Landau and Lawrence-Doniach models for layered superconductors, including those with high critical temperatures. In each case, they have developed or refined the models, derived rigorous mathematical results that enhance the state of understanding of the models and their solutions, and developed, analyzed, and implemented finite element algorithms for the approximate solution of the model equations

  11. 2011 Marine Hydrokinetic Device Modeling Workshop: Final Report; March 1, 2011

    Energy Technology Data Exchange (ETDEWEB)

    Li, Y.; Reed, M.; Smith, B.

    2011-10-01

    This report summarizes the NREL Marine and Hydrokinetic Device Modeling Workshop. The objectives for the modeling workshop were to: (1) Review the designs of existing MHK device prototypes and discuss design and optimization procedures; (2) Assess the utility and limitations of modeling techniques and methods presently used for modeling MHK devices; (3) Assess the utility and limitations of modeling methods used in other areas, such as naval architecture and ocean engineering (e.g., oil & gas industry); and (4) Identify the necessary steps to link modeling with other important components that analyze MHK devices (e.g., tank testing, PTO design, mechanical design).

  12. Search for the Standard Model Higgs Boson in Leptons plus Jets Final States

    Energy Technology Data Exchange (ETDEWEB)

    Nguyen, Huong [Univ. of Virginia, Charlottesville, VA (United States)

    2014-01-01

    Searches for SM Higgs boson production in the leptons plus jets final states with a data set corresponding to 9.7 fb-1 of $\\bar{p}$p collisions at √s = 1.96TeV collected by the DØ Experiment are presented in this thesis. The searches are carried out in two independent analyses, accounting for different signal topologies.

  13. Danubian lowland - ground water model. Final Report. Vol. 1. Summary Report

    International Nuclear Information System (INIS)

    1995-12-01

    The summary report contains the next parts: (0) Executive summary; (1) Introduction; (2) Project staffing; (3) Project management issues; (4) Establishment of the integrated modelling system; (5) Summary of model application; (6) Conclusions and recommendations; and List of references

  14. Automatic component calibration and error diagnostics for model-based accelerator control. Phase I final report

    International Nuclear Information System (INIS)

    Carl Stern; Martin Lee

    1999-01-01

    Phase I work studied the feasibility of developing software for automatic component calibration and error correction in beamline optics models. A prototype application was developed that corrects quadrupole field strength errors in beamline models

  15. Automatic component calibration and error diagnostics for model-based accelerator control. Phase I final report

    CERN Document Server

    Carl-Stern

    1999-01-01

    Phase I work studied the feasibility of developing software for automatic component calibration and error correction in beamline optics models. A prototype application was developed that corrects quadrupole field strength errors in beamline models.

  16. Housing Value Projection Model Related to Educational Planning: The Feasibility of a New Methodology. Final Report.

    Science.gov (United States)

    Helbock, Richard W.; Marker, Gordon

    This study concerns the feasibility of a Markov chain model for projecting housing values and racial mixes. Such projections could be used in planning the layout of school districts to achieve desired levels of socioeconomic heterogeneity. Based upon the concepts and assumptions underlying a Markov chain model, it is concluded that such a model is…

  17. An Investigation of the Mathematical Models of Piaget's Psychological Theory of Cognitive Learning. Final Report.

    Science.gov (United States)

    Kalechofsky, Robert

    This research paper proposes several mathematical models which help clarify Piaget's theory of cognition on the concrete and formal operational stages. Some modified lattice models were used for the concrete stage and a combined Boolean Algebra and group theory model was used for the formal stage. The researcher used experiments cited in the…

  18. Three dimensional global modeling of atmospheric CO2. Final technical report

    International Nuclear Information System (INIS)

    Fung, I.; Hansen, J.; Rind, D.

    1983-01-01

    A modeling effort has been initiated to study the prospects of extracting information on carbon dioxide sources and sinks from observed CO 2 variations. The approach uses a three-dimensional global transport model, based on winds from a 3-D general circulation model (GCM), to advect CO 2 noninteractively, i.e., as a tracer, with specified sources and sinks of CO 2 at the surface. This report identifies the 3-D model employed in this study and discusses biosphere, ocean and fossil fuel sources and sinks. Some preliminary model results are presented. 14 figures

  19. Beyond Standard Model searches in jets plus missing transverse energy final states with the ATLAS experiment at the LHC

    CERN Document Server

    AUTHOR|(INSPIRE)INSPIRE-00414488; Alviggi, Mariagrazia; Conventi, Francesco

    Dark Matter (DM) is currently one of the most challenging goal in the LHC programme: if DM exists it can be pair-produced in proton-proton collisions. Since its weakly-interacting nature, final signatures with high missing momentum and Standard Model (SM) particles are employed in these searches. This thesis presents results on signatures involving bottom quarks in final states, described in models where DM production occurs via massive spin-0 mediators (scalar or pseudoscalar) with a coupling to SM particles proportional to their masses. These collider searches provide an interesting complementarity to DM direct and indirect detection experiments, covering the parameter space with low DM masses. The results shown in the thesis are obtained on the data collected by the ATLAS experiment in 2015 and 2016.

  20. Development Of Robust IFE Laser Mirrors and Multi-Scale Modeling Of Pulsed Radiation Effects. Final Report

    International Nuclear Information System (INIS)

    Ghoniem, Nasr M.

    2009-01-01

    The following has been achieved: (1) Final design of a Deformable Grazing Incidence Mirror, (2) Formulation of a new approach to model surface roughening under laser illumination, and (3) Modeling of radiation hardening under IFE conditions. We discuss here progress made in each one of these areas. The objectives of the Grazing Incidence Metal Mirror (GIMM) are: (1) to reflect the incident laser beam into the direction of the target; (2) to focus the incident beam directly onto the target (3) to withstand the thermomechanical and damage induced by laser beams; (4) to correct the reflective surface so that the focus is permanently on the target; (5) to have a full range of motion so it can be placed anywhere relative to the target. The design was described in our progress report of the period August 15, 2003 through April 15, 2004. In the following, we describe further improvements of the final design.

  1. Therapeutic efficacy of the combination of doxorubicin-loaded liposomes with inertial cavitation generated by confocal ultrasound in AT2 Dunning rat tumour model.

    Science.gov (United States)

    Mestas, Jean-Louis; Fowler, R Andrew; Evjen, Tove J; Somaglino, Lucie; Moussatov, Alexei; Ngo, Jacqueline; Chesnais, Sabrina; Røgnvaldsson, Sibylla; Fossheim, Sigrid L; Nilssen, Esben A; Lafon, Cyril

    2014-09-01

    The combination of liposomal doxorubicin (DXR) and confocal ultrasound (US) was investigated for the enhancement of drug delivery in a rat tumour model. The liposomes, based on the unsaturated phospholipid dierucoylphosphocholine, were designed to be stable during blood circulation in order to maximize accumulation in tumour tissue and to release drug content upon US stimulation. A confocal US setup was developed for delivering inertial cavitation to tumours in a well-controlled and reproducible manner. In vitro studies confirm drug release from liposomes as a function of inertial cavitation dose, while in vivo pharmacokinetic studies show long blood circulation times and peak tumour accumulation at 24-48 h post intravenous administration. Animals injected 6 mg kg(-1) liposomal DXR exposed to US treatment 48 h after administration show significant tumour growth delay compared to control groups. A liposomal DXR dose of 3 mg kg(-1), however, did not induce any significant therapeutic response. This study demonstrates that inertial cavitation can be generated in such a fashion as to disrupt drug carrying liposomes which have accumulated in the tumour, and thereby increase therapeutic effect with a minimum direct effect on the tissue. Such an approach is an important step towards a therapeutic application of cavitation-induced drug delivery and reduced chemotherapy toxicity.

  2. Present Status and Future Challenges of New Therapeutic Targets in Preclinical Models of Stroke in Aged Animals with/without Comorbidities

    Directory of Open Access Journals (Sweden)

    Aurel Popa-Wagner

    2018-01-01

    Full Text Available The aging process, comorbidities, and age-associated diseases are closely dependent on each other. Cerebral ischemia impacts a wide range of systems in an age-dependent manner. However, the aging process has many facets which are influenced by the genetic background and epigenetic or environmental factors, which can explain why some people age differently than others. Therefore, there is an urgent need to identify age-related changes in body functions or structures that increase the risk for stroke and which are associated with a poor outcome. Multimodal imaging, electrophysiology, cell biology, proteomics, and transcriptomics, offer a useful approach to link structural and functional changes in the aging brain, with or without comorbidities, to post-stroke rehabilitation. This can help us to improve our knowledge about senescence firstly, and in this context, aids in elucidating the pathophysiology of age-related diseases that allows us to develop therapeutic strategies or prevent diseases. These processes, including potential therapeutical interventions, need to be studied first in relevant preclinical models using aged animals, with and without comorbidities. Therefore, preclinical research on ischemic stroke should consider age as the most important risk factor for cerebral ischemia. Furthermore, the identification of effective therapeutic strategies, corroborated with successful translational studies, will have a dramatic impact on the lives of millions of people with cerebrovascular diseases.

  3. Drug-like analogues of the parasitic worm-derived immunomodulator ES-62 are therapeutic in the MRL/Lpr model of systemic lupus erythematosus

    Science.gov (United States)

    Rodgers, D T; Pineda, M A; Suckling, C J; Harnett, W

    2015-01-01

    Introduction ES-62, a phosphorylcholine (PC)-containing immunomodulator secreted by the parasitic worm Acanthocheilonema viteae, protects against nephritis in the MRL/Lpr mouse model of systemic lupus erythematosus (SLE). However, ES-62 is not suitable for development as a therapy and thus we have designed drug-like small molecule analogues (SMAs) based around its active PC-moiety. To provide proof of concept that ES-62-based SMAs exhibit therapeutic potential in SLE, we have investigated the capacity of two SMAs to protect against nephritis when administered to MRL/Lpr mice after onset of kidney damage. Methods SMAs 11a and 12b were evaluated for their ability to suppress antinuclear antibody (ANA) generation and consequent kidney pathology in MRL/Lpr mice when administered after the onset of proteinuria. Results SMAs 11a and 12b suppressed development of ANA and proteinuria. Protection reflected downregulation of MyD88 expression by kidney cells and this was associated with reduced production of IL-6, a cytokine that exhibits promise as a therapeutic target for this condition. Conclusions SMAs 11a and 12b provide proof of principle that synthetic compounds based on the safe immunomodulatory mechanisms of parasitic worms can exhibit therapeutic potential as a novel class of drugs for SLE, a disease for which current therapies remain inadequate. PMID:26085597

  4. Modelling gas migration in compacted bentonite: GAMBIT Club Phase 2. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Swift, B.T.; Hoch, A.R.; Rodwell, W.R. [AEA Technology (United Kingdom)

    2001-01-01

    This report describes the second phase of a programme of work to develop a computational model of gas migration through highly compacted bentonite. Experimental data that have appeared since the earlier report are reviewed for the additional information they might provide on the mechanism of gas migration in bentonite. Experiments carried out by Horseman and Harrigton (British Geological Survey) continued to provide the main data sets used in model evaluation. The earlier work (POSIVA Report 98-08) had resulted in a preliminary model of gas migration whose main features are gas invasion by microcrack propagation, and dilation of the pathways formed with increasing gas pressure. New work was carried out to further explore the capabilities of this model. In addition, a feature was added to the model to simulate gas pathway creation by water displacement rather than crack propagation. The development of a new alternative gas migration model is described. This is based on a volume-averaged representation of gas migration rather than on a description of flow in discrete pathways. Evaluation of this alternative model showed that it can produce similar agreement with experimental results to the other models examined. The implications of flow geometry, confining conditions and flow boundary conditions on gas migration behaviour in bentonite are reviewed. Proposals are made for the development of the new model into a tool for simulating gas migration through a bentonite buffer around a waste canister, and for possible enhancements to the model that might remove some of its currently perceived deficiencies. (orig.)

  5. Therapeutic efficacy and toxicity of a single and double application of boron neutron capture therapy (BNCT) in a hamster cheek pouch oral precancer model

    International Nuclear Information System (INIS)

    Monti Hughes, A; Pozzi, E C C; Thorp, S; Garabalino, M A; Farias, R O; Gonzalez, S J; Heber, E M; Itoiz, M E; Aromando, R F; Molinari, A J; Miller, M; Nigg, D W; Curotto, P; Trivillin, V A; Schwint, A E

    2012-01-01

    Tumor development from tissue with potentially malignant disorders (PMD) gives rise to second primary tumors. We previously demonstrated the partial inhibitory effect on tumor development of Boron Neutron Capture Therapy (BNCT) mediated by the boron compounds BPA (boronophenylalanine) and decahydrodecaborate (GB-10) in a hamster pouch oral precancer model. Seeking to optimize BNCT, the aim of the present study was to contribute to the knowledge of BNCT radiobiology for oral precancer and assess new BNCT protocols in terms of inhibition of tumor development and radiotoxicity. Groups of cancerized hamsters were locally exposed to single or double applications (2 weeks apart) of BPA-BNCT or (GB-10 + BPA)-BNCT at a total dose of 8Gy to tissue with PMD; to a single application of BPA-BNCT at 6Gy and to a double application (4 weeks apart) of BPA-BNCT or (BPA + GB-10)-BNCT at a total dose of 10Gy. Cancerized, sham-irradiated hamsters served as controls. Clinical status, tumor development from tissue with PMD and mucositis were followed for 8 months. The marked therapeutic efficacy of single applications of BNCT at 6 and 8Gy were associated to severe radiotoxicity. Dose fractionation into 2 applications reduced mucositis but also reduced therapeutic efficacy, depending on dose and interval between applications. A double application (4 weeks apart) of (GB-10 + BPA)-BNCT at a total dose of 10Gy rendered the best therapeutic advantage, i.e. 63% - 100% inhibition of tumor development with only slight mucositis in 67% of cases. The data reported herein show that issues such as dose levels and dose fractionation, interval between applications, and choice of boron compounds are pivotal to therapeutic advantage and must be tailored for a particular pathology and anatomic site. The present study determined treatment conditions that would contribute to optimize BNCT for precancer and that would warrant cautious assessment in a clinical scenario (author)

  6. Contingency analysis modeling for superfund sites and other sources. Final report

    International Nuclear Information System (INIS)

    Christensen, D.; Kaiser, G.D.

    1993-01-01

    The report provides information on contingency modeling for a wide range of different accidental release scenarios of hazardous air pollutants that might take place at Superfund and other sites. The scenarios are used to illustrate how atmospheric dispersion models, including dense gas models, should be applied. Particular emphasis is made on the input data that is needed for proper applications of models. Flow charts direct the user to specific sections where various scenarios are discussed. A check list of items that should be discussed before running the model is provided. Several examples are provided to specifically show how to apply the models so as to produce a credible analysis for a particular release scenario

  7. Postmodernism, Therapeutic Common Factors, and Innovation: Contemporary Influences Shaping a More Efficient and Effective Model of School Counseling

    Science.gov (United States)

    Klein, James F.; Gee, Corrie R.

    2006-01-01

    School counseling lacks clarity. This confusion is the result of competing models and confusing standards, domains, and competencies. This article offers a simplified model of school counseling entitled the "Six 'C' Model" (i.e., Care, Collaboration, Champion, Challenge, Courage, and Commitment). The interactive model is informed by the…

  8. Critical review of the reactor-safety study radiological health effects model. Final report

    International Nuclear Information System (INIS)

    Cooper, D.W.; Evans, J.S.; Jacob, N.; Kase, K.R.; Maletskos, C.J.; Robertson, J.B.; Smith, D.G.

    1983-03-01

    This review of the radiological health effects models originally presented in the Reactor Safety Study (RSS) and currently used by the US Nuclear Regulatory Commission (NRC) was undertaken to assist the NRC in determining whether or not to revise the models and to aid in the revision, if undertaken. The models as presented in the RSS and as implemented in the CRAC (Calculations of Reactor Accident Consequences) Code are described and critiqued. The major elements analyzed are those concerning dosimetry, early effects, and late effects. The published comments on the models are summarized, as are the important findings since the publication of the RSS

  9. The International Geomagnetic Reference Field (IGRF) generation 12: BGS candidates and final models

    OpenAIRE

    Beggan, Ciaran D.; Hamilton, Brian; Taylor, Victoria; Macmillan, Susan; Thomson, Alan

    2015-01-01

    The International Geomagnetic Reference Field (IGRF) model is a reference main field magnetic model updated on a quinquennial basis. The latest revision (generation 12) was released in January 2015. The IGRF-12 consists of a definitive model (DGRF2010) of the main field for 2010.0, a model for the field at 2015.0 (IGRF2015) and a prediction of secular variation (IGRF-12 SV) for the forthcoming five years until 2020.0. The remaining coefficients of IGRF-12 are unchanged from IGRF-11. Nin...

  10. Final Report on Models, Periodic Progress, Report No D1.3, Globeman21, ESPRIT 26509

    DEFF Research Database (Denmark)

    Pedersen, Jens Dahl; Tølle, Martin; Vesterager, Johan

    1999-01-01

    ), a collection of practical experiences, and requirements for enhanced methods and tools for modelling. First, the deliverable outlines the GM21 understanding regarding extended enterprises and virtual enterprises. This is done by extracting and synthesising the essence of key definitions and concepts...... concepts that have been defined and studied in the project. The aim of the Concept Model is to show how the different concepts are related to each other and to the GM21 pilot projects. Complementary, the Methodology Model models the life cycle based activities of the Extended Enterprise Methodology as well...

  11. Critical review of the reactor-safety study radiological health effects model. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Cooper, D.W.; Evans, J.S.; Jacob, N.; Kase, K.R.; Maletskos, C.J.; Robertson, J.B.; Smith, D.G.

    1983-03-01

    This review of the radiological health effects models originally presented in the Reactor Safety Study (RSS) and currently used by the US Nuclear Regulatory Commission (NRC) was undertaken to assist the NRC in determining whether or not to revise the models and to aid in the revision, if undertaken. The models as presented in the RSS and as implemented in the CRAC (Calculations of Reactor Accident Consequences) Code are described and critiqued. The major elements analyzed are those concerning dosimetry, early effects, and late effects. The published comments on the models are summarized, as are the important findings since the publication of the RSS.

  12. An electrodynamical model for the ion behaviour in the final plasma focus stages

    International Nuclear Information System (INIS)

    Zambreanu, V.; Doloc, C.M.

    1992-01-01

    Plasma focus devices (PFDs) are strong sources of fusion neutrons but the problem of which interactions are responsible for the fusion reactions is still open since neither of the proposed theoretical models has been confirmed experimentally. A model for the trajectories of the deuteron ions in a configuration of selfconsistent electromagnetic fields is proposed starting from an empirical plasma model which describes the plasma focus collapse and column phases. The proposed model is only electrodynamical under the assumption of a uniform current density and an infinite length of the plasma column, not taking into account the fluid characteristics of the plasma. (author)

  13. Major models and data sources for residential and commercial sector energy conservation analysis. Final report

    Energy Technology Data Exchange (ETDEWEB)

    1980-09-01

    Major models and data sources are reviewed that can be used for energy-conservation analysis in the residential and commercial sectors to provide an introduction to the information that can or is available to DOE in order to further its efforts in analyzing and quantifying their policy and program requirements. Models and data sources examined in the residential sector are: ORNL Residential Energy Model; BECOM; NEPOOL; MATH/CHRDS; NIECS; Energy Consumption Data Base: Household Sector; Patterns of Energy Use by Electrical Appliances Data Base; Annual Housing Survey; 1970 Census of Housing; AIA Research Corporation Data Base; RECS; Solar Market Development Model; and ORNL Buildings Energy Use Data Book. Models and data sources examined in the commercial sector are: ORNL Commercial Sector Model of Energy Demand; BECOM; NEPOOL; Energy Consumption Data Base: Commercial Sector; F.W. Dodge Data Base; NFIB Energy Report for Small Businesses; ADL Commercial Sector Energy Use Data Base; AIA Research Corporation Data Base; Nonresidential Buildings Surveys of Energy Consumption; General Electric Co: Commercial Sector Data Base; The BOMA Commercial Sector Data Base; The Tishman-Syska and Hennessy Data Base; The NEMA Commercial Sector Data Base; ORNL Buildings Energy Use Data Book; and Solar Market Development Model. Purpose; basis for model structure; policy variables and parameters; level of regional, sectoral, and fuels detail; outputs; input requirements; sources of data; computer accessibility and requirements; and a bibliography are provided for each model and data source.

  14. The intriguing role of fibroblasts and c-Jun in the chemopreventive and therapeutic effect of finasteride on xenograft models of prostate cancer

    Directory of Open Access Journals (Sweden)

    Yi-Nong Niu

    2016-01-01

    Full Text Available In a large clinical trial, finasteride reduced the rate of low-grade prostate cancer (PCa while increasing the incidence of high-grade cancer. Whether finasteride promotes the development of high-grade tumors remains controversial. We demonstrated the role of fibroblasts and c-Jun in chemopreventive and therapeutic effect of finasteride on xenograft models of PCa. LNCaP (PC3 cells or recombinants of cancer cells and fibroblasts were implanted in male athymic nude mice treated with finasteride. Tumor growth, cell proliferation, apoptosis, p-Akt, and p-ERK1/2 were evaluated. In LNCaP (PC3 mono-grafted models, finasteride did not change the tumor growth. In recombinant-grafted models, fibroblasts and c-Jun promoted tumor growth; finasteride induced proliferation of LNCaP cells and repressed PC3 cell apoptosis. When c-Jun was knocked out, fibroblasts and/or finasteride did not promote the tumor growth. Finasteride inhibited p-Akt and p-ERK1/2 in mono-culture cancer cells while stimulating the same signaling molecules in the presence of fibroblasts. Reduced p-Akt and p-ERK1/2 were noted in the presence of c-Jun−/− fibroblasts. Fibroblasts and c-Jun promote PCa growth; finasteride further stimulates tumor growth with promoted proliferation, repressed apoptosis, and up-regulated pro-proliferative molecular pathway in the presence of fibroblasts and c-Jun. Stromal-epithelial interactions play critical roles in finasteride′s therapeutic effects on PCa. Our findings have preliminary implications in using finasteride as a chemopreventive or therapeutic agent for PCa patients.

  15. GNX-4728, a Novel Small Molecule Drug Inhibitor of Mitochondrial Permeability Transition, is Therapeutic in a Mouse Model of Amyotrophic Lateral Sclerosis

    Directory of Open Access Journals (Sweden)

    Lee J Martin

    2014-12-01

    Full Text Available Amyotrophic lateral sclerosis (ALS is a fatal neurological disorder in humans characterized by progressive degeneration of skeletal muscle and motor neurons in spinal cord, brainstem, and cerebral cortex causing skeletal muscle paralysis, respiratory insufficiency, and death. There are no cures or effective treatments for ALS. ALS can be inherited, but most cases are not associated with a family history of the disease. Mitochondria have been implicated in the pathogenesis but definitive proof of causal mechanisms is lacking. Identification of new clinically translatable disease mechanism-based molecular targets and small molecule drug candidates are needed for ALS patients. We tested the hypothesis in an animal model that drug modulation of the mitochondrial permeability transition pore (mPTP is therapeutic in ALS. A prospective randomized placebo-controlled drug trial was done in a transgenic mouse model of ALS. We explored GNX-4728 as a therapeutic drug. GNX-4728 inhibits mPTP opening as evidenced by increased mitochondrial calcium retention capacity both in vitro and in vivo. Chronic systemic treatment of G37R-human mutant superoxide dismutase-1 (hSOD1 transgenic mice with GNX-4728 resulted in major therapeutic benefits. GNX-4728 slowed disease progression and significantly improved motor function. The survival of ALS mice was increased significantly by GNX-4728 treatment as evidence by a nearly 2-fold extension of lifespan (360 days to 750 days. GNX-4728 protected against motor neuron degeneration and mitochondrial degeneration, attenuated spinal cord inflammation, and preserved neuromuscular junction innervation in the diaphragm in ALS mice. This work demonstrates that a mPTP-acting drug has major disease-modifying efficacy in a preclinical mouse model of ALS and establishes mitochondrial calcium retention, and indirectly the mPTP, as targets for ALS drug development.

  16. Search for beyond standard model physics (non-SUSY) in final states with photons at the Tevatron

    Energy Technology Data Exchange (ETDEWEB)

    Palencia, Jose Enrique; /Fermilab

    2009-01-01

    We present the results of searches for non-standard model phenomena in photon final states. These searches use data from integrated luminosities of {approx} 1-4 fb{sup -1} of p{bar p} collisions at {radical}s = 1.96 TeV, collected with the CDF and D0 detectors at the Fermilab Tevatron. No significant excess in data has been observed. We report limits on the parameters of several BSM models (excluding SUSY) for events containing photons.

  17. Development and validation of models for bubble coalescence and breakup. Final report

    International Nuclear Information System (INIS)

    Liao, Y.; Lucas, D.

    2013-02-01

    A new generalized model for bubble coalescence and breakup has been developed. It is based on physical considerations and takes into account various mechanisms that can lead to bubble coalescence and breakup. First, in a detailed literature review, the available models were compiled and analyzed. It turned out that many of them show a contradictory behaviour. None of these models allows the prediction of the evolution of bubble size distributions along a pipe flow for a wide range of combinations of flow rates of the gas and the liquid phase. The new model has been extensively studied in a simplified Test-Solver. Although this does not cover all details of a developing flow along the pipe, it allows - in contrast to a CFD code - to conduct a large number of variational calculations to investigate the influence of individual sizes and models. Coalescence and breakup cannot be considered separately from other phenomena and models that reflect these phenomena. There are close interactions with the turbulence of the liquid phase and the momentum exchange between phases. Since the dissipation rate of turbulent kinetic energy is a direct input parameter for the new model, the turbulence modelling has been studied very carefully. To validate the model, a special experimental series for air-water flows was used, conducted at the TOPFLOW facility in an 8-meter long DN200 pipe. The data are characterized by high quality and were produced within the TOPFLOW-II project. The test series aims to provide a basis for the work presented here. Predicting the evolution of the bubble size distribution along the pipe could be improved significantly in comparison to the previous standard models for bubble coalescence and breakup implemented in CFX. However some quantitative discrepancies remain. The full model equations as well as an implementation as ''User-FORTRAN'' in CFX are available and can be used for further work on the simulation of poly-disperse bubbly flows.

  18. The therapeutic ratio in BNCT: Assessment using the Rat 9L gliosarcoma brain tumor and spinal cord models

    International Nuclear Information System (INIS)

    Coderre, J.A.; Micca, P.L.; Nawrocky, M.M.; Fisher, C.D.; Bywaters, A.; Morris, G.M.; Hopewell, J.W.

    1996-01-01

    During any radiation therapy, the therapeutic tumor dose is limited by the tolerance of the surrounding normal tissue within the treatment volume. The short ranges of the products of the 10 B(n,α) 7 Li reaction produced during boron neutron capture therapy (BNCT) present an opportunity to increase the therapeutic ratio (tumor dose/normal tissue dose) to levels unprecedented in photon radiotherapy. The mixed radiation field produced during BNCT comprises radiations with different linear energy transfer (LET) and different relative biological effectiveness (RBE). The short ranges of the two high-LET products of the 'B(n,a)'Li reaction make the microdistribution of the boron relative to target cell nuclei of particular importance. Due to the tissue specific distribution of different boron compounds, the term RBE is inappropriate in defining the biological effectiveness of the 10 B(n,α) 7 Li reaction. To distinguish these differences from true RBEs we have used the term open-quotes compound biological effectivenessclose quotes (CBE) factor. The latter can be defined as the product of the true, geometry-independent, RBE for these particles times a open-quotes boron localization factorclose quotes, which will most likely be different for each particular boron compound. To express the total BNCT dose in a common unit, and to compare BNCT doses with the effects of conventional photon irradiation, multiplicative factors (RBEs and CBEs) are applied to the physical absorbed radiation doses from each high-LET component. The total effective BNCT dose is then expressed as the sum of RBE-corrected physical absorbed doses with the unit Gray-equivalent (Gy-Eq)

  19. Modelling gas migration in compacted bentonite: gambit club phase 3. Final report

    International Nuclear Information System (INIS)

    Hoch, A.R.; Cliffe, K.A.; Swift, B.T.; Rodwell, W.R.

    2004-04-01

    This report describes the third phase of a programme of work to develop a computational model of gas migration through highly compacted water-saturated bentonite. One difficulty with this endeavour is the definitive determination of the mechanism of the gas migration from the available experimental data. The report contains a brief review of the experimental data and their interpretation. The model development work reported involves the investigation of two ways of enhancing a model proposed in the previous phase of the programme. This model was based on the concept that gas migration pathways were created by consolidating the clay fabric by application of gas pressure to create porosity through which the gas could flow. The two developments of this model that are separately explored in this work are: (a) The incorporation of a proper treatment of the stress-strain behaviour of the clay in (b) response to gas migration. The previous model had only considered stress effects through simple volume changes to the clay fabric. The inclusion of a dual-porosity feature into the model in an attempt to address the role that the clay fabric might play in gas migration through the clay, in particular the role that pre-existing interstack voids might have in gas migration. The consideration of hysteresis effects was also included in this study. As in previous GAMBIT Club work, the models are tested against the results of laboratory experiments. (orig.)

  20. Danubian lowland - ground water model. Final Report. Vol. 1. Summary Report

    Energy Technology Data Exchange (ETDEWEB)

    Danish Hydraulic Inst. (DK); BV, DHV Consultants [NL; TNO, Inst. of Applied Geoscience (NL); Water Quality Institute (DK); Krueger, I [DK; The Royal Veterinary and Agricultural Univ. (DK); Water Resources Research Institute (SK); Research Institute of Irrigation (SK); Consulting Ltd, Ground Water [SK; Faculty of Natural Sciences, Comenius Univ. (SK)

    1995-12-01

    The summary report contains the next parts: (0) Executive summary; (1) Introduction; (2) Project staffing; (3) Project management issues; (4) Establishment of the integrated modelling system; (5) Summary of model application; (6) Conclusions and recommendations; and List of references. Contains several maps in the parts. figs, tabs, 146 refs.

  1. Flowsheet model for the electrochemical treatment of liquid radioactive wastes. Final report

    International Nuclear Information System (INIS)

    Hobbs, D.T.; Prasad, S.; Farell, A.E.; Weidner, J.W.; White, R.E.

    1995-01-01

    The objective of this report is to describe the modeling and optimization procedure for the electrochemical removal of nitrates and nitrites from low level radioactive wastes. The simulation is carried out in SPEEDUP trademark, which is a state of the art flowsheet modeling package. The flowsheet model will provide a better understanding of the process and aid in the scale-up of the system. For example, the flowsheet model has shown that the electrochemical cell must be operated in batch mode to achieve 95 percent destruction. The flowsheet model is detailed in this report along with a systematic description of the batch optimization of the electrochemical cell. Results from two batch runs and one optimization run are also presented

  2. Biosphere modelling for dose assessments of radioactive waste repositories. Final report

    International Nuclear Information System (INIS)

    Klos, R.

    1996-09-01

    The aims of the Complementary Studies Working Group were: to investigate and explain differences which exist between contemporary models with respect to how, for a given test case, they represent the modelled Features, Events and Processes (FEPs) and how the nature of these representations affects the calculational end-points; to determine the most appropriate ways of representing key FEPs; to identify where knowledge needs to be improved to give better representations of these key FEPs in the future and where simplifications of existing formulations might be possible; to show that the modelling undertaken is suitable for purpose, in that it is robust and that it is unlikely that the radiological consequences calculated by the models would be underestimated (so that any conservative bias in the models is justified); to build confidence in the available modelling tools; to extend the work undertaken in the first phase of BIOMOVS to include consideration of radiological dose. Ten modelling groups from Western Europe and Canada have participated, revealing a variety of representations of radionuclide transport processes and techniques for calculating dose. The exercise has focused on the ways in which key FEPs are represented with the intention of determining the robustness or otherwise of existing representations. This has been achieved by applying a well defined dataset representative of a Central European inland valley. Human habits and lifestyle are chosen to be representative of a subsistence agricultural community. Climatic conditions are those of the present day. Many of the conclusions have relevance beyond the immediate concerns of the Central European biospheres and, although care should be exercised when terms of reference differ greatly from the system detailed here, much has been learned which has wider applicability. The exercise has successfully compared not only the behaviour of biosphere models for waste disposal assessments, but has also provided the

  3. A Combined Tissue Kinetics and Dosimetric Model of Respiratory Tissue Exposed to Radiation. Final Technical Report

    International Nuclear Information System (INIS)

    John R. Ford

    2005-01-01

    Existing dosimetric models of the radiation response of tissues are essentially static. Consideration of changes in the cell populations over time has not been addressed realistically. For a single acute dose this is not a concern, but for modeling chronic exposures or fractionated acute exposures, the natural turnover and progression of cells could have a significant impact on a variety of endpoints. This proposal addresses the shortcomings of current methods by combining current dose-based calculation techniques with information on the cell turnover for a model tissue. The proposed model will examine effects at the single-cell level for an exposure of a section of human bronchiole. The cell model will be combined with Monte Carlo calculations of doses to cells and cell nuclei due to varying dose-rates of different radiation qualities. Predictions from the model of effects on survival, apoptosis rates, and changes in the number of cycling and differentiating cells will be tested experimentally. The availability of dynamic dosimetric models of tissues at the single-cell level will be useful for analysis of low-level radiation exposures and in the development of new radiotherapy protocols

  4. Biosphere modelling for dose assessments of radioactive waste repositories. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Klos, R. [Paul Scherrer Inst., Wuerenlingen (Switzerland)] [and others

    1996-09-01

    The aims of the Complementary Studies Working Group were: to investigate and explain differences which exist between contemporary models with respect to how, for a given test case, they represent the modelled Features, Events and Processes (FEPs) and how the nature of these representations affects the calculational end-points; to determine the most appropriate ways of representing key FEPs; to identify where knowledge needs to be improved to give better representations of these key FEPs in the future and where simplifications of existing formulations might be possible; to show that the modelling undertaken is suitable for purpose, in that it is robust and that it is unlikely that the radiological consequences calculated by the models would be underestimated (so that any conservative bias in the models is justified); to build confidence in the available modelling tools; to extend the work undertaken in the first phase of BIOMOVS to include consideration of radiological dose. Ten modelling groups from Western Europe and Canada have participated, revealing a variety of representations of radionuclide transport processes and techniques for calculating dose. The exercise has focused on the ways in which key FEPs are represented with the intention of determining the robustness or otherwise of existing representations. This has been achieved by applying a well defined dataset representative of a Central European inland valley. Human habits and lifestyle are chosen to be representative of a subsistence agricultural community. Climatic conditions are those of the present day. Many of the conclusions have relevance beyond the immediate concerns of the Central European biospheres and, although care should be exercised when terms of reference differ greatly from the system detailed here, much has been learned which has wider applicability. The exercise has successfully compared not only the behaviour of biosphere models for waste disposal assessments, but has also provided the

  5. Concerted action on assessment of health and environmental impacts. Modeller and experimentalists' forum: final report

    International Nuclear Information System (INIS)

    Simmonds, J.

    2000-07-01

    The behaviour of radionuclides in the environment and the associated risks have to be determined through a combination of experimental and modelling studies. Modelling systems, such as those developed collaboratively in the European Union, are required: (a) to determine the potential consequences of accidental releases, (b) to help in emergency planning, (c) to determine the radiological impact of proposed routine radionuclide releases. Various experimental and environmental monitoring data are used as an input to such systems both directly through the choice of parameter values and indirectly through validation of the models. It is important to establish good contacts between the modelling and experimental communities to contribute towards the harmonisation of environmental modelling and to contribute to the maintenance of the European Commission modelling systems as state of the art. Such contacts are also beneficial in directing future experimental research and modelling programmes. The aspects of environmental transfer considered in this project are terrestrial food chains, external irradiation, resuspension, atmospheric dispersion, and aquatic transfer. To fulfil the objectives of the project, NRPB took the lead, with assistance from the other partners, in organising and hosting regular meetings of researchers in the experimental and modelling communities, setting key issues for discussion at each meeting, and drawing together the conclusions of each meeting. The emphasis of the meetings was on the adequacy of the three principal EC-sponsored computing systems, COSYMA and PC-COSYMA (probabilistic risk assessment systems), PC-CREAM (system for assessing the consequences of routine releases) and RODOS (the EC decision aiding system for emergency response). The meetings considered whether these systems make adequate use of the available experimental data and findings on environmental contamination and transfer. This aim of this study was to consider the models

  6. Final Technical Report - SciDAC Cooperative Agreement: Center for Extended Magnetohydrodynamic Modeling/ Transport and Dynamics in Torodial Fusion System

    International Nuclear Information System (INIS)

    Schanck, Dalton D.

    2010-01-01

    Final technical report for research performed by Professor Dalton D. Schnack on SciDAC Cooperative Agreement: Center for Extended MHD Modeling, DE-FC02-06ER54870, for the period 7/1/06 to 2/15/08. Principal results for this period are: 1. Development of a model for computational modeling for the primitive form of the extended MMD equations. This was reported as Phys. Plasmas 13, 058103 (2006). 2. Comparison between the NIMROD and M3D codes for simulation of the nonlinear sawtooth crash in the CDXU tokamak. This was reported in Phys. Plasmas 14, 056105 (2006). 3. Demonstration of 2-fluid and gyroviscous stabilization of interchange modes using computational extended MHD models. This was reported in Phys. Rev. Letters 101, 085005 (2008). Each of these publications is attached as an Appendix of this report. They should be consulted for technical details.

  7. ALINET: a model for assessing energy conservation opportunities in the food processing industry. Final technical report, September 1977-December 1979

    Energy Technology Data Exchange (ETDEWEB)

    Levis, A H; Ducot, E R; Levis, I S; Webster, T F

    1979-12-01

    ALINET is a network model designed for the analysis of energy use in the food processing and distribution sector and for the evaluation of the potential effectiveness of energy conserving technologies. The conceptual framework of the model, as well as the design and implementation of the computer software are described. The wheat system at the national, state, and facility-specific level is used to illustrate the model's operation and use. A pilot project, carried out in cooperation with industry, is described in which energy use in (a) hard wheat milling, and (b) durum milling and pasta manufacture is analyzed. Finally, the introduction of an alternative technology for pasta drying is assessed in terms of energy conservation and cost. Recommendation for further applications and institutionalization of the model are made.

  8. Validation of Numerical Two-Fluid and Kinetic Plasma Models. Final Report

    International Nuclear Information System (INIS)

    Barnes, Daniel

    2011-01-01

    This was a four year grant commencing October 1, 2003 and finishing September 30, 2007. The funding was primarily used to support the work of the Principal Investigator, who collaborated with Profs. Scott Parker and John Cary at U. Colorado, and with two students, N. Xiang and J. Cheng also of U. Colorado. The technical accomplishments of this grant can be found in the publications listed in the final Section here. The main accomplishments of the grant work were: (1) Development and implementation of time-implicit two-fluid simulation methods in collaboration with the NIMROD team; and (2) Development and testing of a new time-implicit delta-f, energy-conserving method The basic two-fluid method, with many improvements is used in present NIMROD calculations. The energy-conserving delta-f method is under continuing development under contract between Coronado Consulting, a New Mexico sole proprietorship and the Oak Ridge National Laboratory.

  9. Modeling of interaction between steel and concrete in continuously reinforced concrete pavements : final report.

    Science.gov (United States)

    2016-01-01

    Continuously reinforced concrete pavement (CRCP) contains continuous longitudinal reinforcement with no transverse : expansion within the early life of the pavement and can continue to develop cracks in the long-term. The : accurate modeling of CRCPs...

  10. Sensitivity studies using the TRNSM 2 computerized model for the NRC physical protection project. Final report

    International Nuclear Information System (INIS)

    Anderson, G.M.

    1979-08-01

    A computerized model of the transportation system for shipment of nuclear fuel cycle materials is required to investigate the effects on fleet size, fleet composition and efficiency of fleet utilization resulting from changes in a variety of physical and regulatory factors, including shipping requirements, security regulations, work rules, maintenance requirements, and vehicle capacities. Such a model has been developed which provides a capability for complete sizing requirements studies of a combined aircraft and truck fleet. This report presents the results of a series of sensitivity studies performed using this model. These studies include the effects of the intinerary optimization criteria, work rules, and maintenance policies. These results demonstrate the effectiveness and versatility of the model for investigating the effects of a wide variety of physical and regulatory factors on the transportation fleet

  11. Models for the numerical simulation of radionuclide migration in underground storage of radioactive waste. Final report

    International Nuclear Information System (INIS)

    Petschel, M.; Heidenreich, H.; Beger, E.; Schneider, H.

    1992-03-01

    The report contains validation works - implementation, assurance of function, further development of numerical models (where applicable), program and application documentation, data acquisition - for the programs and program systems BIDERA, GEOFIM, GISTZ, KASOMO, APT6 and MARE. (HP) [de

  12. Comparison of source-term calculations using the AREST and SYVAC-Vault models: [Final report

    International Nuclear Information System (INIS)

    Apted, M.J.; Engel, D.W.; Garisto, N.C.; LeNeveu, D.M.

    1988-07-01

    A comparison of the calculated radionuclide release from a waste package in a geologic repository has been performed using the verified SYVAC-Vault Model and AREST Model. the purpose of this comparison is to further establish the credibility of these codes for predictive performance assessment and to identify improvements that may be required. A reference case for a Canadian conceptual design with spent fuel as the waste form was chosen to make an initial comparison. The results from the two models were in good agreement, including peak release rates, time to reach peak release, and long term release rates. Differences in results from the two models are attributed to differences in computational approaches. Studies of the effects of sorption, convective flow, distributed containment failure, and precipitation are identified as key areas for further comparisons and are currently in progress. 11 refs., 3 figs., 5 tabs

  13. ATHENA calculation model for the ITER-FEAT divertor cooling system. Final report with updates

    International Nuclear Information System (INIS)

    Eriksson, John; Sjoeberg, A.; Sponton, L.L.

    2001-05-01

    An ATHENA model of the ITER-FEAT divertor cooling system has been developed for the purpose of calculating and evaluating consequences of different thermal-hydraulic accidents as specified in the Accident Analysis Specifications for the ITER-FEAT Generic Site Safety Report. The model is able to assess situations for a variety of conceivable operational transients from small flow disturbances to more critical conditions such as total blackout caused by a loss of offsite and emergency power. The main objective for analyzing this type of scenarios is to determine margins against jeopardizing the integrity of the divertor cooling system components and pipings. The model of the divertor primary heat transport system encompasses the divertor cassettes, the port limiter systems, the pressurizer, the heat exchanger and all feed and return pipes of these components. The development was pursued according to practices and procedures outlined in the ATHENA code manuals using available modelling components such as volumes, junctions, heat structures and process controls

  14. MOBE: Final report; Modelling and Optimization of Biomass-based Energy production

    Energy Technology Data Exchange (ETDEWEB)

    Trangbaek, K [Aalborg Univ., Institut for Elektroniske Systemer, Aalborg (Denmark); Elmegaard, B [Danmarks Tekniske Univ., Institut for Mekanisk Teknologi, Kgs. Lyngby (Denmark)

    2008-07-01

    The present report is the documentation of the work in the PSO-project MOBE, ''Modelling and Optimization of biomass-based Energy production''. The aim of the project is to develop better control methods for boilers in central power plant units, so the plant will achieve better controllability with respect to load changes. in particular focus is on the low load operation near and below the Benson point. The introduction of the report includes a description of the challenges the central power stations see in the modern electricity market where wind power delivers a significant prioritized production, and thus, in connection with consumption variations, contributes to the load requirements of the central units. The report documents the work on development of a common simulation platform for the partners in the project and for future model work. The result of this is an integration between the DTU simulation code DNA and Matlab. Other possible tools are suggested. The modelling work in the project has resulted in preliminary studies of time constants of evaporator tubes, an analysis that shows that Ledinegg instabilities do not occur in modern boilers even at low load, development of a validated evaporator model that can be coupled to tools for control system development, and an analysis of two different configurations at the low load system of Benson boilers. Based in a validated power plant model different control strategies have been studied. Because constraints on control signals and temperature gradients are dominating, it is recommended to use model predictive control. It is demonstrated, how such a simulator can handle large low gradients without violating the constraints. By switching between different linearized models the whole load range may be covered. The project indicates that Model predictive control can improve the control in low low significantly. This should be studied further in future projects by realistic tests. At first these should be done with

  15. MOBE: Final report; Modelling and Optimization of Biomass-based Energy production

    Energy Technology Data Exchange (ETDEWEB)

    Trangbaek, K. (Aalborg Univ., Institut for Elektroniske Systemer, Aalborg (Denmark)); Elmegaard, B. (Danmarks Tekniske Univ., Institut for Mekanisk Teknologi, Kgs. Lyngby (Denmark))

    2008-07-01

    The present report is the documentation of the work in the PSO-project MOBE, ''Modelling and Optimization of biomass-based Energy production''. The aim of the project is to develop better control methods for boilers in central power plant units, so the plant will achieve better controllability with respect to load changes. in particular focus is on the low load operation near and below the Benson point. The introduction of the report includes a description of the challenges the central power stations see in the modern electricity market where wind power delivers a significant prioritized production, and thus, in connection with consumption variations, contributes to the load requirements of the central units. The report documents the work on development of a common simulation platform for the partners in the project and for future model work. The result of this is an integration between the DTU simulation code DNA and Matlab. Other possible tools are suggested. The modelling work in the project has resulted in preliminary studies of time constants of evaporator tubes, an analysis that shows that Ledinegg instabilities do not occur in modern boilers even at low load, development of a validated evaporator model that can be coupled to tools for control system development, and an analysis of two different configurations at the low load system of Benson boilers. Based in a validated power plant model different control strategies have been studied. Because constraints on control signals and temperature gradients are dominating, it is recommended to use model predictive control. It is demonstrated, how such a simulator can handle large low gradients without violating the constraints. By switching between different linearized models the whole load range may be covered. The project indicates that Model predictive control can improve the control in low low significantly. This should be studied further in future projects by realistic tests. At first these

  16. Final Report Collaborative Project: Improving the Representation of Coastal and Estuarine Processes in Earth System Models

    Energy Technology Data Exchange (ETDEWEB)

    Bryan, Frank [Univ. of Connecticut, Storrs, CT (United States); Dennis, John [Univ. of Connecticut, Storrs, CT (United States); MacCready, Parker [Univ. of Connecticut, Storrs, CT (United States); Whitney, Michael M. [Univ. of Connecticut, Storrs, CT (United States)

    2016-09-30

    This project aimed to improve long term global climate simulations by resolving and enhancing the representation of the processes involved in the cycling of freshwater through estuaries and coastal regions. This was a collaborative multi-institution project consisting of physical oceanographers, climate model developers, and computational scientists. It specifically targeted the DOE objectives of advancing simulation and predictive capability of climate models through improvements in resolution and physical process representation.

  17. Final Report: Legion Core Object Model, March 1, 1996 - September 30, 1999

    Energy Technology Data Exchange (ETDEWEB)

    Grimshaw, Andrew S.

    1999-09-30

    The model specifies the composition and functionality of Legion's core objects - those objects that cooperate to create, locate, manage, and remove objects from the legion project. In particular, the object model facilitates a flexible extensible implementation, provides a single persistent name space, grants site autonomy to participating organizations, and scales to millions of sites and trillions of objects. Further, it offers a framework that is well suited to providing mechanisms for high performance, security, fault tolerance and commerce.

  18. Final Report: A Model Management System for Numerical Simulations of Subsurface Processes

    Energy Technology Data Exchange (ETDEWEB)

    Zachmann, David

    2013-10-07

    The DOE and several other Federal agencies have committed significant resources to support the development of a large number of mathematical models for studying subsurface science problems such as groundwater flow, fate of contaminants and carbon sequestration, to mention only a few. This project provides new tools to help decision makers and stakeholders in subsurface science related problems to select an appropriate set of simulation models for a given field application.

  19. Low Dose Radiation Cancer Risks: Epidemiological and Toxicological Models. Final Technical Report

    International Nuclear Information System (INIS)

    Hoel, David G.

    2012-01-01

    The basic purpose of this one year research grant was to extend the two stage clonal expansion model (TSCE) of carcinogenesis to exposures other than the usual single acute exposure. The two-stage clonal expansion model of carcinogenesis incorporates the biological process of carcinogenesis, which involves two mutations and the clonal proliferation of the intermediate cells, in a stochastic, mathematical way. The current TSCE model serves a general purpose of acute exposure models but requires numerical computation of both the survival and hazard functions. The primary objective of this research project was to develop the analytical expressions for the survival function and the hazard function of the occurrence of the first cancer cell for acute, continuous and multiple exposure cases within the framework of the piece-wise constant parameter two-stage clonal expansion model of carcinogenesis. For acute exposure and multiple exposures of acute series, it is either only allowed to have the first mutation rate vary with the dose, or to have all the parameters be dose dependent; for multiple exposures of continuous exposures, all the parameters are allowed to vary with the dose. With these analytical functions, it becomes easy to evaluate the risks of cancer and allows one to deal with the various exposure patterns in cancer risk assessment. A second objective was to apply the TSCE model with varing continuous exposures from the cancer studies of inhaled plutonium in beagle dogs. Using step functions to estimate the retention functions of the pulmonary exposure of plutonium the multiple exposure versions of the TSCE model was to be used to estimate the beagle dog lung cancer risks. The mathematical equations of the multiple exposure versions of the TSCE model were developed. A draft manuscript which is attached provides the results of this mathematical work. The application work using the beagle dog data from plutonium exposure has not been completed due to the fact

  20. Mathematical approaches for complexity/predictivity trade-offs in complex system models : LDRD final report.

    Energy Technology Data Exchange (ETDEWEB)

    Goldsby, Michael E.; Mayo, Jackson R.; Bhattacharyya, Arnab (Massachusetts Institute of Technology, Cambridge, MA); Armstrong, Robert C.; Vanderveen, Keith

    2008-09-01

    The goal of this research was to examine foundational methods, both computational and theoretical, that can improve the veracity of entity-based complex system models and increase confidence in their predictions for emergent behavior. The strategy was to seek insight and guidance from simplified yet realistic models, such as cellular automata and Boolean networks, whose properties can be generalized to production entity-based simulations. We have explored the usefulness of renormalization-group methods for finding reduced models of such idealized complex systems. We have prototyped representative models that are both tractable and relevant to Sandia mission applications, and quantified the effect of computational renormalization on the predictive accuracy of these models, finding good predictivity from renormalized versions of cellular automata and Boolean networks. Furthermore, we have theoretically analyzed the robustness properties of certain Boolean networks, relevant for characterizing organic behavior, and obtained precise mathematical constraints on systems that are robust to failures. In combination, our results provide important guidance for more rigorous construction of entity-based models, which currently are often devised in an ad-hoc manner. Our results can also help in designing complex systems with the goal of predictable behavior, e.g., for cybersecurity.

  1. Integration of KESS III models in ATHLET-CD and contributions to program verification. Final report

    International Nuclear Information System (INIS)

    Bruder, M.; Schatz, A.

    1994-07-01

    The development of the computer code ATHLET-CD is a contribution to the reactor safety research. ATHLET-CD is an extension of the system code ATHLET by core degradation models especially of the modular software package KESS. The aim of the ATHLET-CD development is the simulation of severe accident sequences from their initialisation to severe core degradation in a continous manner. In the framework of this project the ATHLET-CD development has been focused on the integration of KESS model like the control rod model as well as the models describing chemical interactions and material relocation along a rod and fission product release. The present ATHLET-CD version is able to describe severe accidents in a PWR up to the early core degradation (relocation of material along a rod surface in axial direction). Contributions to the verification of ATHLET-CD comprised calculations of the experiments PHEBUS AIC and PBF SFD 1-4. The PHEBUS AIC calculation was focused on the examination of the control rod model whereas the PBF SFD 1-4 claculation served to check the models describing melting, material relocation and fission product release. (orig.)

  2. Updates to the Demographic and Spatial Allocation Models to Produce Integrated Climate and Land Use Scenarios (ICLUS) (Final Report, Version 2)

    Science.gov (United States)

    EPA's announced the availability of the final report, Updates to the Demographic and Spatial Allocation Models to Produce Integrated Climate and Land Use Scenarios (ICLUS) (Version 2). This update furthered land change modeling by providing nationwide housing developmen...

  3. Thermo-mechanical analyses and model validation in the HAW test field. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Heijdra, J J; Broerse, J; Prij, J

    1995-01-01

    An overview is given of the thermo-mechanical analysis work done for the design of the High Active Waste experiment and for the purpose of validation of the used models through comparison with experiments. A brief treatise is given on the problems of validation of models used for the prediction of physical behaviour which cannot be determined with experiments. The analysis work encompasses investigations into the initial state of stress in the field, the constitutive relations, the temperature rise, and the pressure on the liner tubes inserted in the field to guarantee the retrievability of the radioactive sources used for the experiment. The measurements of temperatures, deformations, and stresses are described and an evaluation is given of the comparison of measured and calculated data. An attempt has been made to qualify or even quantify the discrepancies, if any, between measurements and calculations. It was found that the model for the temperature calculations performed adequately. For the stresses the general tendency was good, however, large discrepancies exist mainly due to inaccuracies in the measurements. For the deformations again the general tendency of the model predictions was in accordance with the measurements. However, from the evaluation it appears that in spite of the efforts to estimate the correct initial rock pressure at the location of the experiment, this pressure has been underestimated. The evaluation has contributed to a considerable increase in confidence in the models and gives no reason to question the constitutive model for rock salt. However, due to the quality of the measurements of the stress and the relatively short period of the experiments no quantitatively firm support for the constitutive model is acquired. Collections of graphs giving the measured and calculated data are attached as appendices. (orig.).

  4. Thermo-mechanical analyses and model validation in the HAW test field. Final report

    International Nuclear Information System (INIS)

    Heijdra, J.J.; Broerse, J.; Prij, J.

    1995-01-01

    An overview is given of the thermo-mechanical analysis work done for the design of the High Active Waste experiment and for the purpose of validation of the used models through comparison with experiments. A brief treatise is given on the problems of validation of models used for the prediction of physical behaviour which cannot be determined with experiments. The analysis work encompasses investigations into the initial state of stress in the field, the constitutive relations, the temperature rise, and the pressure on the liner tubes inserted in the field to guarantee the retrievability of the radioactive sources used for the experiment. The measurements of temperatures, deformations, and stresses are described and an evaluation is given of the comparison of measured and calculated data. An attempt has been made to qualify or even quantify the discrepancies, if any, between measurements and calculations. It was found that the model for the temperature calculations performed adequately. For the stresses the general tendency was good, however, large discrepancies exist mainly due to inaccuracies in the measurements. For the deformations again the general tendency of the model predictions was in accordance with the measurements. However, from the evaluation it appears that in spite of the efforts to estimate the correct initial rock pressure at the location of the experiment, this pressure has been underestimated. The evaluation has contributed to a considerable increase in confidence in the models and gives no reason to question the constitutive model for rock salt. However, due to the quality of the measurements of the stress and the relatively short period of the experiments no quantitatively firm support for the constitutive model is acquired. Collections of graphs giving the measured and calculated data are attached as appendices. (orig.)

  5. Next-Gen3: Sequencing, Modeling, and Advanced Biofuels - Final Technical Report

    Energy Technology Data Exchange (ETDEWEB)

    Zengler, Karsten [Univ. of California, San Diego, CA (United States). Dept. of Pediatrics; Palsson, Bernhard [Univ. of California, San Diego, CA (United States). Dept. of Bioengineering; Lewis, Nathan [Univ. of California, San Diego, CA (United States). Dept. of Pediatrics

    2017-12-27

    Successful, scalable implementation of biofuels is dependent on the efficient and near complete utilization of diverse biomass sources. One approach is to utilize the large recalcitrant biomass fraction (or any organic waste stream) through the thermochemical conversion of organic compounds to syngas, a mixture of carbon monoxide (CO), carbon dioxide (CO2), and hydrogen (H2), which can subsequently be metabolized by acetogenic microorganisms to produce next-gen biofuels. The goal of this proposal was to advance the development of the acetogen Clostridium ljungdahlii as a chassis organism for next-gen biofuel production from cheap, renewable sources and to detail the interconnectivity of metabolism, energy conservation, and regulation of acetogens using next-gen sequencing and next-gen modeling. To achieve this goal we determined optimization of carbon and energy utilization through differential translational efficiency in C. ljungdahlii. Furthermore, we reconstructed a next-generation model of all major cellular processes, such as macromolecular synthesis and transcriptional regulation and deployed this model to predicting proteome allocation, overflow metabolism, and metal requirements in this model acetogen. In addition we explored the evolutionary significance of tRNA operon structure using the next-gen model and determined the optimal operon structure for bioproduction. Our study substantially enhanced the knowledgebaase for chemolithoautotrophs and their potential for advanced biofuel production. It provides next-generation modeling capability, offer innovative tools for genome-scale engineering, and provide novel methods to utilize next-generation models for the design of tunable systems that produce commodity chemicals from inexpensive sources.

  6. Transport in biosphere of radionuclides released from finally disposed nuclear waste - background information for transport and dose model

    International Nuclear Information System (INIS)

    Hulmi, R.; Savolainen, I.

    1981-07-01

    An outline is made about the biosphere transport and dose models employed in the estimation of doses due to releases from finally disposed nuclear waste. The models often divide into two parts; the first one describes the transport of radionuclides in those parts of biosphere where the time scale is large (e.g. soil, sea and sea sediment), the second part of the model describes the transport of nuclides in the systems where the time scale is small (e.g. food chains, plants and animals). The description of biosphere conditions includes remarkable uncertainty due to the complexity of the biosphere and its ecosystems. Therefore studies of scenario type are recommended: some values of parametres describing the conditions are assumed, and the consequences are estimated by using these values. The effect of uncertainty in various factors on the uncertainty of final results should be investigated with the employment of alternative scenarios and parametric sensitivity studies. In addition to the ordinary results, intermediate results should be presented. A proposal for the structure of a transport and dose program based on dynamic linear compartment model is presented and mathematical solution alternatives are studied also

  7. CFD Modelling of Biomass Combustion in Small-Scale Boilers. Final Report

    Energy Technology Data Exchange (ETDEWEB)

    Xue-Song Bai; Griselin, Niklas; Klason, Torbern; Nilsson, Johan [Lund Inst. of Tech. (Sweden). Dept. of Heat and Power Engineering

    2002-10-01

    This project deals with CFD modeling of combustion of wood in fixed bed boilers. A flamelet model for the interaction between turbulence and chemical reactions is developed and applied to study small-scale boiler. The flamelet chemistry employs 43 reactive species and 174 elementary reactions. It gives detailed distributions of important species such as CO and NO{sub x} in the flow field and flue gas. Simulation of a small-scale wood fired boiler measured at SP Boraas (50 KW) shows that the current flamelet model yields results agreeable to the available experimental data. A detailed chemical kinetic model is developed to study the bed combustion process. This model gives boundary conditions for the CFD analysis of gas phase volatile oxidation in the combustion chambers. The model combines a Functional Group submodel with a Depolymerisation, Vaporisation and Crosslinking submodel. The FG submodel simulates how functional groups decompose and form light gas species. The DVC submodell predicts depolymerisation and vaporisation of the macromolecular network and this includes bridge breaking and crosslinking processes, where the wood structure breaks down to fragments. The light fragments form tar and the heavy ones form metaplast. Two boilers firing wood log/chips are studied using the FG-DVC model, one is the SP Boraas small-scale boiler (50 KW) and the other is the Sydkraft Malmoe Vaerme AB's Flintraennan large-scale boiler (55 MW). The fix bed is assumed to be two zones, a partial equilibrium drying/devolatilisation zone and an equilibrium zone. Three typical biomass conversion modes are simulated, a lean fuel combustion mode, a near-stoichiometric combustion and a fuel rich gasification mode. Detailed chemical species and temperatures at different modes are obtained. Physical interpretation is provided. Comparison of the computational results with experimental data shows that the model can reasonably simulate the fixed bed biomass conversion process. CFD

  8. Wavelet applications for modeling in the atmospheric sciences: Current status and potential extensions. Final report

    International Nuclear Information System (INIS)

    Envair, J.H.; Ekstrom, P.

    1995-11-01

    Wavelets are elementary mathematical functions used to construct, transform, and analyze higher functions and observational data. This report describes the results of an exploratory research effort to evaluate wavelet applications for numerically integrating differential equations associated with air pollution transport and conversion models. It is intended to provide a primer on wavelets, and specifically outlines the use of wavelets in a model that addresses derivative-evaluation and boundary-condition problems. Several factors complicate the use of wavelets for integrating differential equations. First, an enormous range of different wavelet types exists, making the choice of wavelet family for a given application challenging. Moreover, in contrast to the Fourier series, the functional derivatives necessary for numerical approximation are difficult to evaluate and consolidate in terms of wavelet expansions, introducing appreciable complexity into any attempt at wavelet-based integration. On the positive side, wavelet techniques do hold promise for effectively interfacing plume and other subgrid-scale phenomena in grid models. Moreover, workable techniques for derivative evaluation and simulation of boundary features appear feasible. Wavelet use may provide a viable, advantageous option for numerically integrating model equations describing fields on all scales of time and distance, especially where inhomogeneous fields exist, and provide a computationally efficient method of focusing on high-variability regions. The potential for wavelets to conduct integrations totally in transform space contrasts with Fourier-based approaches, which essentially preclude such treatments whenever nonlinear chemical processes occur in the modeled system

  9. Final report for sea-level rise response modeling for San Francisco Bay estuary tidal marshes

    Science.gov (United States)

    Takekawa, John Y.; Thorne, Karen M.; Buffington, Kevin J.; Spragens, Kyle A.; Swanson, Kathleen M.; Drexler, Judith Z.; Schoellhamer, David H.; Overton, Cory T.; Casazza, Michael L.

    2013-01-01

    The International Panel on Climate Change has identified coastal ecosystems as areas that will be disproportionally affected by climate change. Current sea-level rise projections range widely with 0.57 to 1.9 meters increase in mea sea level by 2100. The expected accelerated rate of sea-level rise through the 21st century will put many coastal ecosystems at risk, especially those in topographically low-gradient areas. We assessed marsh accretion and plant community state changes through 2100 at 12 tidal salt marshes around San Francisco Bay estuary with a sea-level rise response model. Detailed ground elevation, vegetation, and water level data were collected at all sites between 2008 and 2011 and used as model inputs. Sediment cores (taken by Callaway and others, 2012) at four sites around San Francisco Bay estuary were used to estimate accretion rates. A modification of the Callaway and others (1996) model, the Wetland Accretion Rate Model for Ecosystem Resilience (WARMER), was utilized to run sea-level rise response models for all sites. With a mean sea level rise of 1.24 m by 2100, WARMER projected that the vast majority, 95.8 percent (1,942 hectares), of marsh area in our study will lose marsh plant communities by 2100 and to transition to a relative elevation range consistent with mudflat habitat. Three marshes were projected to maintain marsh vegetation to 2100, but they only composed 4.2 percent (85 hectares) of the total marsh area surveyed.

  10. XSIM Final Report: Modelling the Past and Future of Identity Management for Scientific Collaborations

    Energy Technology Data Exchange (ETDEWEB)

    Cowles, Robert; Jackson, Craig; Welch, Von

    2016-08-31

    The eXtreme Science Identity Management (XSIM1) research project: collected and analyzed real world data on virtual organization (VO) identity management (IdM) representing the last 15+ years of collaborative DOE science; constructed a descriptive VO IdM model based on that data; used the model and existing trends to project the direction for IdM in the 2020 timeframe; and provided guidance to scientific collaborations and resource providers that are implementing or seeking to improve IdM functionality. XSIM conducted over 20 semi­structured interviews of representatives from scientific collaborations and resource providers, both in the US and Europe; the interviewees supported diverse set of scientific collaborations and disciplines. We developed a definition of “trust,” a key concept in IdM, to understand how varying trust models affect where IdM functions are performed. The model identifies how key IdM data elements are utilized in collaborative scientific workflows, and it has the flexibility to describe past, present and future trust relationships and IdM implementations. During the funding period, we gave more than two dozen presentations to socialize our work, encourage feedback, and improve the model; we also published four refereed papers. Additionally, we developed, presented, and received favorable feedback on three white papers providing practical advice to collaborations and/or resource providers.

  11. Final Report Collaborative Project. Improving the Representation of Coastal and Estuarine Processes in Earth System Models

    Energy Technology Data Exchange (ETDEWEB)

    Bryan, Frank [National Center for Atmospheric Research, Boulder, CO (United States); Dennis, John [National Center for Atmospheric Research, Boulder, CO (United States); MacCready, Parker [Univ. of Washington, Seattle, WA (United States); Whitney, Michael [Univ. of Connecticut

    2015-11-20

    This project aimed to improve long term global climate simulations by resolving and enhancing the representation of the processes involved in the cycling of freshwater through estuaries and coastal regions. This was a collaborative multi-institution project consisting of physical oceanographers, climate model developers, and computational scientists. It specifically targeted the DOE objectives of advancing simulation and predictive capability of climate models through improvements in resolution and physical process representation. The main computational objectives were: 1. To develop computationally efficient, but physically based, parameterizations of estuary and continental shelf mixing processes for use in an Earth System Model (CESM). 2. To develop a two-way nested regional modeling framework in order to dynamically downscale the climate response of particular coastal ocean regions and to upscale the impact of the regional coastal processes to the global climate in an Earth System Model (CESM). 3. To develop computational infrastructure to enhance the efficiency of data transfer between specific sources and destinations, i.e., a point-to-point communication capability, (used in objective 1) within POP, the ocean component of CESM.

  12. Center for Extended Magnetohydrodynamic Modeling (CEMM) University of Utah SAPP 2007. Final Status Report

    International Nuclear Information System (INIS)

    Sanderson, Allen R.; Johnson, Christopher R.

    2007-01-01

    During the third and final period of this grant, our goal was to refine the algorithmic approaches used to detect and visualize magnetic islands and their corresponding null points within both the NIMROD and M3D data sets. We refined our geometric approach, which gave a greater confidence in the accuracy of the Poincareplots created. The final results are best demonstrated through Figures 2-6 attached to the report. Technical details this work was reported in both the Physics and Visualization communities. The algorithms used to analyze the magnetic field lines and detect magnetic islands have been packaged into a library and were used within the SCIRun Problem Solving Environment which is being used by members of the CEMM for visualization. In addition, the library interface was developed so that it could be used by both the NIMROD and M3D codes directly. Thus allowing the fusion scientist to perform this analysis while their simulations were actively running. The use of the library for analysis and visualization was not limited to just within the CEMM SciDAC. Other groups such as the SciDAC for the Simulation of Wave Interactions with Magnetohydrodynamics using Silo code have used the tools for the analysis of their simulations, Figure 1. Though the funding of this project had concluded there is still much work to be performed on this analysis. The techniques developed are fast and robust when not in the presence of chaos. Magnetic field lines that are near the separatrices where chaos is most often present can be difficult to analyze yet these are the field lines that are greatest interest. We believe that investigating and developing techniques based on time frequency analysis may hold some promise. Two other issues that need to be address is the ability to automatically search for the magnetic islands and the ability to track the development of the magnetic islands over time. Our initial effort into automatically searching for the islands did not prove as

  13. Fast algorithms for transport models. Final report, June 1, 1993--May 31, 1994

    International Nuclear Information System (INIS)

    Manteuffel, T.

    1994-12-01

    The focus of this project is the study of multigrid and multilevel algorithms for the numerical solution of Boltzmann models of the transport of neutral and charged particles. In previous work a fast multigrid algorithm was developed for the numerical solution of the Boltzmann model of neutral particle transport in slab geometry assuming isotropic scattering. The new algorithm is extremely fast in the thick diffusion limit; the multigrid v-cycle convergence factor approaches zero as the mean-free-path between collisions approaches zero, independent of the mesh. Also, a fast multilevel method was developed for the numerical solution of the Boltzmann model of charged particle transport in the thick Fokker-Plank limit for slab geometry. Parallel implementations were developed for both algorithms

  14. Final Progress Report on Model-Based Diagnosis of Soil Limitations to Forest Productivity

    Energy Technology Data Exchange (ETDEWEB)

    Luxmoore, R.J.

    2004-08-30

    This project was undertaken in support of the forest industry to link modeling of nutrients and productivity with field research to identify methods for enhancing soil quality and forest productivity and for alleviating soil limitations to sustainable forest productivity. The project consisted of a series of related tasks, including (1) simulation of changes in biomass and soil carbon with nitrogen fertilization, (2) development of spreadsheet modeling tools for soil nutrient availability and tree nutrient requirements, (3) additional modeling studies, and (4) evaluation of factors involved in the establishment and productivity of southern pine plantations in seasonally wet soils. This report also describes the two Web sites that were developed from the research to assist forest managers with nutrient management of Douglas-fir and loblolly pine plantations.

  15. Study of GMSB models with photon final states using the ATLAS detector

    CERN Document Server

    Terwort, Mark; Mnich, Joachim; Schleper, Peter

    Models with gauge mediated supersymmetry breaking (GMSB) provide a possible mechanism to mediate supersymmetry breaking to the electroweak scale. In these models the lightest-supersymmetric particle is the gravitino, while the next-to-lightest supersymmetric particle is either the lightest neutralino or a slepton. In the former case nal states with large missing transverse energy from the gravitinos, multiple jets and two hard photons are expected in pp-collisions at the LHC. Depending on the lifetime of the neutralino the photons might not point back to the interaction vertex, which requires dedicated search strategies. Additionally, this feature can be used to measure the neutralino lifetime using either the timing information from the electromagnetic calorimeter or the reconstructed photon direction. Together with the measurements of kinematic endpoints in invariant mass distributions, the lifetime can be used as input for ts of the GMSB model and for the determination of the underlying parameters. The sig...

  16. Final report LDRD project 105816 : model reduction of large dynamic systems with localized nonlinearities.

    Energy Technology Data Exchange (ETDEWEB)

    Lehoucq, Richard B.; Segalman, Daniel Joseph; Hetmaniuk, Ulrich L. (University of Washington, Seattle, WA); Dohrmann, Clark R.

    2009-10-01

    Advanced computing hardware and software written to exploit massively parallel architectures greatly facilitate the computation of extremely large problems. On the other hand, these tools, though enabling higher fidelity models, have often resulted in much longer run-times and turn-around-times in providing answers to engineering problems. The impediments include smaller elements and consequently smaller time steps, much larger systems of equations to solve, and the inclusion of nonlinearities that had been ignored in days when lower fidelity models were the norm. The research effort reported focuses on the accelerating the analysis process for structural dynamics though combinations of model reduction and mitigation of some factors that lead to over-meshing.

  17. Development of models and software for liquidus temperatures of glasses of HWVP products. Final report

    International Nuclear Information System (INIS)

    Hrma, P.R.; Vienna, J.D.; Pelton, A.D.

    1996-03-01

    In an earlier report [92 Pel] was described the development of software and thermodynamic databases for the calculation of liquidus temperatures of glasses of HWVP products containing the components SiO 2 -B 2 O 3 -Na 2 O-Li 2 O-CaO-MgO-Fe 2 O 3 -Al 2 O 3 -ZrO 2 -open-quotes othersclose quotes. The software package developed at that time consisted of the EQUILIB program of the F*A*C*T computer system with special input/output routines. Since then, Battelle has purchased the entire F*A*C*T computer system, and this fully replaces the earlier package. Furthermore, with the entire F*A*C*T system, additional calculations can be performed such as calculations at fixed O 2 , SO 2 etc. pressures, or graphing of output. Furthermore, the public F*A*C*T database of over 5000 gaseous species and condensed phases is now accessible. The private databases for the glass and crystalline phases were developed for Battelle by optimization of thermodynamic and phase diagram data. That is, all available data for 2- and 3-component sub-systems of the 9-component oxide system were collected, and parameters of model equations for the thermodynamic properties were found which best reproduce all the data. For representing the thermodynamic properties of the glass as a function of composition and temperature, the modified quasichemical model was used. This model was described in the earlier report [92 Pel] along with all the optimizations. With the model, it was possible to predict the thermodynamic properties of the 9-component glass, and thereby to calculate liquidus temperatures. Liquidus temperatures measured by Battelle for 123 CVS glass compositions were used to test the model and to refine the model by the addition of further parameters

  18. Using Phenomenological Models to Characterize Transmissibility and Forecast Patterns and Final Burden of Zika Epidemics

    DEFF Research Database (Denmark)

    Chowell, Gerardo; Hincapie-Palacio, Doracelly; Ospina, Juan

    2016-01-01

    BACKGROUND: The World Health Organization declared the ongoing Zika virus (ZIKV) epidemic in the Americas a Public Health Emergency of International Concern on February 1, 2016. ZIKV disease in humans is characterized by a "dengue-like" syndrome including febrile illness and rash. However, ZIKV...... impact. METHODS: We obtained daily counts of suspected Zika cases by date of symptoms onset from the Secretary of Health of Antioquia, Colombia during January-April 2016. We calibrated the generalized Richards model, a phenomenological model that accommodates a variety of early exponential and sub...

  19. Tornado missile simulation and design methodology. Volume 2: model verification and data base updates. Final report

    International Nuclear Information System (INIS)

    Twisdale, L.A.; Dunn, W.L.

    1981-08-01

    A probabilistic methodology has been developed to predict the probabilities of tornado-propelled missiles impacting and damaging nuclear power plant structures. Mathematical models of each event in the tornado missile hazard have been developed and sequenced to form an integrated, time-history simulation methodology. The models are data based where feasible. The data include documented records of tornado occurrence, field observations of missile transport, results of wind tunnel experiments, and missile impact tests. Probabilistic Monte Carlo techniques are used to estimate the risk probabilities. The methodology has been encoded in the TORMIS computer code to facilitate numerical analysis and plant-specific tornado missile probability assessments

  20. Final Report: System Reliability Model for Solid-State Lighting (SSL) Luminaires

    Energy Technology Data Exchange (ETDEWEB)

    Davis, J. Lynn [RTI International, Research Triangle Park, NC (United States)

    2017-05-31

    The primary objectives of this project was to develop and validate reliability models and accelerated stress testing (AST) methodologies for predicting the lifetime of integrated SSL luminaires. This study examined the likely failure modes for SSL luminaires including abrupt failure, excessive lumen depreciation, unacceptable color shifts, and increased power consumption. Data on the relative distribution of these failure modes were acquired through extensive accelerated stress tests and combined with industry data and other source of information on LED lighting. This data was compiled and utilized to build models of the aging behavior of key luminaire optical and electrical components.

  1. Search for Standard Model Higgs boson in the two-photon final state in ATLAS

    Directory of Open Access Journals (Sweden)

    Davignon Olivier

    2012-06-01

    Full Text Available We report on the search for the Standard Model Higgs boson decaying into two photons based on proton-proton collision data with a center-of-mass energy of 7 TeV recorded by the ATLAS experiment at the LHC. The dataset has an integrated luminosity of about 1:08 fb−1. The expected cross section exclusion at 95% confidence level varies between 2:0 and 5:8 times the Standard Model cross section over the diphoton mass range 110 – 150 GeV. The maximum deviations from the background-only expectation are consistent with statistical fluctuations.

  2. Final Report of the Mid-Atlantic Marine Wildlife Surveys, Modeling, and Data

    Energy Technology Data Exchange (ETDEWEB)

    Saracino-Brown, Jocelyn [Energy Efficiency and Renewable Energy (EERE), Washington, DC (United States); Smith, Courtney [Energy Efficiency and Renewable Energy (EERE), Washington, DC (United States); Gilman, Patrick [Energy Efficiency and Renewable Energy (EERE), Washington, DC (United States)

    2013-07-01

    The Wind Program hosted a two-day workshop on July 24-25, 2012 with scientists and regulators engaged in marine ecological survey, modeling, and database efforts pertaining to the waters of the Mid-Atlantic region. The workshop was planned by Federal agency, academic, and private partners to promote collaboration between ongoing offshore ecological survey efforts, and to promote the collaborative development of complementary predictive models and compatible databases. The meeting primarily focused on efforts to establish and predict marine mammal, seabird, and sea turtle abundance, density, and distributions extending from the shoreline to the edge of the Exclusive Economic Zone between Nantucket Sound, Massachusetts and Cape Hatteras, North Carolina.

  3. Therapeutic Effects of TianDiJingWan on the Aβ25–35-Induced Alzheimer’s Disease Model Rats

    Directory of Open Access Journals (Sweden)

    Zhijie Li

    2015-01-01

    Full Text Available The main purpose of this study was to demonstrate the therapeutic effects and mechanism of TDJW, a modern Chinese medicine prescription developed based on the basic traditional Chinese medicine theory of “tonifying the kidney essence,” on the Aβ25–35-induced AD rats. The AD model was established by the intracerebroventricular administrations of Aβ25–35 into the hippocampus CA1 tissue of SD male rats. 72 rats were randomly divided into six groups: sham operation, AD model, donepezil, high TDJW group, medium TDJW group, and low TDJW group. After oral administration of TDJW, the results of Morris water maze and step-down test showed that the learning and memory abilities of AD rats were significantly improved. And biochemical measurement demonstrated that Ach and Glu in hippocampus tissues of AD rats were increased as well. Moreover, the Aβ deposits and p-Tau aggregations in hippocampus CA1 tissues of AD rats were attenuated as observed in the micrographs of immunohistochemistry study, and the results of ELISA indicated that the expressions of TNF-α, IL-1β, and IL-6 in hippocampus tissues were significantly decreased. In conclusion, the present study demonstrated that TDJW could be used as a promising therapeutic agent for the clinical applications of AD treatment in patients.

  4. Preconditioning With Low-Level Laser Irradiation Enhances the Therapeutic Potential of Human Adipose-derived Stem Cells in a Mouse Model of Photoaged Skin.

    Science.gov (United States)

    Liao, Xuan; Li, Sheng-Hong; Xie, Guang-Hui; Xie, Shan; Xiao, Li-Ling; Song, Jian-Xing; Liu, Hong-Wei

    2018-02-19

    This study was conducted to explore the therapeutic potential of human adipose-derived stem cells (ADSCs) irradiated with a low-level laser (LLL). Cultured ADSCs were treated with 650-nm GaAlAs laser irradiation at 2, 4 and 8 J cm -2 . Cell proliferation was quantified by MTT assays, cytokine secretion was determined by enzyme-linked immunosorbent assays, and adipogenic differentiation was examined by oil red O staining. Additionally, the expression profiles of putative ADSC surface markers were analyzed by quantitative real-time PCR. In addition, a mouse photoaged skin model was established by UVB irradiation. Effects of GaAlAs laser-treated ADSCs on the thicknesses of the epidermis and dermis were analyzed by hematoxylin and eosin staining. The results showed that GaAlAs laser treatment of cells at a radiant exposure of 4 J cm -2 enhanced ADSC proliferation and adipogenic differentiation and increased secretion of growth factors. Furthermore, GaAlAs laser irradiation upregulated the expression of putative ADSC surface markers. In the mouse model of photoaged skin, ADSCs treated with GaAlAs laser irradiation had markedly decreased the epidermal thickness and increased the dermal thickness of photoaged mouse skin. Our data indicate that LLL irradiation is an effective biostimulator of ADSCs and might enhance the therapeutic potential of ADSCs for clinical use. © 2018 The American Society of Photobiology.

  5. Using Voter-choice Modeling to Plan Final Campaigns in Runoff Elections

    Directory of Open Access Journals (Sweden)

    Wagner Antonio Kamakura

    2016-11-01

    Full Text Available Embora a eleição em dois estágios seja a forma mais comum de eleição presidencial no mundo, o comportamento do eleitor no pleito em dois estágios ainda não recebeu uma atenção condizente à que merece na literatura. Eleições em dois estágios ou turnos oferecem, aos consultores políticos e aos candidatos, dados ricos e factuais sobre a preferência do eleitor, revelada através do comportamento deste observado no primeiro turno, que pode guiar o planejamento e a implementação da campanha final. Essas eleições em dois turnos também permitem que analistas políticos apliquem seus modelos de escolha eleitoral ao comportamento real (ao invés da intenção de voto numa eleição multipartidária, e validem suas previsões na eleição bipartidária do segundo turno. Nesse estudo, utilizo os resultados das quatro eleições presidenciais mais recentes no Brasil para demonstrar como modelos de escolha do eleitor podem ser aplicados para guiar a campanha política em eleições de dois turnos.

  6. R&D for computational cognitive and social models : foundations for model evaluation through verification and validation (final LDRD report).

    Energy Technology Data Exchange (ETDEWEB)

    Slepoy, Alexander; Mitchell, Scott A.; Backus, George A.; McNamara, Laura A.; Trucano, Timothy Guy

    2008-09-01

    Sandia National Laboratories is investing in projects that aim to develop computational modeling and simulation applications that explore human cognitive and social phenomena. While some of these modeling and simulation projects are explicitly research oriented, others are intended to support or provide insight for people involved in high consequence decision-making. This raises the issue of how to evaluate computational modeling and simulation applications in both research and applied settings where human behavior is the focus of the model: when is a simulation 'good enough' for the goals its designers want to achieve? In this report, we discuss two years' worth of review and assessment of the ASC program's approach to computational model verification and validation, uncertainty quantification, and decision making. We present a framework that extends the principles of the ASC approach into the area of computational social and cognitive modeling and simulation. In doing so, we argue that the potential for evaluation is a function of how the modeling and simulation software will be used in a particular setting. In making this argument, we move from strict, engineering and physics oriented approaches to V&V to a broader project of model evaluation, which asserts that the systematic, rigorous, and transparent accumulation of evidence about a model's performance under conditions of uncertainty is a reasonable and necessary goal for model evaluation, regardless of discipline. How to achieve the accumulation of evidence in areas outside physics and engineering is a significant research challenge, but one that requires addressing as modeling and simulation tools move out of research laboratories and into the hands of decision makers. This report provides an assessment of our thinking on ASC Verification and Validation, and argues for further extending V&V research in the physical and engineering sciences toward a broader program of model

  7. Initial and final estimates of the Bilinear seasonal time series model ...

    African Journals Online (AJOL)

    In getting the estimates of the parameters of this model special attention was paid to the problem of having good initial estimates as it is proposed that with good initial values of the parameters the estimates obtaining by the Newton-Raphson iterative technique usually not only converge but also are good estimates.

  8. Research on a Frame-Based Model of Reading Comprehension. Final Report.

    Science.gov (United States)

    Goldstein, Ira

    This report summarizes computational investigations of language comprehension based on Marvin Minsky's theory of frames, a recent advance in artifical intelligence theories about the representation of knowledge. The investigations discussed explored frame theory as a basis for text comprehension by implementing models of the theory and developing…

  9. Accelerated Climate Modeling for Energy (ACME) Final Scientific/Technical Report

    Energy Technology Data Exchange (ETDEWEB)

    Chaudhary, Aashish [Kitware, Inc.

    2017-10-17

    Seven Department of Energy (DOE) national laboratories, Universities, and Kitware, undertook a coordinated effort to build an Earth system modeling capability tailored to meet the climate change research strategic objectives of the DOE Office of Science, as well as the broader climate change application needs of other DOE programs.

  10. First Principles Diffusion Modeling Final Report CRADA No. TC-1540-98

    Energy Technology Data Exchange (ETDEWEB)

    delaRubia, T. D. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Foad, M. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Giles, M. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

    2017-10-19

    The CRADA participants built on the capabilities LLNL had already developed for ab initio diffusion modeling, extending them to higher doping and damage levels, and applying them to improve the understanding of implant and annealing tradeoffs for technology-relevant conditions. The calculation results and some of the simulation capabilities developed here were transferred to Intel and Applied Materials.

  11. Modeling a Change in Flowrate through Detention or Additional Pavement on the Receiving Stream : Final Report

    Science.gov (United States)

    2017-11-01

    The addition or removal of flow from a stream affects the water surface downstream and possibly upstream. The extent of such effects is generally determined by modeling the receiving stream. Guidance that concisely describes how far up/downstream a h...

  12. Endochronic constitutive model for general hysteretic response of soils. Final report

    International Nuclear Information System (INIS)

    Read, H.E.; Valanis, K.C.

    1979-01-01

    A new endochronic theory of plasticity is presented which can accurately describe the mechanical response of hysteretic materials to complex, three-dimensional deformation histories, including cyclic deformation. The theory is based on several new advancements in the endochronic framework, which broaden its predictive scope. Various features of the resulting model are illustrated, including its ability to describe (1) cyclic simple shear of dry sand and wet clay over many cycles of deformation, (2) response of a real soil (McCormick Ranch soil) to the standard laboratory soil tests, and (3) response of McCormick Ranch soil to cyclic triaxial tests. It is believed that this is the first constitutive model that has demonstrated the capability to realistically describe, for a given soil, both standard laboratory tests and cyclic response under three-dimensional loading conditions. The constitutive model presented here should allow more meaningful analyses to be made in many areas of soil response, particularly for ground motion and soil-structure interaction due to to other seimsic disturbances. The proposed model also has wide application to other materials, such as metals, and could provide improved descriptions of the response of various metallic components under transient loads

  13. Model-Based Engineering and Manufacturing CAD/CAM Benchmark.; FINAL

    International Nuclear Information System (INIS)

    Domm, T.C.; Underwood, R.S.

    1999-01-01

    The Benchmark Project was created from a desire to identify best practices and improve the overall efficiency and performance of the Y-12 Plant's systems and personnel supporting the manufacturing mission. The mission of the benchmark team was to search out industry leaders in manufacturing and evaluate their engineering practices and processes to determine direction and focus for Y-12 modernization efforts. The companies visited included several large established companies and a new, small, high-tech machining firm. As a result of this effort, changes are recommended that will enable Y-12 to become a more modern, responsive, cost-effective manufacturing facility capable of supporting the needs of the Nuclear Weapons Complex (NWC) into the 21st century. The benchmark team identified key areas of interest, both focused and general. The focus areas included Human Resources, Information Management, Manufacturing Software Tools, and Standards/Policies and Practices. Areas of general interest included Infrastructure, Computer Platforms and Networking, and Organizational Structure. The results of this benchmark showed that all companies are moving in the direction of model-based engineering and manufacturing. There was evidence that many companies are trying to grasp how to manage current and legacy data. In terms of engineering design software tools, the companies contacted were somewhere between 3-D solid modeling and surfaced wire-frame models. The manufacturing computer tools were varied, with most companies using more than one software product to generate machining data and none currently performing model-based manufacturing (MBM) from a common model. The majority of companies were closer to identifying or using a single computer-aided design (CAD) system than a single computer-aided manufacturing (CAM) system. The Internet was a technology that all companies were looking to either transport information more easily throughout the corporation or as a conduit for

  14. Therapeutic efficacy and microSPECT/CT imaging of {sup 188}Re-DXR-liposome in a C26 murine colon carcinoma solid tumor model

    Energy Technology Data Exchange (ETDEWEB)

    Chang, Y.-J.; Chang, C.-H.; Yu, C.-Y.; Chang, T.-J.; Chen, L.-C. [Institute of Nuclear Energy Research, Taoyuan, Taiwan (China); Chen, M.-H. [National Health Research Institutes, Miaoli, Taiwan (China); Lee, T.-W. [Institute of Nuclear Energy Research, Taoyuan, Taiwan (China); Ting Gann [National Health Research Institutes, Miaoli, Taiwan (China)], E-mail: gann.ting@msa.hinet.net

    2010-01-15

    Nanocarriers can selectively target cancer sites and carry payloads, thereby improving diagnostic and therapeutic effectiveness and reducing toxicity. The objective of this study was to investigate the therapeutic efficacy of a new co-delivery radiochemotherapeutics of {sup 188}Re-N,N-bis (2-mercaptoethyl)-N',N'-diethylethylenediamine (BMEDA)-labeled pegylated liposomal doxorubicin (DXR) ({sup 188}Re-DXR-liposome) in a C26 murine colon carcinoma solid tumor model. To evaluate the targeting and localization of {sup 188}Re-DXR-liposome in C26 murine tumor-bearing mice, biodistribution, microSPECT/CT imaging and pharmacokinetic studies were performed. The antitumor effect of {sup 188}Re-DXR-liposome was assessed by tumor growth inhibition, survival ratio and histopathological hematoxylin-eosin staining. The tumor target and localization of the nanoliposome delivery radiochemotherapeutics of {sup 188}Re-DXR-liposome were demonstrated in the biodistribution, pharmacokinetics and in vivo nuclear imaging studies. In the study on therapeutic efficacy, the tumor-bearing mice treated with bimodality radiochemotherapeutics of {sup 188}Re-DXR-liposome showed better mean tumor growth inhibition rate (MGI) and longer median survival time (MGI=0.048; 74 days) than those treated with radiotherapeutics of {sup 188}Re-liposome (MGI=0.134; 60 days) and chemotherapeutics of Lipo-Dox (MGI=0.413; 38 days). The synergistic tumor regression effect was observed with the combination index (CI) exceeding 1 (CI=1.145) for co-delivery radiochemotherapeutics of {sup 188}Re-DXR-liposome. Two (25%) of the mice treated with radiochemotherapeutics were completely cured after 120 days. The therapeutic efficacy of radiotherapeutics of {sup 188}Re-liposome and the synergistic effect of the combination radiochemotherapeutics of {sup 188}Re-DXR-liposome have been demonstrated in a C26 murine solid tumor animal model, which pointed to the potential benefit and promise of the co-delivery of

  15. Revised data book for evaluation of combustion and gasification models: Final report, Volume 3

    Energy Technology Data Exchange (ETDEWEB)

    Christensen, K.R.; Rasband, M.W.; Smoot, L.D.

    1987-10-01

    During the previous contract (DE-AC21-81MC16518) a major task was to identify, collect and publish detailed experimental data for evaluation of comprehensive gasification/combustion codes. A review of the literature was completed and prospective data were identified for inclusion in this data book in five categories of increasing complexity: (1) non-reacting, gaseous flows (58 cases); (2) non-reacting, particle-laden flows (43 cases); (3) gaseous combustion (34 cases); (4) pulverized coal combustion (57 cases); (5) entrained coal gasification (6 cases). Selection of these data was based on a set of criteria which included data completeness, availability of detailed, digital profiles for several properties (e.g., species concentrations, velocity, temperature) and data accuracy. From these 198 cases, which were referenced in the final report (Vol. III), the data base was reduced to a total of 35 sets of data from 8 laboratories, with at least 3 cases in each category above. For these 35 cases, the measured data, together with geometrical dimensions and test conditions were documented in a uniform tabular format. These data were also stored on a magnetic tape for distribution. During this follow-on contract (DE-AC21-85MC22059), the accuracy of the data was checked and several additional corrections were made. The format for reporting the data (Appendix B) was simplified. Also, a review of additional data sets available from the Combustion Laboratory and other sources was completed. In all, 213 cases from 52 investigators at 18 laboratories were considered and 37 cases are included in this data book from 22 different investigations at 8 independent laboratories. 81 refs.

  16. Conflicts in the therapeutic field

    Directory of Open Access Journals (Sweden)

    Antonino Aprea

    2012-06-01

    Full Text Available How the analytical knowledge that compare human consciousness with that, even more disturbing, moving behind his fifth can be said to be “for peace”? It can be - and this will be the contribution of the proposal - the same tortuous and enigmatic of therapeutic practice, with its hesitations and his impulses, to outline a path crossing and overcoming the conflict? May, finally, peace, in the sense of feasibility of intra-and interpersonal dialectic instead of tearing and hostileconfrontation with oneself and with the other, to be a reference in some crucial pivot of ethical therapeutic work? To these questions the intervention seeks to answer retracing some of the highlights of almost three years of therapeutic work with a young woman and her family.

  17. The Network Model of Depression as a Basis for New Therapeutic Strategies for Treating Major Depressive Disorder in Parkinson’s Disease

    Science.gov (United States)

    D’Ostilio, Kevin; Garraux, Gaëtan

    2016-01-01

    The high prevalence of major depressive disorder in people with Parkinson’s disease (PD), its negative impact on health-related quality of life and the low response rate to conventional pharmacological therapies call to seek innovative treatments. Here, we review the new approaches for treating major depressive disorder in patients with PD within the framework of the network model of depression. According to this model, major depressive disorder reflects maladaptive neuronal plasticity. Non-invasive brain stimulation (NIBS) using high frequency repetitive transcranial magnetic stimulation (rTMS) over the prefrontal cortex has been proposed as a feasible and effective strategy with minimal risk. The neurobiological basis of its therapeutic effect may involve neuroplastic modifications in limbic and cognitive networks. However, the way this networks reorganize might be strongly influenced by the environment. To address this issue, we propose a combined strategy that includes NIBS together with cognitive and behavioral interventions. PMID:27148016

  18. Final Report Coupling in silico microbial models with reactive transport models to predict the fate of contaminants in the subsurface.

    Energy Technology Data Exchange (ETDEWEB)

    Lovley, Derek R.

    2012-10-31

    This project successfully accomplished its goal of coupling genome-scale metabolic models with hydrological and geochemical models to predict the activity of subsurface microorganisms during uranium bioremediation. Furthermore, it was demonstrated how this modeling approach can be used to develop new strategies to optimize bioremediation. The approach of coupling genome-scale metabolic models with reactive transport modeling is now well enough established that it has been adopted by other DOE investigators studying uranium bioremediation. Furthermore, the basic principles developed during our studies will be applicable to much broader investigations of microbial activities, not only for other types of bioremediation, but microbial metabolism in diversity of environments. This approach has the potential to make an important contribution to predicting the impact of environmental perturbations on the cycling of carbon and other biogeochemical cycles.

  19. Final Report for 'Modeling Electron Cloud Diagnostics for High-Intensity Proton Accelerators'

    International Nuclear Information System (INIS)

    Veitzer, Seth A.

    2009-01-01

    Electron clouds in accelerators such as the ILC degrade beam quality and limit operating efficiency. The need to mitigate electron clouds has a direct impact on the design and operation of these accelerators, translating into increased cost and reduced performance. Diagnostic techniques for measuring electron clouds in accelerating cavities are needed to provide an assessment of electron cloud evolution and mitigation. Accurate numerical modeling of these diagnostics is needed to validate the experimental techniques. In this Phase I, we developed detailed numerical models of microwave propagation through electron clouds in accelerating cavities with geometries relevant to existing and future high-intensity proton accelerators such as Project X and the ILC. Our numerical techniques and simulation results from the Phase I showed that there was a high probability of success in measuring both the evolution of electron clouds and the effects of non-uniform electron density distributions in Phase II.

  20. Modeling of Cation Binding in Hydrated 2:1 Clay Minerals - Final Report

    International Nuclear Information System (INIS)

    Smith, David E.

    2000-01-01

    Hydrated 2:1 clay minerals are high surface area, layered silicates that play a unique role in determining the fate of radionuclides in the environment. This project consisted of developing and implementing computer simulation methods for molecular characterization of the swelling and ion exchange properties of Hydrated 2:1 clay minerals, and the subsequent analysis and theoretical modeling with a view toward improving contaminant transport modeling as well as soil remediation and radionuclide containment strategies. Project results included the (a) development of simulation methods to treat clays under environmentally relevant conditions of variable water vapor pressure; (b) calculation of clay swelling thermodynamics as a function of interlayer ion size and charge (calculated quantities include immersion energies, free energies, and entropies of swelling); and (c) calculation of ion exchange free energies, including contributions from changing interlayer water contents and layer spacing

  1. Numerical modeling of rock stresses within a basaltic nuclear waste repository. Final report

    International Nuclear Information System (INIS)

    Hardy, M.P.; Hocking, G.

    1978-01-01

    The modeling undertaken during this project incorporated a wide range of problems that impact the design of the waste repository. Interaction of groundwater, heat and stress were considered on a regional scale, whereas on the room and canister scale thermo-mechanical analyses were undertaken. In the Phase II report, preliminary guidelines for waste densities were established based primarily on short-term stress criteria required to maintain stability during the retrievability period. Additional analyses are required to evaluate the effect of joints, borehole linings, room support and ventilation on these preliminary waste loading densities. The regional analyses did not indicate any adverse effect that could control the allowable waste loading densities. However, further refinements of geologic structure, hydrologic models, seismicity and possible induced seismicity are required before firm estimates of the loading densities can be made

  2. LDRD final report : mesoscale modeling of dynamic loading of heterogeneous materials

    Energy Technology Data Exchange (ETDEWEB)

    Robbins, Joshua [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Dingreville, Remi Philippe Michel [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Voth, Thomas Eugene [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Furnish, Michael David [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)

    2013-12-01

    Material response to dynamic loading is often dominated by microstructure (grain structure, porosity, inclusions, defects). An example critically important to Sandia's mission is dynamic strength of polycrystalline metals where heterogeneities lead to localization of deformation and loss of shear strength. Microstructural effects are of broad importance to the scientific community and several institutions within DoD and DOE; however, current models rely on inaccurate assumptions about mechanisms at the sub-continuum or mesoscale. Consequently, there is a critical need for accurate and robust methods for modeling heterogeneous material response at this lower length scale. This report summarizes work performed as part of an LDRD effort (FY11 to FY13; project number 151364) to meet these needs.

  3. Computer-assisted modeling: Contributions of computational approaches to elucidating macromolecular structure and function: Final report

    International Nuclear Information System (INIS)

    Walton, S.

    1987-01-01

    The Committee, asked to provide an assessment of computer-assisted modeling of molecular structure, has highlighted the signal successes and the significant limitations for a broad panoply of technologies and has projected plausible paths of development over the next decade. As with any assessment of such scope, differing opinions about present or future prospects were expressed. The conclusions and recommendations, however, represent a consensus of our views of the present status of computational efforts in this field

  4. Accounting for Model Uncertainties Using Reliability Methods - Application to Carbon Dioxide Geologic Sequestration System. Final Report

    International Nuclear Information System (INIS)

    Mok, Chin Man; Doughty, Christine; Zhang, Keni; Pruess, Karsten; Kiureghian, Armen; Zhang, Miao; Kaback, Dawn

    2010-01-01

    A new computer code, CALRELTOUGH, which uses reliability methods to incorporate parameter sensitivity and uncertainty analysis into subsurface flow and transport models, was developed by Geomatrix Consultants, Inc. in collaboration with Lawrence Berkeley National Laboratory and University of California at Berkeley. The CALREL reliability code was developed at the University of California at Berkely for geotechnical applications and the TOUGH family of codes was developed at Lawrence Berkeley National Laboratory for subsurface flow and tranport applications. The integration of the two codes provides provides a new approach to deal with uncertainties in flow and transport modeling of the subsurface, such as those uncertainties associated with hydrogeology parameters, boundary conditions, and initial conditions of subsurface flow and transport using data from site characterization and monitoring for conditioning. The new code enables computation of the reliability of a system and the components that make up the system, instead of calculating the complete probability distributions of model predictions at all locations at all times. The new CALRELTOUGH code has tremendous potential to advance subsurface understanding for a variety of applications including subsurface energy storage, nuclear waste disposal, carbon sequestration, extraction of natural resources, and environmental remediation. The new code was tested on a carbon sequestration problem as part of the Phase I project. Phase iI was not awarded.

  5. Interactive Photochemistry in Earth System Models to Assess Uncertainty in Ozone and Greenhouse Gases. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Prather, Michael J. [Univ. of California, Irvine, CA (United States); Hsu, Juno [Univ. of California, Irvine, CA (United States); Nicolau, Alex [Univ. of California, Irvine, CA (United States); Veidenbaum, Alex [Univ. of California, Irvine, CA (United States); Smith, Philip Cameron [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Bergmann, Dan [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

    2014-11-07

    Atmospheric chemistry controls the abundances and hence climate forcing of important greenhouse gases including N2O, CH4, HFCs, CFCs, and O3. Attributing climate change to human activities requires, at a minimum, accurate models of the chemistry and circulation of the atmosphere that relate emissions to abundances. This DOE-funded research provided realistic, yet computationally optimized and affordable, photochemical modules to the Community Earth System Model (CESM) that augment the CESM capability to explore the uncertainty in future stratospheric-tropospheric ozone, stratospheric circulation, and thus the lifetimes of chemically controlled greenhouse gases from climate simulations. To this end, we have successfully implemented Fast-J (radiation algorithm determining key chemical photolysis rates) and Linoz v3.0 (linearized photochemistry for interactive O3, N2O, NOy and CH4) packages in LLNL-CESM and for the first time demonstrated how change in O2 photolysis rate within its uncertainty range can significantly impact on the stratospheric climate and ozone abundances. From the UCI side, this proposal also helped LLNL develop a CAM-Superfast Chemistry model that was implemented for the IPCC AR5 and contributed chemical-climate simulations to CMIP5.

  6. Toward the Development of a Cold Regions Regional-Scale Hydrologic Model, Final Project Report

    Energy Technology Data Exchange (ETDEWEB)

    Hinzman, Larry D [Univ. of Alaska, Fairbanks, AK (United States); Bolton, William Robert [Univ. of Alaska, Fairbanks, AK (United States); Young-Robertson, Jessica (Cable) [Univ. of Alaska, Fairbanks, AK (United States)

    2018-01-02

    This project improves meso-scale hydrologic modeling in the boreal forest by: (1) demonstrating the importance of capturing the heterogeneity of the landscape using small scale datasets for parameterization for both small and large basins; (2) demonstrating that in drier parts of the landscape and as the boreal forest dries with climate change, modeling approaches must consider the sensitivity of simulations to soil hydraulic parameters - such as residual water content - that are usually held constant. Thus, variability / flexibility in residual water content must be considered for accurate simulation of hydrologic processes in the boreal forest; (3) demonstrating that assessing climate change impacts on boreal forest hydrology through multiple model integration must account for direct effects of climate change (temperature and precipitation), and indirect effects from climate impacts on landscape characteristics (permafrost and vegetation distribution). Simulations demonstrated that climate change will increase runoff, but will increase ET to a greater extent and result in a drying of the landscape; and (4) vegetation plays a significant role in boreal hydrologic processes in permafrost free areas that have deciduous trees. This landscape type results in a decoupling of ET and precipitation, a tight coupling of ET and temperature, low runoff, and overall soil drying.

  7. Approaches for scalable modeling and emulation of cyber systems : LDRD final report.

    Energy Technology Data Exchange (ETDEWEB)

    Mayo, Jackson R.; Minnich, Ronald G.; Armstrong, Robert C.; Rudish, Don W.

    2009-09-01

    The goal of this research was to combine theoretical and computational approaches to better understand the potential emergent behaviors of large-scale cyber systems, such as networks of {approx} 10{sup 6} computers. The scale and sophistication of modern computer software, hardware, and deployed networked systems have significantly exceeded the computational research community's ability to understand, model, and predict current and future behaviors. This predictive understanding, however, is critical to the development of new approaches for proactively designing new systems or enhancing existing systems with robustness to current and future cyber threats, including distributed malware such as botnets. We have developed preliminary theoretical and modeling capabilities that can ultimately answer questions such as: How would we reboot the Internet if it were taken down? Can we change network protocols to make them more secure without disrupting existing Internet connectivity and traffic flow? We have begun to address these issues by developing new capabilities for understanding and modeling Internet systems at scale. Specifically, we have addressed the need for scalable network simulation by carrying out emulations of a network with {approx} 10{sup 6} virtualized operating system instances on a high-performance computing cluster - a 'virtual Internet'. We have also explored mappings between previously studied emergent behaviors of complex systems and their potential cyber counterparts. Our results provide foundational capabilities for further research toward understanding the effects of complexity in cyber systems, to allow anticipating and thwarting hackers.

  8. Evaluation of an anti-tumor necrosis factor therapeutic in a mouse model of Niemann-Pick C liver disease.

    Directory of Open Access Journals (Sweden)

    Melanie Vincent

    2010-09-01

    Full Text Available Niemann-Pick type C (NPC disease is a lysosomal storage disease characterized by the accumulation of cholesterol and glycosphingolipids. The majority of NPC patients die in their teen years due to progressive neurodegeneration; however, half of NPC patients also suffer from cholestasis, prolonged jaundice, and hepatosplenomegaly. We previously showed that a key mediator of NPC liver disease is tumor necrosis factor (TNF α, which is involved in both proinflammatory and apoptotic signaling cascades. In this study, we tested the hypothesis that blocking TNF action with an anti-TNF monoclonal antibody (CNTO5048 will slow the progression of NPC liver disease.Treatment of wild-type C57BL/6 mice with NPC1-specific antisense oligonucleotides led to knockdown of NPC1 protein expression in the liver. This caused classical symptoms of NPC liver disease, including hepatic cholesterol accumulation, hepatomegaly, elevated serum liver enzymes, and lipid laden macrophage accumulation. In addition, there was a significant increase in the number of apoptotic cells and a proliferation of stellate cells. Concurrent treatment of NPC1 knockdown mice with anti-TNF had no effect on the primary lipid storage or accumulation of lipid-laden macrophages. However, anti-TNF treatment slightly blunted the increase in hepatic apoptosis and stellate cell activation that was seen with NPC1 knockdown.Current therapeutic options for NPC disease are limited. Our results provide proof of principle that pharmacologically blocking the TNF-α inflammatory cascade can slightly reduce certain markers of NPC disease. Small molecule inhibitors of TNF that penetrate tissues and cross the blood-brain barrier may prove even more beneficial.

  9. Novel Manganese-Porphyrin Superoxide Dismutase-Mimetic Widens the Therapeutic Margin in a Preclinical Head and Neck Cancer Model

    Energy Technology Data Exchange (ETDEWEB)

    Ashcraft, Kathleen A. [Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina (United States); Boss, Mary-Keara [Department of Molecular Biomedical Sciences, North Carolina State College of Veterinary Medicine, Raleigh, North Carolina (United States); Tovmasyan, Artak [Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina (United States); Roy Choudhury, Kingshuk [Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina (United States); Fontanella, Andrew N. [Department of Biomedical Engineering, Duke University, Durham, North Carolina (United States); Young, Kenneth H.; Palmer, Gregory M.; Birer, Samuel R.; Landon, Chelsea D.; Park, Won [Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina (United States); Das, Shiva K. [Physics and Computing Division, Department of Radiation Oncology, University of North Carolina School of Medicine, Chapel Hill, North Carolina (United States); Weitner, Tin [Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina (United States); Sheng, Huaxin; Warner, David S. [Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina (United States); Brizel, David M. [Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina (United States); Department of Surgery, Duke University Medical Center, Durham, North Carolina (United States); Spasojevic, Ivan [Department of Medicine, Duke University Medical Center, Durham, North Carolina (United States); Batinic-Haberle, Ines [Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina (United States); Dewhirst, Mark W., E-mail: mark.dewhirst@duke.edu [Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina (United States); Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina (United States)

    2015-11-15

    Purpose: To test the effects of a novel Mn porphyrin oxidative stress modifier, Mn(III) meso-tetrakis(N-n-butoxyethylpyridinium-2-yl)porphyrin (MnBuOE), for its radioprotective and radiosensitizing properties in normal tissue versus tumor, respectively. Methods and Materials: Murine oral mucosa and salivary glands were treated with a range of radiation doses with or without MnBuOE to establish the dose–effect curves for mucositis and xerostomia. Radiation injury was quantified by intravital near-infrared imaging of cathepsin activity, assessment of salivation, and histologic analysis. To evaluate effects of MnBuOE on the tumor radiation response, we administered the drug as an adjuvant to fractionated radiation of FaDu xenografts. Again, a range of radiation therapy (RT) doses was administered to establish the radiation dose–effect curve. The 50% tumor control dose values with or without MnBuOE and dose-modifying factor were determined. Results: MnBuOE protected normal tissue by reducing RT-mediated mucositis, xerostomia, and fibrosis. The dose-modifying factor for protection against xerostomia was 0.77. In contrast, MnBuOE increased tumor local control rates compared with controls. The dose-modifying factor, based on the ratio of 50% tumor control dose values, was 1.3. Immunohistochemistry showed that MnBuOE-treated tumors exhibited a significant influx of M1 tumor-associated macrophages, which provides mechanistic insight into its radiosensitizing effects in tumors. Conclusions: MnBuOE widens the therapeutic margin by decreasing the dose of radiation required to control tumor, while increasing normal tissue resistance to RT-mediated injury. This is the first study to quantitatively demonstrate the magnitude of a single drug's ability to radioprotect normal tissue while radiosensitizing tumor.

  10. Final Report for Subcontract B541028, Pore-Scale Modeling to Support 'Pore Connectivity' Research Work

    International Nuclear Information System (INIS)

    Ewing, R.P.

    2009-01-01

    This report covers modeling aspects of a combined experimental and modeling task in support of the DOE Science and Technology Program (formerly OSTI) within the Office of Civilian Radioactive Waste Management (OCRWM). Research Objectives The research for this project dealt with diffusive retardation: solute moving through a fracture diffuses into and out of the rock matrix. This diffusive exchange retards overall solute movement, and retardation both dilutes waste being released, and allows additional decay. Diffusive retardation involves not only fracture conductivity and matrix diffusion, but also other issues and processes: contaminants may sorb to the rock matrix, fracture flow may be episodic, a given fracture may or may not flow depending on the volume of flow and the fracture's connection to the overall fracture network, the matrix imbibes water during flow episodes and dries between episodes, and so on. The objective of the project was to improve understanding of diffusive retardation of radionuclides due to fracture / matrix interactions. Results from combined experimental/modeling work were to (1) determine whether the current understanding and model representation of matrix diffusion is valid, (2) provide insights into the upscaling of laboratory-scale diffusion experiments, and (3) help in evaluating the impact on diffusive retardation of episodic fracture flow and pore connectivity in Yucca Mountain tuffs. Questions explored included the following: (1) What is the relationship between the diffusion coefficient measured at one scale, to that measured or observed at a different scale? In classical materials this relationship is trivial; in low-connectivity materials it is not. (2) Is the measured diffusivity insensitive to the shape of the sample? Again, in classical materials there should be no sample shape effect. (3) Does sorption affect diffusive exchange in low-connectivity media differently than in classical media? (4) What is the effect of matrix

  11. Search for non-standard model signatures in the WZ/ZZ final state at CDF run II

    Energy Technology Data Exchange (ETDEWEB)

    Norman, Matthew [Univ. of California, San Diego, CA (United States)

    2009-01-01

    This thesis discusses a search for non-Standard Model physics in heavy diboson production in the dilepton-dijet final state, using 1.9 fb -1 of data from the CDF Run II detector. New limits are set on the anomalous coupling parameters for ZZ and WZ production based on limiting the production cross-section at high š. Additionally limits are set on the direct decay of new physics to ZZ andWZ diboson pairs. The nature and parameters of the CDF Run II detector are discussed, as are the influences that it has on the methods of our analysis.

  12. Search for non-standard model signatures in the WZ/ZZ final state at CDF Run II

    International Nuclear Information System (INIS)

    Norman, Matthew

    2009-01-01

    This thesis discusses a search for non-Standard Model physics in heavy diboson production in the dilepton-dijet final state, using 1.9 fb -1 of data from the CDF Run II detector. New limits are set on the anomalous coupling parameters for ZZ and WZ production based on limiting the production cross-section at high (cflx s). Additionally limits are set on the direct decay of new physics to ZZ andWZ diboson pairs. The nature and parameters of the CDF Run II detector are discussed, as are the influences that it has on the methods of our analysis.

  13. Aerosol exposure to Rift Valley fever virus causes earlier and more severe neuropathology in the murine model, which has important implications for therapeutic development.

    Directory of Open Access Journals (Sweden)

    Christopher Reed

    Full Text Available Rift Valley fever virus (RVFV is an important mosquito-borne veterinary and human pathogen that can cause severe disease including acute-onset hepatitis, delayed-onset encephalitis, retinitis and blindness, or a hemorrhagic syndrome. Currently, no licensed vaccine or therapeutics exist to treat this potentially deadly disease. Detailed studies describing the pathogenesis of RVFV following aerosol exposure have not been completed and candidate therapeutics have not been evaluated following an aerosol exposure. These studies are important because while mosquito transmission is the primary means for human infection, it can also be transmitted by aerosol or through mucosal contact. Therefore, we directly compared the pathogenesis of RVFV following aerosol exposure to a subcutaneous (SC exposure in the murine model by analyzing survival, clinical observations, blood chemistry, hematology, immunohistochemistry, and virus titration of tissues. Additionally, we evaluated the effectiveness of the nucleoside analog ribavirin administered prophylactically to treat mice exposed by aerosol and SC. The route of exposure did not significantly affect the survival, chemistry or hematology results of the mice. Acute hepatitis occurred despite the route of exposure. However, the development of neuropathology occurred much earlier and was more severe in mice exposed by aerosol compared to SC exposed mice. Mice treated with ribavirin and exposed SC were partially protected, whereas treated mice exposed by aerosol were not protected. Early and aggressive viral invasion of brain tissues following aerosol exposure likely played an important role in ribavirin's failure to prevent mortality among these animals. Our results highlight the need for more candidate antivirals to treat RVFV infection, especially in the case of a potential aerosol exposure. Additionally, our study provides an account of the key pathogenetic differences in RVF disease following two potential

  14. Animal models of cachexia and sarcopenia in chronic illness: Cardiac function, body composition changes and therapeutic results.

    Science.gov (United States)

    Ishida, Junichi; Saitoh, Masakazu; Doehner, Wolfram; von Haehling, Stephan; Anker, Markus; Anker, Stefan D; Springer, Jochen

    2017-07-01

    Cachexia is defined as a complex metabolic syndrome associated with underlying illness that is characterized by the loss of body weight consisting of muscle and fat mass wasting. Sarcopenia is defined as the ageing related loss of muscle mass in health and disease that may not have an effect on body weight. As millions of patients are in cachectic or sarcopenic states, both conditions contribute to high numbers to death worldwide. A number of treatments have been proposed for cachexia and sarcopenia, but these are either in the preclinical stage or in clinical trials and hence not available to the general population. Particularly in cachexia there is a massive problem of recruiting patients for trials and also with the follow-up, due to the seriousness of the disease. This underlines the importance of well-characterized animal models. Obviously, most of the widely used cachexia and sarcopenia animal models have limitations in reproducibility of the condition and novel models are warranted in this context. The key findings of developing models in the field of cachexia and sarcopenia are that more types of the conditions have been taken into the researchers' interest. In cardiac cachexia, technical issues, which limit the preciseness and reproducibility in surgical heart failure models, have been overcome by a combination of surgery and the use of transgenic mouse models or salt sensitive rat models. Fatigue is the most pronounced symptom of cachexia and may be caused by reduced cardiac function independent of the underlying disease. Sarcopenia models often suffer from the use of young animals, due to the limited availability and very high costs of using aged animals. This review will focus on rodent models designed to mimic cachexia and sarcopenia including co-morbidities such as cancer, heart failure, as well as other diseases and conditions. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Tumor-targeting Salmonella typhimurium A1-R is a highly effective general therapeutic for undifferentiated soft tissue sarcoma patient-derived orthotopic xenograft nude-mouse models.

    Science.gov (United States)

    Igarashi, Kentaro; Kawaguchi, Kei; Kiyuna, Tasuku; Miyake, Kentaro; Miyake, Masuyo; Singh, Arun S; Eckardt, Mark A; Nelson, Scott D; Russell, Tara A; Dry, Sarah M; Li, Yunfeng; Yamamoto, Norio; Hayashi, Katsuhiro; Kimura, Hiroaki; Miwa, Shinji; Tsuchiya, Hiroyuki; Singh, Shree Ram; Eilber, Fritz C; Hoffman, Robert M

    2018-03-18

    Undifferentiated soft tissue sarcoma (USTS) is a recalcitrant and heterogeneous subgroup of soft tissue sarcoma with high risk of metastasis and recurrence. Due to heterogeneity of USTS, there is no reliably effective first-line therapy. We have generated tumor-targeting Salmonella typhimurium A1-R (S. typhimurium A1-R), which previously showed strong efficacy on single patient-derived orthotopic xenograft (PDOX) models of Ewing's sarcoma and follicular dendritic cell sarcoma. In the present study, tumor resected from 4 patients with a biopsy-proven USTS (2 undifferentiated pleomorphic sarcoma [UPS], 1 undifferentiated sarcoma not otherwise specified [NOS] and 1 undifferentiated spindle cell sarcoma [USS]) were grown orthotopically in the biceps femoris muscle of mice to establish PDOX models. One USS model and one UPS model were doxorubicin (DOX) resistant. One UPS and the NOS model were partially sensitive to DOX. DOX is first-line therapy for these diseases. S. typhimurium A1-R arrested tumor growth all 4 models. In addition to arresting tumor growth in each case, S. typhimurium A1-R was significantly more efficacious than DOX in each case, thereby surpassing first-line therapy. These results suggest that S. typhimurium A1-R can be a general therapeutic for USTS and possibly sarcoma in general. Published by Elsevier Inc.

  16. Final Report: Model interacting particle systems for simulation and macroscopic description of particulate suspensions

    Energy Technology Data Exchange (ETDEWEB)

    Peter J. Mucha

    2007-08-30

    Suspensions of solid particles in liquids appear in numerous applications, from environmental settings like river silt, to industrial systems of solids transport and water treatment, and biological flows such as blood flow. Despite their importance, much remains unexplained about these complicated systems. Mucha's research aims to improve understanding of basic properties of suspensions through a program of simulating model interacting particle systems with critical evaluation of proposed continuum equations, in close collaboration with experimentalists. Natural to this approach, the original proposal centered around collaboration with studies already conducted in various experimental groups. However, as was detailed in the 2004 progress report, following the first year of this award, a number of the questions from the original proposal were necessarily redirected towards other specific goals because of changes in the research programs of the proposed experimental collaborators. Nevertheless, the modified project goals and the results that followed from those goals maintain close alignment with the main themes of the original proposal, improving efficient simulation and macroscopic modeling of sedimenting and colloidal suspensions. In particular, the main investigations covered under this award have included: (1) Sedimentation instabilities, including the sedimentation analogue of the Rayleigh-Taylor instability (for heavy, particle-laden fluid over lighter, clear fluid). (2) Ageing dynamics of colloidal suspensions at concentrations above the glass transition, using simplified interactions. (3) Stochastic reconstruction of velocity-field dependence for particle image velocimetry (PIV). (4) Stochastic modeling of the near-wall bias in 'nano-PIV'. (5) Distributed Lagrange multiplier simulation of the 'internal splash' of a particle falling through a stable stratified interface. (6) Fundamental study of velocity fluctuations in sedimentation

  17. Final Report - Modeling the Physics of Damage Cluster Formation in a Cellular Environment

    International Nuclear Information System (INIS)

    L.H. Toburen, Principal Investigator; J.L. Shinpaugh; M. Dingfelder; and G. Lapicki; Co-Investigators

    2007-01-01

    Modern tools of radiobiology are leading to many new discoveries regarding how cells and tissues respond to radiation exposure. We can now irradiate single cells and observe responses in adjacent cells. We can also measure clusters of radiation damage produced in DNA. Our primary objective has been to understand the underling physics associated with these new biological responses. The primary tools available to describe the initial spatial pattern of damage formed by the absorption of ionizing radiation are based on Monte Carlo simulation of the structure of charged particle tracks. Although many Monte Carlo codes exist and considerable progress is being made in the incorporation of detailed macromolecular target structures into these codes, much of the interaction physics is still based on gas phase measurements and/or untested theoretical calculations that focus on water as the transport medium. Our objectives were threefold, (1) to expand the applicability of Monte Carlo track structure simulation to tissue-like material beyond the current focus on water, (2) to incorporate the most recent experimental information on electron interactions in biologically relevant material, and (3) to compare recent measurements of electron emissions induced by charged particles in thin foils with Monte Carlo predictions. We addressed these research objectives in three ways. First we applied theoretical techniques, similar to those used to derive data for water, to obtain cross sections for other condensed phase materials. This served two purposes. One was to provide testability of the theoretical technique by comparison to existing experimental data for electron transport (similar data does not exist for water), and the other was to expand the target database for use in modeling tissue. Second, we carefully reviewed published data, and ongoing experiments, for electron interaction cross-sections in biologically relevant condensed phase material. Results for low-energy electron

  18. EERE-VTO T2M Project Final Report - Ideation of a Novel Commercialization Model

    Energy Technology Data Exchange (ETDEWEB)

    Chamberlain, Jeffrey P. [Argonne National Lab. (ANL), Argonne, IL (United States)

    2016-05-03

    The Department of Energy Technology Transfer mission is to expand the commercial impact of DOE's portfolio of R&D activities, providing ongoing economic, security, and environmental benefits for all Americans. To advance this mission, Argonne National Laboratory has executed this Technology-to-Market (T2M) project funded by EERE-VTO. The objective of the project was to ideate an overall business model for a private entity with a mission to develop and deploy technology by identifying, de-risking, and moving scientific advances into commercial use.

  19. Comparative therapeutic activities of Ciprofloxacin, Amoxicillin, Ceftriaxone and Cotrimoxazole in a new model of experimental infection with Escherichia coli

    OpenAIRE

    Hof, H.; Christen, A.; Hacker, Jörg

    2009-01-01

    A new mouse model for systemic infection with Escherichia coli is presented. Whereas in other models 107_108 bacteria have to be injected into an animal to induce toxic effects resulting in death within 24 hours, now, only 103_104 bacteria of an appropriate strain are required to produce a genuine infection characterized by an increase in the bacterial load over several days. The quantitative determination of bacterial counts per liver allows a more sensitive measurement than recording death ...

  20. Computer Hardware, Advanced Mathematics and Model Physics pilot project final report

    International Nuclear Information System (INIS)

    1992-05-01

    The Computer Hardware, Advanced Mathematics and Model Physics (CHAMMP) Program was launched in January, 1990. A principal objective of the program has been to utilize the emerging capabilities of massively parallel scientific computers in the challenge of regional scale predictions of decade-to-century climate change. CHAMMP has already demonstrated the feasibility of achieving a 10,000 fold increase in computational throughput for climate modeling in this decade. What we have also recognized, however, is the need for new algorithms and computer software to capitalize on the radically new computing architectures. This report describes the pilot CHAMMP projects at the DOE National Laboratories and the National Center for Atmospheric Research (NCAR). The pilot projects were selected to identify the principal challenges to CHAMMP and to entrain new scientific computing expertise. The success of some of these projects has aided in the definition of the CHAMMP scientific plan. Many of the papers in this report have been or will be submitted for publication in the open literature. Readers are urged to consult with the authors directly for questions or comments about their papers

  1. Conceptual model for regional radionuclide transport from a basalt repository site. Final draft, technical memorandum

    Energy Technology Data Exchange (ETDEWEB)

    Walton, W.C.; Voorhees, M.L.; Prickett, T.A.

    1980-05-23

    This technical memorandum was prepared to: (1) describe a typical basalt radionuclide repository site, (2) describe geologic and hydrologic processes associated with regional radionuclide transport in basalts, (3) define the parameters required to model regional radionuclide transport from a basalt repository site, and (4) develop a ''conceptual model'' of radionuclide transport from a basalt repository site. In a general hydrological sense, basalts may be described as layered sequences of aquifers and aquitards. The Columbia River Basalt, centered near the semi-arid Pasco Basin, is considered by many to be typical basalt repository host rock. Detailed description of the flow system including flow velocities with high-low hydraulic conductivity sequences are not possible with existing data. However, according to theory, waste-transport routes are ultimately towards the Columbia River and the lengths of flow paths from the repository to the biosphere may be relatively short. There are many physical, chemical, thermal, and nuclear processes with associated parameters that together determine the possible pattern of radionuclide migration in basalts and surrounding formations. Brief process descriptions and associated parameter lists are provided. Emphasis has been placed on the use of the distribution coefficient in simulating ion exchange. The use of the distribution coefficient approach is limited because it takes into account only relatively fast mass transfer processes. In general, knowledge of hydrogeochemical processes is primitive.

  2. Fresh Kills leachate treatment and minimization study: Volume 2, Modeling, monitoring and evaluation. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Fillos, J.; Khanbilvardi, R.

    1993-09-01

    The New York City Department of Sanitation is developing a comprehensive landfill leachate management plan for the Fresh Kills landfill, located on the western shore of Staten Island, New York. The 3000-acre facility, owned and operated by the City of New York, has been developed into four distinct mounds that correspond to areas designated as Sections 1/9, 2/8, 3/4 and 6/7. In developing a comprehensive leachate management plan, the estimating leachate flow rates is important in designing appropriate treatment alternatives to reduce the offsite migration that pollutes both surface water and groundwater resources.Estimating the leachate flow rates from Sections 1/9 and 6/7 was given priority using an available model, hydrologic evaluation of landfill performance (HELP), and a new model, flow investigation for landfill leachate (FILL). The field-scale analysis for leachate flow included data collection of the leachate mound-level from piezometers and monitoring wells installed on-site, for six months period. From the leachate mound-head contours and flow-gradients, Leachate flow rates were computed using Darcy`s Law.

  3. Conceptual model for regional radionuclide transport from a basalt repository site. Final draft, technical memorandum

    International Nuclear Information System (INIS)

    Walton, W.C.; Voorhees, M.L.; Prickett, T.A.

    1980-01-01

    This technical memorandum was prepared to: (1) describe a typical basalt radionuclide repository site, (2) describe geologic and hydrologic processes associated with regional radionuclide transport in basalts, (3) define the parameters required to model regional radionuclide transport from a basalt repository site, and (4) develop a ''conceptual model'' of radionuclide transport from a basalt repository site. In a general hydrological sense, basalts may be described as layered sequences of aquifers and aquitards. The Columbia River Basalt, centered near the semi-arid Pasco Basin, is considered by many to be typical basalt repository host rock. Detailed description of the flow system including flow velocities with high-low hydraulic conductivity sequences are not possible with existing data. However, according to theory, waste-transport routes are ultimately towards the Columbia River and the lengths of flow paths from the repository to the biosphere may be relatively short. There are many physical, chemical, thermal, and nuclear processes with associated parameters that together determine the possible pattern of radionuclide migration in basalts and surrounding formations. Brief process descriptions and associated parameter lists are provided. Emphasis has been placed on the use of the distribution coefficient in simulating ion exchange. The use of the distribution coefficient approach is limited because it takes into account only relatively fast mass transfer processes. In general, knowledge of hydrogeochemical processes is primitive

  4. Atrial Model Development and Prototype Simulations: CRADA Final Report on Tasks 3 and 4

    Energy Technology Data Exchange (ETDEWEB)

    O' Hara, T. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Zhang, X. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Villongco, C. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Lightstone, F. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Richards, D. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

    2016-10-28

    The goal of this CRADA was to develop essential tools needed to simulate human atrial electrophysiology in 3-dimensions using an anatomical image-based anatomy and physiologically detailed human cellular model. The atria were modeled as anisotropic, representing the preferentially longitudinal electrical coupling between myocytes. Across the entire anatomy, cellular electrophysiology was heterogeneous, with left and right atrial myocytes defined differently. Left and right cell types for the “control” case of sinus rhythm (SR) was compared with remodeled electrophysiology and calcium cycling characteristics of chronic atrial fibrillation (cAF). The effects of Isoproterenol (ISO), a beta-adrenergic agonist that represents the functional consequences of PKA phosphorylation of various ion channels and transporters, was also simulated in SR and cAF to represent atrial activity under physical or emotional stress. Results and findings from Tasks 3 & 4 are described. Tasks 3 and 4 are, respectively: Input parameters prepared for a Cardioid simulation; Report including recommendations for additional scenario development and post-processing analytic strategy.

  5. Regional demand forecasting and simulation model: user's manual. Task 4, final report

    Energy Technology Data Exchange (ETDEWEB)

    Parhizgari, A M

    1978-09-25

    The Department of Energy's Regional Demand Forecasting Model (RDFOR) is an econometric and simulation system designed to estimate annual fuel-sector-region specific consumption of energy for the US. Its purposes are to (1) provide the demand side of the Project Independence Evaluation System (PIES), (2) enhance our empirical insights into the structure of US energy demand, and (3) assist policymakers in their decisions on and formulations of various energy policies and/or scenarios. This report provides a self-contained user's manual for interpreting, utilizing, and implementing RDFOR simulation software packages. Chapters I and II present the theoretical structure and the simulation of RDFOR, respectively. Chapter III describes several potential scenarios which are (or have been) utilized in the RDFOR simulations. Chapter IV presents an overview of the complete software package utilized in simulation. Chapter V provides the detailed explanation and documentation of this package. The last chapter describes step-by-step implementation of the simulation package using the two scenarios detailed in Chapter III. The RDFOR model contains 14 fuels: gasoline, electricity, natural gas, distillate and residual fuels, liquid gases, jet fuel, coal, oil, petroleum products, asphalt, petroleum coke, metallurgical coal, and total fuels, spread over residential, commercial, industrial, and transportation sectors.

  6. Computer modelling of the UK wind energy resource: final overview report

    Energy Technology Data Exchange (ETDEWEB)

    Burch, S F; Ravenscroft, F

    1993-12-31

    This report describes the results of a programme of work to estimate the UK wind energy resource. Mean wind speed maps and quantitative resource estimates were obtained using the NOABL mesoscale (1 km resolution) numerical model for the prediction of wind flow over complex terrain. NOABL was used in conjunction with digitised terrain data and wind data from surface meteorological stations for a ten year period (1975-1984) to provide digital UK maps of mean wind speed at 10m, 25m and 45m above ground level. Also included in the derivation of these maps was the use of the Engineering Science Data Unit (ESDU) method to model the effect on wind speed of the abrupt change in surface roughness that occurs at the coast. Existing isovent maps, based on standard meteorological data which take no account of terrain effects, indicate that 10m annual mean wind speeds vary between about 4.5 and 7 m/s over the UK with only a few coastal areas over 6 m/s. The present study indicated that 23% of the UK land area had speeds over 6 m/s, with many hill sites having 10m speeds over 10 m/s. It is concluded that these `first order` resource estimates represent a substantial improvement over the presently available `zero order` estimates. (20 figures, 7 tables, 10 references). (author)

  7. A tetrameric peptide derived from bovine lactoferricin as a potential therapeutic tool for oral squamous cell carcinoma: A preclinical model.

    Science.gov (United States)

    Solarte, Víctor Alfonso; Conget, Paulette; Vernot, Jean-Paul; Rosas, Jaiver Eduardo; Rivera, Zuly Jenny; García, Javier Eduardo; Arango-Rodríguez, Martha Ligia

    2017-01-01

    Oral squamous cell carcinoma is the fifth most common epithelial cancer in the world, and its current clinical treatment has both low efficiency and poor selectivity. Cationic amphipathic peptides have been proposed as new drugs for the treatment of different types of cancer. The main goal of the present work was to determine the potential of LfcinB(20-25)4, a tetrameric peptide based on the core sequence RRWQWR of bovine lactoferricin LfcinB(20-25), for the treatment of OSCC. In brief, OSCC was induced in the buccal pouch of hamsters by applying 7,12-Dimethylbenz(a)anthracene, and tumors were treated with one of the following peptides: LfcinB(20-25)4, LfcinB(20-25), or vehicle (control). Lesions were macroscopically evaluated every two days and both histological and serum IgG assessments were conducted after 5 weeks. The size of the tumors treated with LfcinB(20-25)4 and LfcinB(20-25) was smaller than that of the control group (46.16±4.41 and 33.92±2.74 mm3 versus 88.77±10.61 mm3, respectively). Also, LfcinB(20-25)4 caused acellularity in the parenchymal tumor compared with LfcinB(20-25) and vehicle treatments. Furthermore, our results demonstrated that both LfcinB(20-25)4 and LfcinB(20-25) induced higher degree of apoptosis relative to the untreated tumors (75-86% vs 8%, respectively). Moreover, although the lowest inflammatory response was achieved when LfcinB(20-25)4 was used, this peptide appeared to induce higher levels of IgG antibodies relative to the vehicle and LfcinB(20-25). In addition the cellular damage and selectivity of the LfcinB(20-25)4 peptide was evaluated in vitro. These assays showed that LfcinB(20-25)4 triggers a selective necrotic effect in the carcinoma cell line. Cumulatively, these data indicate that LfcinB(20-25)4 could be considered as a new therapeutic agent for the treatment of OSCC.

  8. A tetrameric peptide derived from bovine lactoferricin as a potential therapeutic tool for oral squamous cell carcinoma: A preclinical model.

    Directory of Open Access Journals (Sweden)

    Víctor Alfonso Solarte

    Full Text Available Oral squamous cell carcinoma is the fifth most common epithelial cancer in the world, and its current clinical treatment has both low efficiency and poor selectivity. Cationic amphipathic peptides have been proposed as new drugs for the treatment of different types of cancer. The main goal of the present work was to determine the potential of LfcinB(20-254, a tetrameric peptide based on the core sequence RRWQWR of bovine lactoferricin LfcinB(20-25, for the treatment of OSCC. In brief, OSCC was induced in the buccal pouch of hamsters by applying 7,12-Dimethylbenz(aanthracene, and tumors were treated with one of the following peptides: LfcinB(20-254, LfcinB(20-25, or vehicle (control. Lesions were macroscopically evaluated every two days and both histological and serum IgG assessments were conducted after 5 weeks. The size of the tumors treated with LfcinB(20-254 and LfcinB(20-25 was smaller than that of the control group (46.16±4.41 and 33.92±2.74 mm3 versus 88.77±10.61 mm3, respectively. Also, LfcinB(20-254 caused acellularity in the parenchymal tumor compared with LfcinB(20-25 and vehicle treatments. Furthermore, our results demonstrated that both LfcinB(20-254 and LfcinB(20-25 induced higher degree of apoptosis relative to the untreated tumors (75-86% vs 8%, respectively. Moreover, although the lowest inflammatory response was achieved when LfcinB(20-254 was used, this peptide appeared to induce higher levels of IgG antibodies relative to the vehicle and LfcinB(20-25. In addition the cellular damage and selectivity of the LfcinB(20-254 peptide was evaluated in vitro. These assays showed that LfcinB(20-254 triggers a selective necrotic effect in the carcinoma cell line. Cumulatively, these data indicate that LfcinB(20-254 could be considered as a new therapeutic agent for the treatment of OSCC.

  9. Therapeutic efficacy of human hepatocyte transplantation in a SCID/uPA mouse model with inducible liver disease.

    Directory of Open Access Journals (Sweden)

    Donna N Douglas

    2010-02-01

    Full Text Available Severe Combined Immune Deficient (SCID/Urokinase-type Plasminogen Activator (uPA mice undergo liver failure and are useful hosts for the propagation of transplanted human hepatocytes (HH which must compete with recipient-derived hepatocytes for replacement of the diseased liver parenchyma. While partial replacement by HH has proven useful for studies with Hepatitis C virus, complete replacement of SCID/uPA mouse liver by HH has never been achieved and limits the broader application of these mice for other areas of biomedical research. The herpes simplex virus type-1 thymidine kinase (HSVtk/ganciclovir (GCV system is a powerful tool for cell-specific ablation in transgenic animals. The aim of this study was to selectively eliminate murine-derived parenchymal liver cells from humanized SCID/uPA mouse liver in order to achieve mice with completely humanized liver parenchyma. Thus, we reproduced the HSVtk (vTK/GCV system of hepatic failure in SCID/uPA mice.In vitro experiments demonstrated efficient killing of vTK expressing hepatoma cells after GCV treatment. For in vivo experiments, expression of vTK was targeted to the livers of FVB/N and SCID/uPA mice. Hepatic sensitivity to GCV was first established in FVB/N mice since these mice do not undergo liver failure inherent to SCID/uPA mice. Hepatic vTK expression was found to be an integral component of GCV-induced pathologic and biochemical alterations and caused death due to liver dysfunction in vTK transgenic FVB/N and non-transplanted SCID/uPA mice. In SCID/uPA mice with humanized liver, vTK/GCV caused death despite extensive replacement of the mouse liver parenchyma with HH (ranging from 32-87%. Surprisingly, vTK/GCV-dependent apoptosis and mitochondrial aberrations were also localized to bystander vTK-negative HH.Extensive replacement of mouse liver parenchyma by HH does not provide a secure therapeutic advantage against vTK/GCV-induced cytotoxicity targeted to residual mouse hepatocytes

  10. Preparation of 125IUdR and its evaluation in animal tumour model as a potential therapeutic agent

    International Nuclear Information System (INIS)

    Korde, A.; Venkatesh, M.; Banerjee, S.; Pillai, M.R.A.; Sarma, H.D.

    1998-01-01

    5-Iodo-2'-deoxyuridine or iodoxyuridine (IUdR), an analogue of thymidine, is taken up by the proliferating cells during DNA synthesis. Radioiodinated IUdR is a potential therapeutic agent since radiohalogenated thymidine analogues are used for in-vivo tumour targeting and Auger electrons from radionuclides such as 123 I and 125 I are very effective in cell destruction when internalised. 125 IUdR was prepared and studied for its suitability as an in-vivo tumour therapy agent. 125 IUdR was prepared both by direct iodination of 2'-deoxyuridine and iododemercuration of 5-chloromercury-2'-deoxyuridine. Radioiodination yields were between 60-80% at pH 7. Iododemercuration was preferred since with direct iodination poor yields were observed when high specific activity product was desired and also the purification procedure was lengthier. The identity of 125 IUdR was established by comparison of TLC and HPLC patterns with those of authentic IUdR. The purified 125 IUdR had radiochemical purity >95% and was stable for 20 days at 4 deg. C and for a week at 23 deg. C and 37 deg. C. Bio-uptake of 125 IUdR was studied by injecting the tracer in tumour bearing mice (Sarcoma S-180). The uptake in tumour cells was 4.28 +- 2.7% per gram at 3 h and 1.48 +- 0.19% at 24 h post injection. In-vivo deiodination of the product was observed as seen by the uptake of the activity in the thyroid. About 40% the activity from all other organs was excreted in 70 h. The optimum time for injection of the tracer for therapy was studied by observing the delay in tumour growth and survival rate in mice injected at 0,3,9 and 12 days after tumour induction. Injection of the tracer on the third day was found to be the most beneficial for retardation of tumour growth, while injection of the activity on the zeroth and ninth day had no effect. (author)

  11. Final Report: Phase II Nevada Water Resources Data, Modeling, and Visualization (DMV) Center

    Energy Technology Data Exchange (ETDEWEB)

    Jackman, Thomas [Desert Research Institute; Minor, Timothy [Desert Research Institute; Pohll, Gregory [Desert Research Institute

    2013-07-22

    Water is unquestionably a critical resource throughout the United States. In the semi-arid west -- an area stressed by increase in human population and sprawl of the built environment -- water is the most important limiting resource. Crucially, science must understand factors that affect availability and distribution of water. To sustain growing consumptive demand, science needs to translate understanding into reliable and robust predictions of availability under weather conditions that could be average but might be extreme. These predictions are needed to support current and long-term planning. Similar to the role of weather forecast and climate prediction, water prediction over short and long temporal scales can contribute to resource strategy, governmental policy and municipal infrastructure decisions, which are arguably tied to the natural variability and unnatural change to climate. Change in seasonal and annual temperature, precipitation, snowmelt, and runoff affect the distribution of water over large temporal and spatial scales, which impact the risk of flooding and the groundwater recharge. Anthropogenic influences and impacts increase the complexity and urgency of the challenge. The goal of this project has been to develop a decision support framework of data acquisition, digital modeling, and 3D visualization. This integrated framework consists of tools for compiling, discovering and projecting our understanding of processes that control the availability and distribution of water. The framework is intended to support the analysis of the complex interactions between processes that affect water supply, from controlled availability to either scarcity or deluge. The developed framework enables DRI to promote excellence in water resource management, particularly within the Lake Tahoe basin. In principle, this framework could be replicated for other watersheds throughout the United States. Phase II of this project builds upon the research conducted during

  12. Evaluation of 188Re-labeled PEGylated nanoliposome as a radionuclide therapeutic agent in an orthotopic glioma-bearing rat model

    Directory of Open Access Journals (Sweden)

    Huang FYJ

    2015-01-01

    Full Text Available Feng-Yun J Huang,1 Te-Wei Lee,2 Chih-Hsien Chang,2 Liang-Cheng Chen,2 Wei-Hsin Hsu,2 Chien-Wen Chang,1 Jem-Mau Lo1 1Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan; 2Institute of Nuclear Energy Research, Longtan, Taiwan Purpose: In this study, the 188Re-labeled PEGylated nanoliposome (188Re-liposome was prepared and evaluated as a therapeutic agent for glioma.Materials and methods: The reporter cell line, F98luc was prepared via Lentivector expression kit system and used to set up the orthotopic glioma-bearing rat model for non-invasive bioluminescent imaging. The maximum tolerated dose applicable in Fischer344 rats was explored via body weight monitoring of the rats after single intravenous injection of 188Re-liposome with varying dosages before the treatment study. The OLINDA/EXM 1.1 software was utilized for estimating the radiation dosimetry. To assess the therapeutic efficacy, tumor-bearing rats were intravenously administered 188Re-liposome or normal saline followed by monitoring of the tumor growth and animal survival time. In addition, the histopathological examinations of tumors were conducted on the 188Re-liposome-treated rats.Results: By using bioluminescent imaging, the well-established reporter cell line (F98luc showed a high relationship between cell number and its bioluminescent intensity (R2=0.99 in vitro; furthermore, it could also provide clear tumor imaging for monitoring tumor growth in vivo. The maximum tolerated dose of 188Re-liposome in Fischer344 rats was estimated to be 333 MBq. According to the dosimetry results, higher equivalent doses were observed in spleen and kidneys while very less were in normal brain, red marrow, and thyroid. For therapeutic efficacy study, the progression of tumor growth in terms of tumor volume and/or tumor weight was significantly slower for the 188Re-liposome-treated group than the control group (P<0.05. As a result, the

  13. Evaluation in zebrafish model of the toxicity of rhodamine B-conjugated crotamine, a peptide potentially useful for diagnostics and therapeutics.

    Science.gov (United States)

    Chan, Judy Yuet-Wa; Zhou, Hefeng; Kwan, Yiu Wa; Chan, Shun Wan; Radis-Baptista, Gandhi; Lee, Simon Ming-Yuen

    2017-11-01

    Crotamine is defensin-like cationic peptide from rattlesnake venom that possesses anticancer, antimicrobial, and antifungal properties. Despite these promising biological activities, toxicity is a major concern associated with the development of venom-derived peptides as therapeutic agents. In the present study, we used zebrafish as a system model to evaluate the toxicity of rhodamine B-conjugated (RhoB) crotamine derivative. The lethal toxic concentration of RhoB-crotamine was as low as 4 μM, which effectively kill zebrafish larvae in less than 10 min. With non-lethal concentrations (<1 μM), crotamine caused malformation in zebrafish embryos, delayed or completely halted hatching, adversely affected embryonic developmental programming, decreased the cardiac functions, and attenuated the swimming distance of zebrafish. The RhoB-crotamine translocated across vitelline membrane and accumulated in zebrafish yolk sac. These results demonstrate the sensitive responsivity of zebrafish to trial crotamine analogues for the development of novel therapeutic peptides with improved safety, bioavailability, and efficacy profiles. © 2017 Wiley Periodicals, Inc.

  14. Protocol for an HTA report: Does therapeutic writing help people with long-term conditions? Systematic review, realist synthesis and economic modelling.

    Science.gov (United States)

    Meads, C; Nyssen, O P; Wong, G; Steed, L; Bourke, L; Ross, C A; Hayman, S; Field, V; Lord, J; Greenhalgh, T; Taylor, S J C

    2014-02-18

    Long-term medical conditions (LTCs) cause reduced health-related quality of life and considerable health service expenditure. Writing therapy has potential to improve physical and mental health in people with LTCs, but its effectiveness is not established. This project aims to establish the clinical and cost-effectiveness of therapeutic writing in LTCs by systematic review and economic evaluation, and to evaluate context and mechanisms by which it might work, through realist synthesis. Included are any comparative study of therapeutic writing compared with no writing, waiting list, attention control or placebo writing in patients with any diagnosed LTCs that report at least one of the following: relevant clinical outcomes; quality of life; health service use; psychological, behavioural or social functioning; adherence or adverse events. Searches will be conducted in the main medical databases including MEDLINE, EMBASE, PsycINFO, The Cochrane Library and Science Citation Index. For the realist review, further purposive and iterative searches through snowballing techniques will be undertaken. Inclusions, data extraction and quality assessment will be in duplicate with disagreements resolved through discussion. Quality assessment will include using Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria. Data synthesis will be narrative and tabular with meta-analysis where appropriate. De novo economic modelling will be attempted in one clinical area if sufficient evidence is available and performed according to the National Institute for Health and Care Excellence (NICE) reference case.

  15. Co-culturing of Fungal Strains Against Botrytis cinerea as a Model for the Induction of Chemical Diversity and Therapeutic Agents

    Directory of Open Access Journals (Sweden)

    Olga Genilloud

    2017-04-01

    Full Text Available New fungal SMs (SMs have been successfully described to be produced by means of in vitro-simulated microbial community interactions. Co-culturing of fungi has proved to be an efficient way to induce cell–cell interactions that can promote the activation of cryptic pathways, frequently silent when the strains are grown in laboratory conditions. Filamentous fungi represent one of the most diverse microbial groups known to produce bioactive natural products. Triggering the production of novel antifungal compounds in fungi could respond to the current needs to fight health compromising pathogens and provide new therapeutic solutions. In this study, we have selected the fungus Botrytis cinerea as a model to establish microbial interactions with a large set of fungal strains related to ecosystems where they can coexist with this phytopathogen, and to generate a collection of extracts, obtained from their antagonic microbial interactions and potentially containing new bioactive compounds. The antifungal specificity of the extracts containing compounds induced after B. cinerea interaction was determined against two human fungal pathogens (Candida albicans and Aspergillus fumigatus and three phytopathogens (Colletotrichum acutatum, Fusarium proliferatum, and Magnaporthe grisea. In addition, their cytotoxicity was also evaluated against the human hepatocellular carcinoma cell line (HepG2. We have identified by LC-MS the production of a wide variety of known compounds induced from these fungal interactions, as well as novel molecules that support the potential of this approach to generate new chemical diversity and possible new therapeutic agents.

  16. Protocol for an HTA report: Does therapeutic writing help people with long-term conditions? Systematic review, realist synthesis and economic modelling

    Science.gov (United States)

    Meads, C; Nyssen, O P; Wong, G; Steed, L; Bourke, L; Ross, C A; Hayman, S; Field, V; Lord, J; Greenhalgh, T; Taylor, S J C

    2014-01-01

    Introduction Long-term medical conditions (LTCs) cause reduced health-related quality of life and considerable health service expenditure. Writing therapy has potential to improve physical and mental health in people with LTCs, but its effectiveness is not established. This project aims to establish the clinical and cost-effectiveness of therapeutic writing in LTCs by systematic review and economic evaluation, and to evaluate context and mechanisms by which it might work, through realist synthesis. Methods Included are any comparative study of therapeutic writing compared with no writing, waiting list, attention control or placebo writing in patients with any diagnosed LTCs that report at least one of the following: relevant clinical outcomes; quality of life; health service use; psychological, behavioural or social functioning; adherence or adverse events. Searches will be conducted in the main medical databases including MEDLINE, EMBASE, PsycINFO, The Cochrane Library and Science Citation Index. For the realist review, further purposive and iterative searches through snowballing techniques will be undertaken. Inclusions, data extraction and quality assessment will be in duplicate with disagreements resolved through discussion. Quality assessment will include using Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria. Data synthesis will be narrative and tabular with meta-analysis where appropriate. De novo economic modelling will be attempted in one clinical area if sufficient evidence is available and performed according to the National Institute for Health and Care Excellence (NICE) reference case. PMID:24549165

  17. Final Report: Simulation Tools for Parallel Microwave Particle in Cell Modeling

    International Nuclear Information System (INIS)

    Stoltz, Peter H.

    2008-01-01

    Transport of high-power rf fields and the subsequent deposition of rf power into plasma is an important component of developing tokamak fusion energy. Two limitations on rf heating are: (i) breakdown of the metallic structures used to deliver rf power to the plasma, and (ii) a detailed understanding of how rf power couples into a plasma. Computer simulation is a main tool for helping solve both of these problems, but one of the premier tools, VORPAL, is traditionally too difficult to use for non-experts. During this Phase II project, we developed the VorpalView user interface tool. This tool allows Department of Energy researchers a fully graphical interface for analyzing VORPAL output to more easily model rf power delivery and deposition in plasmas.

  18. Physics modeling support for the International Thermonuclear Experimental Reactor: Final report

    International Nuclear Information System (INIS)

    1988-01-01

    There are two major sections to this report. The first section of the report is an executive summary of the work done this year. For each task, the major results are condensed for the reader's convenience. The major result of each memo, report or presentation is summarized briefly in this section. The second section of the report is a collection of appendices containing reports, memos, and presentations written this year. Here, the interested reader can investigate any topic discussed in the summary in more detail. The documentation is presented in chronological order, and we would like to note that the content of later documents may supercede that of earlier ones. The summaries are divided into sections, corresponding to the tasks outlined in the original proposal for the work. These sections are: MUMAK code development and application; Alfven wave stability problem; TETRA systems code development and application; lower hybrid heating and current drive; and advanced blanket modeling

  19. Mathematical model of a utility firm. Final technical report, Part I

    Energy Technology Data Exchange (ETDEWEB)

    1983-08-21

    Utility companies are in the predicament of having to make forecasts, and draw up plans for the future, in an increasingly fluid and volatile socio-economic environment. The project being reported is to contribute to an understanding of the economic and behavioral processes that take place within a firm, and without it. Three main topics are treated. One is the representation of the characteristics of the members of an organization, to the extent to which characteristics seem pertinent to the processes of interest. The second is the appropriate management of the processes of change by an organization. The third deals with the competitive striving towards an economic equilibrium among the members of a society in the large, on the theory that this process might be modeled in a way which is similar to the one for the intra-organizational ones. This volume covers mainly the first topic.

  20. Physics modeling support for the International Thermonuclear Experimental Reactor: Final report

    Energy Technology Data Exchange (ETDEWEB)

    1988-09-30

    There are two major sections to this report. The first section of the report is an executive summary of the work done this year. For each task, the major results are condensed for the reader's convenience. The major result of each memo, report or presentation is summarized briefly in this section. The second section of the report is a collection of appendices containing reports, memos, and presentations written this year. Here, the interested reader can investigate any topic discussed in the summary in more detail. The documentation is presented in chronological order, and we would like to note that the content of later documents may supercede that of earlier ones. The summaries are divided into sections, corresponding to the tasks outlined in the original proposal for the work. These sections are: MUMAK code development and application; Alfven wave stability problem; TETRA systems code development and application; lower hybrid heating and current drive; and advanced blanket modeling.

  1. Solar radio continuum storms and a breathing magnetic field model. Final report

    International Nuclear Information System (INIS)

    1975-01-01

    Radio noise continuum emissions observed in metric and decametric wave frequencies are, in general, associated with actively varying sunspot groups accompanied by the S-component of microwave radio emissions. These continuum emission sources, often called type I storm sources, are often associated with type III burst storm activity from metric to hectometric wave frequencies. This storm activity is, therefore, closely connected with the development of these continuum emission sources. It is shown that the S-component emission in microwave frequencies generally precedes, by several days, the emission of these noise continuum storms of lower frequencies. In order for these storms to develop, the growth of sunspot groups into complex types is very important in addition to the increase of the average magnetic field intensity and area of these groups. After giving a review on the theory of these noise continuum storm emissions, a model is briefly considered to explain the relation of the emissions to the storms

  2. Final Report for Subcontract B541028,Pore-Scale Modeling to Support 'Pore Connectivity' Research Work

    International Nuclear Information System (INIS)

    Ewing, R.P.

    2008-01-01

    A central concept for the geological barrier at the proposed Yucca Mountain radioactive waste repository is diffusive retardation: solute moving through a fracture diffuses into and out of the rock matrix. This diffusive exchange retards overall solute movement, and retardation both dilutes waste being released, and allows additional decay. The original concept of diffusive retardation required knowledge only of the fracture conductivity and the matrix diffusion. But that simple concept is unavoidably complicated by other issues and processes: contaminants may sorb to the rock matrix, fracture flow may be episodic, a given fracture may or may not flow depending on the volume of flow and the fracture's connection to the overall fracture network, the matrix imbibes water during flow episodes and dries between episodes, and so on. Some of these issues have been examined by other projects. This particular project is motivated by a simple fact: Yucca Mountain tuff has low pore connectivity. This fact is not widely recognized, nor are its implications widely appreciated. Because low pore connectivity affects many processes, it may invalidate many assumptions that are basic (though perhaps not stated) to other investigations. The overall project's objective statement (from the proposal) was: This proposal aims to improve our understanding of diffusive retardation of radionuclides due to fracture/matrix interactions. Results from this combined experimental/modeling work will (1) determine whether the current understanding and model representation of matrix diffusion is valid, (2) provide insights into the upscaling of laboratory-scale diffusion experiments, and (3) evaluate the impact on diffusive retardation of episodic fracture flow and pore connectivity in Yucca Mountain tuffs. An obvious data gap addressed by the project was that there were only a few limited measurements of the diffusion coefficient of the rock at the repository level. That is, at the time we wrote

  3. Using Bayesian Belief Network (BBN) modelling for rapid source term prediction. Final report

    International Nuclear Information System (INIS)

    Knochenhauer, M.; Swaling, V.H.; Dedda, F.D.; Hansson, F.; Sjoekvist, S.; Sunnegaerd, K.

    2013-10-01

    The project presented in this report deals with a number of complex issues related to the development of a tool for rapid source term prediction (RASTEP), based on a plant model represented as a Bayesian belief network (BBN) and a source term module which is used for assigning relevant source terms to BBN end states. Thus, RASTEP uses a BBN to model severe accident progression in a nuclear power plant in combination with pre-calculated source terms (i.e., amount, composition, timing, and release path of released radio-nuclides). The output is a set of possible source terms with associated probabilities. One major issue has been associated with the integration of probabilistic and deterministic analyses are addressed, dealing with the challenge of making the source term determination flexible enough to give reliable and valid output throughout the accident scenario. The potential for connecting RASTEP to a fast running source term prediction code has been explored, as well as alternative ways of improving the deterministic connections of the tool. As part of the investigation, a comparison of two deterministic severe accident analysis codes has been performed. A second important task has been to develop a general method where experts' beliefs can be included in a systematic way when defining the conditional probability tables (CPTs) in the BBN. The proposed method includes expert judgement in a systematic way when defining the CPTs of a BBN. Using this iterative method results in a reliable BBN even though expert judgements, with their associated uncertainties, have been used. It also simplifies verification and validation of the considerable amounts of quantitative data included in a BBN. (Author)

  4. Biofuel and Bioenergy implementation scenarios. Final report of VIEWLS WP5, modelling studies

    International Nuclear Information System (INIS)

    Wakker, A.; Egging, R.; Van Thuijl, E.; Van Tilburg, X.; Deurwaarder, E.P.; De Lange, T.J.; Berndes, G.; Hansson, J.

    2005-11-01

    This report is published within the framework of the European Commission-supported project 'Clear Views on Clean Fuels' or VIEWLS. The overall objectives of this project are to provide structured and clear data on the availability and performance of biofuel and to identify the possibilities and strategies towards large-scale sustainable production, use and trading of biofuels for the transport sector in Europe, including Central and Eastern European Countries (CEEC). This reports constitutes the outcome of the Work Package 5 (WP5) of the VIEWLS project. In WP5 the EU biofuels and bioenergy markets are modelled with the aim to conduct quantitative analyses on the production and costs of biofuels and on the resulting market structure and supply chains. In a bigger context, where possible, WP5 aims also to provide insight into larger socio-economic impacts of bioenergy trade within Europe. The objective of this research is to develop a cost efficient biofuel strategy for Europe in terms of biofuel production, cost and trade, and to assess its larger impact on bioenergy markets and trade up to 2030. Based on the biomass availability and associated costs within EU25, under different conditions, scenarios for biofuels production and cost can be constructed using quantitative modelling tools. Combining this with (cost) data on biofuel conversion technologies and transport of biomass and biofuels, the lowest cost biofuel supply chain given a certain demand predetermined by the biofuels Directive can be designed. In a broader context, this is supplemented by a design of a sustainable bioenergy supply chain in view of the fact that biomass-heat, biomass-electricity and biofuels are competing for the same biomass resources. In other words, the scarcity of bioenergy crops, as manifested through overall bioenergy demand, is an essential variable in bioenergy scenarios

  5. Final report of MoReMO 2011-2012. Modelling resilience for maintenance and outage

    International Nuclear Information System (INIS)

    Gotcheva, N.; Macchi, L.; Oedewald, P.; Eitrheim, M.H.R.; Axelsson, C.; Reiman, T.; Pietikaeinen, E.

    2013-04-01

    The project Modelling Resilience for Maintenance and Outage (MoReMO) represents a two-year joint effort by VTT Technical Research Centre of Finland, Institute for Energy Technology (IFE, Norway) and Vattenfall (Sweden) to develop and test new approaches for safety management. The overall goal of the project was to present concepts on how resilience can be operationalized and built in a safety critical and socio-technical context. Furthermore, the project also aimed at providing guidance for other organizations that strive to develop and improve their safety performance in a business driven industry. We have applied four approaches in different case studies: Organisational Core Task modelling (OCT), Functional Resonance Analysis Method (FRAM), Efficiency Thoroughness Trade-Off (ETTO) analysis, and Work Practice and Culture Characterisation. During 2011 and 2012 the MoReMO project team has collected data through field observations, interviews, workshops, and document analysis on the work practices and adjustments in maintenance and outage in Nordic NPPs. The project consisted of two sub-studies, one focused on identifying and assessing adjustments and supporting resilient work practices in maintenance activities, while the other focused on handling performance trade-offs in maintenance and outage, as follows: A. Adjustments in maintenance work in Nordic nuclear power plants (VTT and Vattenfall). B. Handling performance trade-offs - the support of adaptive capacities (IFE and Vattenfall). The historical perspective of maintenance and outage management (Chapter 1.1) was provided by Vattenfall. Together, the two sub-studies have provided valuable insights for understanding the rationale behind work practices and adjustments, their effects on resilience, promoting flexibility and balancing between flexibility and reliability. (Author)

  6. Final report of MoReMO 2011-2012. Modelling resilience for maintenance and outage

    Energy Technology Data Exchange (ETDEWEB)

    Gotcheva, N.; Macchi, L.; Oedewald, P. [Technical Research Centre of Finland (VTT), Espoo (Finland); Eitrheim, M.H.R. [Institute for Energy Technology (IFE) (Norway); Axelsson, C.; Reiman, T.; Pietikaeinen, E. [Ringhals AB (NPP), Vattenfall AB (Sweden)

    2013-04-15

    The project Modelling Resilience for Maintenance and Outage (MoReMO) represents a two-year joint effort by VTT Technical Research Centre of Finland, Institute for Energy Technology (IFE, Norway) and Vattenfall (Sweden) to develop and test new approaches for safety management. The overall goal of the project was to present concepts on how resilience can be operationalized and built in a safety critical and socio-technical context. Furthermore, the project also aimed at providing guidance for other organizations that strive to develop and improve their safety performance in a business driven industry. We have applied four approaches in different case studies: Organisational Core Task modelling (OCT), Functional Resonance Analysis Method (FRAM), Efficiency Thoroughness Trade-Off (ETTO) analysis, and Work Practice and Culture Characterisation. During 2011 and 2012 the MoReMO project team has collected data through field observations, interviews, workshops, and document analysis on the work practices and adjustments in maintenance and outage in Nordic NPPs. The project consisted of two sub-studies, one focused on identifying and assessing adjustments and supporting resilient work practices in maintenance activities, while the other focused on handling performance trade-offs in maintenance and outage, as follows: A. Adjustments in maintenance work in Nordic nuclear power plants (VTT and Vattenfall). B. Handling performance trade-offs - the support of adaptive capacities (IFE and Vattenfall). The historical perspective of maintenance and outage management (Chapter 1.1) was provided by Vattenfall. Together, the two sub-studies have provided valuable insights for understanding the rationale behind work practices and adjustments, their effects on resilience, promoting flexibility and balancing between flexibility and reliability. (Author)

  7. Using Bayesian Belief Network (BBN) modelling for rapid source term prediction. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Knochenhauer, M.; Swaling, V.H.; Dedda, F.D.; Hansson, F.; Sjoekvist, S.; Sunnegaerd, K. [Lloyd' s Register Consulting AB, Sundbyberg (Sweden)

    2013-10-15

    The project presented in this report deals with a number of complex issues related to the development of a tool for rapid source term prediction (RASTEP), based on a plant model represented as a Bayesian belief network (BBN) and a source term module which is used for assigning relevant source terms to BBN end states. Thus, RASTEP uses a BBN to model severe accident progression in a nuclear power plant in combination with pre-calculated source terms (i.e., amount, composition, timing, and release path of released radio-nuclides). The output is a set of possible source terms with associated probabilities. One major issue has been associated with the integration of probabilistic and deterministic analyses are addressed, dealing with the challenge of making the source term determination flexible enough to give reliable and valid output throughout the accident scenario. The potential for connecting RASTEP to a fast running source term prediction code has been explored, as well as alternative ways of improving the deterministic connections of the tool. As part of the investigation, a comparison of two deterministic severe accident analysis codes has been performed. A second important task has been to develop a general method where experts' beliefs can be included in a systematic way when defining the conditional probability tables (CPTs) in the BBN. The proposed method includes expert judgement in a systematic way when defining the CPTs of a BBN. Using this iterative method results in a reliable BBN even though expert judgements, with their associated uncertainties, have been used. It also simplifies verification and validation of the considerable amounts of quantitative data included in a BBN. (Author)

  8. Processes and parameters involved in modeling radionuclide transport from bedded salt repositories. Final report. Technical memorandum

    International Nuclear Information System (INIS)

    Evenson, D.E.; Prickett, T.A.; Showalter, P.A.

    1979-07-01

    The parameters necessary to model radionuclide transport in salt beds are identified and described. A proposed plan for disposal of the radioactive wastes generated by nuclear power plants is to store waste canisters in repository sites contained in stable salt formations approximately 600 meters below the ground surface. Among the principal radioactive wastes contained in these canisters will be radioactive isotopes of neptunium, americium, uranium, and plutonium along with many highly radioactive fission products. A concern with this form of waste disposal is the possibility of ground-water flow occurring in the salt beds and endangering water supplies and the public health. Specifically, the research investigated the processes involved in the movement of radioactive wastes from the repository site by groundwater flow. Since the radioactive waste canisters also generate heat, temperature is an important factor. Among the processes affecting movement of radioactive wastes from a repository site in a salt bed are thermal conduction, groundwater movement, ion exchange, radioactive decay, dissolution and precipitation of salt, dispersion and diffusion, adsorption, and thermomigration. In addition, structural changes in the salt beds as a result of temperature changes are important. Based upon the half-lives of the radioactive wastes, he period of concern is on the order of a million years. As a result, major geologic phenomena that could affect both the salt bed and groundwater flow in the salt beds was considered. These phenomena include items such as volcanism, faulting, erosion, glaciation, and the impact of meteorites. CDM reviewed all of the critical processes involved in regional groundwater movement of radioactive wastes and identified and described the parameters that must be included to mathematically model their behavior. In addition, CDM briefly reviewed available echniques to measure these parameters

  9. Novel therapeutic approach for pulmonary emphysema using gelatin microspheres releasing basic fibroblast growth factor in a canine model.

    Science.gov (United States)

    Chang, Sung Soo; Yokomise, Hiroyasu; Matsuura, Natsumi; Gotoh, Masashi; Tabata, Yasuhiko

    2014-08-01

    The prognosis of patients with emphysema is poor as there is no truly effective treatment. Our previous study showed that the alveolar space was smaller and the microvessel density was higher in a canine emphysema model after the intrapulmonary arterial administration of gelatin microspheres slowly releasing basic fibroblast growth factor (bFGF-GMS). In the present study, we evaluated the functional effect of injecting bFGF-GMS via the pulmonary artery in this canine pulmonary emphysema model. Using the porcine pancreatic elastase (PPE)-induced total emphysema model, we approximated the value of lung compliance with a Power Lab System, and performed blood gas analysis in a control group, a total emphysema group, and a bFGF group in which bFGF-GMS were injected toward the whole pulmonary artery via the femoral vein. Each group comprised five dogs. Lung compliance was higher in the total emphysema group than in the control group (p = 0.031), and the bFGF group showed no significant improvement of lung compliance vs. the total emphysema group (p = 0.112). PaO2 (partial pressure of oxygen in arterial blood) was improved by administering bFGF-GMS in the total emphysema model (p = 0.027). In the canine total emphysema model, blood gas parameters were improved by the whole pulmonary arterial administration of bFGF-GMS. This method has the potential to be an effective novel therapy for pulmonary emphysema.

  10. Final report of the TRUE Block Scale project. 1. Characterisation and model development

    Energy Technology Data Exchange (ETDEWEB)

    Andersson, Peter; Byegaard, Johan [Geosigma AB, Uppsala (Sweden); Dershowitz, Bill; Doe, Thomas [Golder Associates Inc., Redmond, WA (United States); Hermanson, Jan [Golder Associates AB (Sweden); Meier, Peter [ANDRA, Chatenay-Malabry (France); Tullborg, Eva-Lena [Terralogica AB (Sweden); Winberg, Anders (ed.) [Conterra AB, Partille (Sweden)

    2002-04-01

    The general objectives of the TRUE Block Scale Project were to 1) increase understanding of tracer transport in a fracture network and to improve predictive capabilities, 2) assess the importance of tracer retention mechanisms (diffusion and sorption) in a fracture network, and 3) assess the link between flow and transport data as a means for predicting transport phenomena. During the period mid 1996 through mid 1999 a 200x250x100 m rock volume was characterised with the purpose of furnishing the basis for successful tracer experiments in a network of conductive structures in the block scale (10-100 m). In total five cored boreholes were drilled as part of the project in an iterative mode with a period of analysis following completion of characterisation, and with a strong component of inter activity with numerical modelling and experimental design, particularly towards the end of the characterisation. The combined use of pressure responses due to drilling and drilling records provided important early information/confirmation of the existence and location of a given structure. Verification of conductors identified from pressure responses was achieved through the use of various flow logging techniques. The usage of the Posiva difference flow log towards the end of the characterisation work enabled identification of discrete conductive fractures with a high resolution. Pressure responses collected during drilling were used to obtain a first assessment of connectivity between boreholes. The transient behaviour of the responses collected during cross-hole interference tests in packed-off boreholes were used to identify families of responses, which correlated well with the identified principal families of structures/fracture networks. The conductive geometry of the investigated rock block is made up of steeply dipping deterministic NW structures and NNW structures. High inflows in the boreholes were for the most part associated with geologically/geometrically identified

  11. Final report of the TRUE Block Scale project. 1. Characterisation and model development

    International Nuclear Information System (INIS)

    Andersson, Peter; Byegaard, Johan; Dershowitz, Bill; Doe, Thomas; Hermanson, Jan; Meier, Peter; Tullborg, Eva-Lena; Winberg, Anders

    2002-04-01

    The general objectives of the TRUE Block Scale Project were to 1) increase understanding of tracer transport in a fracture network and to improve predictive capabilities, 2) assess the importance of tracer retention mechanisms (diffusion and sorption) in a fracture network, and 3) assess the link between flow and transport data as a means for predicting transport phenomena. During the period mid 1996 through mid 1999 a 200x250x100 m rock volume was characterised with the purpose of furnishing the basis for successful tracer experiments in a network of conductive structures in the block scale (10-100 m). In total five cored boreholes were drilled as part of the project in an iterative mode with a period of analysis following completion of characterisation, and with a strong component of inter activity with numerical modelling and experimental design, particularly towards the end of the characterisation. The combined use of pressure responses due to drilling and drilling records provided important early information/confirmation of the existence and location of a given structure. Verification of conductors identified from pressure responses was achieved through the use of various flow logging techniques. The usage of the Posiva difference flow log towards the end of the characterisation work enabled identification of discrete conductive fractures with a high resolution. Pressure responses collected during drilling were used to obtain a first assessment of connectivity between boreholes. The transient behaviour of the responses collected during cross-hole interference tests in packed-off boreholes were used to identify families of responses, which correlated well with the identified principal families of structures/fracture networks. The conductive geometry of the investigated rock block is made up of steeply dipping deterministic NW structures and NNW structures. High inflows in the boreholes were for the most part associated with geologically/geometrically identified

  12. Kaiser Permanente/Sandia National health care model. Phase I prototype final report. Part 1 - model overview

    Energy Technology Data Exchange (ETDEWEB)

    Edwards, D.; Yoshimura, A.; Butler, D.; Judson, R. [and others

    1996-11-01

    This report describes the results of a Cooperative Research and Development Agreement between Sandia National Laboratories and Kaiser Permanente Southern California to develop a prototype computer model of Kaiser Permanente`s health care delivery system. As a discrete event simulation, SimHCO models for each of 100,000 patients the progression of disease, individual resource usage, and patient choices in a competitive environment. SimHCO is implemented in the object-oriented programming language C++, stressing reusable knowledge and reusable software components. The versioned implementation of SimHCO showed that the object-oriented framework allows the program to grow in complexity in an incremental way. Furthermore, timing calculations showed that SimHCO runs in a reasonable time on typical workstations, and that a second phase model will scale proportionally and run within the system constraints of contemporary computer technology. This report is published as two documents: Model Overview and Domain Analysis. A separate Kaiser-proprietary report contains the Disease and Health Care Organization Selection Models.

  13. Putative therapeutic targets for symptom subtypes of adult ADHD: D4 receptor agonism and COMT inhibition improve attention and response inhibition in a novel translational animal model.

    Science.gov (United States)

    Tomlinson, Anneka; Grayson, Ben; Marsh, Samuel; Hayward, Andrew; Marshall, Kay M; Neill, Joanna C

    2015-04-01

    Prefrontal cortical dopamine plays an important role in cognitive control, specifically in attention and response inhibition; the core deficits in ADHD. We have previously shown that methylphenidate and atomoxetine differentially improve these deficits dependent on baseline performance. The present study extends this work to investigate the effects of putative therapeutic targets in our model. A selective dopamine D4 receptor agonist (A-412997) and the catechol-O-methyl-transferase (COMT) inhibitor; tolcapone, were investigated in the combined subtype of adult ADHD (ADHD-C). Adult female rats were trained to criterion in the 5C-CPT (5-Choice Continuous Performance Task) and then separated into subgroups according to baseline levels of sustained attention, vigilance, and response disinhibition. The subgroups included: high-attentive (HA) and low-attentive with high response disinhibition (ADHD-C). The ADHD-C subgroup was selected to represent the combined subtype of adult ADHD. Effects of tolcapone (3.0, 10.0, 15.0mg/kg) and A-412997 (0.1, 0.3, 1.0µmol/kg) were tested by increasing the variable inter-trial-interval (ITI) duration in the 5C-CPT. Tolcapone (15mg/kg) significantly increased sustained attention, vigilance and response inhibition in ADHD-C animals, and impaired attention in HA animals. A-412997 (1.0µmol/kg) significantly increased vigilance and response inhibition in ADHD-C animals only, with no effect in HA animals. This is the first study to use the translational 5C-CPT to model the adult ADHD-C subtype in rats and to study new targets in this model. Both tolcapone and A-412997 increased vigilance and response inhibition in the ADHD-C subgroup. D4 and COMT are emerging as important potential therapeutic targets in adult ADHD that warrant further investigation. Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.

  14. Modeling of Filtration Processes—Microfiltration and Depth Filtration for Harvest of a Therapeutic Protein Expressed in Pichia pastoris at Constant Pressure

    Directory of Open Access Journals (Sweden)

    Muthukumar Sampath

    2014-12-01

    Full Text Available Filtration steps are ubiquitous in biotech processes due to the simplicity of operation, ease of scalability and the myriad of operations that they can be used for. Microfiltration, depth filtration, ultrafiltration and diafiltration are some of the most commonly used biotech unit operations. For clean feed streams, when fouling is minimal, scaling of these unit operations is performed linearly based on the filter area per unit volume of feed stream. However, for cases when considerable fouling occurs, such as the case of harvesting a therapeutic product expressed in Pichia pastoris, linear scaling may not be possible and current industrial practices involve use of 20–30% excess filter area over and above the calculated filter area to account for the uncertainty in scaling. In view of the fact that filters used for harvest are likely to have a very limited lifetime, this oversizing of the filters can add considerable cost of goods for the manufacturer. Modeling offers a way out of this conundrum. In this paper, we examine feasibility of using the various proposed models for filtration of a therapeutic product expressed in Pichia pastoris at constant pressure. It is observed that none of the individual models yield a satisfactory fit of the data, thus indicating that more than one fouling mechanism is at work. Filters with smaller pores were found to undergo fouling via complete pore blocking followed by cake filtration. On the other hand, filters with larger pores were found to undergo fouling via intermediate pore blocking followed by cake filtration. The proposed approach can be used for more accurate sizing of microfilters and depth filters.

  15. MODELLING OF RING-SHAPED ULTRASONIC WAVEGUIDES FOR TESTING OF MECHANICAL PROPERTIES AND THERAPEUTIC TREATMENT OF BIOLOGICAL TISSUES

    Directory of Open Access Journals (Sweden)

    V. T. Minchenya

    2011-01-01

    Full Text Available The article presents results of modelling of ring-shaped waveguide tool for ultrasonic treatment of biological materials, particularly malignant tumours, and testing of their mechanical properties. Harmonic analysis of forced flexural vibration of the waveguide using ANSYS software and APDL programming language was implemented for determination of waveguide geometric parameters providing its resonance for the given excitation frequency. The developed finite element model accounts for interaction between the waveguide and tumour tissue as well as initial prestressing of tissue radially compressed by the waveguide. Resonant curves of the waveguide in terms of its thickness and diameter are calculated and presented. Principle of application of the developed modeling technique for extraction of diagnostic data on mechanical properties of biological tissues is described.

  16. Mathematical model of a NiOOH/metal hydride cell. Final report, September 15, 1993--November 14, 1996

    Energy Technology Data Exchange (ETDEWEB)

    White, R.E.; Popov, B.N.

    1996-12-31

    One of the objectives of work on the nickel/metal hydride cell has been to develop a mathematical model of the performance of the cell. This is a summary of work to date and is meant to be a Final Report of the BES project. Mathematical model of the nickel/metal hydride cell depends on the kinetics, thermodynamics, and transport properties of the metal hydride electrode. Consequently, investigations were carried out to determine: (1) the exchange current density and the equilibrium potential as a function of hydrogen content in the electrode; (2) the hydrogen diffusion coefficient in the bulk of the alloy; (3) the hydrogen reaction rate order; (4) the symmetry factor for hydrogen evolution reaction and (5) to determine the reaction mechanisms of the hydrogen charge and discharge processes including overcharge and overdischarge mechanism.

  17. Radiotherapy-induced anti-tumor immunity contributes to the therapeutic efficacy of irradiation and can be augmented by CTLA-4 blockade in a mouse model.

    Directory of Open Access Journals (Sweden)

    Yuya Yoshimoto

    Full Text Available PURPOSE: There is growing evidence that tumor-specific immune responses play an important role in anti-cancer therapy, including radiotherapy. Using mouse tumor models we demonstrate that irradiation-induced anti-tumor immunity is essential for the therapeutic efficacy of irradiation and can be augmented by modulation of cytotoxic T lymphocyte (CTL activity. METHODS AND MATERIALS: C57BL/6 mice, syngeneic EL4 lymphoma cells, and Lewis lung carcinoma (LL/C cells were used. Cells were injected into the right femurs of mice. Ten days after inoculation, tumors were treated with 30 Gy of local X-ray irradiation and their growth was subsequently measured. The effect of irradiation on tumor growth delay (TGD was defined as the time (in days for tumors to grow to 500 mm3 in the treated group minus that of the untreated group. Cytokine production and serum antibodies were measured by ELISA and flow cytometry. RESULTS: In the EL4 tumor model, tumors were locally controlled by X-ray irradiation and re-introduced EL4 cells were completely rejected. Mouse EL4-specific systemic immunity was confirmed by splenocyte cytokine production and detection of tumor-specific IgG1 antibodies. In the LL/C tumor model, X-ray irradiation also significantly delayed tumor growth (TGD: 15.4 days and prolonged median survival time (MST to 59 days (versus 28 days in the non-irradiated group. CD8(+ cell depletion using an anti-CD8 antibody significantly decreased the therapeutic efficacy of irradiation (TGD, 8.7 days; MST, 49 days. Next, we examined whether T cell modulation affected the efficacy of radiotherapy. An anti-CTLA-4 antibody significantly increased the anti-tumor activity of radiotherapy (TGD was prolonged from 13.1 to 19.5 days, while anti-FR4 and anti-GITR antibodies did not affect efficacy. CONCLUSIONS: Our results indicate that tumor-specific immune responses play an important role in the therapeutic efficacy of irradiation. Immunomodulation, including CTLA-4

  18. Radiotherapy-Induced Anti-Tumor Immunity Contributes to the Therapeutic Efficacy of Irradiation and Can Be Augmented by CTLA-4 Blockade in a Mouse Model

    Science.gov (United States)

    Yoshimoto, Yuya; Suzuki, Yoshiyuki; Mimura, Kousaku; Ando, Ken; Oike, Takahiro; Sato, Hiro; Okonogi, Noriyuki; Maruyama, Takanori; Izawa, Shinichiro; Noda, Shin-ei; Fujii, Hideki; Kono, Koji; Nakano, Takashi

    2014-01-01

    Purpose There is growing evidence that tumor-specific immune responses play an important role in anti-cancer therapy, including radiotherapy. Using mouse tumor models we demonstrate that irradiation-induced anti-tumor immunity is essential for the therapeutic efficacy of irradiation and can be augmented by modulation of cytotoxic T lymphocyte (CTL) activity. Methods and Materials C57BL/6 mice, syngeneic EL4 lymphoma cells, and Lewis lung carcinoma (LL/C) cells were used. Cells were injected into the right femurs of mice. Ten days after inoculation, tumors were treated with 30 Gy of local X-ray irradiation and their growth was subsequently measured. The effect of irradiation on tumor growth delay (TGD) was defined as the time (in days) for tumors to grow to 500 mm3 in the treated group minus that of the untreated group. Cytokine production and serum antibodies were measured by ELISA and flow cytometry. Results In the EL4 tumor model, tumors were locally controlled by X-ray irradiation and re-introduced EL4 cells were completely rejected. Mouse EL4-specific systemic immunity was confirmed by splenocyte cytokine production and detection of tumor-specific IgG1 antibodies. In the LL/C tumor model, X-ray irradiation also significantly delayed tumor growth (TGD: 15.4 days) and prolonged median survival time (MST) to 59 days (versus 28 days in the non-irradiated group). CD8(+) cell depletion using an anti-CD8 antibody significantly decreased the therapeutic efficacy of irradiation (TGD, 8.7 days; MST, 49 days). Next, we examined whether T cell modulation affected the efficacy of radiotherapy. An anti-CTLA-4 antibody significantly increased the anti-tumor activity of radiotherapy (TGD was prolonged from 13.1 to 19.5 days), while anti-FR4 and anti-GITR antibodies did not affect efficacy. Conclusions Our results indicate that tumor-specific immune responses play an important role in the therapeutic efficacy of irradiation. Immunomodulation, including CTLA-4 blockade, may be a

  19. Constraints on models for the Higgs boson with exotic spin and parity in VH → Vbb final states.

    Science.gov (United States)

    Abazov, V M; Abbott, B; Acharya, B S; Adams, M; Adams, T; Agnew, J P; Alexeev, G D; Alkhazov, G; Alton, A; Askew, A; Atkins, S; Augsten, K; Avila, C; Badaud, F; Bagby, L; Baldin, B; Bandurin, D V; Banerjee, S; Barberis, E; Baringer, P; Bartlett, J F; Bassler, U; Bazterra, V; Bean, A; Begalli, M; Bellantoni, L; Beri, S B; Bernardi, G; Bernhard, R; Bertram, I; Besançon, M; Beuselinck, R; Bhat, P C; Bhatia, S; Bhatnagar, V; Blazey, G; Blessing, S; Bloom, K; Boehnlein, A; Boline, D; Boos, E E; Borissov, G; Borysova, M; Brandt, A; Brandt, O; Brock, R; Bross, A; Brown, D; Bu, X B; Buehler, M; Buescher, V; Bunichev, V; Burdin, S; Buszello, C P; Camacho-Pérez, E; Casey, B C K; Castilla-Valdez, H; Caughron, S; Chakrabarti, S; Chan, K M; Chandra, A; Chapon, E; Chen, G; Cho, S W; Choi, S; Choudhary, B; Cihangir, S; Claes, D; Clutter, J; Cooke, M; Cooper, W E; Corcoran, M; Couderc, F; Cousinou, M-C; Cutts, D; Das, A; Davies, G; de Jong, S J; De La Cruz-Burelo, E; Déliot, F; Demina, R; Denisov, D; Denisov, S P; Desai, S; Deterre, C; DeVaughan, K; Diehl, H T; Diesburg, M; Ding, P F; Dominguez, A; Dubey, A; Dudko, L V; Duperrin, A; Dutt, S; Eads, M; Edmunds, D; Ellison, J; Elvira, V D; Enari, Y; Evans, H; Evdokimov, V N; Fauré, A; Feng, L; Ferbel, T; Fiedler, F; Filthaut, F; Fisher, W; Fisk, H E; Fortner, M; Fox, H; Fuess, S; Garbincius, P H; Garcia-Bellido, A; García-González, J A; Gavrilov, V; Geng, W; Gerber, C E; Gershtein, Y; Ginther, G; Gogota, O; Golovanov, G; Grannis, P D; Greder, S; Greenlee, H; Grenier, G; Gris, Ph; Grivaz, J-F; Grohsjean, A; Grünendahl, S; Grünewald, M W; Guillemin, T; Gutierrez, G; Gutierrez, P; Haley, J; Han, L; Harder, K; Harel, A; Hauptman, J M; Hays, J; Head, T; Hebbeker, T; Hedin, D; Hegab, H; Heinson, A P; Heintz, U; Hensel, C; Heredia-De La Cruz, I; Herner, K; Hesketh, G; Hildreth, M D; Hirosky, R; Hoang, T; Hobbs, J D; Hoeneisen, B; Hogan, J; Hohlfeld, M; Holzbauer, J L; Howley, I; Hubacek, Z; Hynek, V; Iashvili, I; Ilchenko, Y; Illingworth, R; Ito, A S; Jabeen, S; Jaffré, M; Jayasinghe, A; Jeong, M S; Jesik, R; Jiang, P; Johns, K; Johnson, E; Johnson, M; Jonckheere, A; Jonsson, P; Joshi, J; Jung, A W; Juste, A; Kajfasz, E; Karmanov, D; Katsanos, I; Kehoe, R; Kermiche, S; Khalatyan, N; Khanov, A; Kharchilava, A; Kharzheev, Y N; Kiselevich, I; Kohli, J M; Kozelov, A V; Kraus, J; Kumar, A; Kupco, A; Kurča, T; Kuzmin, V A; Lammers, S; Lebrun, P; Lee, H S; Lee, S W; Lee, W M; Lei, X; Lellouch, J; Li, D; Li, H; Li, L; Li, Q Z; Lim, J K; Lincoln, D; Linnemann, J; Lipaev, V V; Lipton, R; Liu, H; Liu, Y; Lobodenko, A; Lokajicek, M; Lopes de Sa, R; Luna-Garcia, R; Lyon, A L; Maciel, A K A; Madar, R; Magaña-Villalba, R; Malik, S; Malyshev, V L; Mansour, J; Martínez-Ortega, J; McCarthy, R; McGivern, C L; Meijer, M M; Melnitchouk, A; Menezes, D; Mercadante, P G; Merkin, M; Meyer, A; Meyer, J; Miconi, F; Mondal, N K; Mulhearn, M; Nagy, E; Narain, M; Nayyar, R; Neal, H A; Negret, J P; Neustroev, P; Nguyen, H T; Nunnemann, T; Orduna, J; Osman, N; Osta, J; Pal, A; Parashar, N; Parihar, V; Park, S K; Partridge, R; Parua, N; Patwa, A; Penning, B; Perfilov, M; Peters, Y; Petridis, K; Petrillo, G; Pétroff, P; Pleier, M-A; Podstavkov, V M; Popov, A V; Prewitt, M; Price, D; Prokopenko, N; Qian, J; Quadt, A; Quinn, B; Ratoff, P N; Razumov, I; Ripp-Baudot, I; Rizatdinova, F; Rominsky, M; Ross, A; Royon, C; Rubinov, P; Ruchti, R; Sajot, G; Sánchez-Hernández, A; Sanders, M P; Santos, A S; Savage, G; Savitskyi, M; Sawyer, L; Scanlon, T; Schamberger, R D; Scheglov, Y; Schellman, H; Schwanenberger, C; Schwienhorst, R; Sekaric, J; Severini, H; Shabalina, E; Shary, V; Shaw, S; Shchukin, A A; Simak, V; Skubic, P; Slattery, P; Smirnov, D; Snow, G R; Snow, J; Snyder, S; Söldner-Rembold, S; Sonnenschein, L; Soustruznik, K; Stark, J; Stoyanova, D A; Strauss, M; Suter, L; Svoisky, P; Titov, M; Tokmenin, V V; Tsai, Y-T; Tsybychev, D; Tuchming, B; Tully, C; Uvarov, L; Uvarov, S; Uzunyan, S; Van Kooten, R; van Leeuwen, W M; Varelas, N; Varnes, E W; Vasilyev, I A; Verkheev, A Y; Vertogradov, L S; Verzocchi, M; Vesterinen, M; Vilanova, D; Vokac, P; Wahl, H D; Wang, M H L S; Warchol, J; Watts, G; Wayne, M; Weichert, J; Welty-Rieger, L; Williams, M R J; Wilson, G W; Wobisch, M; Wood, D R; Wyatt, T R; Xie, Y; Yamada, R; Yang, S; Yasuda, T; Yatsunenko, Y A; Ye, W; Ye, Z; Yin, H; Yip, K; Youn, S W; Yu, J M; Zennamo, J; Zhao, T G; Zhou, B; Zhu, J; Zielinski, M; Zieminska, D; Zivkovic, L

    2014-10-17

    We present constraints on models containing non-standard-model values for the spin J and parity P of the Higgs boson H in up to 9.7 fb(-1) of pp collisions at sqrt[s] = 1.96 TeV collected with the D0 detector at the Fermilab Tevatron Collider. These are the first studies of Higgs boson J(P) with fermions in the final state. In the ZH → ℓℓbb, WH → ℓνbb, and ZH → ννbb final states, we compare the standard model (SM) Higgs boson prediction, J(P) = 0(+), with two alternative hypotheses, J(P) = 0(-) and J(P) = 2(+). We use a likelihood ratio to quantify the degree to which our data are incompatible with non-SM J(P) predictions for a range of possible production rates. Assuming that the production rate in the signal models considered is equal to the SM prediction, we reject the J(P) = 0(-) and J(P) = 2(+) hypotheses at the 97.6% CL and at the 99.0% CL, respectively. The expected exclusion sensitivity for a J(P) = 0(-) (J(P) = 2(+)) state is at the 99.86% (99.94%) CL. Under the hypothesis that our data are the result of a combination of the SM-like Higgs boson and either a J(P) = 0(-) or a J(P) = 2(+) signal, we exclude a J(P) = 0(-) fraction above 0.80 and a J(P) = 2(+) fraction above 0.67 at the 95% CL. The expected exclusion covers J(P) = 0(-) (J(P) = 2(+)) fractions above 0.54 (0.47).

  20. Final Report, Nuclear Energy Research Initiative (NERI) Project: An Innovative Reactor Analysis Methodology Based on a Quasidiffusion Nodal Core Model

    International Nuclear Information System (INIS)

    Anistratov, Dmitriy Y.; Adams, Marvin L.; Palmer, Todd S.; Smith, Kord S.; Clarno, Kevin; Hikaru Hiruta; Razvan Nes

    2003-01-01

    OAK (B204) Final Report, NERI Project: ''An Innovative Reactor Analysis Methodology Based on a Quasidiffusion Nodal Core Model'' The present generation of reactor analysis methods uses few-group nodal diffusion approximations to calculate full-core eigenvalues and power distributions. The cross sections, diffusion coefficients, and discontinuity factors (collectively called ''group constants'') in the nodal diffusion equations are parameterized as functions of many variables, ranging from the obvious (temperature, boron concentration, etc.) to the more obscure (spectral index, moderator temperature history, etc.). These group constants, and their variations as functions of the many variables, are calculated by assembly-level transport codes. The current methodology has two main weaknesses that this project addressed. The first weakness is the diffusion approximation in the full-core calculation; this can be significantly inaccurate at interfaces between different assemblies. This project used the nodal diffusion framework to implement nodal quasidiffusion equations, which can capture transport effects to an arbitrary degree of accuracy. The second weakness is in the parameterization of the group constants; current models do not always perform well, especially at interfaces between unlike assemblies. The project developed a theoretical foundation for parameterization and homogenization models and used that theory to devise improved models. The new models were extended to tabulate information that the nodal quasidiffusion equations can use to capture transport effects in full-core calculations

  1. A model independent search for new physics in final states containing leptons at the D0 experiment

    International Nuclear Information System (INIS)

    Piper, Joel Michael

    2009-01-01

    The standard model is known to be the low energy limit of a more general theory. Several consequences of the standard model point to a strong probability of new physics becoming experimentally visible in high energy collisions of a few TeV, resulting in high momentum objects. The specific signatures of these collisions are topics of much debate. Rather than choosing a specific signature, this analysis broadly searches the data, preferring breadth over sensitivity. In searching for new physics, several different approaches are used. These include the comparison of data with standard model background expectation in overall number of events, comparisons of distributions of many kinematic variables, and finally comparisons on the tails of distributions that sum the momenta of the objects in an event. With 1.07 fb -1 at the D0 experiment, we find no evidence of physics beyond the standard model. Several discrepancies from the standard model were found, but none of these provide a compelling case for new physics.

  2. A model independent search for new physics in final states containing leptons at the D0 experiment

    Energy Technology Data Exchange (ETDEWEB)

    Piper, Joel Michael [Michigan State Univ., East Lansing, MI (United States)

    2009-01-01

    The standard model is known to be the low energy limit of a more general theory. Several consequences of the standard model point to a strong probability of new physics becoming experimentally visible in high energy collisions of a few TeV, resulting in high momentum objects. The specific signatures of these collisions are topics of much debate. Rather than choosing a specific signature, this analysis broadly searches the data, preferring breadth over sensitivity. In searching for new physics, several different approaches are used. These include the comparison of data with standard model background expectation in overall number of events, comparisons of distributions of many kinematic variables, and finally comparisons on the tails of distributions that sum the momenta of the objects in an event. With 1.07 fb-1 at the D0 experiment, we find no evidence of physics beyond the standard model. Several discrepancies from the standard model were found, but none of these provide a compelling case for new physics.

  3. The TREAT-NMD advisory committee for therapeutics (TACT): an innovative de-risking model to foster orphan drug development

    NARCIS (Netherlands)

    Heslop, Emma; Csimma, Cristina; Straub, Volker; McCall, John; Nagaraju, Kanneboyina; Wagner, Kathryn R.; Caizergues, Didier; Korinthenberg, Rudolf; Flanigan, Kevin M.; Kaufmann, Petra; McNeil, Elizabeth; Mendell, Jerry; Hesterlee, Sharon; Wells, Dominic J.; Bushby, Kate; McNeil, Dawn Elizabeth; Allen, Hugh; Bourke, John; Burghes, Arthur; Buyse, Gunnar; Catlin, Nick; Clemens, Paula; Cnaan, Avital; Comi, Giacomo; Connor, Edward; de Luca, Annamaria; de Montleau, Béatrice; de Visser, Marianne; Day, Simon; Dittrich, Sven; Dubrosky, Alberto; Eagle, Michelle; Finkel, Richard; Fishbeck, Kenneth; Furlong, Patricia; Grounds, Miranda; Hauschke, Dieter; Hoffman, Eric; Irwin, Joseph; Jarecki, Jill; Kelly, Michael; Laforêt, Pascal; Lovering, Richard; Larkindale, Jane; Mayer, Henry; McDonald, Robert; McNally, Elizabeth; Miller, Debra; North, Kathryn; Ouillade, Marie-Christine

    2015-01-01

    Despite multiple publications on potential therapies for neuromuscular diseases (NMD) in cell and animal models only a handful reach clinical trials. The ability to prioritise drug development according to objective criteria is particularly critical in rare diseases with large unmet needs and a

  4. Fluid sampling and chemical modeling of geopressured brines containing methane. Final report, March 1980-February 1981

    Energy Technology Data Exchange (ETDEWEB)

    Dudak, B.; Galbraith, R.; Hansen, L.; Sverjensky, D.; Weres, O.

    1982-07-01

    The development of a flowthrough sampler capable of obtaining fluid samples from geopressured wells at temperatures up to 400/sup 0/F and pressures up to 20,000 psi is described. The sampler has been designed, fabricated from MP35N alloy, laboratory tested, and used to obtain fluid samples from a geothermal well at The Geysers, California. However, it has not yet been used in a geopressured well. The design features, test results, and operation of this device are described. Alternative sampler designs are also discussed. Another activity was to review the chemistry and geochemistry of geopressured brines and reservoirs, and to evaluate the utility of available computer codes for modeling the chemistry of geopressured brines. The thermodynamic data bases for such codes are usually the limiting factor in their application to geopressured systems, but it was concluded that existing codes can be updated with reasonable effort and can usefully explain and predict the chemical characteristics of geopressured systems, given suitable input data.

  5. Properties of parameter estimation techniques for a beta-binomial failure model. Final technical report

    International Nuclear Information System (INIS)

    Shultis, J.K.; Buranapan, W.; Eckhoff, N.D.

    1981-12-01

    Of considerable importance in the safety analysis of nuclear power plants are methods to estimate the probability of failure-on-demand, p, of a plant component that normally is inactive and that may fail when activated or stressed. Properties of five methods for estimating from failure-on-demand data the parameters of the beta prior distribution in a compound beta-binomial probability model are examined. Simulated failure data generated from a known beta-binomial marginal distribution are used to estimate values of the beta parameters by (1) matching moments of the prior distribution to those of the data, (2) the maximum likelihood method based on the prior distribution, (3) a weighted marginal matching moments method, (4) an unweighted marginal matching moments method, and (5) the maximum likelihood method based on the marginal distribution. For small sample sizes (N = or < 10) with data typical of low failure probability components, it was found that the simple prior matching moments method is often superior (e.g. smallest bias and mean squared error) while for larger sample sizes the marginal maximum likelihood estimators appear to be best

  6. Operationalisation of the model 'risk-sovereignty' in the field of radiation protection. Final report

    International Nuclear Information System (INIS)

    Renn, Ortwin; Ruddat, Michael; Sautter, Alexander

    2007-01-01

    The central aim of the BfS research project titled ''operationalization of the 'risk sovereignty model' with special consideration to lifestyle and value approaches as a basis for risk communication in the field of radiation protection'' was the identification of suitable measures to enhance the degree of risk sovereignty of the German population with regard to radiation risks (mobile telephony, nuclear power, ultraviolet radiation and X-rays). This requires the development of a measuring instrument for capturing the prevailing degree of risk sovereignty in the whole population or in certain subgroups with regard to radiation risks empirically. In the first two phases of the project suitable instruments for the construct ''risk sovereignty'' have been developed. Furthermore a value-typology for the identification of different groups of persons as well as independent variables likely to have an influence on 'risk sovereignty' (information behavior, communication or participation intention) were included in the study. The empirical research is divided into a quantitative and a qualitative inquiry. Based on the empirical studies, a guidance document to improve the cognitive capability of people to build up risk sovereignty, in particular in relation to radiation was developed. For the three types of respondents, different strategies were recommended taking into account their needs and information seeking behavior

  7. Scalable Nonlinear Solvers for Fully Implicit Coupled Nuclear Fuel Modeling. Final Report

    International Nuclear Information System (INIS)

    Cai, Xiao-Chuan; Yang, Chao; Pernice, Michael

    2014-01-01

    The focus of the project is on the development and customization of some highly scalable domain decomposition based preconditioning techniques for the numerical solution of nonlinear, coupled systems of partial differential equations (PDEs) arising from nuclear fuel simulations. These high-order PDEs represent multiple interacting physical fields (for example, heat conduction, oxygen transport, solid deformation), each is modeled by a certain type of Cahn-Hilliard and/or Allen-Cahn equations. Most existing approaches involve a careful splitting of the fields and the use of field-by-field iterations to obtain a solution of the coupled problem. Such approaches have many advantages such as ease of implementation since only single field solvers are needed, but also exhibit disadvantages. For example, certain nonlinear interactions between the fields may not be fully captured, and for unsteady problems, stable time integration schemes are difficult to design. In addition, when implemented on large scale parallel computers, the sequential nature of the field-by-field iterations substantially reduces the parallel efficiency. To overcome the disadvantages, fully coupled approaches have been investigated in order to obtain full physics simulations.

  8. Final Report for NFE-07-00912: Development of Model Fuels Experimental Engine Data Base & Kinetic Modeling Parameter Sets

    Energy Technology Data Exchange (ETDEWEB)

    Bunting, Bruce G [ORNL

    2012-10-01

    The automotive and engine industries are in a period of very rapid change being driven by new emission standards, new types of after treatment, new combustion strategies, the introduction of new fuels, and drive for increased fuel economy and efficiency. The rapid pace of these changes has put more pressure on the need for modeling of engine combustion and performance, in order to shorten product design and introduction cycles. New combustion strategies include homogeneous charge compression ignition (HCCI), partial-premixed combustion compression ignition (PCCI), and dilute low temperature combustion which are being developed for lower emissions and improved fuel economy. New fuels include bio-fuels such as ethanol or bio-diesel, drop-in bio-derived fuels and those derived from new crude oil sources such as gas-to-liquids, coal-to-liquids, oil sands, oil shale, and wet natural gas. Kinetic modeling of the combustion process for these new combustion regimes and fuels is necessary in order to allow modeling and performance assessment for engine design purposes. In this research covered by this CRADA, ORNL developed and supplied experimental data related to engine performance with new fuels and new combustion strategies along with interpretation and analysis of such data and consulting to Reaction Design, Inc. (RD). RD performed additional analysis of this data in order to extract important parameters and to confirm engine and kinetic models. The data generated was generally published to make it available to the engine and automotive design communities and also to the Reaction Design Model Fuels Consortium (MFC).

  9. Alligator Rivers Analogue project. Geochemical modelling of secondary uranium ore formation. Final Report - Volume 11

    International Nuclear Information System (INIS)

    Sverjensky, D.; Bennett, D.G.; Read, D.

    1992-01-01

    The purpose of the present study was to establish how the uranyl phosphate zone at the Koongarra site was formed. The overall approach taken in the present study employed theoretical chemical mass transfer calculations and models that permit investigation and reconstruction of the kinds of waters that could produce the uranyl phosphate zone. These calculations have used the geological and mineralogical data for the Koongarra weathered zone (Volumes 2, 8, and 9 of this series), to constrain the initial compositions and reactions undergone by groundwater during the formation of the uranyl phosphate zone. In carrying out these calculations the present-day analyses of Koongarra waters are used only as a guide to the possible initial composition of the fluids associated with the formation of the phosphate zone. Aqueous speciation, saturation state and chemical mass transfer calculations were carried out using the computer programs EQ3NR and EQ6 (Wolery, 1983; Wolery et al., 1984) and a thermodynamic database generated at The Johns Hopkins University over the last eight years which is tabulated in the Appendix 1 to Volume 12 of this series. Despite uncertainties in the thermodynamic characterisation of species, all the above calculations suggest that the uranyl phosphate zone at Koongarra has not formed from present-day groundwaters (Volume 12 of this series). The present-day groundwaters in the weathered zone (eg. at 13 m depth) appear to be undersaturated with respect to saleeite. Furthermore, as present-day groundwaters descend below the water table they rapidly lose their atmospheric oxygen imprint, as is typical of most groundwaters, and become even more reducing in character. Under these circumstances, the groundwaters become more undersaturated with respect to saleeite than the shallow groundwaters. Because much of the phosphate zone is currently below the water table, under saturated zone conditions, it is suggested in the present study that the uranyl phosphate

  10. Alligator Rivers Analogue project. Geochemical modelling of secondary uranium ore formation. Final Report - Volume 11

    Energy Technology Data Exchange (ETDEWEB)

    Sverjensky, D [The John Hopkins Univ, Dept of Earth and Planetary Sciences, Baltimore (United States); Bennett, D G; Read, D [W.S. Atkins Science and Technology, Epsom Surrey, (United Kingdom)

    1993-12-31

    The purpose of the present study was to establish how the uranyl phosphate zone at the Koongarra site was formed. The overall approach taken in the present study employed theoretical chemical mass transfer calculations and models that permit investigation and reconstruction of the kinds of waters that could produce the uranyl phosphate zone. These calculations have used the geological and mineralogical data for the Koongarra weathered zone (Volumes 2, 8, and 9 of this series), to constrain the initial compositions and reactions undergone by groundwater during the formation of the uranyl phosphate zone. In carrying out these calculations the present-day analyses of Koongarra waters are used only as a guide to the possible initial composition of the fluids associated with the formation of the phosphate zone. Aqueous speciation, saturation state and chemical mass transfer calculations were carried out using the computer programs EQ3NR and EQ6 (Wolery, 1983; Wolery et al., 1984) and a thermodynamic database generated at The Johns Hopkins University over the last eight years which is tabulated in the Appendix 1 to Volume 12 of this series. Despite uncertainties in the thermodynamic characterisation of species, all the above calculations suggest that the uranyl phosphate zone at Koongarra has not formed from present-day groundwaters (Volume 12 of this series). The present-day groundwaters in the weathered zone (eg. at 13 m depth) appear to be undersaturated with respect to saleeite. Furthermore, as present-day groundwaters descend below the water table they rapidly lose their atmospheric oxygen imprint, as is typical of most groundwaters, and become even more reducing in character. Under these circumstances, the groundwaters become more undersaturated with respect to saleeite than the shallow groundwaters. Because much of the phosphate zone is currently below the water table, under saturated zone conditions, it is suggested in the present study that the uranyl phosphate

  11. Alligator Rivers Analogue project. Geochemical modelling of secondary uranium ore formation. Final Report - Volume 11

    Energy Technology Data Exchange (ETDEWEB)

    Sverjensky, D. [The John Hopkins Univ, Dept of Earth and Planetary Sciences, Baltimore (United States); Bennett, D.G.; Read, D. [W.S. Atkins Science and Technology, Epsom Surrey, (United Kingdom)

    1992-12-31

    The purpose of the present study was to establish how the uranyl phosphate zone at the Koongarra site was formed. The overall approach taken in the present study employed theoretical chemical mass transfer calculations and models that permit investigation and reconstruction of the kinds of waters that could produce the uranyl phosphate zone. These calculations have used the geological and mineralogical data for the Koongarra weathered zone (Volumes 2, 8, and 9 of this series), to constrain the initial compositions and reactions undergone by groundwater during the formation of the uranyl phosphate zone. In carrying out these calculations the present-day analyses of Koongarra waters are used only as a guide to the possible initial composition of the fluids associated with the formation of the phosphate zone. Aqueous speciation, saturation state and chemical mass transfer calculations were carried out using the computer programs EQ3NR and EQ6 (Wolery, 1983; Wolery et al., 1984) and a thermodynamic database generated at The Johns Hopkins University over the last eight years which is tabulated in the Appendix 1 to Volume 12 of this series. Despite uncertainties in the thermodynamic characterisation of species, all the above calculations suggest that the uranyl phosphate zone at Koongarra has not formed from present-day groundwaters (Volume 12 of this series). The present-day groundwaters in the weathered zone (eg. at 13 m depth) appear to be undersaturated with respect to saleeite. Furthermore, as present-day groundwaters descend below the water table they rapidly lose their atmospheric oxygen imprint, as is typical of most groundwaters, and become even more reducing in character. Under these circumstances, the groundwaters become more undersaturated with respect to saleeite than the shallow groundwaters. Because much of the phosphate zone is currently below the water table, under saturated zone conditions, it is suggested in the present study that the uranyl phosphate

  12. Alligator Rivers Analogue project. Geochemical modelling of present-day groundwaters. Final Report - Volume 12

    Energy Technology Data Exchange (ETDEWEB)

    Sverjensky, D A [The John Hopkins Univ, Dept of Earth and Planetary Sciences, Baltimore (United States)

    1993-12-31

    The main purpose of this report is to summarize geochemical modeling studies of the present-day Koongarra groundwaters. Information on the present-day geochemistry and geochemical processes at Koongarra forms a basis for a present-day analogue for nuclear waste migration. The present-day analogue is built on studies of the mineralogy and petrology of the Koongarra deposit, and chemical analyses of present-day groundwaters from the deposit. The overall approach taken in the present study has been to carry out a series of aqueous speciation and state of saturation calculations, including chemical mass transfer calculations, to address the possible control over the chemistry of the present-day for the groundwaters at Koongarra. The most important implication of the present study for the migration of radionuclides is the strong role played by the water-rock interactions, both above and below the water table, influencing the overall chemical evolution of the groundwaters. Thus, the results show that the chemical evolution of waters is strongly controlled by the initial availability of CO{sub 2} and the mineral assemblage encountered, which together determine the major element evolution of the waters by controlling the pH. The relative rates of evolution of the pH and the oxidation state of the groundwaters are also critical to the mobility of uranium. The shallow Koongarra waters are sufficiently oxidising that they can dissolve and transport uranium even under acidic conditions. Under the more reducing condition of the deep groundwaters, is the pH level that permits uranium transport as carbonate complexes. However, if the oxidation state decreases to much lower levels, it would be expected that uranium become immobile. All the speciation and state of saturation calculations carried out in the present study are available from the author, on request 22 refs., 7 tabs., 18 figs.

  13. Search for the standard model higgs boson in eτ final states

    Energy Technology Data Exchange (ETDEWEB)

    Howley, Ian James [Univ. of Texas, Arlington, TX (United States)

    2013-05-01

    Presented in this dissertation is a search for the standard model (SM) Higgs boson using the DØ detector at Fermilab in Batavia, IL. The SM is a fantastically accurate theory describing the fundamental interactions and particles of the Universe. The only undiscovered particle in the SM is the Higgs boson, which is hypothesized to be responsible for electroweak symmetry breaking and giving mass to all other particles. Considered in this search is the process H + X → eτhjj, where e is an electron, τh is the hadronic decay of a tau, and j is a jet, using p $\\bar{p}$ collisions at center of mass energy√s = 1.96 TeV. This search includes three production modes: associated production, gluon fusion and vector boson fusion. It also utilizes two decay channels: H→ ττ and H → WW. A new technique, dubbed the Global Boosted Decision Tree, is introduced which offers a means of providing continuity to a multivariate search as a function of a particular parameter, in this case, the mass of the Higgs boson. The observed (expected) limit on the ratio of cross section times branching fraction to the SM at 95% confidence level is 14.6 (16.0) at mH = 125 GeV. This result is combined with the related channel H + X → μτhjj and produced an observed (expected) limit of 9.0 (11.3) at mH = 125 GeV.

  14. Alligator Rivers Analogue project. Geochemical modelling of present-day groundwaters. Final Report - Volume 12

    Energy Technology Data Exchange (ETDEWEB)

    Sverjensky, D. A. [The John Hopkins Univ, Dept of Earth and Planetary Sciences, Baltimore (United States)

    1992-12-31

    The main purpose of this report is to summarize geochemical modeling studies of the present-day Koongarra groundwaters. Information on the present-day geochemistry and geochemical processes at Koongarra forms a basis for a present-day analogue for nuclear waste migration. The present-day analogue is built on studies of the mineralogy and petrology of the Koongarra deposit, and chemical analyses of present-day groundwaters from the deposit. The overall approach taken in the present study has been to carry out a series of aqueous speciation and state of saturation calculations, including chemical mass transfer calculations, to address the possible control over the chemistry of the present-day for the groundwaters at Koongarra. The most important implication of the present study for the migration of radionuclides is the strong role played by the water-rock interactions, both above and below the water table, influencing the overall chemical evolution of the groundwaters. Thus, the results show that the chemical evolution of waters is strongly controlled by the initial availability of CO{sub 2} and the mineral assemblage encountered, which together determine the major element evolution of the waters by controlling the pH. The relative rates of evolution of the pH and the oxidation state of the groundwaters are also critical to the mobility of uranium. The shallow Koongarra waters are sufficiently oxidising that they can dissolve and transport uranium even under acidic conditions. Under the more reducing condition of the deep groundwaters, is the pH level that permits uranium transport as carbonate complexes. However, if the oxidation state decreases to much lower levels, it would be expected that uranium become immobile. All the speciation and state of saturation calculations carried out in the present study are available from the author, on request 22 refs., 7 tabs., 18 figs.

  15. ICRF antenna modeling and simulation. Final report, March 1, 1993--May 31, 1996

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1996-08-30

    SAIC has undergone a three year research and development program in support of the DOE Office of Fusion Energy`s (OFE) program in Ion Cyclotron Range of Frequencies (ICRF) heating of present, next generation, and future plasma fusion devices. The effort entailed advancing theoretical models and numerical simulation technology of ICRF physics and engineering issues associated predominately with, but not limited to, tokamak Ion Cyclotron Heating (ICH) and fast wave current drive (FWCD). Ion cyclotron heating and current drive is a central element in all current and planned large fusion experiments. In recent years, the variety of uses for ICRF systems has expanded, and includes the following: (1) Heating sufficient to drive plasma to ignition. (a) Second-harmonic T heating. (b) He{sup 3} minority heating. (2) Second-harmonic He{sup 4} heating in H plasma (for non-activated phase). (3) Detailed equilibrium profile control minority heating. (a) Ion minority (He{sup 3}) CD (for profile control on inside of plasma). (b) Ion minority (He{sup 3}) CD (for profile control on outside of plasma). (4) Ion-ion hybrid regime majority ion heating. (5) Electron current drive. (6) Mode conversion to drive current. (7) Deuterium minority heating. (8) Sawtooth instability stabilization. (9) Alpha particle parameter enhancement. (10) The generation of minority tails by ICRF to simulate D-T plasma particle physics in a deuterium plasma. Optimization of ICRF antenna performance for either heating or current drive depends critically on the complex balance and interplay between the plasma physics and the electromechanical system requirements. For example, ITER IC rf designs call for an IC. system frequency range from 20 MHz to 100 MHz. Additionally, antenna designs and operational modes that minimize impurity production and induced sheath formation may degrade current drive efficiency. Such effects have been observed in experiments involving it versus zero antenna phasing.

  16. ICRF antenna modeling and simulation. Final report, March 1, 1993--May 31, 1996

    International Nuclear Information System (INIS)

    1996-01-01

    SAIC has undergone a three year research and development program in support of the DOE Office of Fusion Energy's (OFE) program in Ion Cyclotron Range of Frequencies (ICRF) heating of present, next generation, and future plasma fusion devices. The effort entailed advancing theoretical models and numerical simulation technology of ICRF physics and engineering issues associated predominately with, but not limited to, tokamak Ion Cyclotron Heating (ICH) and fast wave current drive (FWCD). Ion cyclotron heating and current drive is a central element in all current and planned large fusion experiments. In recent years, the variety of uses for ICRF systems has expanded, and includes the following: (1) Heating sufficient to drive plasma to ignition. (a) Second-harmonic T heating. (b) He 3 minority heating. (2) Second-harmonic He 4 heating in H plasma (for non-activated phase). (3) Detailed equilibrium profile control minority heating. (a) Ion minority (He 3 ) CD (for profile control on inside of plasma). (b) Ion minority (He 3 ) CD (for profile control on outside of plasma). (4) Ion-ion hybrid regime majority ion heating. (5) Electron current drive. (6) Mode conversion to drive current. (7) Deuterium minority heating. (8) Sawtooth instability stabilization. (9) Alpha particle parameter enhancement. (10) The generation of minority tails by ICRF to simulate D-T plasma particle physics in a deuterium plasma. Optimization of ICRF antenna performance for either heating or current drive depends critically on the complex balance and interplay between the plasma physics and the electromechanical system requirements. For example, ITER IC rf designs call for an IC. system frequency range from 20 MHz to 100 MHz. Additionally, antenna designs and operational modes that minimize impurity production and induced sheath formation may degrade current drive efficiency. Such effects have been observed in experiments involving it versus zero antenna phasing

  17. Project ANSICHT. Final repository concept and backfilling and sealing concept for the final repository site model SUeD; Projekt ANSICHT. Endlagerkonzept sowie Verfuell- und Verschlusskonzept fuer das Endlagerstandortmodell SUeD. Technischer Bericht

    Energy Technology Data Exchange (ETDEWEB)

    Jobmann, Michael; Lommerzheim, Andree

    2015-08-03

    In the frame of ANSICHT the methodology for the demonstration of safe enclosure for high-level heat generating radioactive wastes is described. The report is based on the safety requirements for final repository concepts and shows a first backfilling and sealing concept that was developed for the final repository site model SUeD. The final repository model SUeD is based on a horizontal line storage concept, the Gorleben (VSG) and ERATO container concept and the mine layout were adopted and adapted to the given conditions. The backfill and sealing concept includes migration barriers, line closures and shaft closures in the frame of a redundant and diverse enclosure system. For all technical and geotechnical barrier components the long-term functional requirements were defined. The backfilling concept of underground cavities considers the variety of possible cavities in the line and infrastructure areas.

  18. Novel Therapeutic Approaches for the Treatment of Depression and Cognitive Deficits in a Rodent Model of Gulf War Veterans Illness

    Science.gov (United States)

    2015-10-01

    forced swim test. No two tests were carried out on the same day. Depression is a complex psychological phenomenon and as such is difficult to analyze...grant has also given both of us professional development opportunities. Our abstract has been accepted for presentation at American Epilepsy ...and neurologists at the 2015 American Epilepsy Society annual meeting. Our work on model development is currently under-review at “Neurotoxicology

  19. Generation and Characterization of a Double Recombinant Monkeypox Virus for use in Animal Model Development and Therapeutic Evaluation

    Science.gov (United States)

    2012-09-27

    protect the virions from normal host immune responses (4, 41). Orthopoxviruses are genetically and antigenically similar. The central regions of...model for smallpox disease (35). Challenges associated with working with MPXV include the use of Bio Safety Level 3+ (BSL-3+) facilities in...release of weaponized variola or monkeypox, and ongoing monkeypox outbreaks in Africa have prompted investigations into the development of new vaccine

  20. Modeling hemoglobin and hemoglobin:haptoglobin complex clearance in a non-rodent species–pharmacokinetic and therapeutic implications

    OpenAIRE

    Boretti, Felicitas S.; Baek, Jin Hyen; Palmer, Andre F.; Schaer, Dominik J.; Buehler, Paul W.

    2014-01-01

    Background: Haptoglobin (Hp) prevents hemoglobin (Hb) extravasation and attenuates Hb induced tissue oxidation and vasoconstriction. Small animal models such as mouse, rat and guinea pig appear to demonstrate proof-of-concept for Hb neutralization by Hp in diverse pre-clinical conditions. However, these species differ significantly from humans in the clearance of Hb:Hp and demonstrate long persistence of circulating Hb:Hp complexes. Objective: The focus of this study is to understand Hb:Hp...

  1. Patient-Specific Dosimetry and Radiobiological Modeling of Targeted Radionuclide Therapy Grant - final report

    Energy Technology Data Exchange (ETDEWEB)

    George Sgouros, Ph.D.

    2007-03-20

    The broad, long-term objectives of this application are to 1. develop easily implementable tools for radionuclide dosimetry that can be used to predict normal organ toxicity and tumor response in targeted radionuclide therapy; and 2. to apply these tools to the analysis of clinical trial data in order to demonstrate dose-response relationships for radionuclide therapy treatment planning. The work is founded on the hypothesis that robust dose-response relationships have not been observed in targeted radionuclide therapy studies because currently available internal dosimetry methodologies are inadequate, failing to adequately account for individual variations in patient anatomy, radionuclide activity distribution/kinetics, absorbed dose-distribution, and absorbed dose-rate. To reduce development time the previously available software package, 3D-ID, one of the first dosimetry software packages to incorporate 3-D radionuclide distribution with individual patient anatomy; and the first to be applied for the comprehensive analysis of patient data, will be used as a platform to build the functionality listed above. The following specific aims are proposed to satisfy the long-term objectives stated above: 1. develop a comprehensive and validated methodology for converting one or more SPECT images of the radionuclide distribution to a 3-D representation of the cumulated activity distribution; 2. account for differences in tissue density and atomic number by incorporating an easily implementable Monte Carlo methodology for the 3-D dosimetry calculations; 3. incorporate the biologically equivalent dose (BED) and equivalent uniform dose (EUD) models to convert the spatial distribution of absorbed dose and dose-rate into equivalent single values that account for differences in dose uniformity and rate and that may be correlated with tumor response and normal organ toxicity; 4. test the hypothesis stated above by applying the resulting package to patient trials of targeted

  2. Medicare Program; Cancellation of Advancing Care Coordination Through Episode Payment and Cardiac Rehabilitation Incentive Payment Models; Changes to Comprehensive Care for Joint Replacement Payment Model: Extreme and Uncontrollable Circumstances Policy for the Comprehensive Care for Joint Replacement Payment Model. Final rule; interim final rule with comment period.

    Science.gov (United States)

    2017-12-01

    This final rule cancels the Episode Payment Models (EPMs) and Cardiac Rehabilitation (CR) Incentive Payment Model and rescinds the regulations governing these models. It also implements certain revisions to the Comprehensive Care for Joint Replacement (CJR) model, including: Giving certain hospitals selected for participation in the CJR model a one-time option to choose whether to continue their participation in the model; technical refinements and clarifications for certain payment, reconciliation and quality provisions; and a change to increase the pool of eligible clinicians that qualify as affiliated practitioners under the Advanced Alternative Payment Model (Advanced APM) track. An interim final rule with comment period is being issued in conjunction with this final rule in order to address the need for a policy to provide some flexibility in the determination of episode costs for providers located in areas impacted by extreme and uncontrollable circumstances.

  3. Assessment of Safety and Functional Efficacy of Stem Cell-Based Therapeutic Approaches Using Retinal Degenerative Animal Models

    Directory of Open Access Journals (Sweden)

    Tai-Chi Lin

    2017-01-01

    Full Text Available Dysfunction and death of retinal pigment epithelium (RPE and or photoreceptors can lead to irreversible vision loss. The eye represents an ideal microenvironment for stem cell-based therapy. It is considered an “immune privileged” site, and the number of cells needed for therapy is relatively low for the area of focused vision (macula. Further, surgical placement of stem cell-derived grafts (RPE, retinal progenitors, and photoreceptor precursors into the vitreous cavity or subretinal space has been well established. For preclinical tests, assessments of stem cell-derived graft survival and functionality are conducted in animal models by various noninvasive approaches and imaging modalities. In vivo experiments conducted in animal models based on replacing photoreceptors and/or RPE cells have shown survival and functionality of the transplanted cells, rescue of the host retina, and improvement of visual function. Based on the positive results obtained from these animal experiments, human clinical trials are being initiated. Despite such progress in stem cell research, ethical, regulatory, safety, and technical difficulties still remain a challenge for the transformation of this technique into a standard clinical approach. In this review, the current status of preclinical safety and efficacy studies for retinal cell replacement therapies conducted in animal models will be discussed.

  4. The Therapeutic Potential of CRISPR/Cas9 Systems in Oncogene-Addicted Cancer Types: Virally Driven Cancers as a Model System

    Directory of Open Access Journals (Sweden)

    Luqman Jubair

    2017-09-01

    Full Text Available The field of gene editing is undergoing unprecedented growth. The first ex vivo human clinical trial in China started in 2016, more than 1000 US patents have been filed, and there is exponential growth in publications. The ability to edit genes with high fidelity is promising for the development of new treatments for a range of diseases, particularly inherited conditions, infectious diseases, and cancers. For cancer, a major issue is the identification of driver mutations and oncogenes to target for therapeutic effect, and this requires the development of robust models with which to prove their efficacy. The challenge is that there is rarely a single critical gene. However, virally driven cancers, in which cells are addicted to the expression of a single viral oncogene in some cases, may serve as model systems for CRISPR/Cas therapies, as they did for RNAi. These models and systems offer an excellent opportunity to test both preclinical models and clinical conditions to examine the effectiveness of gene editing, and here we review the options and offer a way forward. Keywords: CRISPR/Cas9, virally-driven cancers, cervical cancer, oncogene-addiction

  5. Induced Pluripotent Stem Cells for Disease Modeling and Evaluation of Therapeutics for Niemann-Pick Disease Type A.

    Science.gov (United States)

    Long, Yan; Xu, Miao; Li, Rong; Dai, Sheng; Beers, Jeanette; Chen, Guokai; Soheilian, Ferri; Baxa, Ulrich; Wang, Mengqiao; Marugan, Juan J; Muro, Silvia; Li, Zhiyuan; Brady, Roscoe; Zheng, Wei

    2016-12-01

    : Niemann-Pick disease type A (NPA) is a lysosomal storage disease caused by mutations in the SMPD1 gene that encodes acid sphingomyelinase (ASM). Deficiency in ASM function results in lysosomal accumulation of sphingomyelin and neurodegeneration. Currently, there is no effective treatment for NPA. To accelerate drug discovery for treatment of NPA, we generated induced pluripotent stem cells from two patient dermal fibroblast lines and differentiated them into neural stem cells. The NPA neural stem cells exhibit a disease phenotype of lysosomal sphingomyelin accumulation and enlarged lysosomes. By using this disease model, we also evaluated three compounds that reportedly reduced lysosomal lipid accumulation in Niemann-Pick disease type C as well as enzyme replacement therapy with ASM. We found that α-tocopherol, δ-tocopherol, hydroxypropyl-β-cyclodextrin, and ASM reduced sphingomyelin accumulation and enlarged lysosomes in NPA neural stem cells. Therefore, the NPA neural stem cells possess the characteristic NPA disease phenotype that can be ameliorated by tocopherols, cyclodextrin, and ASM. Our results demonstrate the efficacies of cyclodextrin and tocopherols in the NPA cell-based model. Our data also indicate that the NPA neural stem cells can be used as a new cell-based disease model for further study of disease pathophysiology and for high-throughput screening to identify new lead compounds for drug development. Currently, there is no effective treatment for Niemann-Pick disease type A (NPA). To accelerate drug discovery for treatment of NPA, NPA-induced pluripotent stem cells were generated from patient dermal fibroblasts and differentiated into neural stem cells. By using the differentiated NPA neuronal cells as a cell-based disease model system, α-tocopherol, δ-tocopherol, and hydroxypropyl-β-cyclodextrin significantly reduced sphingomyelin accumulation in these NPA neuronal cells. Therefore, this cell-based NPA model can be used for further study of

  6. The Role of the Two-Pore Domain Potassium Channel TREK-1 in the Therapeutic Effects of Escitalopram in a Rat Model of Poststroke Depression.

    Science.gov (United States)

    Lin, Dai-Hua; Zhang, Xiang-Rong; Ye, Dong-Qing; Xi, Guang-Jun; Hui, Jiao-Jie; Liu, Shan-Shan; Li, Lin-Jiang; Zhang, Zhi-Jun

    2015-06-01

    Poststroke depression (PSD) is one of the most common neuropsychiatric complications after stroke. TREK-1, a two-pore-domain potassium channel, has been implicated in the pathogenesis of stroke and depression. The aim of this study was to investigate whether TREK-1 plays a role in the therapeutic effects of the selective serotonin reuptake inhibitor (SSRI) escitalopram in a rat PSD model. The whole-cell patch-clamp technique was performed to assess the effect of escitalopram on recombinant TREK-1 currents in HEK293 cells. The expression of TREK-1 mRNA and protein was measured in the hippocampus and prefrontal cortex (PFC), and neural stem cell (NSC) proliferation was detected in the hippocampal dentate gyrus (DG) in PSD rats after 3 weeks of escitalopram administration. Escitalopram reversibly inhibited TREK-1 currents in a concentration-dependent manner. Chronic treatment with escitalopram significantly reversed the reductions in weight gain, locomotor activity, and sucrose preference in PSD rats. The expressions of TREK-1 mRNA and protein were significantly increased in hippocampal CA1, CA3, DG, and PFC in PSD rats, with the exception of TREK-1 mRNA in hippocampal CA1. NSC proliferation was significantly decreased in hippocampal DG of PSD rats. Escitalopram significantly reversed the regional increases of TREK-1 expression and the reduction of hippocampal NSC proliferation in PSD rats. TREK-1 plays an important role in the therapeutic effects of the SSRI escitalopram in PSD model, making TREK-1 an attractive candidate molecule for further understanding the pathophysiology and treatment of PSD. © 2015 John Wiley & Sons Ltd.

  7. In Vivo Visualizing the IFN-β Response Required for Tumor Growth Control in a Therapeutic Model of Polyadenylic-Polyuridylic Acid Administration.

    Science.gov (United States)

    Nocera, David Andrés; Roselli, Emiliano; Araya, Paula; Nuñez, Nicolás Gonzalo; Lienenklaus, Stefan; Jablonska, Jadwiga; Weiss, Siegfried; Gatti, Gerardo; Brinkmann, Melanie M; Kröger, Andrea; Morón, Gabriel; Maccioni, Mariana

    2016-03-15

    The crucial role that endogenously produced IFN-β plays in eliciting an immune response against cancer has recently started to be elucidated. Endogenous IFN-β has an important role in immune surveillance and control of tumor development. Accordingly, the role of TLR agonists as cancer therapeutic agents is being revisited via the strategy of intra/peritumoral injection with the idea of stimulating the production of endogenous type I IFN inside the tumor. Polyadenylic-polyuridylic acid (poly A:U) is a dsRNA mimetic explored empirically in cancer immunotherapy a long time ago with little knowledge regarding its mechanisms of action. In this work, we have in vivo visualized the IFN-β required for the antitumor immune response elicited in a therapeutic model of poly A:U administration. In this study, we have identified the role of host type I IFNs, cell populations that are sources of IFN-β in the tumor microenvironment, and other host requirements for tumor control in this model. One single peritumoral dose of poly A:U was sufficient to induce IFN-β, readily visualized in vivo. IFN-β production relied mainly on the activation of the transcription factor IFN regulatory factor 3 and the molecule UNC93B1, indicating that TLR3 is required for recognizing poly A:U. CD11c(+) cells were an important, but not the only source of IFN-β. Host type I IFN signaling was absolutely required for the reduced tumor growth, prolonged mice survival, and the strong antitumor-specific immune response elicited upon poly A:U administration. These findings add new perspectives to the use of IFN-β-inducing compounds in tumor therapy. Copyright © 2016 by The American Association of Immunologists, Inc.

  8. Collaborative Visualization for Large-Scale Accelerator Electromagnetic Modeling (Final Report)

    International Nuclear Information System (INIS)

    Schroeder, William J.

    2011-01-01

    This report contains the comprehensive summary of the work performed on the SBIR Phase II, Collaborative Visualization for Large-Scale Accelerator Electromagnetic Modeling at Kitware Inc. in collaboration with Stanford Linear Accelerator Center (SLAC). The goal of the work was to develop collaborative visualization tools for large-scale data as illustrated in the figure below. The solutions we prop