WorldWideScience

Sample records for therapeutic models final

  1. Evaluation of final-year dental students concerning therapeutic decision making for proximal caries

    Directory of Open Access Journals (Sweden)

    Juliane Bervian

    2009-03-01

    Full Text Available This cross-sectional study aimed to determine the radiographic criteria used by final-year dental students when defining the need for restorative treatment for proximal caries, as well as investigating potentially associated factors in this therapeutic decision. A questionnaire with two schematic diagrams presenting five levels of proximal lesion penetration was administered to students attending the six private and three public dental schools in the state of Rio Grande do Sul, Southern Brazil. Absolute and relative frequencies were described and inferential statistics involving Chi-square and McNemar tests and simple logistic regression were carried out to assess variations in therapeutic decisions related to patient dentition (deciduous/permanent and gender, age and dental school (public/private. Of the 346 dental students assessed, 28.6% (99/346 indicated restorative treatment for lesions restricted to the enamel in deciduous teeth and 38.2% (132/346 indicated the same for permanent teeth, revealing a statistically significant difference (p = 0.001. Student gender and age were not associated with the therapeutic decision; however, a significant difference between dental schools was found when comparing restorative criteria in deciduous (p < 0.001 and permanent molars (p < 0.001. The odds of restorative decision in permanent teeth when the caries lesion was restricted to the enamel was 72% higher for students graduating from private schools compared to public schools (Odds Ratio: 1.72; 95% Confidence Interval: 1.03-2.90. These data demonstrate a large variation between the therapeutic decisions regarding proximal caries reported by final-year dental students and suggest that deep reflection is needed on the part of faculty in order to provide an evidence-based education.

  2. Evaluation of final-year dental students concerning therapeutic decision making for proximal caries.

    Science.gov (United States)

    Bervian, Juliane; Tovo, Maximiano Ferreira; Feldens, Carlos Alberto; Brusco, Larissa Corrêa; Rosa, Francinne Miranda da

    2009-01-01

    This cross-sectional study aimed to determine the radiographic criteria used by final-year dental students when defining the need for restorative treatment for proximal caries, as well as investigating potentially associated factors in this therapeutic decision. A questionnaire with two schematic diagrams presenting five levels of proximal lesion penetration was administered to students attending the six private and three public dental schools in the state of Rio Grande do Sul, Southern Brazil. Absolute and relative frequencies were described and inferential statistics involving Chi-square and McNemar tests and simple logistic regression were carried out to assess variations in therapeutic decisions related to patient dentition (deciduous/permanent) and gender, age and dental school (public/private). Of the 346 dental students assessed, 28.6% (99/346) indicated restorative treatment for lesions restricted to the enamel in deciduous teeth and 38.2% (132/346) indicated the same for permanent teeth, revealing a statistically significant difference (p = 0.001). Student gender and age were not associated with the therapeutic decision; however, a significant difference between dental schools was found when comparing restorative criteria in deciduous (p caries lesion was restricted to the enamel was 72% higher for students graduating from private schools compared to public schools (Odds Ratio: 1.72; 95% Confidence Interval: 1.03-2.90). These data demonstrate a large variation between the therapeutic decisions regarding proximal caries reported by final-year dental students and suggest that deep reflection is needed on the part of faculty in order to provide an evidence-based education.

  3. Video Editing and Medication to Produce a Therapeutic Self Model

    Science.gov (United States)

    Dowrick, Peter W.; Raeburn, John M.

    1977-01-01

    Self-modeling requires the production of a videotape in which the subject is seen to perform in a model way. A 4-year-old "hyperactive" boy, initially under psychotropic medication, was unable to role play suitable behaviors. Video editing was used to produce a videotape that when watched by the subject, had therapeutic effects as compared with an…

  4. A systematic review of prion therapeutics in experimental models.

    Science.gov (United States)

    Trevitt, Clare R; Collinge, John

    2006-09-01

    Prion diseases are transmissible, invariably fatal, neurodegenerative diseases which include Creutzfeldt-Jakob disease (CJD) in humans and bovine spongiform encephalopathy and scrapie in animals. A large number of putative treatments have been studied in experimental models over the past 30 years, with at best modest disease-modifying effects. The arrival of variant CJD in the UK in the 1990s has intensified the search for effective therapeutic agents, using an increasing number of animal, cellular and in vitro models with some recent promising proof of principle studies. Here, for the first time, we present a comprehensive systematic, rather than selective, review of published data on experimental approaches to prion therapeutics to provide a scientific resource for informing future therapeutics research, both in laboratory models and in clinical studies.

  5. Synaptic plasticity model of therapeutic sleep deprivation in major depression.

    Science.gov (United States)

    Wolf, Elias; Kuhn, Marion; Normann, Claus; Mainberger, Florian; Maier, Jonathan G; Maywald, Sarah; Bredl, Aliza; Klöppel, Stefan; Biber, Knut; van Calker, Dietrich; Riemann, Dieter; Sterr, Annette; Nissen, Christoph

    2016-12-01

    Therapeutic sleep deprivation (SD) is a rapid acting treatment for major depressive disorder (MDD). Within hours, SD leads to a dramatic decrease in depressive symptoms in 50-60% of patients with MDD. Scientifically, therapeutic SD presents a unique paradigm to study the neurobiology of MDD. Yet, up to now, the neurobiological basis of the antidepressant effect, which is most likely different from today's first-line treatments, is not sufficiently understood. This article puts the idea forward that sleep/wake-dependent shifts in synaptic plasticity, i.e., the neural basis of adaptive network function and behavior, represent a critical mechanism of therapeutic SD in MDD. Particularly, this article centers on two major hypotheses of MDD and sleep, the synaptic plasticity hypothesis of MDD and the synaptic homeostasis hypothesis of sleep-wake regulation, and on how they can be integrated into a novel synaptic plasticity model of therapeutic SD in MDD. As a major component, the model proposes that therapeutic SD, by homeostatically enhancing cortical synaptic strength, shifts the initially deficient inducibility of associative synaptic long-term potentiation (LTP) in patients with MDD in a more favorable window of associative plasticity. Research on the molecular effects of SD in animals and humans, including observations in the neurotrophic, adenosinergic, monoaminergic, and glutamatergic system, provides some support for the hypothesis of associative synaptic plasticity facilitation after therapeutic SD in MDD. The model proposes a novel framework for a mechanism of action of therapeutic SD that can be further tested in humans based on non-invasive indices and in animals based on direct studies of synaptic plasticity. Further determining the mechanisms of action of SD might contribute to the development of novel fast acting treatments for MDD, one of the major health problems worldwide. Copyright © 2015 Elsevier Ltd. All rights reserved.

  6. 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.

  7. Investigating Supervisory Relationships and Therapeutic Alliances Using Structural Equation Modeling

    Science.gov (United States)

    DePue, Mary Kristina; Lambie, Glenn W.; Liu, Ren; Gonzalez, Jessica

    2016-01-01

    The authors used structural equation modeling to examine the contribution of supervisees' supervisory relationship levels to therapeutic alliance (TA) scores with their clients in practicum. Results showed that supervisory relationship scores positively contributed to the TA. Client and counselor ratings of the TA also differed.

  8. Animal Models, Prophylaxis, and Therapeutics for Arenavirus Infections

    Directory of Open Access Journals (Sweden)

    Eric Vela

    2012-09-01

    Full Text Available Arenaviruses are enveloped, bipartite negative single-stranded RNA viruses that can cause a wide spectrum of disease in humans and experimental animals including hemorrhagic fever. The majority of these viruses are rodent-borne and the arenavirus family can be divided into two groups: the Lassa-Lymphocytic choriomeningitis serocomplex and the Tacaribe serocomplex. Arenavirus-induced disease may include characteristic symptoms ranging from fever, malaise, body aches, petechiae, dehydration, hemorrhage, organ failure, shock, and in severe cases death. Currently, there are few prophylactic and therapeutic treatments available for arenavirus-induced symptoms. Supportive care and ribavirin remain the predominant strategies for treating most of the arenavirus-induced diseases. Therefore, efficacy testing of novel therapeutic and prophylactic strategies in relevant animal models is necessary. Because of the potential for person-to-person spread, the ability to cause lethal or debilitating disease in humans, limited treatment options, and potential as a bio-weapon, the development of prophylactics and therapeutics is essential. This article reviews the current arenavirus animal models and prophylactic and therapeutic strategies under development to treat arenavirus infection.

  9. Elaborating the assimilation model: Introduction to a special section on case studies of setbacks within sessions and therapeutic collaboration.

    Science.gov (United States)

    Caro Gabalda, Isabel; Stiles, William B

    2016-11-01

    This article introduces a Special Section of case studies that focus on therapeutic collaboration and setbacks in the process of assimilation with the aim of contributing to the evolution of the assimilation model of therapeutic change. The first study examined setbacks in two depression cases (a good vs. a poor outcome) treated with emotion-focused therapy. The second article traced how therapist activities and positions toward internal voices were associated with setbacks in a case treated with linguistic therapy of evaluation. The third article studied contributions of therapeutic collaboration for both advances and setbacks in assimilation in two contrasting cases treated with emotion-focused therapy. The fourth and final article analyzed the therapeutic collaboration in episodes of ambivalence in two cases of narrative therapy (one good outcome, one poor outcome) reflecting on the implications for the assimilation model's perspective on the therapeutic relationship. This Introduction concludes by offering some suggestions for theory-building within the assimilation model.

  10. 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

  11. 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...

  12. Zebrafish: predictive model for targeted cancer therapeutics from nature.

    Science.gov (United States)

    Zulkhernain, Nursafwana Syazwani; Teo, Soo Hwang; Patel, Vyomesh; Tan, Pei Jean

    2014-01-01

    Targeted therapy, the treatment of cancer based on an underlying genetic alteration, is rapidly gaining favor as the preferred therapeutic approach. To date, although natural products represent a rich resource of bio-diverse drug candidates, only a few have been identified to be effective as targeted cancer therapies largely due to the incompatibilities to current high-throughput screening methods. In this article, we review the utility of a zebrafish developmental screen for bioactive natural product-based compounds that target signaling pathways that are intimately shared with those in humans. Any bioactive compound perturbing signaling pathways identified from phenotypic developmental defects in zebrafish embryos provide an opportunity for developing targeted therapies for human cancers. This model provides a promising tool in the search for targeted cancer therapeutics from natural products.

  13. Mining and modeling human genetics for autism therapeutics.

    Science.gov (United States)

    Smith, Daniel G; Ehlers, Michael D

    2012-10-01

    A growing understanding of the genetic origins of autism spectrum disorders (ASDs) and the impact of ASD risk genes on synaptic function presents new opportunities for drug discovery. Large-scale human genetics studies have begun to reveal molecular pathways and potential therapeutic drug targets. Subsequent validation and characterization of ASD risk genes in mouse models holds promise for defining relevant cellular mechanisms and brain circuits associated with the core behavioral symptoms of autism. Here we review recent advances in the molecular therapeutics in ASDs and discuss opportunities and obstacles for converting emerging biology into new medicines. We present emerging concepts on the impact of risk genes during development and adulthood that define points of intervention. We further highlight ongoing clinical trials in patients with syndromic forms of autism. These clinical studies will be an important test of the utility of human genetics as a starting point for drug discovery in ASDs. Copyright © 2012 Elsevier Ltd. All rights reserved.

  14. [Stage models of homosexual identity formation. Implications for therapeutic practice].

    Science.gov (United States)

    Mijas, Magdalena; Iniewicz, Grzegorz; Grabski, Bartosz

    2012-01-01

    The authors discuss stage models of gay and lesbian identity formation first proposed during the 1970s within affirmative approaches to homosexuality. The process of developing homosexual identity is characterized here with linearly ordered stages distinguished around major developmental events leading to new self-definition. Among many stage proposals the authors have chosen and presented two: by Vivienne Cass and Susan McCarn with Ruth Fassinger. The presented models were analysed in terms of their usefulness in therapeutic practice aimed at promoting the formation of gay identity, for which they have been originally designed. An important part of this discussion is evaluation of the accuracy of developmental process descriptions contained in stage models.

  15. The Atavistic Model of Cancer: Evidence, Objections, Therapeutic Value

    Science.gov (United States)

    Lineweaver, Charles

    2014-03-01

    As cancer progresses tumor cells dedifferentiate. In the atavistic model this dedifferentiation is interpreted as a reversion to phylogenetically earlier capabilities (Davies & Lineweaver 2011). Since there is an identifiable order to the evolution of capabilities, the more recently evolved capabilities are more likely to be compromised first during cancer progression. A loss of capabilities based on the phylogenetic order of evolution suggests a therapeutic strategy for targeting cancer - design challenges that can only be met by the recently evolved capabilities still intact in normal cells, but lost in cancer cells. Such a target-the-weakness therapeutic strategy contrasts with most current therapies that target the main strength of cancer: cell proliferation. Here, we describe several examples of this target-the-weakness strategy. Our most detailed example involves the immune system. As cancer progresses, the atavistic model suggests that cancer cells lose contact with the more recently evolved adaptive immune system of the host (the basis of vaccination). The absence of adaptive immunity in immunosuppressed tumor environments is an irreversible weakness of cancer that can be exploited by creating a challenge that only the presence of adaptive immunity can meet. Thus, we propose the post-vaccination inoculation of disease at dosages that the recently evolved (and vaccination-primed) adaptive immune system will be able to destroy in normal cells, but not in the immunosuppressed microenvironment of tumor cells. Co-author: Paul Davies (Arizona State University)

  16. Neonatal Hypoxia Ischaemia: Mechanisms, Models, and Therapeutic Challenges

    Directory of Open Access Journals (Sweden)

    Lancelot J. Millar

    2017-05-01

    Full Text Available Neonatal hypoxia-ischaemia (HI is the most common cause of death and disability in human neonates, and is often associated with persistent motor, sensory, and cognitive impairment. Improved intensive care technology has increased survival without preventing neurological disorder, increasing morbidity throughout the adult population. Early preventative or neuroprotective interventions have the potential to rescue brain development in neonates, yet only one therapeutic intervention is currently licensed for use in developed countries. Recent investigations of the transient cortical layer known as subplate, especially regarding subplate’s secretory role, opens up a novel set of potential molecular modulators of neonatal HI injury. This review examines the biological mechanisms of human neonatal HI, discusses evidence for the relevance of subplate-secreted molecules to this condition, and evaluates available animal models. Neuroserpin, a neuronally released neuroprotective factor, is discussed as a case study for developing new potential pharmacological interventions for use post-ischaemic injury.

  17. Neonatal Hypoxia Ischaemia: Mechanisms, Models, and Therapeutic Challenges.

    Science.gov (United States)

    Millar, Lancelot J; Shi, Lei; Hoerder-Suabedissen, Anna; Molnár, Zoltán

    2017-01-01

    Neonatal hypoxia-ischaemia (HI) is the most common cause of death and disability in human neonates, and is often associated with persistent motor, sensory, and cognitive impairment. Improved intensive care technology has increased survival without preventing neurological disorder, increasing morbidity throughout the adult population. Early preventative or neuroprotective interventions have the potential to rescue brain development in neonates, yet only one therapeutic intervention is currently licensed for use in developed countries. Recent investigations of the transient cortical layer known as subplate, especially regarding subplate's secretory role, opens up a novel set of potential molecular modulators of neonatal HI injury. This review examines the biological mechanisms of human neonatal HI, discusses evidence for the relevance of subplate-secreted molecules to this condition, and evaluates available animal models. Neuroserpin, a neuronally released neuroprotective factor, is discussed as a case study for developing new potential pharmacological interventions for use post-ischaemic injury.

  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. SEISMIC MODELING ENGINES PHASE 1 FINAL REPORT

    Energy Technology Data Exchange (ETDEWEB)

    BRUCE P. MARION

    2006-02-09

    Seismic modeling is a core component of petroleum exploration and production today. Potential applications include modeling the influence of dip on anisotropic migration; source/receiver placement in deviated-well three-dimensional surveys for vertical seismic profiling (VSP); and the generation of realistic data sets for testing contractor-supplied migration algorithms or for interpreting AVO (amplitude variation with offset) responses. This project was designed to extend the use of a finite-difference modeling package, developed at Lawrence Berkeley Laboratories, to the advanced applications needed by industry. The approach included a realistic, easy-to-use 2-D modeling package for the desktop of the practicing geophysicist. The feasibility of providing a wide-ranging set of seismic modeling engines was fully demonstrated in Phase I. The technical focus was on adding variable gridding in both the horizontal and vertical directions, incorporating attenuation, improving absorbing boundary conditions and adding the optional coefficient finite difference methods.

  20. iFlorida model deployment final evaluation report.

    Science.gov (United States)

    2009-01-01

    This document is the final report for the evaluation of the USDOT-sponsored Surface Transportation Security and Reliability Information System Model Deployment, or iFlorida Model Deployment. This report discusses findings in the following areas: ITS ...

  1. 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. Welfare...... 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......, acceptable welfare and not classified. This evaluation model is tuned according to the views of experts from animal and social sciences, and stakeholders....

  2. Therapeutic liver repopulation in a mouse model of hypercholesterolemia.

    Science.gov (United States)

    Mitchell, C; Mignon, A; Guidotti, J E; Besnard, S; Fabre, M; Duverger, N; Parlier, D; Tedgui, A; Kahn, A; Gilgenkrantz, H

    2000-07-01

    Liver repopulation constitutes an attractive approach for the treatment of liver disorders or of diseases requiring abundant secretion of an active protein. We have described previously a model of selective repopulation of a normal liver by Fas/CD95-resistant hepatocytes, in which we achieved up to 16% hepatocyte repopulation. In the present study, we investigated the therapeutic efficacy of this strategy. With this aim, apolipoprotein E (ApoE) knockout mice were transplanted with Fas/CD95-resistant hepatocytes which constitutively express ApoE. Transplanted mice were submitted to weekly injections of non-lethal doses of the Fas agonist antibody Jo2. After 8 weeks of treatment, we obtained up to 30% of the normal level of plasma ApoE. ApoE secretion was accompanied by a drastic and significant decrease in total plasma cholesterol, which even fell to normal levels. Moreover, this secretion was sufficient to markedly reduce the progression of atherosclerosis. These results demonstrate the efficacy of this repopulation approach for correcting a deficiency in a protein secreted by the liver.

  3. 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

  4. Role Playing Using a Simulated Pharmacy and Therapeutics Committee Model

    Science.gov (United States)

    Fletcher, H. Patrick; Popvich, Nicholas G.

    1977-01-01

    Within a simulated Pharmacy and Therapeutics Committee format, role play is used at Purdue University to illustrate to students the concepts of drug product evaluation and selection as these apply to a hospital formulary system. (Author/LBH)

  5. Demonstration of Therapeutic Equivalence of Fluconazole Generic Products in the Neutropenic Mouse Model of Disseminated Candidiasis

    National Research Council Canada - National Science Library

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

    2015-01-01

    .... We used the neutropenic mice model of disseminated candidiasis to challenge the therapeutic equivalence of three generic products of fluconazole compared with the innovator in terms of concentration...

  6. Predictive modelling of boiler fouling. Final report.

    Energy Technology Data Exchange (ETDEWEB)

    Chatwani, A

    1990-12-31

    A spectral element method embodying Large Eddy Simulation based on Re- Normalization Group theory for simulating Sub Grid Scale viscosity was chosen for this work. This method is embodied in a computer code called NEKTON. NEKTON solves the unsteady, 2D or 3D,incompressible Navier Stokes equations by a spectral element method. The code was later extended to include the variable density and multiple reactive species effects at low Mach numbers, and to compute transport of large particles governed by inertia. Transport of small particles is computed by treating them as trace species. Code computations were performed for a number of test conditions typical of flow past a deep tube bank in a boiler. Results indicate qualitatively correct behavior. Predictions of deposition rates and deposit shape evolution also show correct qualitative behavior. These simulations are the first attempts to compute flow field results at realistic flow Reynolds numbers of the order of 10{sup 4}. Code validation was not done; comparison with experiment also could not be made as many phenomenological model parameters, e.g., sticking or erosion probabilities and their dependence on experimental conditions were not known. The predictions however demonstrate the capability to predict fouling from first principles. Further work is needed: use of large or massively parallel machine; code validation; parametric studies, etc.

  7. Transgenic Mouse Models of Alzheimer Disease: Developing a Better Model as a Tool for Therapeutic Interventions

    Science.gov (United States)

    Kitazawa, Masashi; Medeiros, Rodrigo; LaFerla, Frank M.

    2015-01-01

    Alzheimer disease (AD) is the leading cause of dementia among elderly. Currently, no effective treatment is available for AD. Analysis of transgenic mouse models of AD has facilitated our understanding of disease mechanisms and provided valuable tools for evaluating potential therapeutic strategies. In this review, we will discuss the strengths and weaknesses of current mouse models of AD and the contribution towards understanding the pathological mechanisms and developing effective therapies. PMID:22288400

  8. 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…

  9. Characterising the tumour morphological response to therapeutic intervention: an ex vivo model

    Directory of Open Access Journals (Sweden)

    Anne Savage

    2013-01-01

    In cancer, morphological assessment of histological tissue samples is a fundamental part of both diagnosis and prognosis. Image analysis offers opportunities to support that assessment through quantitative metrics of morphology. Generally, morphometric analysis is carried out on two-dimensional tissue section data and so only represents a small fraction of any tumour. We present a novel application of three-dimensional (3D morphometrics for 3D imaging data obtained from tumours grown in a culture model. Minkowski functionals, a set of measures that characterise geometry and topology in n-dimensional space, are used to quantify tumour topology in the absence of and in response to therapeutic intervention. These measures are used to stratify the morphological response of tumours to therapeutic intervention. Breast tumours are characterised by estrogen receptor (ER status, human epidermal growth factor receptor (HER2 status and tumour grade. Previously, we have shown that ER status is associated with tumour volume in response to tamoxifen treatment ex vivo. Here, HER2 status is found to predict the changes in morphology other than volume as a result of tamoxifen treatment ex vivo. Finally, we show the extent to which Minkowski functionals might be used to predict tumour grade. Minkowski functionals are generalisable to any 3D data set, including in vivo and cellular systems. This quantitative topological analysis can provide a valuable link among biomarkers, drug intervention and tumour morphology that is complementary to existing, non-morphological measures of tumour response to intervention and could ultimately inform patient treatment.

  10. Neonatal Hypoxia Ischaemia: Mechanisms, Models, and Therapeutic Challenges

    OpenAIRE

    Millar, Lancelot J.; Shi, Lei; Hoerder-Suabedissen, Anna; Molnár, Zoltán

    2017-01-01

    Neonatal hypoxia-ischaemia (HI) is the most common cause of death and disability in human neonates, and is often associated with persistent motor, sensory, and cognitive impairment. Improved intensive care technology has increased survival without preventing neurological disorder, increasing morbidity throughout the adult population. Early preventative or neuroprotective interventions have the potential to rescue brain development in neonates, yet only one therapeutic intervention is currentl...

  11. The final size of a SARS epidemic model without quarantine

    Science.gov (United States)

    Hsu, Sze-Bi; Roeger, Lih-Ing W.

    2007-09-01

    In this article, we present the continuing work on a SARS model without quarantine by Hsu and Hsieh [Sze-Bi Hsu, Ying-Hen Hsieh, Modeling intervention measures and severity-dependent public response during severe acute respiratory syndrome outbreak, SIAM J. Appl. Math. 66 (2006) 627-647]. An "acting basic reproductive number" [psi] is used to predict the final size of the susceptible population. We find the relation among the final susceptible population size S[infinity], the initial susceptible population S0, and [psi]. If [psi]>1, the disease will prevail and the final size of the susceptible, S[infinity], becomes zero; therefore, everyone in the population will be infected eventually. If [psi]0 which means part of the population will never be infected. Also, when S[infinity]>0, S[infinity] is increasing with respect to the initial susceptible population S0, and decreasing with respect to the acting basic reproductive number [psi].

  12. 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.

  13. Final Report Fermionic Symmetries and Self consistent Shell Model

    Energy Technology Data Exchange (ETDEWEB)

    Larry Zamick

    2008-11-07

    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.

  14. 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.

  15. Organic acid modeling and model validation: Workshop summary. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Sullivan, T.J.; Eilers, J.M.

    1992-08-14

    A workshop was held in Corvallis, Oregon on April 9--10, 1992 at the offices of E&S Environmental Chemistry, Inc. The purpose of this workshop was to initiate research efforts on the entitled ``Incorporation of an organic acid representation into MAGIC (Model of Acidification of Groundwater in Catchments) and testing of the revised model using Independent data sources.`` The workshop was attended by a team of internationally-recognized experts in the fields of surface water acid-bass chemistry, organic acids, and watershed modeling. The rationale for the proposed research is based on the recent comparison between MAGIC model hindcasts and paleolimnological inferences of historical acidification for a set of 33 statistically-selected Adirondack lakes. Agreement between diatom-inferred and MAGIC-hindcast lakewater chemistry in the earlier research had been less than satisfactory. Based on preliminary analyses, it was concluded that incorporation of a reasonable organic acid representation into the version of MAGIC used for hindcasting was the logical next step toward improving model agreement.

  16. Outcome Evaluation of Therapeutic Community Model in Iran

    Directory of Open Access Journals (Sweden)

    Nasrindokht Sadir

    2013-01-01

    Full Text Available BackgroundEvaluation of treatment programs in addiction field is a prerequisite to improve the quality of care. This study aimed to investigate the effectiveness of Therapeutic Community (TC program in Iran. MethodsIndividuals who had voluntarily enrolled in the TC center within a period of seven years, from early 2005 to late 2011, entered the study. Those who successfully completed the 14-week residential course were considered as ‘completers’. They were subsequently called in for urine test and interviews using Maudsley Addiction Profile. Urine test was conducted to determine if they were positive for heroin, opium, methadone, methamphetamine, bupronorphine, hashish, and tramadol. ResultsA number of 378 individuals with mean (± SD age of 32.5 ± 7.8 enrolled in the TC program during the study period, 240 individuals of whom completed the 14 weeks course (69.0%. At the end of the sixth year, 22% of the participants were in abstinence. Physical and mental health in abstainers proved to be of better conditions than those of non-abstainers (P<0.05. ConclusionConsidering the TC outcome in other countries, it seems that TC maintains an acceptable effectiveness in Iran. Prospective controlled studies are warranted to investigate the outcomes in more details.

  17. Computer Implementation of a New Therapeutic Model for GBM Tumor

    Directory of Open Access Journals (Sweden)

    Ali Jamali Nazari

    2014-01-01

    Full Text Available Modeling the tumor behavior in the host organ as function of time and radiation dose has been a major study in the previous decades. Here the effort in estimation of cancerous and normal cell proliferation and growth in glioblastoma multiform (GBM tumor is presented. This paper introduces a new mathematical model in the form of differential equation of tumor growth. The model contains dose delivery amount in the treatment scheme as an input term. It also can be utilized to optimize the treatment process in order to increase the patient survival period. Gene expression programming (GEP as a new concept is used for estimating this model. The LQ model has also been applied to GEP as an initial value, causing acceleration and improvement of the algorithm estimation. The model shows the number of the tumor and normal brain cells during the treatment process using the status of normal and cancerous cells in the initiation of treatment, the timing and amount of dose delivery to the patient, and a coefficient that describes the brain condition. A critical level is defined for normal cell when the patient’s death occurs. In the end the model has been verified by clinical data obtained from previous accepted formulae and some of our experimental resources. The proposed model helps to predict tumor growth during treatment process in which further treatment processes can be controlled.

  18. 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; Crawley, Jacqueline N

    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.

  19. 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.

  20. Exploitation of parallelism in climate models. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Baer, Ferdinand; Tribbia, Joseph J.; Williamson, David L.

    2001-02-05

    This final report includes details on the research accomplished by the grant entitled 'Exploitation of Parallelism in Climate Models' to the University of Maryland. The purpose of the grant was to shed light on (a) how to reconfigure the atmospheric prediction equations such that the time iteration process could be compressed by use of MPP architecture; (b) how to develop local subgrid scale models which can provide time and space dependent parameterization for a state-of-the-art climate model to minimize the scale resolution necessary for a climate model, and to utilize MPP capability to simultaneously integrate those subgrid models and their statistics; and (c) how to capitalize on the MPP architecture to study the inherent ensemble nature of the climate problem. In the process of addressing these issues, we created parallel algorithms with spectral accuracy; we developed a process for concurrent climate simulations; we established suitable model reconstructions to speed up computation; we identified and tested optimum realization statistics; we undertook a number of parameterization studies to better understand model physics; and we studied the impact of subgrid scale motions and their parameterization in atmospheric models.

  1. Therapeutic alliance and treatment outcome in the primary care behavioral health model.

    Science.gov (United States)

    Corso, Kent A; Bryan, Craig J; Corso, Meghan L; Kanzler, Kathryn E; Houghton, David C; Ray-Sannerud, Bobbie; Morrow, Chad E

    2012-06-01

    The current study investigated therapeutic alliance and clinical improvement within an integrated primary care behavioral health model. Participants included 542 primary care patients seen in two large family medicine clinics. Mental health symptoms and functioning were assessed using the 20-item Behavioral Health Measure (Kopta & Lowery, 2002) at the beginning of each patient appointment. Therapeutic alliance was measured with the Therapeutic Bond Scale (CelestHealth Solutions, 2008) following an initial appointment with one of 22 behavioral health consultants (BHCs). Primary care patients rated their therapeutic alliance following a first appointment with a BHC as statistically stronger than alliance ratings from a previously reported sample of outpatient psychotherapy patients after the second, third, and fourth psychotherapy sessions (Kopta, Saunders, Lutz, Kadison, & Hirsch, 2009). Results of a bootstrapped linear regression analysis indicated that therapeutic alliance assessed after the first primary care behavioral health appointment was not associated with eventual clinical change in mental health symptoms and functioning. A strong therapeutic alliance was able to be formed in a primary care behavioral health modality. This exceeded the magnitude found in outpatient psychotherapy alliance ratings. Early therapeutic alliance was unrelated to overall clinical improvement in primary care.

  2. Theoretical Modeling of Coagulation Management With Therapeutic Plasma or Prothrombin Complex Concentrate.

    Science.gov (United States)

    Schöchl, Herbert; Grottke, Oliver; Sutor, Ken; Dony, Kieron; Schreiber, Martin; Ranucci, Marco; Collins, Peter W

    2017-11-01

    Prothrombin complex concentrates (PCCs) have been associated with a possible risk of thromboembolic complications, potentially attributable to an increased ratio of the plasma concentration of factor II (FII) to antithrombin (AT). We developed a mathematical model to examine the relationship between amounts of PCC or therapeutic plasma administered, and plasma levels of FII and AT. The model showed that PCC produces substantial increases in plasma levels of FII but only small changes in AT, increasing the FII:AT ratio. Therapeutic plasma was shown to have only modest effects on levels of FII or AT, unless high doses are used.

  3. The pig as a large preclinical model for therapeutic human anti-cancer vaccine development

    DEFF Research Database (Denmark)

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

    2016-01-01

    Development of therapeutic cancer vaccines has largely been based on rodent models and the majority failed to establish therapeutic responses in clinical trials. We therefore used pigs as a large animal model for human cancer vaccine development due to the large similarity between the porcine...... response. To test the CTL functionality we designed an in vivo cytotoxicity assay, where purified autologous PBMCs fluorescently labelled and pulsed with IDO-derived target peptides were administered intravenously into each donor and killing capacity was measured by flow cytometry. All animals receiving 10...

  4. A novel approach to modeling unstable EOR displacements. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Peters, E.J.

    1994-04-01

    Most enhanced oil recovery schemes involve the displacement of a more dense and more viscous oil by a less dense and less viscous fluid in a heterogeneous porous medium. The interaction of heterogeneity with the several competing forces, namely, viscous, capillary, gravitational, and dispersive forces, can conspire to make the displacements unstable and difficult to model and to predict. The objective of this research was to develop a systematic methodology for modeling unstable fluid displacements in heterogeneous media. Flow visualization experiments were conducted using X-ray computed tomography imaging and a video imaging workstation to gain insights into the dynamics of unstable displacements, acquire detailed quantitative experimental image data for calibrating numerical models of unstable displacements, and image and characterize heterogeneities in laboratory cores geostatistically. High-resolution numerical models modified for use on vector-architecture supercomputers were used to replicate the image data. Geostatistical models of reservoir heterogeneity were incorporated in order to study the interaction of hydrodynamic instability and heterogeneity in reservoir displacements. Finally, a systematic methodology for matching the experimental data with the numerical models and scaling the laboratory results to other systems were developed. The result is a new method for predicting the performance of unstable EOR displacements in the field based on small-scale displacements in the laboratory. The methodology is general and can be applied to forecast the performance of most processes that involve fluid flow and transport in porous media. Therefore, this research should be of interest to those involved in forecasting the performance of enhanced oil recovery processes and the spreading of contaminants in heterogeneous aquifers.

  5. Mammalian Models of Duchenne Muscular Dystrophy: Pathological Characteristics and Therapeutic Applications

    Directory of Open Access Journals (Sweden)

    Akinori Nakamura

    2011-01-01

    Full Text Available Duchenne muscular dystrophy (DMD is a devastating X-linked muscle disorder characterized by muscle wasting which is caused by mutations in the DMD gene. The DMD gene encodes the sarcolemmal protein dystrophin, and loss of dystrophin causes muscle degeneration and necrosis. Thus far, therapies for this disorder are unavailable. However, various therapeutic trials based on gene therapy, exon skipping, cell therapy, read through therapy, or pharmaceutical agents have been conducted extensively. In the development of therapy as well as elucidation of pathogenesis in DMD, appropriate animal models are needed. Various animal models of DMD have been identified, and mammalian (murine, canine, and feline models are indispensable for the examination of the mechanisms of pathogenesis and the development of therapies. Here, we review the pathological features of DMD and therapeutic applications, especially of exon skipping using antisense oligonucleotides and gene therapies using viral vectors in murine and canine models of DMD.

  6. HPV as a model for the development of prophylactic and therapeutic cancer vaccines.

    Science.gov (United States)

    Samara, Raed N; Khleif, Samir N

    2009-08-01

    HPV has been linked to many human malignancies and, as such, represents a major public health crisis. The understanding of HPV biology, however, has helped tremendously in developing prophylactic vaccines, which should help in decreasing mortality due to HPV infections. Understanding HPV biology has allowed researchers to use the virus as a model for the development of not only prophylactic vaccines, but also therapeutic ones. The advantages of HPV as a model stem from the limited number of proteins encoded by the HPV genome that can be targeted by vaccines, and also from the restricted expression of certain viral proteins during different stages of infection. In this review, we discuss how HPV can be used as a model for the development of both prophylactic and therapeutic vaccines.

  7. Online learning applied to a course on rational therapeutics: an international comparison between final year students of two medical schools.

    Science.gov (United States)

    Likic, Robert; White, Casey; Cinti, Sandro; Purkiss, Joel; Fantone, Joseph; Chapman, Chris; Bielen, Luka; Francetic, Igor; Engleberg, Cary

    2013-02-01

    Poor prescribing is probably the most common cause of preventable medication errors and many of these events involve junior doctors. In 2009, an electronic problem-based therapeutics course developed at the University of Michigan Medical School (UMMS) was translated and adapted for use at the University of Zagreb Medical School (UZMS). After students from both schools took the course in 2010, we compared their responses with an online questionnaire addressing the course quality and its effectiveness. There were no statistically significant differences in the overall average grades awarded for the course (UZMS 4.11 ± 0.86 vs. UMMS 3.96 ± 0.93; 95% CI mean difference (MD) -0.36, 0.07; P = 0.175) with both student groups expressing high satisfaction rates with its quality, accessibility and overall design. UZMS students reported spending less time working through the course than their American colleagues (2.14 ± 1.01 vs. 2.89 ± 1.02 on a five point Likert scale; 95% CI MD 0.51, 0.99; P students indicated greater difficulty with course materials (3.54 ± 0.59 vs. 3.25 ± 0.59; 95% CI MD -0.42, -0.15; P students. It is possible to adapt and translate successfully whole online teaching resources and implement them internationally in different countries and health care systems, achieving similar, high student satisfaction rates while decreasing administrative and cost burdens. Web based learning may have great potential to offer a cost effective and safe environment in which prescribing skills can be improved. © 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

  8. 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.

  9. Therapeutic effects of hyaluronidase on acquired lymphedema using a newly developed mouse limb model

    Science.gov (United States)

    Roh, Kangsan; Cho, Sungrae; Park, Jae-hyun; Yoo, Byong Chul; Kim, Won-Ki; Kim, Seok-ki; Park, Kyewon; Kang, Hee; Ku, Jin-mo; Yeom, Chang-Hwan; Lee, Kyunghoon

    2017-01-01

    Acquired lymphedema is one of the most dreaded side effects of cancer treatment, such as surgical treatment or irradiation. However, due to the lack of appropriate animal models, there is no effective therapeutic method to cure acquired lymphedema. To develop a reproducible acquired lymphedema animal model, we devised a mouse hind limb model by removing a superficial inguinal lymph node, a popliteal lymph node, a deep inguinal lymph node, and the femoral lymphatic vessel. We measured the volume of lymphedematous leg and observed the change in level of hyaluronic acid (HA) and lymphangiogenic factors after injecting hyaluronidase. Our model showed the distinguishable swelling and the reliable symptoms compared to previously reported models. In the lymphedematous regions of our model, we confirmed that HA, a major component of extracellular matrix, accumulated to higher levels than in a normal mouse. This lymphedema volume was rapidly reduced by treating hyaluronidase. Following hyaluronidase injection, the lymphedematous region of our model resembled a normal hind limb. Our findings indicated that hyaluronidase promoted lymphangiogenesis on the lymphedematous limb. Based on hyaluronidase treatment in the lymphedematous region, this could potentially be a new therapeutic approach for acquired lymphedema mediated through the modification of the size of HA fragments. Impact statement In this manuscript, the essence of the work described in this manuscript involves the development of (1) a mouse limb model showing acquired lymphedema and (2) a potent therapeutic treatment using hyaluronidase to remedy acquired lymphedema in our model. In order to develop a reproducible acquired lymphedema animal model that reflects the most common symptoms experienced by lymphedema patients, we devised a mouse hind limb model by removing lymph nodes and lymphatics. Our model showed the distinguishable swelling and the reliable symptoms compared to previously reported models. In the

  10. 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.

    2011-01-01

    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. PMID:22088026

  11. Chronic inflammatory demyelinating polyradiculoneuropathy: A new animal model for new therapeutic targets.

    Science.gov (United States)

    de Sèze, J; Kremer, L; Alves do Rego, C; Taleb, O; Lam, D; Beiano, W; Mensah-Nyagan, G; Trifilieff, E; Brun, S

    2016-12-01

    Animal models are fundamental to advance knowledge of disease pathogenesis and to test/develop new therapeutic strategies. Most of the current knowledge about the pathogenic mechanisms underpinning autoimmune demyelination processes implicating autoantigens has been obtained using the Experimental Autoimmune Neuritis (EAN) animal model. The most widely used EAN model is obtained by active immunization of Lewis rats using a peptide, P0 (180-199), issuing from the major peripheral nervous system myelin protein. But this model mimics only the classical monophasic acute form of demyelinating polyradiculoneuropathy, i.e. Guillain-Barré syndrome (GBS). We developed a new model by immunizing Lewis rats using the same immunodominant neuritogenic peptide P0 (180-199) but this time with its S-palmitoyl derivative, S-palm P0 (180-199). All of the animals immunized with the S-palm P0 (180-199) peptide developed a chronic relapsing-remitting form of the disease corresponding to the electrophysiological criteria of demyelination (slow sensory nerve conduction velocity, prolonged motor nerve latency, partial motor nerve conduction blocks) with axon degeneration. These findings were confirmed by immunohistopathology study and thus, appear to mimic human chronic inflammatory demyelinating polyradiculopathy (CIDP). This new model opens up new avenues of research for testing new anti-inflammatory and neuroprotective therapeutic strategies. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  12. Sensory and vascular changes in a rat monoarthritis model: prophylactic and therapeutic effects of meloxicam

    Science.gov (United States)

    Hashmi, Javeria Ali; Yashpal, Kiran; Holdsworth, David W.

    2016-01-01

    Objective and design The objective of this study was to determine the ability of meloxicam prophylaxis and therapy to blunt the effect of complete Freund’s adjuvant (CFA) induced monoarthritis. Materials and methods First the validity of this animal model was established by examining joint changes at multiple levels after injecting CFA into the tibio-tarsal joint. Next, meloxicam (5 mg/kg) or vehicle was administered on days 0–7 (prophylactic) and on days 7–16 (therapeutic) in separate groups of animals. Results The CFA-injected joint demonstrated hallmark histological and structural changes such as pannus formation, bone remodeling, cartilage erosion and immune cell infiltration. Both prophylactic and therapeutic treatment with meloxicam effectively reduced swelling (ankle circumference), oedema and extravasation of Evans blue dye in the affected joint. Moreover, meloxicam reduced loss in range of motion and also reduced mechanical stimulus evoked pain scores. Notably, these effects persisted after discontinuing drug treatment. Conclusion The present study provides a unique comparison of prophylactic versus therapeutic effects of meloxicam in the CFA-induced model of monoarthritis. PMID:20349327

  13. Glycoengineering in cancer therapeutics: a review with fucose-depleted trastuzumab as the model.

    Science.gov (United States)

    Listinsky, Jay J; Siegal, Gene P; Listinsky, Catherine M

    2013-03-01

    Experimentally modified trastuzumab antibodies show increased cytotoxic potency when used with human effector cells against HER2-overexpressing human breast cancer cells in vitro and ex vivo. Furthermore, the superior efficacy of 'glycoengineered' trastuzumab has been confirmed in vivo utilizing a preclinical xenograft model of human HER2-amplified, trastuzumab-resistant human breast cancer. The increased cytotoxic potency coupled with other improvements are achieved by a seemingly modest change in trastuzumab's structure, that is, depletion of two α-L-fucose residues from trastuzumab's heavy chains. Fucose-free trastuzumab binds with much greater affinity to human natural killer cells. This improved binding induces much greater antibody-dependent cellular cytotoxicity against HER2-overexpressing cells. The pharmaceutical industry has recognized the advantages of fucose-free therapeutic antibodies and has developed technologies that aim to mass produce such antibodies for human use. Here, we summarize data from multiple academic and pharmaceutical laboratories highlighting fucose depletion of antibodies as a key strategy of glycoengineering in cancer therapeutics. We use fucose-depleted trastuzumab as a model to show the advantages of this new class of anticancer agents. We predict that these advantages will translate clinically into improved therapeutics for many patients including those with HER2-overexpressing neoplasms.

  14. Human Disease Models in Drosophila melanogaster and the Role of the Fly in Therapeutic Drug Discovery

    Science.gov (United States)

    Pandey, Udai Bhan

    2011-01-01

    The common fruit fly, Drosophila melanogaster, is a well studied and highly tractable genetic model organism for understanding molecular mechanisms of human diseases. Many basic biological, physiological, and neurological properties are conserved between mammals and D. melanogaster, and nearly 75% of human disease-causing genes are believed to have a functional homolog in the fly. In the discovery process for therapeutics, traditional approaches employ high-throughput screening for small molecules that is based primarily on in vitro cell culture, enzymatic assays, or receptor binding assays. The majority of positive hits identified through these types of in vitro screens, unfortunately, are found to be ineffective and/or toxic in subsequent validation experiments in whole-animal models. New tools and platforms are needed in the discovery arena to overcome these limitations. The incorporation of D. melanogaster into the therapeutic discovery process holds tremendous promise for an enhanced rate of discovery of higher quality leads. D. melanogaster models of human diseases provide several unique features such as powerful genetics, highly conserved disease pathways, and very low comparative costs. The fly can effectively be used for low- to high-throughput drug screens as well as in target discovery. Here, we review the basic biology of the fly and discuss models of human diseases and opportunities for therapeutic discovery for central nervous system disorders, inflammatory disorders, cardiovascular disease, cancer, and diabetes. We also provide information and resources for those interested in pursuing fly models of human disease, as well as those interested in using D. melanogaster in the drug discovery process. PMID:21415126

  15. Angiogenic factor AGGF1 promotes therapeutic angiogenesis in a mouse limb ischemia model.

    Directory of Open Access Journals (Sweden)

    Qiulun Lu

    Full Text Available BACKGROUND: Peripheral arterial disease (PAD is a common disease accounting for about 12% of the adult population, and causes significant morbidity and mortality. Therapeutic angiogenesis using angiogenic factors has been considered to be a potential treatment option for PAD patients. In this study, we assessed the potential of a new angiogenic factor AGGF1 for therapeutic angiogenesis in a critical limb ischemia model in mice for PAD. METHODS AND RESULTS: We generated a unilateral hindlimb ischemia model in mice by ligation of the right common iliac artery and femoral artery. Ischemic mice with intrasmuscular administration of DNA for an expression plasmid for human AGGF1 (AGGF1 group resulted in increased expression of both AGGF1 mRNA and protein after the administration compared with control mice with injection of the empty vector (control group. Color PW Doppler echocardiography showed that the blood flow in ischemic hindlimbs was significantly increased in the AGGF1 group compared to control mice at time points of 7, 14, and 28 days after DNA administration (n = 9/group, P = 0.049, 0.001, and 0.001, respectively. Increased blood flow in the AGGF1 group was correlated to increased density of CD31-positive vessels and decreased necrosis in muscle tissues injected with AGGF1 DNA compared with the control tissue injected with the empty vector. Ambulatory impairment was significantly reduced in the AGGF1 group compared to the control group (P = 0.004. The effect of AGGF1 was dose-dependent. At day 28 after gene transfer, AGGF1 was significantly better in increasing blood flow than FGF-2 (P = 0.034, although no difference was found for tissue necrosis and ambulatory impairment. CONCLUSIONS: These data establish AGGF1 as a candidate therapeutic agent for therapeutic angiogenesis to treat PAD.

  16. 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

  17. 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 ...

  18. 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.

  19. 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.

  20. A novel mouse model identifies cooperating mutations and therapeutic targets critical for chronic myeloid leukemia progression

    Science.gov (United States)

    Giotopoulos, George; van der Weyden, Louise; Osaki, Hikari; Rust, Alistair G.; Gallipoli, Paolo; Meduri, Eshwar; Horton, Sarah J.; Chan, Wai-In; Foster, Donna; Prinjha, Rab K.; Pimanda, John E.; Tenen, Daniel G.; Vassiliou, George S.; Koschmieder, Steffen; Adams, David J.

    2015-01-01

    The introduction of highly selective ABL-tyrosine kinase inhibitors (TKIs) has revolutionized therapy for chronic myeloid leukemia (CML). However, TKIs are only efficacious in the chronic phase of the disease and effective therapies for TKI-refractory CML, or after progression to blast crisis (BC), are lacking. Whereas the chronic phase of CML is dependent on BCR-ABL, additional mutations are required for progression to BC. However, the identity of these mutations and the pathways they affect are poorly understood, hampering our ability to identify therapeutic targets and improve outcomes. Here, we describe a novel mouse model that allows identification of mechanisms of BC progression in an unbiased and tractable manner, using transposon-based insertional mutagenesis on the background of chronic phase CML. Our BC model is the first to faithfully recapitulate the phenotype, cellular and molecular biology of human CML progression. We report a heterogeneous and unique pattern of insertions identifying known and novel candidate genes and demonstrate that these pathways drive disease progression and provide potential targets for novel therapeutic strategies. Our model greatly informs the biology of CML progression and provides a potent resource for the development of candidate therapies to improve the dismal outcomes in this highly aggressive disease. PMID:26304963

  1. Therapeutic effects of cannabinoids in animal models of seizures, epilepsy, epileptogenesis, and epilepsy-related neuroprotection.

    Science.gov (United States)

    Rosenberg, Evan C; Patra, Pabitra H; Whalley, Benjamin J

    2017-05-01

    The isolation and identification of the discrete plant cannabinoids in marijuana revived interest in analyzing historical therapeutic claims made for cannabis in clinical case studies and anecdotes. In particular, sources as old as the 11th and 15th centuries claimed efficacy for crude marijuana extracts in the treatment of convulsive disorders, prompting a particularly active area of preclinical research into the therapeutic potential of plant cannabinoids in epilepsy. Since that time, a large body of literature has accumulated describing the effects of several of the >100 individual plant cannabinoids in preclinical models of seizures, epilepsy, epileptogenesis, and epilepsy-related neuroprotection. We surveyed the literature for relevant reports of such plant cannabinoid effects and critically reviewed their findings. We found that acute CB 1 R agonism in simple models of acute seizures in rodents typically produces anti-convulsant effects whereas CB 1 R antagonists exert converse effects in the same models. However, when the effects of such ligands are examined in more complex models of epilepsy, epileptogenesis and neuroprotection, a less simplistic narrative emerges. Here, the complex interactions between (i) brain regions involved in a given model, (ii) relative contributions of endocannabinoid signaling to modulation of synaptic transmission in such areas, (iii) multi-target effects, (iv) cannabinoid type 1 and type 2 receptor signaling interactions and, (v) timing, (vi) duration and (vii) localization of ligand administration suggest that there is both anti-epileptic therapeutic potential and a pro-epileptic risk in up- and down-regulation of endocannabinoid signaling in the central nervous system. Factors such receptor desensitization and specific pharmacology of ligands used (e.g. full vs partial agonists and neutral antagonists vs inverse agonists) also appear to play an important role in the effects reported. Furthermore, the effects of several plant

  2. Different Therapeutic Outcomes of Benznidazole and VNI Treatments in Different Genders in Mouse Experimental Models of Trypanosoma cruzi Infection

    National Research Council Canada - National Science Library

    Guedes-da-Silva, F H; Batista, D G J; da Silva, C F; Meuser, M B; Simões-Silva, M R; de Araújo, J S; Ferreira, C G; Moreira, O C; Britto, C; Lepesheva, G I; Soeiro, Maria de Nazaré C

    2015-01-01

    ...) and with the potent experimental T. cruzi CYP51 inhibitor VNI in mouse models of Chagas disease by using different animal genders and parasite strains and employing distinct types of therapeutic schemes...

  3. 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.

  4. Increased plasma colloid osmotic pressure facilitates the uptake of therapeutic macromolecules in a xenograft tumor model.

    Science.gov (United States)

    Hofmann, Matthias; McCormack, Emmet; Mujić, Maja; Rossberg, Maila; Bernd, August; Bereiter-Hahn, Jürgen; Gjertsen, Bjørn Tore; Wiig, Helge; Kippenberger, Stefan

    2009-08-01

    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.

  5. VALMET: a valley air pollution model. Final report. Revision 1

    Energy Technology Data Exchange (ETDEWEB)

    Whiteman, C.D.; Allwine, K.J.

    1985-04-01

    An air quality model is described for predicting air pollution concentrations in deep mountain valleys arising from nocturnal down-valley transport and diffusion of an elevated pollutant plume, and the fumigation of the plume on the valley floor and sidewalls after sunrise. Included is a technical description of the model, a discussion of the model's applications, the required model inputs, sample calculations and model outputs, and a full listing of the FORTRAN computer program. 55 refs., 27 figs., 6 tabs.

  6. 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

  7. Comparison of models for predicting landfill methane recovery. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Vogt, W.G. [SCS Engineers, Reston, VA (United States); Augenstein, D. [Institute for Environmental Management, Palo Alto, CA (United States)

    1997-03-01

    Landfill methane models are tools used to project methane generation over time from a mass of landfilled waste. These models are used for sizing landfill gas (LFG) collection systems, evaluations and projections of LFG energy uses, and regulatory purposes. The objective of this project was to select various landfill methane models and to provide a comparison of model outputs to actual long-term gas recovery data from a number of well managed and suitable landfills. Another objective was to use these data to develop better estimates of confidence limits that can be assigned to model projections. This project assessed trial model forms against field data from available landfills where methane extraction was maximized, waste filling history was well-documented, and other pertinent site information was of superior quality. Data were obtained from 18 US landfills. Four landfill methane models were compared: a zero-order, a simple first order, a modified first order, and a multi-phase first order model. Models were adjusted for best fit to field data to yield parameter combinations based on the minimized residual errors between predicted and experienced methane recovery. The models were optimized in this way using two data treatments: absolute value of the differences (arithmetic error minimization) and absolute value of the natural log of the ratios (logarithmic error minimization).

  8. The TAR model: use of therapeutic state transitions for quality assurance reporting in chronic disease management.

    Science.gov (United States)

    Gaikwad, R; Warren, J; Kenealy, T

    2007-01-01

    Chronic disease management represents one of the challenges for health informatics and demands the appropriate application of information technology for improved patient care. This paper presents an approach to quality assurance reporting wherein the recommendations of evidence-based clinical practice guidelines are considered in the context of empirical therapeutic state-transitions (in terms of changes in individual patient prescriptions over time). We apply a Transition-based Audit Report (TAR) model to antihypertensive prescribing and related data as stored in a New Zealand General Practice Management System database. The results provide a set of quality indicators and specific patient cohorts for potential practice quality improvement with strong linkage to the selected guidelines and observed practice patterns. We see the TAR model primarily as a tool to enable internal quality improvement efforts, but also to be of relevance for focusing pay-for-performance programs.

  9. Dealing with mentally ill domestic violence perpetrators: A therapeutic jurisprudence judicial model.

    Science.gov (United States)

    Winick, Bruce J; Wiener, Richard; Castro, Anthony; Emmert, Aryn; Georges, Leah S

    2010-01-01

    People suffering from mental illness are increasingly referred to the domestic violence court. Yet the typical diversion programs available, including batterer's intervention programs, are inappropriate for those with serious mental illness. As a result, the Miami-Dade Domestic Violence Court has developed a new approach for dealing with this population that applies mental health court techniques in domestic violence court. This article will describe and discuss this pioneering model. It also will situate this model within the context of other problem-solving courts and discuss how the court uses principles and approaches of therapeutic jurisprudence. The paper presents some preliminary data that describe the social and legal characteristics of 20 defendants in the Domestic Violence Mental Health Court followed over a two year period between 2005 and 2007. Copyright © 2010 Elsevier Ltd. All rights reserved.

  10. 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.

  11. 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

  12. Power Management and Distribution (PMAD) Model Development: Final Report

    Science.gov (United States)

    Metcalf, Kenneth J.

    2011-01-01

    Power management and distribution (PMAD) models were developed in the early 1990's to model candidate architectures for various Space Exploration Initiative (SEI) missions. They were used to generate "ballpark" component mass estimates to support conceptual PMAD system design studies. The initial set of models was provided to NASA Lewis Research Center (since renamed Glenn Research Center) in 1992. They were developed to estimate the characteristics of power conditioning components predicted to be available in the 2005 timeframe. Early 90's component and device designs and material technologies were projected forward to the 2005 timeframe, and algorithms reflecting those design and material improvements were incorporated into the models to generate mass, volume, and efficiency estimates for circa 2005 components. The models are about ten years old now and NASA GRC requested a review of them to determine if they should be updated to bring them into agreement with current performance projections or to incorporate unforeseen design or technology advances. This report documents the results of this review and the updated power conditioning models and new transmission line models generated to estimate post 2005 PMAD system masses and sizes. This effort continues the expansion and enhancement of a library of PMAD models developed to allow system designers to assess future power system architectures and distribution techniques quickly and consistently.

  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. Great Plains ASPEN model development: Phosam section. Final topical report

    Energy Technology Data Exchange (ETDEWEB)

    Stern, S S; Kirman, J J

    1985-02-01

    An ASPEN model has been developed of the PHOSAM Section, Section 4600, of the Great Plains Gasification Plant. The bases for this model are the process description given in Section 6.18 of the Great Plains Project Management Plan and the Lummus Phosam Schematic Process Flow Diagram, Dwg. No. SKD-7102-IM-O. The ASPEN model that has been developed contains the complete set of components that are assumed to be in the gasifier effluent. The model is primarily a flowsheet simulation that will give the material and energy balance and equipment duties for a given set of process conditions. The model is unable to predict fully changes in process conditions that would result from load changes on equipment of fixed sizes, such as a rating model would predict. The model can be used to simulate the steady-state operation of the plant at or near design conditions or to design other PHOSAM units. Because of the limited amount of process information that was available, several major process assumptions had to be made in the development of the flowsheet model. Patent literature was consulted to establish the ammonia concentration in the circulating fluid. Case studies were made with the ammonia content of the feed 25% higher and 25% lower than the base feed. Results of these runs show slightly lower recoveries of ammonia with less ammonia in the feed. As expected, the duties of the Stripper and Fractionator reboilers were higher with more ammonia in the feed. 63 references.

  15. 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.

  16. 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.

  17. 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.

  18. 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

    1992-12-31

    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

  19. A Systematic Review of the Effect of Therapists' Internalized Models of Relationships on the Quality of the Therapeutic Relationship.

    Science.gov (United States)

    Steel, Catherine; Macdonald, James; Schroder, Thomas

    2017-05-15

    Previous reviews have found equivocal evidence of an association between therapists' internalized relational models and the therapeutic relationship and have neglected empirical literature based on Sullivan's notion of introject. This review expanded upon previous reviews to examine the effect of therapist internalized relational models on a broader conceptualization of the therapeutic relationship. Systematic search processes identified 22 papers measuring therapist attachment and/or introject and therapeutic relationship: 19 on therapist attachment, 5 on introject with 2 overlapping. Overall, despite heterogeneity in design and variable methodological quality, evidence suggests that therapist attachment affects therapeutic relationship quality, observed in client-rated evaluation, therapist negative countertransference, empathy, and problems in therapy. Interaction effects between client and therapist attachment style were also found. Evidence suggesting that therapist introject also affects therapeutic relationship quality, including therapists' manner and feelings toward their clients, was stronger. Evidence clearly shows that therapists' internalized relational models affect the therapeutic relationship. More research is necessary to clarify exactly how therapist and client internalized relational models interact and translate these findings into clinical practice. © 2017 Wiley Periodicals, Inc.

  20. 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.

  1. 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.

  2. Geothermal modeling of Jackson Hole, Teton County Wyoming: Final report

    Energy Technology Data Exchange (ETDEWEB)

    Heasler, H.P.

    1987-04-01

    This study investigated the possibility of high-temperature-heat sources (greater than 300/sup 0/C) in the area of Jackson Hole, northwestern Wyoming. Analytical and finite-difference numerical models describing conductive and convective terrestrial heat transport were utilized in an attempt to define the thermal regime of this area. This report presents data which were used as constraints for the analytic and numerical thermal models. These data include a general discussion of geology of the area, thermal spring information, subsurface temperature information, and hydrology of the area. Model results are presented with a discussion of interpretations and implications for the existence of high-temperature heat sources in the Jackson Hole area.

  3. 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

  4. 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.

  5. Evaluating resveratrol as a therapeutic bone agent: preclinical evidence from rat models of osteoporosis.

    Science.gov (United States)

    Tou, Janet C

    2015-08-01

    Resveratrol (RSV) is a naturally occurring plant polyphenol that has potential to attenuate osteoporosis with distinct pathologies. This review evaluates preclinical evidence regarding the efficacy and safety of RSV as a therapeutic bone agent using different rat models. Limitations of these animal models are discussed, and suggestions for strengthening the experimental design of future studies are provided. The ovariectomized rat model of postmenopausal osteoporosis reported that RSV supplementation attenuated estrogen deficiency-induced bone loss and trabecular structural deterioration. RSV safety was indicated by the absence of stimulation of estrogen-sensitive tissue. Providing RSV to rats aged >6 months attenuated age-related bone mass loss and structural deterioration but produced inconsistent effects on bones in rats aged osteoporosis reported that RSV attenuated bone loss in old rats, but higher doses and longer duration supplementation before mechanical loading were required for younger rats. Limitations common to studies using rat models of osteoporosis include requirements to include animals that are skeletally mature, longer study durations, and to adjust for potential confounding effects due to altered body weight and endocrine function. Strengthening experimental design can contribute to translation of animal results to clinically relevant recommendations for humans. Published 2015. This article is U.S. Government work and is in the public domain in the USA.

  6. Ambient Weather Model Research and Development: Final Report.

    Energy Technology Data Exchange (ETDEWEB)

    Walker, Stel Nathan; Wade, John Edward

    1990-08-31

    Ratings for Bonneville Power Administration (BPA) transmission lines are based upon the IEEE Standard for Calculation of Bare Overhead Conductor Temperatures and Ampacity under Steady-State Conditions (1985). This steady-state model is very sensitive to the ambient weather conditions of temperature and wind speed. The model does not account for wind yaw, turbulence, or conductor roughness as proposed by Davis (1976) for a real time rating system. The objective of this research has been to determine (1) how conservative the present rating system is for typical ambient weather conditions, (2) develop a probability-based methodology, (3) compile available weather data into a compatible format, and (4) apply the rating methodology to a hypothetical line. The potential benefit from this research is to rate transmission lines statistically which will allow BPA to take advantage of any unknown thermal capacity. The present deterministic weather model is conservative overall and studies suggest a refined model will uncover additional unknown capacity. 14 refs., 40 figs., 7 tabs.

  7. Dental Health Care Models of Southwest Cultures. Final Report.

    Science.gov (United States)

    Pettibone, Timothy J.; Solis, Enrique, Jr.

    The major goal of this research was the development and validation of cultural models of dental health practices. The specific objectives were to determine if 3 cultural groups (American Indians, Mexican Americans, and Anglo Americans) differ in the dental health hygiene indices, characteristics, psychological factors, or social factors; to…

  8. A Model for Self-Directed Problem-Based Learning for Renal Therapeutics

    Science.gov (United States)

    Grant, Daniel T.

    2010-01-01

    Objective To introduce a new approach to problem-based learning (PBL) for self-directed learning in renal therapeutics. Design This 5-week course, designed for large student cohorts using minimal teaching resources, was based on a series of case studies and subsequent pharmaceutical care plans, followed by intensive and regular feedback from the instructor. Assessment Assessment of achievement of the learning outcomes was based on weekly-graded care plans and peer review assessment, allowing each student to judge the contributions of each group member and their own, along with a written case-study based examination. The pharmaceutical care plan template, designed using a “tick-box” system, significantly reduced staff time for feedback and scoring. Conclusion The proposed instructional model achieved the desired learning outcomes with appropriate student feedback, while promoting skills that are essential for the students' future careers as health care professionals. PMID:21301607

  9. How Darwinian models inform therapeutic failure initiated by clonal heterogeneity in cancer medicine

    Science.gov (United States)

    Gerlinger, M; Swanton, C

    2010-01-01

    Carcinogenesis is an evolutionary process that establishes the ‘hallmarks of cancer' by natural selection of cell clones that have acquired advantageous heritable characteristics. Evolutionary adaptation has also been proposed as a mechanism that promotes drug resistance during systemic cancer therapy. This review summarises the evidence for the evolution of resistance to cytotoxic and targeted anti-cancer drugs according to Darwinian models and highlights the roles of genomic instability and high intra-tumour genetic heterogeneity as major accelerators of this evolutionary process. Clinical implications and strategies that may prevent the evolution of resistance or target the origins of genetic heterogeneity are discussed. New technologies to measure intra-tumour heterogeneity and translational research on serial biopsies of cancer lesions during and after therapeutic intervention are identified as key areas to further the understanding of determinants and mechanisms of the evolution of drug resistance. PMID:20877357

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. Genetic rodent models of brain disorders: Perspectives on experimental approaches and therapeutic strategies.

    Science.gov (United States)

    McGraw, Christopher M; Ward, Christopher S; Samaco, Rodney C

    2017-09-01

    Neurobehavioral disorders comprised of neurodegenerative, neurodevelopmental, and psychiatric disorders together represent leading causes of morbidity and mortality. Despite significant academic research and industry efforts to elucidate the disease mechanisms operative in these disorders and to develop mechanism-based therapies, our understanding remains incomplete and our access to tractable therapeutic interventions severely limited. The magnitude of these short-comings can be measured by the growing list of disappointing clinical trials based on initially promising compounds identified in genetic animal models. This review and commentary will explore why this may be so, focusing on the central role that genetic models of neurobehavioral disorders have come to occupy in current efforts to identify disease mechanisms and therapies. In particular, we will highlight the unique pitfalls and challenges that have hampered success in these models as compared to genetic models of non-neurological diseases as well as to symptom-based models of the early 20th century that led to the discovery of all major classes of psychoactive pharmaceutical compounds still used today. Using examples from specific genetic rodent models of human neurobehavioral disorders, we will highlight issues of reproducibility, construct validity, and translational relevance in the hopes that these examples will be instructive toward greater success in future endeavors. Lastly, we will champion a two-pronged approach toward identifying novel therapies for neurobehavioral disorders that makes greater use of the historically more successful symptom-based approaches in addition to more mechanism-based approaches. © 2017 The Authors. American Journal of Medical Genetics Part C Published by Wiley Periodicals, Inc.

  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...... describes the work completed by DTU in general. The sub-tasks are: Subtask 4.1 Experimental Techniques Subtask 4.2 Cold forming Subtask 4.3 Warm/hot forming Subtask 4.4 Tests on complex industrial geometries....

  17. Therapeutic Effects of S-Petasin on Disease Models of Asthma and Peritonitis

    Science.gov (United States)

    Lee, Kyoung-Pil; Kang, Saeromi; Noh, Min-Soo; Park, Soo-Jin; Kim, Jung-Min; Chung, Hae Young; Je, Nam Kyung; Lee, Young-Geun; Choi, Young-Whan; Im, Dong-Soon

    2015-01-01

    To explore the anti-allergic and anti-inflammatory effects of extracts of Petasites genus, we studied the effects of s-petasin, a major sesquiterpene from Petasites formosanus (a butterbur species) on asthma and peritonitis models. In an ovalbumin-induced mouse asthma model, s-petasin significantly inhibited the accumulations of eosinophils, macrophages, and lymphocytes in bronchoalveolar fluids. S-petasin inhibited the antigen-induced degranulation of β-hexosamidase but did not inhibit intracellular Ca2+ increase in RBL-2H3 mast cells. S-petasin inhibited the LPS induction of iNOS at the RNA and protein levels in mouse peritoneal macrophages. Furthermore, s-petasin inhibited the production of NO (the product of iNOS) in a concentration-dependent manner in the macrophages. Furthermore, in an LPS-induced mouse model of peritonitis, s-petasin significantly inhibited the accumulation of polymorpho nuclear and mononuclear leukocytes in peritoneal cavity. This study shows that s-petasin in Petasites genus has therapeutic effects on allergic and inflammatory diseases, such as, asthma and peritonitis through degranulation inhibition in mast cells, suppression of iNOS induction and production of NO in macrophages, and suppression of inflammatory cell accumulation. PMID:25593643

  18. Therapeutic efficacy and immunological response of CCL5 antagonists in models of contact skin reaction.

    Directory of Open Access Journals (Sweden)

    Miriam Canavese

    Full Text Available Skin-infiltrating T-cells play a predominant role in allergic and inflammatory skin diseases such as atopic dermatitis, psoriasis and allergic contact dermatitis. These T-cells are attracted by several chemotactic factors including the chemokine CCL5/RANTES, a CC chemokine inducing both the migration and activation of specific leukocyte subsets. CCL5 has been found to be associated with various cell-mediated hypersensitive disorders such as psoriasis, atopic dermatitis and irritant contact dermatitis. We have used two antagonists, the first, Met-CCL5, a dual CCR1/CCR5 antagonist and the second, a variant in which GAG binding is abrogated, (44AANA(47-CCL5, which acts as a dominant negative inhibitor of CCL5. The antagonists were tested in two models of contact skin reaction. The first, irritant contact dermatitis (ICD is a pathological non-specific inflammatory skin condition arising from the release of pro-inflammatory cytokines by keratinocytes in response to haptens, usually chemicals. The second, contact hypersensitivity (CHS is a T-cell dependent model, mimicking in part the T-cell-mediated skin diseases such as psoriasis. In both models, the CCL5 antagonists showed therapeutic efficacy by reducing swelling by 50% as well as the reduction of soluble mediators in homogenates derived from challenged ears. These results demonstrate that blocking the receptor or the ligand are both effective strategies to inhibit skin inflammation.

  19. 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.

  20. 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

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

    Science.gov (United States)

    Beheshti, Siamak; Aghaie, Rezvan

    2016-01-01

    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 (pfrankincense for 21 days did not affect learning parameters, but injection of it for 42 days, significantly increased step-through latency (pfrankincense has the potential to improve dementia type of AD induced by i.c.v injection of streptozotocin in a time-dependent manner. PMID:27516988

  2. Exploring New Physics Beyond the Standard Model: Final Technical Report

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Liantao [Univ. of Chicago, IL (United States)

    2016-10-17

    This grant in 2015 to 2016 was for support in the area of theoretical High Energy Physics. The research supported focused mainly on the energy frontier, but it also has connections to both the cosmic and intensity frontiers. Lian-Tao Wang (PI) focused mainly on signal of new physics at colliders. The year 2015 - 2016, covered by this grant, has been an exciting period of digesting the influx of LHC data, understanding its meaning, and using it to refine strategies for deeper exploration. The PI proposed new methods of searching for new physics at the LHC, such as for the compressed stops. He also investigated in detail the signal of composite Higgs models, focusing on spin-1 composite resonances in the di-boson channel. He has also considered di-photon as a probe for such models. He has also made contributions in formulating search strategies of dark matter at the LHC, resulting in two documents with recommendations. The PI has also been active in studying the physics potential of future colliders, including Higgs factories and 100 TeV pp colliders. He has given comprehensive overview of the physics potential of the high energy proton collider, and outline its luminosity targets. He has also studied the use of lepton colliders to probe fermionic Higgs portal and bottom quark couplings to the Z boson.

  3. 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.

  4. 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

    This deliverable D1.3 is the third and final deliverable of WP1 - Global Manufacturing Concept of the European part of the Globeman21 project. The report essentially presents the final models on generic Extended Enterprise Management (EEM) and generic Product Life Cycle Management (PLCM), a colle...

  5. 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…

  6. 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.)

  7. A hierarchy of thermohaline circulation models. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Cessi, P.; Young, W.R.

    1998-04-01

    The objectives of this effort were: (1) to understand the variability caused by the competitive roles of salt and heat in the ocean circulation; (2) to understand the effect of differential advection of active tracers, such as temperature, salinity and angular momentum; and (3) to improve the parametrization of convection in models of the ocean circulation. One result of the project is the discovery that the characteristics of the quasi-periodic centennial and millennial oscillations found in OGCM`s, associated with alternating suppression and activation of high latitude convection, are extremely sensitive to the salinity flux and specific choice of convective adjustment scheme. In particular, the period of the oscillation depends crucially on the salinity fluxes (whether deterministic or with a stochastic component) and can be arbitrarily long. This result has clarified that these long-period oscillations (termed flushes) are not the result of the excitation of an intrinsic linear eigenmode of the system, but rather are relaxation-oscillations towards one of the several equilibria available to the system. This implies that it is the amplitude, rather than the period, of the oscillation which is almost independent of the salinity flux.

  8. 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.

  9. 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

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

    Directory of Open Access Journals (Sweden)

    Jagannathan NR

    2008-09-01

    Full Text Available Abstract 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.

  11. Development of a risk-analysis model. Final report

    Energy Technology Data Exchange (ETDEWEB)

    1979-10-01

    This report consists of a main body, which provides a presentation of risk analysis and its general and specific application to the needs of the Office of Buildings and Community Systems of the Department of Energy; and several case studies employing the risk-analysis model developed. The highlights include a discussion of how risk analysis is currently used in the private, regulated, and public sectors and how this methodology can be employed to meet the policy-analysis needs of the Office of Buildings and Community Systems of the Department of Energy (BCS/DOE). After a review of the primary methodologies available for risk analysis, it was determined that Monte Carlo simulation techniques provide the greatest degree of visibility into uncertainty in the decision-making process. Although the data-collection requirements can be demanding, the benefits, when compared to other methods, are substantial. The data-collection problem can be significantly reduced, without sacrificing proprietary-information rights, if prior arrangements are made with RD and D contractors to provide responses to reasonable requests for base-case data. A total of three case studies were performed on BCS technologies: a gas-fired heat pump; a 1000 ton/day anaerobic digestion plant; and a district heating and cooling system. The three case studies plus the risk-analysis methodology were issued as separate reports. It is concluded that, based on the overall research of risk analysis and the case-study experience, that the risk-analysis methodology has significant potential as a policy-evaluation tool within BCS.

  12. Testing the Therapeutic Potential of Doxycycline in a Drosophila melanogaster Model of Alzheimer Disease*

    Science.gov (United States)

    Costa, Rita; Speretta, Elena; Crowther, Damian C.; Cardoso, Isabel

    2011-01-01

    Therapies for Alzheimer disease that reduce the production of pathogenic amyloid β (Aβ) peptides have been associated with a range of unwanted effects. For this reason, alternative strategies that promote the clearance of the peptide by preventing its aggregation and deposition in the brain have been favored. In this context we have studied doxycycline, a member of the tetracycline family of antibiotics that has shown neuroprotective effects in a number of models of neurodegenerative disease. We investigated the neuroprotective potential of doxycycline in a Drosophila model of Aβ toxicity and sought to correlate any effects with the aggregation state of the peptide. We found that administration of doxycycline to Aβ42-expressing flies did not improve their lifespan but was able to slow the progression of their locomotor deficits. We also measured the rough eye phenotype of transgenic flies expressing the E22G variant of Aβ42 and showed that doxycycline administration partially rescued the toxicity of Aβ in the developing eye. We correlated these in vivo effects with in vitro observations using transmission electron microscopy, dynamic light scattering, and thioflavin T binding. We found that doxycycline prevents Aβ fibrillization and favors the generation of smaller, non-amyloid structures that were non-toxic as determined by the lack of caspase 3 activation in a neuroblastoma cell line. Our confirmation that doxycycline can prevent amyloid β toxicity both in vitro and in vivo supports its therapeutic potential in AD. PMID:21998304

  13. 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.

  14. Citral: a monoterpene with prophylactic and therapeutic anti-nociceptive effects in experimental models of acute and chronic pain.

    Science.gov (United States)

    Nishijima, Catarine M; Ganev, Ellen G; Mazzardo-Martins, Leidiane; Martins, Daniel F; Rocha, Lúcia R M; Santos, Adair R S; Hiruma-Lima, Clelia A

    2014-08-05

    Citral (3,7-dimethyl-2,6-octadienal) is an open-chain monoterpenoid present in the essential oils of several medicinal plants. The aim of this work was to evaluate the effects of orally administered citral in experimental models of acute and chronic nociception, inflammation, and gastric ulcers caused by non-steroidal anti-inflammatory drugs (NSAIDs). Oral treatment with citral significantly inhibited the neurogenic and inflammatory pain responses induced by intra-plantar injection of formalin. Citral also had prophylactic and therapeutic anti-nociceptive effects against mechanical hyperalgesia in plantar incision surgery, chronic regional pain syndrome, and partial ligation of sciatic nerve models, without producing any significant motor dysfunction. In addition, citral markedly attenuated the pain response induced by intra-plantar injection of glutamate and phorbol 12-myristate 13-acetate (PMA, a protein kinase C activator), as well as by intrathecal (i.t.) injection of ionotropic and metabotropic glutamate receptor agonists (N-methyl-D-aspartic acid [NMDA] and 1-amino-1,3-dicarboxycyclopentane [trans-ACPD], respectively), substance P, and cytokine tumour necrosis factor-α. However, citral potentiated behaviours indicative of pain caused by i.t., but not intra-plantar, injection of a transient receptor potential vanilloid receptor type 1 (TRPV1) agonist. Finally, the anti-nociceptive action of citral was found to involve significant activation of the 5-HT2A serotonin receptor. The effect of citral was accompanied by a gastro-protective effect against NSAID-induced ulcers. Together, these results show the potential of citral as a new drug for the treatment of pain. Copyright © 2014 Elsevier B.V. All rights reserved.

  15. CRISPR-Cas9 systems: versatile cancer modelling platforms and promising therapeutic strategies.

    Science.gov (United States)

    Wen, Wan-Shun; Yuan, Zhi-Min; Ma, Shi-Jie; Xu, Jiang; Yuan, Dong-Tang

    2016-03-15

    The RNA-guided nuclease CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats-CRISPR associated nuclease 9) and its variants such as nickase Cas9, dead Cas9, guide RNA scaffolds and RNA-targeting Cas9 are convenient and versatile platforms for site-specific genome editing and epigenome modulation. They are easy-to-use, simple-to-design and capable of targeting multiple loci simultaneously. Given that cancer develops from cumulative genetic and epigenetic alterations, CRISPR-Cas9 and its variants (hereafter referred to as CRISPR-Cas9 systems) hold extensive application potentials in cancer modeling and therapy. To date, they have already been applied to model oncogenic mutations in cell lines (e.g., Choi and Meyerson, Nat Commun 2014;5:3728) and in adult animals (e.g., Xue et al., Nature 2014;514:380-4), as well as to combat cancer by disabling oncogenic viruses (e.g., Hu et al., Biomed Res Int 2014;2014:612823) or by manipulating cancer genome (e.g., Liu et al., Nat Commun 2014;5:5393). Given the importance of epigenome and transcriptome in tumourigenesis, manipulation of cancer epigenome and transcriptome for cancer modeling and therapy is a promising area in the future. Whereas (epi)genetic modifications of cancer microenvironment with CRISPR-Cas9 systems for therapeutic purposes represent another promising area in cancer research. Herein, we introduce the functions and mechanisms of CRISPR-Cas9 systems in genome editing and epigenome modulation, retrospect their applications in cancer modelling and therapy, discuss limitations and possible solutions and propose future directions, in hope of providing concise and enlightening information for readers interested in this area. © 2015 UICC.

  16. 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...

  17. [FY 2014 Final report]: Native Prairie Adaptive Management Database Archive and Competing Model Linkage

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — The final report for the Native Prairie Adaptive Management Database Archive and Competing Model Linkage project covers activities during FY2014. The overall goal of...

  18. An Experimental Toxoplasma gondii Dose Response Challenge Model to Study Therapeutic or Vaccine Efficacy in Cats

    Science.gov (United States)

    Cornelissen, Jan B. W. J.; van der Giessen, Joke W. B.; Takumi, Katsuhisa; Teunis, Peter F. M.; Wisselink, Henk 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. 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. PMID:25184619

  19. Therapeutic Role for TSP-2 Antibody in a Murine Asthma Model.

    Science.gov (United States)

    Li, Kai; Huang, En Ping; Su, Jin; Zhu, Ping; Lin, Jun; Luo, Shen Qiu; Yang, Cui Lan

    2018-01-27

    Specific immunotherapy, including agonists for Toll-like receptor 2 (TLR2), have been shown to protect from allergies and to have a high immunomodulatory capacity. A new antibody, TSP-2, reactive against an epitope of the extracellular domain of TLR2, was identified. The effect of the antibody on dendritic cells was assessed by immunohistochemistry, Western blot, and flow cytometric analysis. The effect of TSP-2 in a murine asthma model induced with ovalbumin (OVA) was assessed. The model is a form of airway hyperresponsiveness (AHR) and was analyzed by whole-body plethysmography, the measurement of Th1/Th2 cytokines in bronchial alveolar lavage fluid (BALF) and serum by ELISA, and the CCK-8 assay for lymphocyte proliferation. The effect of TSP-2 on the maturation of bone marrow-derived dendritic cells (BMDCs) was assessed by flow cytometric analysis. TSP-2 promoted the maturation of dendritic cells and the proliferation of lymphocyte in vitro and in vivo. The effect of TSP-2 on T helper 1 (Th1)/Th2 cytokine secretion was slightly more powerful than that of Pam3CSK4. TSP-2 antibody reduced AHR and OVA-specific IgE levels in allergic asthma. TSP-2 antibody also reduced lung inflammation and decreased leukocyte numbers in an OVA-sensitized and challenged asthma model. TSP-2 antibody increased OVA-stimulated I-A, CD80, CD86, and MHC-II levels on BMDCs. This study identifies a novel therapeutic strategy for AHR, which uses antibodies reactive against TLR2. It also provides theoretical evidence for the control of allergic asthma by targeting TLR2. © 2018 S. Karger AG, Basel.

  20. Therapeutic trial of metformin and bortezomib in a mouse model of tuberous sclerosis complex (TSC.

    Directory of Open Access Journals (Sweden)

    Neil Auricchio

    Full Text Available Tuberous sclerosis complex (TSC is a human genetic disorder in which loss of either TSC1 or TSC2 leads to development of hamartoma lesions, which can progress and be life-threatening or fatal. The TSC1/TSC2 protein complex regulates the state of activation of mTORC1. Tsc2(+/- mice develop renal cystadenoma lesions which grow progressively. Both bortezomib and metformin have been proposed as potential therapeutics in TSC. We examined the potential benefit of 1 month treatment with bortezomib, and 4 month treatment with metformin in Tsc2(+/- mice. Results were compared to vehicle treatment and treatment with the mTORC1 inhibitor rapamycin for 1 month. We used a quantitative tumor volume measurement on stained paraffin sections to assess the effect of these drugs. The median tumor volume per kidney was decreased by 99% in mice treated with rapamycin (p = 0.0004. In contrast, the median tumor volume per kidney was not significantly reduced for either the bortezomib cohort or the metformin cohort. Biochemical studies confirmed that bortezomib and metformin had their expected pharmacodynamic effects. We conclude that neither bortezomib nor metformin has significant benefit in this native Tsc2(+/- mouse model, which suggests limited benefit of these compounds in the treatment of TSC hamartomas and related lesions.

  1. Effect of bovine lactoferrin in a therapeutic hamster model of hepatic amoebiasis.

    Science.gov (United States)

    Ordaz-Pichardo, Cynthia; León-Sicairos, Nidia; Hernández-Ramírez, Verónica Ivonne; Talamás-Rohana, Patricia; de la Garza, Mireya

    2012-06-01

    Entamoeba histolytica is the causative agent of amoebiasis, a disease that produces dysentery as a result of the perforation of the large intestine. This parasite often invades other organs, primarily the liver, leading to an amoebic liver abscess (ALA), which can cause death. Metronidazole is the drug of choice for the treatment of ALA; however, it produces toxic side effects in patients. Lactoferrin (Lf) is a glycoprotein of the innate immune response that sequesters iron in the mucosae. Lf possesses immune-regulatory properties, such as antiinflammatory and antioxidant activities. Moreover, the microbicidal activity of apoLf, which lacks bound iron, has been shown. In this study, we evaluated the therapeutic effect of bovine Lf (bLf) against ALA in a model of hepatic amoebiasis in hamsters. Interestingly, hamsters treated intragastrically with Lf (2.5 mg/100 g mass) over a period of 8 days showed no clinical signs of disease and ALA was effectively decreased, with only 0.63% detectable lesion, compared with 63% in untreated animals. Furthermore, liver function and blood cells approached normal levels among those receiving bLf treatment. These results suggest that bLf may aid in the therapy of amoebiasis, likely without producing undesirable effects in patients.

  2. Targeting of beta adrenergic receptors results in therapeutic efficacy against models of hemangioendothelioma and angiosarcoma.

    Directory of Open Access Journals (Sweden)

    Jessica M Stiles

    Full Text Available Therapeutic targeting of the beta-adrenergic receptors has recently shown remarkable efficacy in the treatment of benign vascular tumors such as infantile hemangiomas. As infantile hemangiomas are reported to express high levels of beta adrenergic receptors, we examined the expression of these receptors on more aggressive vascular tumors such as hemangioendotheliomas and angiosarcomas, revealing beta 1, 2, and 3 receptors were indeed present and therefore aggressive vascular tumors may similarly show increased susceptibility to the inhibitory effects of beta blockade. Using a panel of hemangioendothelioma and angiosarcoma cell lines, we demonstrate that beta adrenergic inhibition blocks cell proliferation and induces apoptosis in a dose dependent manner. Beta blockade is selective for vascular tumor cells over normal endothelial cells and synergistically effective when combined with standard chemotherapeutic or cytotoxic agents. We demonstrate that inhibition of beta adrenergic signaling induces large scale changes in the global gene expression patterns of vascular tumors, including alterations in the expression of established cell cycle and apoptotic regulators. Using in vivo tumor models we demonstrate that beta blockade shows remarkable efficacy as a single agent in reducing the growth of angiosarcoma tumors. In summary, these experiments demonstrate the selective cytotoxicity and tumor suppressive ability of beta adrenergic inhibition on malignant vascular tumors and have laid the groundwork for a promising treatment of angiosarcomas in humans.

  3. Therapeutic Mechanisms of Human Adipose-Derived Mesenchymal Stem Cells in a Rat Tendon Injury Model.

    Science.gov (United States)

    Lee, Sang Yoon; Kwon, Bomi; Lee, Kyoungbun; Son, Young Hoon; Chung, Sun G

    2017-05-01

    Although survival of transplanted stem cells in vivo and differentiation of stem cells into tenocytes in vitro have been reported, there have been no in vivo studies demonstrating that mesenchymal stem cells (MSCs) could secrete their own proteins as differentiated tenogenic cells. Purpose/Hypothesis: Using a xenogeneic MSC transplantation model, we aimed to investigate whether MSCs could differentiate into the tenogenic lineage and secrete their own proteins. The hypothesis was that human MSCs would differentiate into the human tenogenic lineage and the cells would be able to secrete human-specific proteins in a rat tendon injury model. Controlled laboratory study. The Achilles tendons of 57 Sprague Dawley rats received full-thickness rectangular defects. After the modeling, the defective tendons were randomly assigned to 3 groups: (1) cell group, implantation with human adipose-derived mesenchymal stem cells (hASCs) and fibrin glue (106 cells in 60 μL); (2) fibrin group, implantation with fibrin glue and same volume of cell media; and (3) sham group, identical surgical procedure without any treatment. Gross observation and biomechanical, histopathological, immunohistochemistry, and Western blot analyses were performed at 2 and 4 weeks after modeling. hASCs implanted into the defective rat tendons were viable for 4 weeks as detected by immunofluorescence staining. Tendons treated with hASCs showed better gross morphological and biomechanical recovery than those in the fibrin and sham groups. Furthermore, the expression of both human-specific collagen type I and tenascin-C was significantly higher in the cell group than in the other 2 groups. Transplantation of hASCs enhanced rat tendon healing biomechanically. hASCs implanted into the rat tendon defect model survived for at least 4 weeks and secreted human-specific collagen type I and tenascin-C. These findings suggest that transplanted MSCs may be able to differentiate into the tenogenic lineage and contribute

  4. Modeling middle and final flush effects of urban runoff pollution in an urbanizing catchment

    Science.gov (United States)

    Qin, Hua-peng; He, Kang-mao; Fu, Guangtao

    2016-03-01

    In current literature, the first flush effect of urban runoff pollution has been studied and reported extensively. However, the effects of middle and final flushes on pollutant flushing were not given much attention. In addition, few previous studies have discussed the suitability of the widely used exponential wash-off model for describing the middle or final flush processes. In this paper, the Shiyan River catchment, a typical rapidly urbanizing catchment in China, is chosen as a study area to analyze the effects of first, middle and final flushes based on monitoring hydrographs and pollutographs. In order to simulate the middle and final flush processes observed in storm events, a new, realistically simple, parsimonious model (named as logistic wash-off model) is developed with the assumption that surface pollutant loads available for wash-off increase with cumulative runoff volume following a logistic curve. The popular exponential wash-off model and the newly developed model are used and compared in simulating the flush processes in storm events. The results indicate that all the three types of pollutant flushing are observed in the experiment; however, the first flush effect is weak, while the middle and final flush effects are substantial. The exponential model has performed well in simulating the first flush process but failed to simulate well the middle and final flush processes. However, the logistic wash-off model has effectively simulated all the three types of pollutant flush, and particularly, it has performed better in simulating the middle and final flush processes than the exponential model.

  5. Therapeutic effects of rosmarinic acid on airway responses in a murine model of asthma.

    Science.gov (United States)

    Liang, Zhengmin; Nie, Haiying; Xu, Yangfeng; Peng, Jianbo; Zeng, Yun; Wei, Yingyi; Wen, Xuemei; Qiu, Jiaming; Zhong, Weiting; Deng, Xuming; He, Jiakang

    2016-12-01

    Rosmarinic acid (RA) is an active component of a traditional Chinese herbal medicine. Previously, we reported that RA exerted a strong anti-inflammatory effect in a mouse acute lung injury model. Therefore, we hypothesized that RA might also have potential therapeutic effects in a murine model of asthma. In this study, we aimed to evaluate the anti-asthmatic activity of RA and explored its possible molecular mechanisms of action. Female BALB/c mice that had been sensitized to and challenged with ovalbumin (Ova) were treated with RA (20mg/kg) 1h after challenge. The results showed that RA greatly diminished the number of inflammatory cells and the production of Th2 cytokines in the bronchoalveolar lavage fluid (BALF); significantly reduced the secretion of total IgE, Ova-specific IgE, and eotaxin; and markedly ameliorated airway hyperresponsiveness (AHR) compared with Ova-induced mice. Histological studies further revealed that RA substantially decreased inflammatory cells infiltration and mucus hypersecretion compared with Ova-induced mice. Moreover, our results suggested that the protective effects of RA were mediated by the inhibition of JNK and p38 MAPK phosphorylation and nuclear factor-κB (NF-κB) activation. Furthermore, RA treatment resulted in a significant reduction in the mRNA expression of AMCase, CCL11, CCR3, Ym2 and E-selectin in lung tissue. These findings suggest that RA may effectively delay the development of airway inflammation and could thus be used as a therapy for allergic asthma. Copyright © 2016 Elsevier B.V. All rights reserved.

  6. Defining immunological impact and therapeutic benefit of mild heating in a murine model of arthritis.

    Directory of Open Access Journals (Sweden)

    Chen-Ting Lee

    Full Text Available Traditional treatments, including a variety of thermal therapies have been known since ancient times to provide relief from rheumatoid arthritis (RA symptoms. However, a general absence of information on how heating affects molecular or immunological targets relevant to RA has limited heat treatment (HT to the category of treatments known as "alternative therapies". In this study, we evaluated the effectiveness of mild HT in a collagen-induced arthritis (CIA model which has been used in many previous studies to evaluate newer pharmacological approaches for the treatment of RA, and tested whether inflammatory immune activity was altered. We also compared the effect of HT to methotrexate, a well characterized pharmacological treatment for RA. CIA mice were treated with either a single HT for several hours or daily 30 minute HT. Disease progression and macrophage infiltration were evaluated. We found that both HT regimens significantly reduced arthritis disease severity and macrophage infiltration into inflamed joints. Surprisingly, HT was as efficient as methotrexate in controlling disease progression. At the molecular level, HT suppressed TNF-α while increasing production of IL-10. We also observed an induction of HSP70 and a reduction in both NF-κB and HIF-1α in inflamed tissues. Additionally, using activated macrophages in vitro, we found that HT reduced production of pro-inflammatory cytokines, an effect which is correlated to induction of HSF-1 and HSP70 and inhibition of NF-κB and STAT activation. Our findings demonstrate a significant therapeutic benefit of HT in controlling arthritis progression in a clinically relevant mouse model, with an efficacy similar to methotrexate. Mechanistically, HT targets highly relevant anti-inflammatory pathways which strongly support its increased study for use in clinical trials for RA.

  7. Enhanced immunity in a mouse model of malignant glioma is mediated by a therapeutic ketogenic diet.

    Science.gov (United States)

    Lussier, Danielle M; Woolf, Eric C; Johnson, John L; Brooks, Kenneth S; Blattman, Joseph N; Scheck, Adrienne C

    2016-05-13

    Glioblastoma multiforme is a highly aggressive brain tumor with a poor prognosis, and advances in treatment have led to only marginal increases in overall survival. We and others have shown previously that the therapeutic ketogenic diet (KD) prolongs survival in mouse models of glioma, explained by both direct tumor growth inhibition and suppression of pro-inflammatory microenvironment conditions. The aim of this study is to assess the effects of the KD on the glioma reactive immune response. The GL261-Luc2 intracranial mouse model of glioma was used to investigate the effects of the KD on the tumor-specific immune response. Tumor-infiltrating CD8+ T cells, CD4+ T cells and natural killer (NK) cells were analyzed by flow cytometry. The expression of immune inhibitory receptors cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death 1 (PD-1) on CD8+ T cells were also analyzed by flow cytometry. Analysis of intracellular cytokine production was used to determine production of IFN, IL-2 and IFN- in tumor-infiltrating CD8+ T and natural killer (NK) cells and IL-10 production by T regulatory cells. We demonstrate that mice fed the KD had increased tumor-reactive innate and adaptive immune responses, including increased cytokine production and cytolysis via tumor-reactive CD8+ T cells. Additionally, we saw that mice maintained on the KD had increased CD4 infiltration, while T regulatory cell numbers stayed consistent. Lastly, mice fed the KD had a significant reduction in immune inhibitory receptor expression as well as decreased inhibitory ligand expression on glioma cells. The KD may work in part as an immune adjuvant, boosting tumor-reactive immune responses in the microenvironment by alleviating immune suppression. This evidence suggests that the KD increases tumor-reactive immune responses, and may have implications in combinational treatment approaches.

  8. Therapeutic effects of traditional Chinese medicine Niubeixiaohe in mouse tuberculosis models.

    Science.gov (United States)

    Liang, Yan; Wang, Xiaomei; Song, Jinying; Wang, Lan; Chen, Dan; Yang, Yourong; Bai, Xuejuan; Wang, Jie; Shi, Yingchang; Chen, Shibing; Liu, Jun; Yang, Cunwei; Luo, Huafeng; Liu, Guangling; Wu, Xueqiong

    2017-01-04

    The traditional Chinese medicine Niubeixiaohe (NBXH) is an effective anti-tuberculosis prescription, which is made up of Bulbus Fritillariae Cirrhosae, Rhizoma Bletillae, Radix Platycodonis, Fructus Arctii, Herba Houttuyniae and Glutinous rice. In this study, NBXH powder (I) and three kinds of NBXH extracts (II, III, and IV) were prepared. The water decoction of NBXH had been used to treat TB in clinic sixteen years suggested that it was effective to treat TB. This study evaluated the effects of different processing products of NBXH on mouse TB model in vivo and provide a new Chinese medicine for the clinical treatment of TB. In this study, 120 female BALB/c mice infected with Mycobacterium tuberculosis H37Rv, were treated with distilled water, M. vaccae vaccine, the low, middle and high doses of NBXH I, the low, middle and high doses of NBXH II, the low, middle and high doses of NBXH III, the low, middle and high doses of NBXH IV for 12 weeks, respectively. The body weights of mice in all NBXH groups were higher than that in the water group. The weight indexes of the spleens in M. vaccae group, the middle dose of NBXH II group, the low dose of NBXH IV group and in the high dose of NBXH IV group were significantly lower than that in the water group(Ptraditional Chinese medicine NBXH all had anti-tuberculosis therapeutic effects on mouse tuberculosis model, and this study provided a base for the further development of Chinese patent medicine NBXH. Also, this is the first report on comprehensive experimental research of NBXH extracts coming from six kinds of traditional Chinese medicine. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  9. Rational evaluation of the therapeutic effect and dosimetry of auger electrons for radionuclide therapy in a cell culture model.

    Science.gov (United States)

    Shinohara, Ayaka; Hanaoka, Hirofumi; Sakashita, Tetsuya; Sato, Tatsuhiko; Yamaguchi, Aiko; Ishioka, Noriko S; Tsushima, Yoshito

    2017-12-13

    Radionuclide therapy with low-energy auger electron emitters may provide high antitumor efficacy while keeping the toxicity to normal organs low. Here we evaluated the usefulness of an auger electron emitter and compared it with that of a beta emitter for tumor treatment in in vitro models and conducted a dosimetry simulation using radioiodine-labeled metaiodobenzylguanidine (MIBG) as a model compound. We evaluated the cellular uptake of 125I-MIBG and the therapeutic effects of 125I- and 131I-MIBG in 2D and 3D PC-12 cell culture models. We used a Monte Carlo simulation code (PHITS) to calculate the absorbed radiation dose of 125I or 131I in computer simulation models for 2D and 3D cell cultures. In the dosimetry calculation for the 3D model, several distribution patterns of radionuclide were applied. A higher cumulative dose was observed in the 3D model due to the prolonged retention of MIBG compared to the 2D model. However, 125I-MIBG showed a greater therapeutic effect in the 2D model compared to the 3D model (respective EC50 values in the 2D and 3D models: 86.9 and 303.9 MBq/cell), whereas 131I-MIBG showed the opposite result (respective EC50 values in the 2D and 3D models: 49.4 and 30.2 MBq/cell). The therapeutic effect of 125I-MIBG was lower than that of 131I-MIBG in both models, but the radionuclide-derived difference was smaller in the 2D model. The dosimetry simulation with PHITS revealed the influence of the radiation quality, the crossfire effect, radionuclide distribution, and tumor shape on the absorbed dose. Application of the heterogeneous distribution series dramatically changed the radiation dose distribution of 125I-MIBG, and mitigated the difference between the estimated and measured therapeutic effects of 125I-MIBG. The therapeutic effect of 125I-MIBG was comparable to that of 131I-MIBG in the 2D model, but the efficacy was inferior to that of 131I-MIBG in the 3D model, since the crossfire effect is negligible and the homogeneous distribution

  10. 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

    in this cascade produces depressive symptoms and memory impairments, and inhibiting this system with pharmacological or genetic manipulation affords...1 AWARD NUMBER: W81XWH-14-1-0478 TITLE: Novel Therapeutic Approaches for the Treatment of Depression and Cognitive Deficits in a Rodent Model...the Treatment of Depression and Cognitive Deficits in a Rodent Model of Gulf War Veterans’ Illness 5b. GRANT NUMBER W81XWH-14-1-0478 5c

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

    OpenAIRE

    R Mark Buller; Jill Schriewer; George Painter; Akbar M. Siddiqui; Scott Parker

    2010-01-01

    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 ectrome...

  12. New insights into the molecular pathophysiology of fragile X syndrome and therapeutic perspectives from the animal model.

    Science.gov (United States)

    Busquets-Garcia, Arnau; Maldonado, Rafael; Ozaita, Andrés

    2014-08-01

    Fragile X syndrome is the most common monogenetic form of intellectual disability and is a leading cause of autism. This syndrome is produced by the reduced transcription of the fragile X mental retardation (FMR1) gene, and it is characterized by a range of symptoms heterogeneously expressed in patients such as cognitive impairment, seizure susceptibility, altered pain sensitivity and anxiety. The recent advances in the understanding of the pathophysiological mechanisms involved have opened novel potential therapeutic approaches identified in preclinical rodent models as a necessary preliminary step for the subsequent evaluation in patients. Among those possible therapeutic approaches, the modulation of the metabotropic glutamate receptor signaling or the GABA receptor signaling have focused most of the attention. New findings in the animal models open other possible therapeutic approaches such as the mammalian target of rapamycin signaling pathway or the endocannabinoid system. This review summarizes the emerging data recently obtained in preclinical models of fragile X syndrome supporting these new therapeutic perspectives. Copyright © 2014 Elsevier Ltd. All rights reserved.

  13. Identification of potential therapeutic compounds for Parkinson's disease using Drosophila and human cell models.

    Science.gov (United States)

    Sanz, Francisco José; Solana-Manrique, Cristina; Muñoz-Soriano, Verónica; Calap-Quintana, Pablo; Moltó, María Dolores; Paricio, Nuria

    2017-07-01

    Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. It is caused by a loss of dopaminergic neurons in the substantia nigra pars compacta, leading to a decrease in dopamine levels in the striatum and thus producing movement impairment. Major physiological causes of neurodegeneration in PD are oxidative stress (OS) and mitochondrial dysfunction; these pathophysiological changes can be caused by both genetic and environmental factors. Although most PD cases are sporadic, it has been shown that 5-10% of them are familial forms caused by mutations in certain genes. One of these genes is the DJ-1 oncogene, which is involved in an early-onset recessive PD form. Currently, PD is an incurable disease for which existing therapies are not sufficiently effective to counteract or delay the progression of the disease. Therefore, the discovery of alternative drugs for the treatment of PD is essential. In this study we used a Drosophila PD model to identify candidate compounds with therapeutic potential for this disease. These flies carry a loss-of-function mutation in the DJ-1β gene, the Drosophila ortholog of human DJ-1, and show locomotor defects reflected by a reduced climbing ability. A pilot modifier chemical screen was performed, and several candidate compounds were identified based on their ability to improve locomotor activity of PD model flies. We demonstrated that some of them were also able to reduce OS levels in these flies. To validate the compounds identified in the Drosophila screen, a human cell PD model was generated by knocking down DJ-1 function in SH-SY5Y neuroblastoma cells. Our results showed that some of the compounds were also able to increase the viability of the DJ-1-deficient cells subjected to OS, thus supporting the use of Drosophila for PD drug discovery. Interestingly, some of them have been previously proposed as alternative therapies for PD or tested in clinical trials and others are first

  14. The evaluation of the therapeutic efficacy and side effects of a macromolecular dexamethasone prodrug in the collagen-induced arthritis mouse model

    Science.gov (United States)

    Quan, Lingdong; Zhang, Yijia; Dusad, Anand; Ren, Ke; Purdue, P. Edward; Goldring, Steven R.; Wang, Dong

    2015-01-01

    PURPOSE To investigate the efficacy and safety of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-dexamethasone conjugate (P-Dex) in the collagen-induced arthritis (CIA) mouse model. METHODS HPMA copolymer labeled with a near infrared fluorescence (NIRF) dye was administered to mice with CIA to validate its passive targeting to inflamed joints and utility as a drug carrier system. The CIA mice were treated with P-Dex, dexamethasone (Dex) or saline and the therapeutic efficacy and skeletal toxicity evaluated using clinical scoring and micro-computed tomography (µ-CT). RESULTS The NIRF signal of the HPMA copolymer localized to arthritic joints consistent with its passive targeting to sites of inflammation. While the CIA mice responded more rapidly to P-Dex compared to Dex, the final clinical score and endpoint µ-CT analyses of localized bone erosions indicated that both single dose P-Dex and dose equivalent daily Dex led to comparable clinical efficacy after 30 days. µ-CT analysis of the proximal tibial metaphyses showed that P-Dex treatment was associated with significantly higher BMD and BV/TV compared to Dex and the saline control, consistent with reduced glucocorticoid (GC) skeletal toxicity. CONCLUSION These results validate the therapeutic efficacy of P-Dex in the CIA mouse model. P-Dex treatment averted the adverse effects of GC’s on systemic bone loss, supporting its utility in clinical development for the management of rheumatoid arthritis. PMID:26286188

  15. Heel melanoma: the final result of wrong diagnostic and therapeutic approach in another bulgarian patient. First documented case from the board of the “adcrstr-association for dermatohistopathologic control, reevaluation and subsequent therapeutic recomme.

    Science.gov (United States)

    Chokoeva, A A; Tchernev, G; Gianfaldoni, S; Patterson, J W; Wollina, U; Lotti, T

    2015-01-01

    Difficulties with frequent misdiagnoses and incorrectly defined tumor thicknesses applied to the same histopathological preparation occurring among Bulgarian patients, has led to the creation of national and/or international associations or boards for control in problematic circumstances, particularly for patients with melanocytic and non melanocytic cutaneous tumors. Once again we report a problematic case of a patient with acral lentiginous melanomа, localized in the heel area of the right foot, in an otherwise healthy 69-year old woman. A pigmented lesion gradually developed in her heel area, where the patient had been previously treated several times with invasive therapeutic methods (cryosurgery, shave curettage) due to misdiagnosis as a verrucous lesion or as a viral wart in the absence of any prior histopathology report. Years later, the lesion progressed and changed in color, leading to surgical removal, followed by several histopathological evaluations that produced very different results on three separate occasions. The first result described the lesion as melanocytic nevus, and removed with tumor-free margins. The second report from the Department of Dermatology and Venereology, Military Academy in Sofia , Bulgaria, stated “no data for Verrucous carcinoma”. Only on the third assessment the correct diagnosis of “malignant melanoma” was given. A relapse of the melanoma occurred as only at the time of the last histopathologic evaluation, (following surgical resection of the lesion with adequate margins, performed in the “Onkoderma”- Policlinic for Dermatology, Venereology and Dermatologic Surgery, Sofia, Bulgaria) were criteria followed for appropriate pathological evaluation consistent with the recommendations of the AJCC for reporting of melanomas. Tumor thickness at that time was 1.31 mm. Removal of the draining lymph node, followed by inguinal lymphadenectomy was performed in the National Oncological Hospital in accordance with the

  16. Windows of vulnerability to psychopathology and therapeutic strategy in the adolescent rodent model.

    Science.gov (United States)

    Adriani, W; Laviola, G

    2004-09-01

    Adolescence comes in association with puberty, when maturation and rearrangement of major neurotransmitter pathways and functions are still taking place. The neurobiological processes occurring in the brain during this developmental period have been so far poorly investigated. Yet, it is during adolescence that some major neuropsychiatric disorders may become evident, including ADHD, schizophrenia, and drug abuse. Moreover, the age-related neurobehavioural plasticity renders adolescents particularly vulnerable to the consequences of psychoactive drug exposure. In this view, there is an increased likelihood that addiction will develop when psychoactive drug use starts early during adolescence. From all these observations adolescence emerges as a critical phase in development. In the present review, we focus on recent neurobiological characterization of adolescent rats and mice. As for vulnerability to addictive behaviour, nicotine exposure during adolescence dose-dependently down-regulated levels of AMPA GluR2/3 subunits in the striatum, suggesting a reduced neurobehavioural plasticity in adult subjects. Comparable exposure during adulthood had opposite effects. It was found consistently that exposure to nicotine during adolescence, but not similar exposure in the post-adolescent period, increased the expression of specific subunits of the acetylcholine receptor in adult rats, thus enhancing the reinforcing efficacy of nicotine in a self-administration paradigm. The present data identified a specific age-window, characterized by long-term effects on behavioural and neurochemical indexes, of vulnerability. With respect to potential therapeutic approaches in ADHD, we studied the adolescent spontaneously-hypertensive-rat (SHR) in an intolerance-to-delay operant-behaviour paradigm. The model was further validated by the finding that impulsivity was reduced by chronic methylphenidate administration. Impulsive SHR animals were characterized by reduced cannabinoid CB1

  17. Inducibility of ventricular fibrillation during mild therapeutic hypothermia: electrophysiological study in a swine model.

    Science.gov (United States)

    Kudlicka, Jaroslav; Mlcek, Mikulas; Belohlavek, Jan; Hala, Pavel; Lacko, Stanislav; Janak, David; Havranek, Stepan; Malik, Jan; Janota, Tomas; Ostadal, Petr; Neuzil, Petr; Kittnar, Otomar

    2015-02-22

    Mild therapeutic hypothermia (MTH) is being used after cardiac arrest for its expected improvement in neurological outcome. Safety of MTH concerning inducibility of malignant arrhythmias has not been satisfactorily demonstrated. This study compares inducibility of ventricular fibrillation (VF) before and after induction of MTH in a whole body swine model and evaluates possible interaction with changing potassium plasma levels. The extracorporeal cooling was introduced in fully anesthetized swine (n = 6) to provide MTH. Inducibility of VF was studied by programmed ventricular stimulation three times in each animal under the following: during normothermia (NT), after reaching the core temperature of 32°C (HT) and after another 60 minutes of stable hypothermia (HT60). Inducibility of VF, effective refractory period of the ventricles (ERP), QTc interval and potassium plasma levels were measured. Starting at normothermia of 38.7 (IQR 38.2; 39.8)°C, HT was achieved within 54 (39; 59) minutes and the core temperature was further maintained constant. Overall, the inducibility of VF was 100% (18/18 attempts) at NT, 83% (15/18) after reaching HT (P = 0.23) and 39% (7/18) at HT60 (P = 0.0001) using the same protocol. Similarly, ERP prolonged from 140 (130; 150) ms at NT to 206 (190; 220) ms when reaching HT (P < 0.001) and remained 206 (193; 220) ms at HT60. QTc interval was inversely proportional to the core temperature and extended from 376 (362; 395) at NT to 570 (545; 599) ms at HT. Potassium plasma level changed spontaneously: decreased during cooling from 4.1 (3.9; 4.8) to 3.7 (3.4; 4.1) mmol/L at HT (P < 0.01), then began to increase and returned to baseline level at HT60 (4.6 (4.4; 5.0) mmol/L, P = NS). According to our swine model, MTH does not increase the risk of VF induction by ventricular pacing in healthy hearts. Moreover, when combined with normokalemia, MTH exerts an antiarrhythmic effect despite prolonged QTc interval.

  18. 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.

  19. Therapeutic effects of intra-articular ultra-purified low endotoxin alginate administration on an experimental canine osteoarthritis model.

    Science.gov (United States)

    Tsukuda, Yukinori; Onodera, Tomohiro; Ito, Masayuki; Izumisawa, Yasuharu; Kasahara, Yasuhiko; Igarashi, Tatsuya; Ohzawa, Nobuo; Todoh, Masahiro; Tadano, Shigeru; Iwasaki, Norimasa

    2015-11-01

    This study aimed to elucidate the therapeutic effects of intra-articular administration of ultra-purified low endotoxin alginate (UPLE-alginate) on osteoarthritis (OA) using a canine anterior cruciate ligament transection (ACLT) model. We used 20 beagle dogs. ACLT was performed on the left knee of each dog and a sham operation was performed on the right knee as a control. All animals were randomly divided into the control (saline) and therapeutic (UPLE-alginate) groups. Animals in the control and therapeutic groups received weekly injections with 0.7 mL normal saline or 0.7 mL 0.5% UPLE-alginate, respectively, from 0 to 3 weeks after ACLT or sham operation. At 9 weeks after ACLT, the knee joints of all animals were observed using arthroscopy. All animals were euthanized at 14 weeks after ACLT and evaluated using morphologic assessment, histologic assessment, and biomechanical testing. Arthroscopic findings showed intact cartilage surface in both groups. Morphologic findings in the therapeutic group showed milder degeneration compared with those of the control group, but there were no significant differences between groups. Histologic scores of the medial femoral condyle (MFC) and lateral femoral condyle (LFC) were better in the therapeutic group than the control group (MFC: p = 0.009, LFC: p = 0.009). Joint lubrication did not differ significantly between groups. Intra-articular administration of UPLE-alginate in the early stage of OA slowed disease progression in canines. UPLE-alginate may have potential as a therapeutic agent for OA patients and reduce the number of patients who need to undergo total joint arthroplasty. © 2015 Wiley Periodicals, Inc.

  20. 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;

  1. Therapeutic efficacy of the F8-IL2 immunocytokine in a metastatic mouse model of lung adenocarcinoma.

    Science.gov (United States)

    Wieckowski, Sébastien; Hemmerle, Teresa; Prince, Spasenja Savic; Schlienger, Béatrice Dolder; Hillinger, Sven; Neri, Dario; Zippelius, Alfred

    2015-04-01

    Antibody-cytokine fusion proteins (immunocytokines) represent a novel class of armed antibodies in oncology. In particular, IL2- and TNF-based immunocytokines targeting the EDB domain of fibronectin and the A1 domain of tenascin-C have demonstrated promising anti-tumor activity and are currently investigated in Phase I and Phase II clinical trials. To advance the development of immunocytokines for NSCLC, we here report on the therapeutic efficacy of F8-IL2, an immunocytokine directed against the alternatively spliced EDA domain of fibronectin in a fully immunocompetent, orthotopic model of NSCLC, and the characterization of the target antigen expression in human NSCLC specimens. We evaluated the therapeutic efficacy of the F8-IL2 immunocytokine utilizing a K-ras mutant, p53 deficient metastatic mouse model of NSCLC derived from the latest generation of genetically engineered and conditional tumor models. In parallel, we assessed the presence of the EDA domain of fibronectin by immunofluorescence in lung biopsies obtained from patients with NSCLC. The EDA domain of fibronectin was broadly expressed in lung metastases obtained from our model. Treatment with F8-IL2 induced substantial local changes within immune effector cell populations and demonstrated promising therapeutic efficacy as monotherapy. The target of F8-IL2, the EDA domain of fibronectin, was present in all human lung adenocarcinoma specimens tested. Both the therapeutic efficacy in a metastatic mouse model of NSCLC and the extensive presence of the EDA domain of fibronectin in human NSCLC biopsies support the rational development of therapies based on the F8-IL2 immunocytokine for the treatment of NSCLC. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  2. 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

  3. 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

  4. 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

  5. [Establishment of animal model with B lineage acute leukemia in nude mice for evaluation of new therapeutic agents].

    Science.gov (United States)

    Li, Li-xia; Tang, Yong-min; Gu, Wei-zhong; Tang, Hong-feng; Qian, Bai-qin; Shen, Hong-qiang; Luo, Chun-fang

    2008-09-01

    To establish an acute leukemia animal model for testing new therapeutic agents in vivo. Nude mice were intraperitoneally injected with 2 mg cyclophosphamide, 24 h later 5 x 10(6) acute B-cell leukemia Nalm-6 cells was inoculated via the tail vein, then monitored daily. When animals were paralyzed or dying, the organs including the liver, spleen, lung, heart, kidney, brain, bone marrow, pancreas, testes were removed and fixed with formalin, examined by routine histopathology. After Nalm-6 cells were inoculated the mean survival of mice were( 19.4+/-0.55)d (n=6). The paralysis of mice was followed by weight loss, bent spines, hogback, cachexia and death. Histopathological examination showed that the tumor cells infiltrated liver, spleen, kidney, lung, meninges, interior cerebrum, the liver and kidney were the most affected organs. B lineage acute leukemia animal model has been successfully established in the nude mice, which is suitable for testing new therapeutic agents.

  6. The Attending Nurse Caring Model: integrating theory, evidence and advanced caring-healing therapeutics for transforming professional practice.

    Science.gov (United States)

    Watson, Jean; Foster, Roxie

    2003-05-01

    This paper presents a proposed model: The Attending Nursing Caring Model (ANCM) as an exemplar for advancing and transforming nursing practice within a reflective, theoretical and evidence-based context. Watson's theory of human caring is used as a guide for integrating theory, evidence and advanced therapeutics in the area of children's pain. The ANCM is offered as a programme for renewing the profession and its professional practices of caring-healing arts and science, during an era of decline, shortages, and crises in care, safety, and hospital and health reform. The ANCM elevates contemporary nursing's caring values, relationships, therapeutics and responsibilities to a higher/deeper order of caring science and professionalism, intersecting with other professions, while sustaining the finest of its heritage and traditions of healing.

  7. A Final Focus Model for Heavy Ion Fusion Driver System Codes

    Energy Technology Data Exchange (ETDEWEB)

    Barnard, J J; Bangerter, R O; Henestroza, E; Kaganovich, I D; Logan, B G; Meier, W R; Rose, D V; Santhanam, P; Sharp, W M; Welch, D R; Yu, S S

    2004-12-15

    The need to reach high temperatures in an inertial fusion energy (IFE) target (or a target for the study of High Energy Density Physics, HEDP) requires the ability to focus ion beams down to a small spot. System models indicate that within the accelerator, the beam radius will be of order centimeters, whereas at the final focal spot on the target, a beam radius of order millimeters is required, so radial compression factors of order ten are required. The IFE target gain (and hence the overall cost of electricity) and the HEDP target temperature are sensitive functions of the final spot radius on target. Because of this sensitivity, careful attention needs to be paid to the spot radius calculation. We review our current understanding of the elements that enter into a systems model (such as emittance growth from chromatic, geometric, and non-linear space charge forces) for the final focus based on a quadrupolar magnet system.

  8. Gas Transport Parameters for Landfill Final Cover Soil: Measurements and Model Modification by Dry Bulk Density

    Science.gov (United States)

    Wickramarachchi, P. N.; Kawamoto, K.; Hamamoto, S.; Nagamori, M.; Moldrup, P.; Komatsu, T.

    2011-12-01

    Landfill sites have been emerging in greenhouse warming scenarios as a significant source of atmospheric methane (CH4). Until recently, landfill management strategies have mainly addressed the problem of preventing groundwater contamination and reduction of leachate generation. Being one of the largest sources of anthropogenic CH4 emission, the final cover system should also be designed for minimizing the greenhouse gases migration into the atmosphere or the areas surrounding the landfill while securing the hydraulic performance. Compared to the intensive research efforts on hydraulic performances of landfill final cover soil, few studies about gas transport characteristics of landfill cover soils have been done. However, recent soil-gas studies implied that the effects of soil physical properties such as bulk density (i.e., compaction level), soil particle size are key parameters to understand landfill gaseous performance. The gas exchange through the final cover soils is controlled by advective and diffusive gas transport. Air permeability (ka) governs the advective gas transport while the soil-gas diffusion coefficient (Dp) governs diffusive gas transport. In this study, the effects of compaction level and particle size fraction effects on ka and Dp for landfill final cover soil was investigated. The disturbed soil samples were taken from landfill final cover in Japan. A compaction tests were performed for the soil samples with two different size fractions (networks that are available for gas transport through the porous material. Then, the famous predictive models, the water induced linear reduction (WLR) model for Dp and the reference point law (RPL) model for ka were modified with reference point measurements (dry conditions) and model parameters and they correlated linearly to dry bulk density values for both fractions of landfill final cover soil.

  9. 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

  10. 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...

  11. SKI-178: A Multitargeted Inhibitor of Sphingosine Kinase and Microtubule Dynamics Demonstrating Therapeutic Efficacy in Acute Myeloid Leukemia Models.

    Science.gov (United States)

    Hengst, Jeremy A; Dick, Taryn E; Sharma, Arati; Doi, Kenichiro; Hegde, Shailaja; Tan, Su-Fern; Geffert, Laura M; Fox, Todd E; Sharma, Arun K; Desai, Dhimant; Amin, Shantu; Kester, Mark; Loughran, Thomas P; Paulson, Robert F; Claxton, David F; Wang, Hong-Gang; Yun, Jong K

    2017-01-01

    To further characterize the selectivity, mechanism-of-action and therapeutic efficacy of the novel small molecule inhibitor, SKI-178. Using the state-of-the-art Cellular Thermal Shift Assay (CETSA) technique to detect "direct target engagement" of proteins intact cells, in vitro and in vivo assays, pharmacological assays and multiple mouse models of acute myeloid leukemia (AML). Herein, we demonstrate that SKI-178 directly target engages both Sphingosine Kinase 1 and 2. We also present evidence that, in addition to its actions as a Sphingosine Kinase Inhibitor, SKI-178 functions as a microtubule network disrupting agent both in vitro and in intact cells. Interestingly, we separately demonstrate that simultaneous SphK inhibition and microtubule disruption synergistically induces apoptosis in AML cell lines. Furthermore, we demonstrate that SKI-178 is well tolerated in normal healthy mice. Most importantly, we demonstrate that SKI-178 has therapeutic efficacy in several mouse models of AML. SKI-178 is a multi-targeted agent that functions both as an inhibitor of the SphKs as well as a disruptor of the microtubule network. SKI-178 induced apoptosis arises from a synergistic interaction of these two activities. SKI-178 is safe and effective in mouse models of AML, supporting its further development as a multi-targeted anti-cancer therapeutic agent.

  12. A descriptive and broadly applicable model of therapeutic and stray absorbed dose from 6 to 25 MV photon beams.

    Science.gov (United States)

    Schneider, Christopher W; Newhauser, Wayne D; Wilson, Lydia J; Schneider, Uwe; Kaderka, Robert; Miljanić, Saveta; Knežević, Željka; Stolarcyzk, Liliana; Durante, Marco; Harrison, Roger M

    2017-07-01

    To develop a simple model of therapeutic and stray absorbed dose for a variety of treatment machines and techniques without relying on proprietary machine-specific parameters. Dosimetry measurements conducted in this study and from the literature were used to develop an analytical model of absorbed dose from a variety of treatment machines and techniques in the 6 to 25 MV interval. A modified one-dimensional gamma-index analysis was performed to evaluate dosimetric accuracy of the model on an independent dataset consisting of measured dose profiles from seven treatment units spanning four manufacturers. The average difference between the calculated and measured absorbed dose values was 9.9% for those datasets on which the model was trained. Additionally, these results indicate that the model can provide accurate calculations of both therapeutic and stray radiation dose from a wide variety of radiotherapy units and techniques. We have developed a simple analytical model of absorbed dose from external beam radiotherapy treatments in the 6 to 25 MV beam energy range. The model has been tested on measured data from multiple treatment machines and techniques, and is broadly applicable to contemporary external beam radiation therapy. © 2017 American Association of Physicists in Medicine.

  13. Novel therapeutic mechanisms determine the effectiveness of lipid-core nanocapsules on melanoma models.

    Science.gov (United States)

    Drewes, Carine C; Fiel, Luana A; Bexiga, Celina G; Asbahr, Ana Carolina C; Uchiyama, Mayara K; Cogliati, Bruno; Araki, Koiti; Guterres, Sílvia S; Pohlmann, Adriana R; Farsky, Sandra P

    2016-01-01

    Melanoma is a severe metastatic skin cancer with poor prognosis and no effective treatment. Therefore, novel therapeutic approaches using nanotechnology have been proposed to improve therapeutic effectiveness. Lipid-core nanocapsules (LNCs), prepared with poly(ε-caprolactone), capric/caprylic triglyceride, and sorbitan monostearate and stabilized by polysorbate 80, are efficient as drug delivery systems. Here, we investigated the effects of acetyleugenol-loaded LNC (AcE-LNC) on human SK-Mel-28 melanoma cells and its therapeutic efficacies on melanoma induced by B16F10 in C57B6 mice. LNC and AcE-LNC had z-average diameters and zeta potential close to 210 nm and -10.0 mV, respectively. CytoViva(®) microscopy images showed that LNC and AcE-LNC penetrated into SK-Mel-28 cells, and remained in the cytoplasm. AcE-LNC in vitro treatment (18-90×10(9) particles/mL; 1 hour) induced late apoptosis and necrosis; LNC and AcE-LNC (3-18×10(9) particles/mL; 48 hours) treatments reduced cell proliferation and delayed the cell cycle. Elevated levels of nitric oxide were found in supernatant of LNC and AcE-LNC, which were not dependent on nitric oxide synthase expressions. Daily intraperitoneal or oral treatment (days 3-10 after tumor injection) with LNC or AcE-LNC (1×10(12) particles/day), but not with AcE (50 mg/kg/day, same dose as AcE-LNC), reduced the volume of the tumor; nevertheless, intraperitoneal treatment caused toxicity. Oral LNC treatment was more efficient than AcE-LNC treatment. Moreover, oral treatment with nonencapsulated capric/caprylic triglyceride did not inhibit tumor development, implying that nanocapsule supramolecular structure is important to the therapeutic effects. Together, data herein presented highlight the relevance of the supramolecular structure of LNCs to toxicity on SK-Mel-28 cells and to the therapeutic efficacy on melanoma development in mice, conferring novel therapeutic mechanisms to LNC further than a drug delivery system.

  14. NGF and therapeutic prospective: what have we learned from the NGF transgenic models?

    Directory of Open Access Journals (Sweden)

    Luigi Aloe

    2015-03-01

    Full Text Available It has been shown that topical nerve growth factor (NGF administration induces healing action on human cutaneous, corneal and pressure ulcers, glaucoma, maculopathy and retinitis pigmentosa suggesting a therapeutic potential of NGF in human ophthalmology and cutaneous ulcers. A similar therapeutic suggestion has emerged for the NGF gene therapy of Alzheimer's disease and ischemic heart injury. Moreover, over the last few years, the role and biological properties of NGF have also been investigated with transgenic mice over-expressing and down-expressing NGF. However, the results obtained with these transgenic mice seem suitable to confirm and/or support the evidence obtained with exogenous administration of NGF regarding the suggested clinical potentiality of NGF. The aim of the present brief review is to report and comment on these two different findings of NGF's healing properties.

  15. Determination of Therapeutic Equivalence of Generic Products of Gentamicin in the Neutropenic Mouse Thigh Infection Model

    Science.gov (United States)

    Zuluaga, Andres F.; Agudelo, Maria; Cardeño, John J.; Rodriguez, Carlos A.; Vesga, Omar

    2010-01-01

    Background Drug regulatory agencies (DRA) support prescription of generic products of intravenous antibiotics assuming therapeutic equivalence from pharmaceutical equivalence. Recent reports of deaths associated with generic heparin and metoprolol have raised concerns about the efficacy and safety of DRA-approved drugs. Methodology/Principal Findings To challenge the assumption that pharmaceutical equivalence predicts therapeutic equivalence, we determined in vitro and in vivo the efficacy of the innovator product and 20 pharmaceutically equivalent generics of gentamicin. The data showed that, while only 1 generic product failed in vitro (MIC = 45.3 vs. 0.7 mg/L, Pproducts (including gentamicin reference powder) failed in vivo against E. coli due to significantly inferior efficacy (Emax = 4.81 to 5.32 vs. 5.99 log10 CFU/g, P≤0.043). Although the design lacked power to detect differences in survival after thigh infection with P. aeruginosa, dissemination to vital organs was significantly higher in animals treated with generic gentamicin despite 4 days of maximally effective treatment. Conclusion Pharmaceutical equivalence does not predict therapeutic equivalence of generic gentamicin. Stricter criteria based on solid experimental evidence should be required before approval for human use. PMID:20505762

  16. Determination of therapeutic equivalence of generic products of gentamicin in the neutropenic mouse thigh infection model.

    Directory of Open Access Journals (Sweden)

    Andres F Zuluaga

    Full Text Available BACKGROUND: Drug regulatory agencies (DRA support prescription of generic products of intravenous antibiotics assuming therapeutic equivalence from pharmaceutical equivalence. Recent reports of deaths associated with generic heparin and metoprolol have raised concerns about the efficacy and safety of DRA-approved drugs. METHODOLOGY/PRINCIPAL FINDINGS: To challenge the assumption that pharmaceutical equivalence predicts therapeutic equivalence, we determined in vitro and in vivo the efficacy of the innovator product and 20 pharmaceutically equivalent generics of gentamicin. The data showed that, while only 1 generic product failed in vitro (MIC = 45.3 vs. 0.7 mg/L, P<0.05, 10 products (including gentamicin reference powder failed in vivo against E. coli due to significantly inferior efficacy (E(max = 4.81 to 5.32 vs. 5.99 log(10 CFU/g, Ptherapeutic equivalence of generic gentamicin. Stricter criteria based on solid experimental evidence should be required before approval for human use.

  17. Therapeutic effects of intranigral transplantation of mesenchymal stem cells in rat models of Parkinson's disease.

    Science.gov (United States)

    Chen, Dandan; Fu, Wenyu; Zhuang, Wenxin; Lv, Cui; Li, Fengjie; Wang, Xin

    2017-03-01

    Stem cell transplantation is a promising tool for the treatment of neurodegenerative disorders, including Parkinson's disease (PD); however, the therapeutic routes and mechanisms of mechanical approaches to stem cell transplantation must be explored. This study tests the therapeutic effect of transplantation of rat bone marrow mesenchymal stem cells (MSCs) into the substantia nigra (SN) of the PD rat. 5-Bromo-2-deoxyuridine-labeled rat MSCs were transplanted into the SN of the 6-hydroxydopamine-injected side of PD rat brains. The behavioral changes in PD rats were examined before and 4 and 8 weeks after MSC transplantation. The expression of tyrosine hydroxylase (TH) in the SN and the striatum and the survival and differentiation of MSCs were assessed by immunohistochemical and double immunofluorescence techniques. Abnormal behavior of PD rats was significantly improved by the administration of bone marrow MSCs, and the number of TH-positive cells in the SN and the optical density of TH-positive fibers in the striatum were markedly increased. Transplanted MSCs can survive and migrate in the brain and differentiate into nestin-, neuron-specific enolase-, and GFAP-positive cells. Our findings suggest that transplantation of rat bone marrow MSCs into the SN of PD rats may provide therapeutic effects. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  18. 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.

  19. 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.

  20. 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.

  1. 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.

  2. The Domestic Cat as a Large Animal Model for Characterization of Disease and Therapeutic Intervention in Hereditary Retinal Blindness

    Directory of Open Access Journals (Sweden)

    Kristina Narfström

    2011-01-01

    Full Text Available Large mammals, including canids and felids, are affected by spontaneously occurring hereditary retinal diseases with similarities to those of humans. The large mammal models may be used for thorough clinical characterization of disease processes, understanding the effects of specific mutations, elucidation of disease mechanisms, and for development of therapeutic intervention. Two well-characterized feline models are addressed in this paper. The first model is the autosomal recessive, slowly progressive, late-onset, rod-cone degenerative disease caused by a mutation in the CEP290 gene. The second model addressed in this paper is the autosomal dominant early onset rod cone dysplasia, putatively caused by the mutation found in the CRX gene. Therapeutic trials have been performed mainly in the former type including stem cell therapy, retinal transplantation, and development of ocular prosthetics. Domestic cats, having large human-like eyes with comparable spontaneous retinal diseases, are also considered useful for gene replacement therapy, thus functioning as effective model systems for further research.

  3. Monitoring Disease Progression and Therapeutic Response in a Disseminated Tumor Model for Non-Hodgkin Lymphoma by Bioluminescence Imaging

    Directory of Open Access Journals (Sweden)

    Margarethe Köberle

    2015-07-01

    Full Text Available Xenograft tumor models are widely studied in cancer research. Our aim was to establish and apply a model for aggressive CD20-positive B-cell non-Hodgkin lymphomas, enabling us to monitor tumor growth and shrinkage in a noninvasive manner. By stably transfecting a luciferase expression vector, we created two bioluminescent human non-Hodgkin lymphoma cell lines, Jeko1(luci and OCI-Ly3(luci, that are CD20 positive, a prerequisite to studying rituximab, a chimeric anti-CD20 antibody. To investigate the therapy response in vivo, we established a disseminated xenograft tumor model injecting these cell lines in NOD/SCID mice. We observed a close correlation of bioluminescence intensity and tumor burden, allowing us to monitor therapy response in the living animal. Cyclophosphamide reduced tumor burden in mice injected with either cell line in a dose-dependent manner. Rituximab alone was effective in OCI-Ly3(luci-injected mice and acted additively in combination with cyclophosphamide. In contrast, it improved the therapeutic outcome of Jeko1(luci-injected mice only in combination with cyclophosphamide. We conclude that well-established bioluminescence imaging is a valuable tool in disseminated xenograft tumor models. Our model can be translated to other cell lines and used to examine new therapeutic agents and schedules.

  4. 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.

  5. A poetry program for the very elderly-Narrative perspective on one therapeutic model.

    Science.gov (United States)

    Wexler, Marvin

    2014-03-01

    The focus of this report is a poetry program that the author has been conducting at a nursing home/short-stay rehabilitation facility for the past three and a half years. The program involves reading poetry to groups of very elderly residents who have significant mental and/or physical disabilities. This article includes a description of the program and the author's observations of its beneficial effects. Poetry readings were also given to individual seniors who have significant dementia. The therapeutic value of the program to the elders and to the person reading the poetry to the elders is discussed.

  6. A poetry program for the very elderly—Narrative perspective on one therapeutic model

    Science.gov (United States)

    Wexler, Marvin

    2014-01-01

    The focus of this report is a poetry program that the author has been conducting at a nursing home/short-stay rehabilitation facility for the past three and a half years. The program involves reading poetry to groups of very elderly residents who have significant mental and/or physical disabilities. This article includes a description of the program and the author's observations of its beneficial effects. Poetry readings were also given to individual seniors who have significant dementia. The therapeutic value of the program to the elders and to the person reading the poetry to the elders is discussed. PMID:24899783

  7. Generalized equilibrium modeling: the methodology of the SRI-Gulf energy model. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Gazalet, E.G.

    1977-05-01

    The report provides documentation of the generalized equilibrium modeling methodology underlying the SRI-Gulf Energy Model and focuses entirely on the philosophical, mathematical, and computational aspects of the methodology. The model is a highly detailed regional and dynamic model of the supply and demand for energy in the US. The introduction emphasized the need to focus modeling efforts on decisions and the coordinated decomposition of complex decision problems using iterative methods. The conceptual framework is followed by a description of the structure of the current SRI-Gulf model and a detailed development of the process relations that comprise the model. The network iteration algorithm used to compute a solution to the model is described and the overall methodology is compared with other modeling methodologies. 26 references.

  8. Therapeutic effects of umbilical cord blood plasma in a rat model of acute ischemic stroke.

    Science.gov (United States)

    Yoo, Jongman; Kim, Han-Soo; Seo, Jin-Ju; Eom, Jang-Hyoun; Choi, Seong-Mi; Park, Sanghyun; Kim, Dong-Wook; Hwang, Dong-Youn

    2016-11-29

    Umbilical cord blood plasma (UCB-PL) contains various cytokines, growth factors, and immune modulatory factors that regulate the proliferation and function of immune cells and adult stem cells. Despite its therapeutic potential, the effects of UCB-PL treatment in conditions of ischemic brain injury have yet to be investigated. In this study, we demonstrated that both behavioral and structural impairments resulting from ischemic brain injury were significantly prevented/reversed after intravenous administration of UCB-PL relative to the vehicle control. As early as 1-week post-ischemia, an increased number of newborn cells in the subventricular zone and a reduced number of activated microglial cells in the peri-infarct area were observed in the UCB-PL group, suggesting that enhanced neurogenesis and/or the suppression of inflammation may have contributed to functional protection/recovery. Moreover, UCB-PL was more effective than plasma derived from a 65-year-old healthy adult for the treatment of ischemia-related structural and functional deficits, indicating that UCB-PL had greater therapeutic potential. This study provides valuable insights into the development of a safe, effective, and cell-free strategy for the treatment of ischemic brain damage and a much-needed alternative for patients who are ineligible for thrombolytic therapy.

  9. Different Therapeutic Outcomes of Benznidazole and VNI Treatments in Different Genders in Mouse Experimental Models of Trypanosoma cruzi Infection.

    Science.gov (United States)

    Guedes-da-Silva, F H; Batista, D G J; da Silva, C F; Meuser, M B; Simões-Silva, M R; de Araújo, J S; Ferreira, C G; Moreira, O C; Britto, C; Lepesheva, G I; Soeiro, Maria de Nazaré C

    2015-12-01

    The lack of translation between preclinical assays and clinical trials for novel therapies for Chagas disease (CD) indicates a need for more feasible and standardized protocols and experimental models. Here, we investigated the effects of treatment with benznidazole (Bz) and with the potent experimental T. cruzi CYP51 inhibitor VNI in mouse models of Chagas disease by using different animal genders and parasite strains and employing distinct types of therapeutic schemes. Our findings confirm that female mice are less vulnerable to the infection than males, show that male models are less susceptible to treatment with both Bz and VNI, and thus suggest that male models are much more suitable for selection of the most promising antichagasic agents. Additionally, we have found that preventive protocols (compound given at 1 dpi) result in higher treatment success rates, which also should be avoided during advanced steps of in vivo trials of novel anti-T. cruzi drug candidates. Another consideration is the relevance of immunosuppression methods in order to verify the therapeutic profile of novel compounds, besides the usefulness of molecular diagnostic tools (quantitative PCR) to ascertain compound efficacy in experimental animals. Our study aims to contribute to the development of more reliable methods and decision gates for in vivo assays of novel antiparasitic compounds in order to move them from preclinical to clinical trials for CD. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  10. 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).

  11. The immunocytokine F8-IL2 improves the therapeutic performance of sunitinib in a mouse model of renal cell carcinoma.

    Science.gov (United States)

    Frey, Katharina; Schliemann, Christoph; Schwager, Kathrin; Giavazzi, Raffaella; Johannsen, Manfred; Neri, Dario

    2010-12-01

    We investigated the therapeutic action of F8-IL2, a fusion protein consisting of the F8 antibody specific to the alternatively spliced extradomain-A of fibronectin, in diabody format and of human interleukin-2 in the Caki-1 (ATCC®) model of human renal cell carcinoma grafted subcutaneously in nude mice. F8-IL2 was cloned, expressed in CHO cells and purified to homogeneity. This immunocytokine was administered alone or combined with 3 standard drugs commonly used as therapy for kidney cancer, including sunitinib, sorafenib and interferon-α, in 2 sets of doses and treatment schedules. Neither F8-IL2 nor any other therapeutic agent cured tumor bearing mice when used as a single agent. The best therapeutic results were observed for the combination of sunitinib with F8-IL2 in a continuous administration schedule, which yielded a 28% cure rate and substantial tumor growth retardation. Considering that recombinant interleukin-2 based immunocytokines are now being investigated in several clinical trials in patients with cancer alone or combined with chemotherapy our preclinical results provide a motivation to study F8-IL2 combined with sunitinib in clinical trials in patients with kidney cancer. Copyright © 2010 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  12. 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.

  13. Final report: Constructing comprehensive models of grain boundaries using high-throughput experiments

    Energy Technology Data Exchange (ETDEWEB)

    Demkowicz, Michael [Texas A & M Univ., College Station, TX (United States); Schuh, Christopher [Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States); Marzouk, Youssef [Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States)

    2016-08-29

    This is the final report on project DE-SC0008926. The goal of this project was to create capabilities for constructing, analyzing, and modeling experimental databases of the crystallographic characters and physical properties of thousands of individual grain boundaries (GBs) in polycrystalline metals. This project focused on gallium permeation through aluminum (Al) GBs and hydrogen uptake into nickel (Ni) GBs as model problems. This report summarizes the work done within the duration of this project (including the original three-year award and the subsequent one-year renewal), i.e. from August 1, 2012 until April 30, 2016.

  14. Review of the physics and response models for burnout of semiconductor devices. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Orvis, W.J.; Khanaka, G.H.; Yee, J.H.

    1984-12-01

    Physical mechanisms that cause semiconductor devices to fail from electrical overstress - particularly, EMP-induced electrical stress - are described in light of the current literature and the authors' own research. A major concern is the cause and effects of second breakdown phenomena in p-n junction devices. Models of failure thresholds are evaluated for their inherent errors and for their ability to represent the relevant physics. Finally, the response models that relate electromagnetic stress parameters to appropriate failure-threshold parameters are discussed.

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

    DEFF Research Database (Denmark)

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

    Summary of key findings The concept of interpreted computational fluid dynamic (iCFD) modelling and the development methodology are presented (Fig. 1). The 1-D advection-dispersion model along with the statistically generated, meta-model for pseudo-dispersion constitutes the newly developed i...... for the SST through the proposed methodology is able to predict solid distribution with high accuracy -- taking a reasonable computational effort -- when compared to multi-dimensional numerical experiments, under a wide range of flow and design conditions. The iCFD models developed are intended to comply...... with the consistent modelling methodology (1). iCFD tools could play an important role in reliably predicting WWTP performance under normal and shock-loading (7). Background and relevance System analysis tools typically comprise numerous sub-models, identified so that the computational effort taken through system...

  16. 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.

  17. Ectromelia virus infections of mice as a model to support the licensure of anti-orthopoxvirus therapeutics.

    Science.gov (United States)

    Parker, Scott; Siddiqui, Akbar M; Painter, George; Schriewer, Jill; Buller, R Mark

    2010-09-01

    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.

  18. 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.

  19. [Pharmacokinetics of methotrexate and therapeutic drug monitoring in children with osteosarcoma. Computer simulation using a pharmacokinetic model].

    Science.gov (United States)

    Piekarczyk, A; Zimak, J; Taljański, W

    2000-01-01

    The pharmacokinetics of methotrexate (MTX) and the therapeutic drug monitoring (TDM) in children treated-with high-dose of MTX (HD MTX) have been discussed. The pharmacokinetics of MTX was studied in 15 children (54 courses) with osteosarcoma, treated with HD MTX (8, 10 and 12 g/m2; 4 h i.v. infusion). Pharmacokinetic analysis was performed by standard non-compartmental methods and using two-compartment nonlinear model with coexistence of additional, parallel linear route of elimination from the central compartment. This proposed model can be used for computer simulation and prognosis of the serum-level curve course depending on the simulated dosage, enhanced diuresis and simulated kidney or liver insufficiency during the dose individualisation. The usage of the pharmacokinetic model for computer simulations may improve the understanding of MTX kinetics and can optimalise dosage regimens for the next cycles of chemotherapy.

  20. 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.

  1. Increased Plasma Colloid Osmotic Pressure Facilitates the Uptake of Therapeutic Macromolecules in a Xenograft Tumor Model1

    Science.gov (United States)

    Hofmann, Matthias; McCormack, Emmet; Mujiç, Maja; Roßberg, Maila; Bernd, August; Bereiter-Hahn, Jürgen; Gjertsen, Bjørn Tore; Wiig, Helge; Kippenberger, Stefan

    2009-01-01

    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. PMID:19649211

  2. A novel nanoparticulate formulation of arsenic trioxide with enhanced therapeutic efficacy in a murine model of breast cancer.

    Science.gov (United States)

    Ahn, Richard W; Chen, Feng; Chen, Haimei; Stern, Stephan T; Clogston, Jeffrey D; Patri, Anil K; Raja, Meera R; Swindell, Elden P; Parimi, Vamsi; Cryns, Vincent L; O'Halloran, Thomas V

    2010-07-15

    The clinical success of arsenic trioxide (As(2)O(3)) in hematologic malignancies has not been replicated in solid tumors due to poor pharmacokinetics and dose-limiting toxicity. We have developed a novel nanoparticulate formulation of As(2)O(3) encapsulated in liposomal vesicles or "nanobins" [(NB(Ni,As)] to overcome these hurdles. We postulated that nanobin encapsulation of As(2)O(3) would improve its therapeutic index against clinically aggressive solid tumors, such as triple-negative breast carcinomas. The cytotoxicity of NB(Ni,As), the empty nanobin, and free As(2)O(3) was evaluated against a panel of human breast cancer cell lines. The plasma pharmacokinetics of NB(Ni,As) and free As(2)O(3) were compared in rats to measure drug exposure. In addition, the antitumor activity of these agents was evaluated in an orthotopic model of human triple-negative breast cancer. The NB(Ni,As) agent was much less cytotoxic in vitro than free As(2)O(3) against a panel of human breast cancer cell lines. In contrast, NB(Ni,As) dramatically potentiated the therapeutic efficacy of As(2)O(3) in vivo in an orthotopic model of triple-negative breast cancer. Reduced plasma clearance, enhanced tumor uptake, and induction of tumor cell apoptosis were observed for NB(Ni,As). Nanobin encapsulation of As(2)O(3) improves the pharmacokinetics and antitumor efficacy of this cytotoxic agent in vivo. Our findings demonstrate the therapeutic potential of this nanoscale agent and provide a foundation for future clinical studies in breast cancer and other solid tumors. Copyright 2010 AACR.

  3. 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.

  4. Potential new therapeutic modality revealed through agent-based modeling of the neuromuscular junction and acetylcholinesterase inhibition.

    Science.gov (United States)

    Chapleau, Richard R; Robinson, Peter J; Schlager, John J; Gearhart, Jeffery M

    2014-10-02

    One of the leading causes of death and illness within the agriculture industry is through unintentionally ingesting or inhaling organophosphate pesticides. OP intoxication directly inhibits acetylcholinesterase, resulting in an excitatory signaling cascade leading to fasciculation, loss of control of bodily fluids, and seizures. Our model was developed using a discrete, rules-based modeling approach in NetLogo. This model includes acetylcholinesterase, the nicotinic acetylcholine receptor responsible for signal transduction, a single release of acetylcholine, organophosphate inhibitors, and a theoretical novel medical countermeasure. We have parameterized the system considering the molecular reaction rate constants in an agent-based approach, as opposed to apparent macroscopic rates used in differential equation models. Our model demonstrates how the cholinergic crisis can be mitigated by therapeutic intervention with an acetylcholinesterase activator. Our model predicts signal rise rates and half-lives consistent with in vitro and in vivo data in the absence and presence of inhibitors. It also predicts the efficacy of theoretical countermeasures acting through three mechanisms: increasing catalytic turnover of acetylcholine, increasing acetylcholine binding affinity to the enzyme, and decreasing binding rates of inhibitors. We present a model of the neuromuscular junction confirming observed acetylcholine signaling data and suggesting that developing a countermeasure capable of reducing inhibitor binding, and not activator concentration, is the most important parameter for reducing organophosphate (OP) intoxication.

  5. Therapeutic effect of a TM4SF5-specific peptide vaccine against colon cancer in a mouse model.

    Science.gov (United States)

    Kwon, Sanghoon; Kim, Young-Eun; Park, Jeong-A; Kim, Doo-Sik; Kwon, Hyung-Joo; Lee, Younghee

    2014-04-01

    Molecular-targeted therapy has gained attention because of its high efficacy and weak side effects. Previously, we confirmed that transmembrane 4 superfamily member 5 protein (TM4SF5) can serve as a molecular target to prevent or treat hepatocellular carcinoma (HCC). We recently extended the application of the peptide vaccine, composed of CpG-DNA, liposome complex, and TM4SF5 peptide, to prevent colon cancer in a mouse model. Here, we first implanted mice with mouse colon cancer cells and then checked therapeutic effects of the vaccine against tumor growth. Immunization with the peptide vaccine resulted in robust production of TM4SF5-specific antibodies, alleviated tumor growth, and reduced survival rate of the tumor-bearing mice. We also found that serum levels of VEGF were markedly reduced in the mice immunized with the peptide vaccine. Therefore, we suggest that the TM4SF5-specific peptide vaccine has a therapeutic effect against colon cancer in a mouse model.

  6. 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.

  7. 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.

  8. Therapeutic Benefit for Late, but Not Early, Passage Mesenchymal Stem Cells on Pain Behaviour in an Animal Model of Osteoarthritis

    Directory of Open Access Journals (Sweden)

    Victoria Chapman

    2017-01-01

    Full Text Available Background. Mesenchymal stem cells (MSCs have a therapeutic potential for the treatment of osteoarthritic (OA joint pathology and pain. The aims of this study were to determine the influence of a passage number on the effects of MSCs on pain behaviour and cartilage and bone features in a rodent model of OA. Methods. Rats underwent either medial meniscal transection (MNX or sham surgery under anaesthesia. Rats received intra-articular injection of either 1.5 × 106 late passage MSCs labelled with 10 μg/ml SiMAG, 1.5 × 106 late passage mesenchymal stem cells, the steroid Kenalog (200 μg/20 μL, 1.5 × 106 early passage MSCs, or serum-free media (SFM. Sham-operated rats received intra-articular injection of SFM. Pain behaviour was quantified until day 42 postmodel induction. Magnetic resonance imaging (MRI was used to localise the labelled cells within the knee joint. Results. Late passage MSCs and Kenalog attenuated established pain behaviour in MNX rats, but did not alter MNX-induced joint pathology at the end of the study period. Early passage MSCs exacerbated MNX-induced pain behaviour for up to one week postinjection and did not alter joint pathology. Conclusion. Our data demonstrate for the first time the role of a passage number in influencing the therapeutic effects of MSCs in a model of OA pain.

  9. [Patient-centred prescription model to improve adequate prescription and therapeutic adherence in patients with multiple disorders].

    Science.gov (United States)

    Espaulella-Panicot, Joan; Molist-Brunet, Núria; Sevilla-Sánchez, Daniel; González-Bueno, Javier; Amblàs-Novellas, Jordi; Solà-Bonada, Núria; Codina-Jané, Carles

    Patients with multiple disorders and on multiple medication are often associated with clinical complexity, defined as a situation of uncertainty conditioned by difficulties in establishing a situational diagnosis and decision-making. The patient-centred care approach in this population group seems to be one of the best therapeutic options. In this context, the preparation of an individualised therapeutic plan is the most relevant practical element, where the pharmacological plan maintains an important role. There has recently been a significant increase in knowledge in the area of adequacy of prescription and adherence. In this context, we must find a model must be found that incorporates this knowledge into clinical practice by the professionals. Person-centred prescription is a medication review model that includes different strategies in a single intervention. It is performed by a multidisciplinary team, and allows them to adapt the pharmacological plan of patients with clinical complexity. Copyright © 2017 SEGG. Publicado por Elsevier España, S.L.U. All rights reserved.

  10. Genetically engineered murine models--contribution to our understanding of the genetics, molecular pathology and therapeutic targeting of neuroblastoma.

    Science.gov (United States)

    Chesler, Louis; Weiss, William A

    2011-10-01

    Genetically engineered mouse models (GEMM) have made major contributions to a molecular understanding of several adult cancers and these results are increasingly being translated into the pre-clinical setting where GEMM will very likely make a major impact on the development of targeted therapeutics in the near future. The relationship of pediatric cancers to altered developmental programs, and their genetic simplicity relative to adult cancers provides unique opportunities for the application of new advances in GEMM technology. In neuroblastoma the well-characterized TH-MYCN GEMM is increasingly used for a variety of molecular-genetic, developmental and pre-clinical therapeutics applications. We discuss: the present and historical application of GEMM to neuroblastoma research, future opportunities, and relevant targets suitable for new GEMM strategies in neuroblastoma. We review the potential of these models to contribute both to an understanding of the developmental nature of neuroblastoma and to improved therapy for this disease. Copyright © 2011 Elsevier Ltd. All rights reserved.

  11. Evaluation of therapeutic potential of nanosilver particles synthesised using aloin in experimental murine mastitis model.

    Science.gov (United States)

    Chaitanya Kumar, Thota Venkata; Muralidhar, Yegireddy; Prasad, Pagadala Eswara; Prasad, Tollamadugu Naga Venkata Krishna Vara; Alpha Raj, Mekapogu

    2013-09-01

    Nanobiotechnology is an emerging biological branch of nanotechnology. Application of nanoparticles with specific size and shape in biology has already shown unforeseen and interesting results. A study was conducted to evaluate the therapeutic potential of phytogenically derived aloin mediated nanosilver particles (AAgNPs), prepared by reduction of silver nitrate with aloin, in Staphylococcus aureus induced murine mastitis. A total of 40 female mice were divided into five groups of eight animals each. Group I served as lactating control, groups II-V were inoculated with 20 μl of 24 h broth culture of S. aureus containing 4.0 × 105 cfu/quarter under ketamine anaesthesia. After 6 h post inoculation, groups III and IV received 20 μl of aloin nanosilver (AAgNPs) through intramammary and intraperitoneal routes, respectively. Group V received antibiotic cefepime at 1 mg/kg body weight through the intra-peritoneal route. After 18 h post-treatment, serum C reactive protein, weights of mammary glands, mammary gland bacterial load, thiobarbituric acid reactive substances content, reduced glutathione content, superoxide dismutase activity and catalase activity and histopathology were determined. The compound showed a minimum inhibitory concentration of 21.8 ng/ml against S. aureus. Significant reduction (98%) in poly-morpho nuclear cell infiltration was observed with AAgNPs than antibiotic (50%).

  12. 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

  13. Therapeutic Remyelination Strategies in a Novel Model of Multiple Sclerosis: Japanese Macaque Encephalomyelitis

    Science.gov (United States)

    2012-05-01

    686. 10. Dal Canto MC, Lipton HL. Multiple sclerosis. Animal model: Theiler’s virus infection in mice. Am J Pathol 1977;88:497–500. 11. Clatch RJ...Melvold RW, Dal Canto MC, Miller SD, Lipton HL. The Theiler’s murine encephalomyelitis virus (TMEV) model for multiple sclerosis shows a strong influence

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

    DEFF Research Database (Denmark)

    Sardar, Samra; Andersson, Åsa

    2016-01-01

    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...

  15. Final safety analysis report for the Galileo Mission: Volume 2, Book 2: Accident model document: Appendices

    Energy Technology Data Exchange (ETDEWEB)

    1988-12-15

    This section of the Accident Model Document (AMD) presents the appendices which describe the various analyses that have been conducted for use in the Galileo Final Safety Analysis Report II, Volume II. Included in these appendices are the approaches, techniques, conditions and assumptions used in the development of the analytical models plus the detailed results of the analyses. Also included in these appendices are summaries of the accidents and their associated probabilities and environment models taken from the Shuttle Data Book (NSTS-08116), plus summaries of the several segments of the recent GPHS safety test program. The information presented in these appendices is used in Section 3.0 of the AMD to develop the Failure/Abort Sequence Trees (FASTs) and to determine the fuel releases (source terms) resulting from the potential Space Shuttle/IUS accidents throughout the missions.

  16. Finite element analysis of a model of a therapeutic shoe: effect of material selection for the outsole.

    Science.gov (United States)

    Lewis, Gladius

    2003-01-01

    The finite element analysis method was used to perform a sensitivity study of the effect of the materials used for the two layers of the outsole (high-density polyethylene, HDPE, and polyurethane, PU) of a "solid rocker-bottom" design of a therapeutic shoe on the responses (stresses and displacements) of a model of the shoe. It was found that the aforementioned materials choice affected the model responses in a noticeable manner. For example, when HDPE was used for the top layer of the outsole, the von Mises stress at the interface between the bottom of the foot and the top layer of the insole ranged from being about 8% lower to being about 62% higher compared to when PU was used. The implications of this finding are discussed.

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

    Science.gov (United States)

    Tuñón, María-Jesús; Alvarez, Marcelino; Culebras, Jesús-M; González-Gallego, Javier

    2009-07-07

    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 means of 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.

  18. Pharmacologically induced mouse model of adult spinal muscular atrophy to evaluate effectiveness of therapeutics after disease onset.

    Science.gov (United States)

    Feng, Zhihua; Ling, Karen K Y; Zhao, Xin; Zhou, Chunyi; Karp, Gary; Welch, Ellen M; Naryshkin, Nikolai; Ratni, Hasane; Chen, Karen S; Metzger, Friedrich; Paushkin, Sergey; Weetall, Marla; Ko, Chien-Ping

    2016-03-01

    Spinal muscular atrophy (SMA) is a genetic disease characterized by atrophy of muscle and loss of spinal motor neurons. SMA is caused by deletion or mutation of the survival motor neuron 1 (SMN1) gene, and the nearly identical SMN2 gene fails to generate adequate levels of functional SMN protein due to a splicing defect. Currently, several therapeutics targeted to increase SMN protein are in clinical trials. An outstanding issue in the field is whether initiating treatment in symptomatic older patients would confer a therapeutic benefit, an important consideration as the majority of patients with milder forms of SMA are diagnosed at an older age. An SMA mouse model that recapitulates the disease phenotype observed in adolescent and adult SMA patients is needed to address this important question. We demonstrate here that Δ7 mice, a model of severe SMA, treated with a suboptimal dose of an SMN2 splicing modifier show increased SMN protein, survive into adulthood and display SMA disease-relevant pathologies. Increasing the dose of the splicing modifier after the disease symptoms are apparent further mitigates SMA histopathological features in suboptimally dosed adult Δ7 mice. In addition, inhibiting myostatin using intramuscular injection of AAV1-follistatin ameliorates muscle atrophy in suboptimally dosed Δ7 mice. Taken together, we have developed a new murine model of symptomatic SMA in adolescents and adult mice that is induced pharmacologically from a more severe model and demonstrated efficacy of both SMN2 splicing modifiers and a myostatin inhibitor in mice at later disease stages. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  19. Therapeutic effect of mesenchymal stem cells transplantation on pulmonary hypertension model rats

    Directory of Open Access Journals (Sweden)

    Ke-yan ZHAO

    2013-11-01

    Full Text Available Objective  To observe the therapeutic effect of mesenchymal stem cells (MSCs transplantation on monocrotaline (MCT-induced pulmonary hypertension in rats. Methods MSCs were isolated from Wistar rats and cultivated by bone marrow adherent culture. The third to fifth passages of MSCs were used for cell transplantation. Forty male Wistar rats were randomly divided into control group, MCT group, MCT/MSCs 5×105 group and MCT/MSCs 1×106 group (10 each. MCT was injected intraperitoneally (60mg/kg, and MSCs were transplanted into rats through external jugular vein. Right ventricular systolic pressure (RVSP of rats was determined, then the animals were sacrificed and the ventricular ratio (i.e. the mass ratio of right to left ventricle plus interventricular septum was calculated. The lung tissue was observed by light microscopy after HE staining, orcein staining and smooth muscle actin immunohistochemical staining. Results Four weeks after MSCs administration, the RVSP and ventricular ratio were 35.6±8.4mmHg and 0.357±0.092 in MCT/MSCs 1×106 group respectively, and significantly lower than those in MCT group (47.2±10.5mmHg and 0.445±0.094, respectively, P0.05. Pathological observation found the intima-media thickness of pulmonary arterioles was 19.2%±3.8% in MCT/MSCs 1×106 group, and significantly thinner than that in MCT group (26.4%±4.9%, P0.05. Conclusion  Intravenous MSCs administration could inhibit the MCT-induced pulmonary hypertension and 1×106 is the optimal number of MSCs for transplantation. DOI: 10.11855/j.issn.0577-7402.2013.10.010

  20. 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.

  1. 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.

  2. 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

  3. 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.

  4. 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…

  5. Tapping into Salmonella typhimurium LT2 genome in a quest to explore its therapeutic arsenal: A metabolic network modeling approach.

    Science.gov (United States)

    Mehla, Kusum; Ramana, Jayashree

    2017-02-01

    S. typhimurium, the classical broad-host-range serovar is a widely distributed cause of food-borne illness. Escalating antibiotic resistance and potential of conjugal transmission to other pathogens attributable to its broad spectrum host specificities have aided S. typhimurium to emerge as a global health threat. To keep pace with ever evolving bacterial defenses, there is dire need to restock the antibiotic pipeline. Genome scale metabolic reconstructions present immense possibilities to decipher physiological properties of an organism using constraint-based methods The systems-level approaches of genome scale metabolic networks interrogation open up new avenues of drug target identification against deadly infectious diseases. We performed flux balance analysis and minimization of metabolic adjustment studies of genome scale reconstruction model of S. typhimurium targeted at identifying large number of metabolites with a potential to be utilized as therapeutic drug targets. These constraint based approaches initially predict a set of genes indispensable to bacterial survival by performing gene knockout studies which are then prioritized through a multistep process. Metabolites involved in l-rhamnose biosynthesis, peptidoglycan biosynthesis, fatty acid biosynthesis, and folate biosynthesis pathways were prioritized as candidate drug targets. This study provides a general therapeutic approach which can be effectively applied to other pathogens as well. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  6. A patient tumor transplant model of squamous cell cancer identifies PI3K inhibitors as candidate therapeutics in defined molecular bins.

    Science.gov (United States)

    Keysar, Stephen B; Astling, David P; Anderson, Ryan T; Vogler, Brian W; Bowles, Daniel W; Morton, J Jason; Paylor, Jeramiah J; Glogowska, Magdalena J; Le, Phuong N; Eagles-Soukup, Justin R; Kako, Severine L; Takimoto, Sarah M; Sehrt, Daniel B; Umpierrez, Adrian; Pittman, Morgan A; Macfadden, Sarah M; Helber, Ryan M; Peterson, Scott; Hausman, Diana F; Said, Sherif; Leem, Ted H; Goddard, Julie A; Arcaroli, John J; Messersmith, Wells A; Robinson, William A; Hirsch, Fred R; Varella-Garcia, Marileila; Raben, David; Wang, Xiao-Jing; Song, John I; Tan, Aik-Choon; Jimeno, Antonio

    2013-08-01

    Targeted therapy development in head and neck squamous cell carcinoma (HNSCC) is challenging given the rarity of activating mutations. Additionally, HNSCC incidence is increasing related to human papillomavirus (HPV). We sought to develop an in vivo model derived from patients reflecting the evolving HNSCC epidemiologic landscape, and use it to identify new therapies. Primary and relapsed tumors from HNSCC patients, both HPV+ and HPV-, were implanted on mice, giving rise to 25 strains. Resulting xenografts were characterized by detecting key mutations, measuring protein expression by IHC and gene expression/pathway analysis by mRNA-sequencing. Drug efficacy studies were run with representative xenografts using the approved drug cetuximab as well as the new PI3K inhibitor PX-866. Tumors maintained their original morphology, genetic profiles and drug susceptibilities through serial passaging. The genetic makeup of these tumors was consistent with known frequencies of TP53, PI3KCA, NOTCH1 and NOTCH2 mutations. Because the EGFR inhibitor cetuximab is a standard HNSCC therapy, we tested its efficacy and observed a wide spectrum of efficacy. Cetuximab-resistant strains had higher PI3K/Akt pathway gene expression and protein activation than cetuximab-sensitive strains. The PI3K inhibitor PX-866 had anti-tumor efficacy in HNSCC models with PIK3CA alterations. Finally, PI3K inhibition was effective in two cases with NOTCH1 inactivating mutations. In summary, we have developed an HNSCC model covering its clinical spectrum whose major genetic alterations and susceptibility to anticancer agents represent contemporary HNSCC. This model enables to prospectively test therapeutic-oriented hypotheses leading to personalized medicine. Copyright © 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  7. 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

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

    Energy Technology Data Exchange (ETDEWEB)

    Abazov, Victor Mukhamedovich; et al.

    2012-08-01

    We present a search for the standard model Higgs boson in final states with an electron or muon and a hadronically decaying tau lepton in association with zero, one, or two or more jets using data corresponding to an integrated luminosity of up to 7.3 fb{sup -1} collected with the D0 detector at the Fermilab Tevatron collider. The analysis is sensitive to Higgs boson production via gluon gluon fusion, associated vector boson production, and vector boson fusion, and to Higgs boson decays to tau lepton pairs or W boson pairs. Observed (expected) limits are set on the ratio of 95% C.L. upper limits on the cross section times branching ratio, relative to those predicted by the Standard Model, of 14 (22) at a Higgs boson mass of 115 GeV and 7.7 (6.8) at 165 GeV.

  9. Establishment of Patient-Derived Tumor Xenograft Models of Epithelial Ovarian Cancer for Preclinical Evaluation of Novel Therapeutics.

    Science.gov (United States)

    Liu, Joyce F; Palakurthi, Sangeetha; Zeng, Qing; Zhou, Shan; Ivanova, Elena; Huang, Wei; Zervantonakis, Ioannis K; Selfors, Laura M; Shen, Yiping; Pritchard, Colin C; Zheng, Mei; Adleff, Vilmos; Papp, Eniko; Piao, Huiying; Novak, Marian; Fotheringham, Susan; Wulf, Gerburg M; English, Jessie; Kirschmeier, Paul T; Velculescu, Victor E; Paweletz, Cloud; Mills, Gordon B; Livingston, David M; Brugge, Joan S; Matulonis, Ursula A; Drapkin, Ronny

    2017-03-01

    Purpose: Ovarian cancer is the leading cause of death from gynecologic malignancy in the United States, with high rates of recurrence and eventual resistance to cytotoxic chemotherapy. Model systems that allow for accurate and reproducible target discovery and validation are needed to support further drug development in this disease.Experimental Design: Clinically annotated patient-derived xenograft (PDX) models were generated from tumor cells isolated from the ascites or pleural fluid of patients undergoing clinical procedures. Models were characterized by IHC and by molecular analyses. Each PDX was luciferized to allow for reproducible in vivo assessment of intraperitoneal tumor burden by bioluminescence imaging (BLI). Plasma assays for CA125 and human LINE-1 were developed as secondary tests of in vivo disease burden.Results: Fourteen clinically annotated and molecularly characterized luciferized ovarian PDX models were generated. Luciferized PDX models retain fidelity to both the nonluciferized PDX and the original patient tumor, as demonstrated by IHC, array CGH, and targeted and whole-exome sequencing analyses. Models demonstrated diversity in specific genetic alterations and activation of PI3K signaling pathway members. Response of luciferized PDX models to standard-of-care therapy could be reproducibly monitored by BLI or plasma markers.Conclusions: We describe the establishment of a collection of 14 clinically annotated and molecularly characterized luciferized ovarian PDX models in which orthotopic tumor burden in the intraperitoneal space can be followed by standard and reproducible methods. This collection is well suited as a platform for proof-of-concept efficacy and biomarker studies and for validation of novel therapeutic strategies in ovarian cancer. Clin Cancer Res; 23(5); 1263-73. ©2016 AACR. ©2016 American Association for Cancer Research.

  10. Blooms' separation of the final exam of Engineering Mathematics II: Item reliability using Rasch measurement model

    Science.gov (United States)

    Fuaad, Norain Farhana Ahmad; Nopiah, Zulkifli Mohd; Tawil, Norgainy Mohd; Othman, Haliza; Asshaari, Izamarlina; Osman, Mohd Hanif; Ismail, Nur Arzilah

    2014-06-01

    In engineering studies and researches, Mathematics is one of the main elements which express physical, chemical and engineering laws. Therefore, it is essential for engineering students to have a strong knowledge in the fundamental of mathematics in order to apply the knowledge to real life issues. However, based on the previous results of Mathematics Pre-Test, it shows that the engineering students lack the fundamental knowledge in certain topics in mathematics. Due to this, apart from making improvements in the methods of teaching and learning, studies on the construction of questions (items) should also be emphasized. The purpose of this study is to assist lecturers in the process of item development and to monitor the separation of items based on Blooms' Taxonomy and to measure the reliability of the items itself usingRasch Measurement Model as a tool. By using Rasch Measurement Model, the final exam questions of Engineering Mathematics II (Linear Algebra) for semester 2 sessions 2012/2013 were analysed and the results will provide the details onthe extent to which the content of the item providesuseful information about students' ability. This study reveals that the items used in Engineering Mathematics II (Linear Algebra) final exam are well constructed but the separation of the items raises concern as it is argued that it needs further attention, as there is abig gap between items at several levels of Blooms' cognitive skill.

  11. The Drosophila melanogaster model for Cornelia de Lange syndrome: Implications for etiology and therapeutics.

    Science.gov (United States)

    Dorsett, Dale

    2016-06-01

    Discovery of genetic alterations that cause human birth defects provide key opportunities to improve the diagnosis, treatment, and family counseling. Frequently, however, these opportunities are limited by the lack of knowledge about the normal functions of the affected genes. In many cases, there is more information about the gene's orthologs in model organisms, including Drosophila melanogaster. Despite almost a billion years of evolutionary divergence, over three-quarters of genes linked to human diseases have Drosophila homologs. With a short generation time, a twenty-fold smaller genome, and unique genetic tools, the conserved functions of genes are often more easily elucidated in Drosophila than in other organisms. Here we present how this applies to Cornelia de Lange syndrome, as a model for how Drosophila can be used to increase understanding of genetic syndromes caused by mutations with broad effects on gene transcription and exploited to develop novel therapies. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  12. 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

  13. 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

  14. 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

  15. Hexokinase 2 is required for tumor initiation and maintenance and its systemic deletion is therapeutic in mouse models of cancer.

    Science.gov (United States)

    Patra, Krushna C; Wang, Qi; Bhaskar, Prashanth T; Miller, Luke; Wang, Zebin; Wheaton, Will; Chandel, Navdeep; Laakso, Markku; Muller, William J; Allen, Eric L; Jha, Abhishek K; Smolen, Gromoslaw A; Clasquin, Michelle F; Robey, Brooks; Hay, Nissim

    2013-08-12

    Accelerated glucose metabolism is a common feature of cancer cells. Hexokinases catalyze the first committed step of glucose metabolism. Hexokinase 2 (HK2) is expressed at high level in cancer cells, but only in a limited number of normal adult tissues. Using Hk2 conditional knockout mice, we showed that HK2 is required for tumor initiation and maintenance in mouse models of KRas-driven lung cancer, and ErbB2-driven breast cancer, despite continued HK1 expression. Similarly, HK2 ablation inhibits the neoplastic phenotype of human lung and breast cancer cells in vitro and in vivo. Systemic Hk2 deletion is therapeutic in mice bearing lung tumors without adverse physiological consequences. Hk2 deletion in lung cancer cells suppressed glucose-derived ribonucleotides and impaired glutamine-derived carbon utilization in anaplerosis. Copyright © 2013 Elsevier Inc. All rights reserved.

  16. Therapeutic misadventure.

    Science.gov (United States)

    Langford, N J

    2010-10-01

    Therapeutic misadventure can be defined as an injury or an adverse event caused by medical management rather than by an underlying disease. Within the National Health Service there were over 86,000 reported adverse incidents in 2007. In the USA medication errors have been rated as the fourth highest cause of death. Unfortunately one of the greatest contributors to iatrogenic injury is human error. The potential types of misadventure are infinite. Medication errors are a major part of this, being responsible for over 70% of cases that cause serious harm. However, many medication errors caused by slips, lapses, technical errors and mistakes are preventable; intentional violations of safe operating procedures are not. While medication errors were tolerated by society in the past, the readiness to institute criminal proceedings against health-care professionals has increased greatly in the UK over the last decade. The medication process consists of writing prescriptions, dispensing the product, administering it and monitoring its effects. Prescription errors arise owing to incomplete information, lack of appropriate labelling, environmental factors and human blunders. Even with a perfect prescription the right medication must be dispensed and appropriately labelled. Dispensing errors are not uncommon and may be compounded by non-clinical considerations. Administration of a drug by injection is one of the most dangerous aspects of the medication process, especially in inexperienced hands. The final component of medication supply is monitoring the effect of the medication. With short courses of medication such monitoring is easy, but with long-term medication, particularly with potent drugs where the margin between efficacy and toxicity is small, active procedures may be required to ensure toxicity does not ensue. Despite the endeavour of health-care professions to stick to the rule of 'first, do no harm', in reality this is difficult to achieve all of the time. When

  17. 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

  18. 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.

  19. Modeling new immunoregulatory therapeutics as antimicrobial alternatives for treating Clostridium difficile infection.

    Science.gov (United States)

    Leber, Andrew; Hontecillas, Raquel; Abedi, Vida; Tubau-Juni, Nuria; Zoccoli-Rodriguez, Victoria; Stewart, Caroline; Bassaganya-Riera, Josep

    2017-05-01

    The current treatment paradigm in Clostridium difficile infection is the administration of antibiotics contributing to the high rates of recurrent infections. Recent alternative strategies, such as fecal microbiome transplantation and anti-toxin antibodies, have shown similar efficacy in the treatment of C. difficile associated disease (CDAD). However, barriers exist for either treatment or other novel treatments to displace antibiotics as the standard of care. To aid in the comparison of these and future treatments in CDAD, we developed an in silico pipeline to predict clinical efficacy with nonclinical results. The pipeline combines an ordinary differential equation (ODE)-based model, describing the immunological and microbial interactions in the gastrointestinal (GI) mucosa, with machine learning algorithms to translate simulated output quantities (i.e. time of clearance, quantity of commensal bacteria, T cell ratios) into clinical predictions based on prior preclinical, translational and clinical trial data. As a use case, we compare the efficacy of lanthionine synthetase C-like 2 (LANCL2), a novel immunoregulatory target with promising efficacy in inflammatory bowel disease (IBD), activation with antibiotics, fecal microbiome transplantation and anti-toxin antibodies in the treatment of CDAD. We further validate the potential of LANCL2 pathway activation, in a mouse model of C. difficile infection in which it displays an ability to decrease weight loss and inflammatory cell types while protecting against mortality. The computational pipeline can serve as an important resource in the development of new treatment modalities. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. 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.

  1. RPGR-associated retinopathy: clinical features, molecular genetics, animal models and therapeutic options.

    Science.gov (United States)

    Tee, James J L; Smith, Alexander J; Hardcastle, Alison J; Michaelides, Michel

    2016-08-01

    Retinitis pigmentosa GTPase regulator (RPGR) gene sequence variants account for the vast majority of X linked retinitis pigmentosa (RP), which is one of the most severe forms of RP. Symptoms of nyctalopia typically begin in childhood, with increasing loss of peripheral visual field during teenage years, and progressive central visual loss during the second to fourth decade of life. There is however marked intrafamilial and interfamilial phenotypic heterogeneity in affected males and carrier females. There is now a far greater understanding of the range of phenotypes associated with variants in this gene; including rod-cone dystrophy, cone-rod dystrophy, cone dystrophy, macular dystrophy and non-ocular phenotypes. There are also increasingly established genotype-phenotype associations and structure-function correlations. RPGR is involved in ciliary function, with ciliary dysfunction now recognised as the mechanism underlying a large proportion of inherited retinal disease. There has been significant progress in identifying naturally occurring animal models and developing novel models to define the underlying disease mechanisms and to test gene replacement therapy, in addition to advances in human retinal imaging, culminating in completed and planned clinical trials. These significant developments will be discussed. 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/

  2. 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.

  3. Respiratory flows during early childhood: Computational models to examine therapeutic aerosols in the developing airways

    Science.gov (United States)

    Tenenbaum-Katan, Janna; Hofemeier, Philipp; Sznitman, Josué; Janna Tenenbaum-Katan Team

    2015-11-01

    Inhalation therapy is the cornerstone of early-childhood respiratory treatments, as well as a rising potential for systemic drug delivery and pulmonary vaccination. As such, indispensable understanding of respiratory flow phenomena, coupled with particle transport at the deep regions of children's lungs is necessary to attain efficient targeting of aerosol therapy. However, fundamental research of pulmonary transport is overwhelmingly focused on adults. In our study, we have developed an anatomically-inspired computational model of representing pulmonary acinar regions at several age points during a child's development. Our numerical simulations examine respiratory flows and particle deposition maps within the acinar model, accounting for varying age dependant anatomical considerations and ventilation patterns. Resulting deposition maps of aerosols alter with age, such findings might suggest that medication protocols of inhalation therapy in young children should be considered to be accordingly amended with the child's development. Additionally to understanding basic scientific concepts of age effects on aerosol deposition, our research can potentially contribute practical guidelines to therapy protocols, and its' necessary modifications with age. We acknowledge the support of the ISF and the Israeli ministry of Science.

  4. 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

  5. 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 hyaluronate/sinomenine hydrochloride groups, statistical significance was uniformly obtained. Moreover, sodium hyaluronate and sinomenine hydrochloride treatments showed significant improvement over the modeling control (P hyaluronate vs. sinomenine hydrochloride

  6. 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.)

  7. Final Report: Natural State Models of The Geysers Geothermal System, Sonoma County, California

    Energy Technology Data Exchange (ETDEWEB)

    T. H. Brikowski; D. L. Norton; D. D. Blackwell

    2001-12-31

    Final project report of natural state modeling effort for The Geysers geothermal field, California. Initial models examined the liquid-dominated state of the system, based on geologic constraints and calibrated to match observed whole rock delta-O18 isotope alteration. These models demonstrated that the early system was of generally low permeability (around 10{sup -12} m{sup 2}), with good hydraulic connectivity at depth (along the intrusive contact) and an intact caprock. Later effort in the project was directed at development of a two-phase, supercritical flow simulation package (EOS1sc) to accompany the Tough2 flow simulator. Geysers models made using this package show that ''simmering'', or the transient migration of vapor bubbles through the hydrothermal system, is the dominant transition state as the system progresses to vapor-dominated. Such a system is highly variable in space and time, making the rock record more difficult to interpret, since pressure-temperature indicators likely reflect only local, short duration conditions.

  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. Computational modeling of glucose transport in pancreatic β-cells identifies metabolic thresholds and therapeutic targets in diabetes.

    Directory of Open Access Journals (Sweden)

    Camilla Luni

    Full Text Available Pancreatic β-cell dysfunction is a diagnostic criterion of Type 2 diabetes and includes defects in glucose transport and insulin secretion. In healthy individuals, β-cells maintain plasma glucose concentrations within a narrow range in concert with insulin action among multiple tissues. Postprandial elevations in blood glucose facilitate glucose uptake into β-cells by diffusion through glucose transporters residing at the plasma membrane. Glucose transport is essential for glycolysis and glucose-stimulated insulin secretion. In human Type 2 diabetes and in the mouse model of obesity-associated diabetes, a marked deficiency of β-cell glucose transporters and glucose uptake occurs with the loss of glucose-stimulated insulin secretion. Recent studies have shown that the preservation of glucose transport in β-cells maintains normal insulin secretion and blocks the development of obesity-associated diabetes. To further elucidate the underlying mechanisms, we have constructed a computational model of human β-cell glucose transport in health and in Type 2 diabetes, and present a systems analysis based on experimental results from human and animal studies. Our findings identify a metabolic threshold or "tipping point" whereby diminished glucose transport across the plasma membrane of β-cells limits intracellular glucose-6-phosphate production by glucokinase. This metabolic threshold is crossed in Type 2 diabetes and results in β-cell dysfunction including the loss of glucose stimulated insulin secretion. Our model further discriminates among molecular control points in this pathway wherein maximal therapeutic intervention is achieved.

  10. 7-Difluoromethyl-5,4'-dimethoxygenistein, a novel genistein derivative, has therapeutic effects on atherosclerosis in a rabbit model.

    Science.gov (United States)

    Zhao, Hong; Li, Cheng; Cao, Jian-Guo; Xiang, Hong-Lin; Yang, Hua-Zhong; You, Ji-Liang; Li, Cheng-Long; Fu, Xiao-Hua

    2009-11-01

    Genistein is a phytoestrogen that is known to have a protective effect on the vascular endothelial wall. However, it exhibits poor bioavailability, which limits the use of genistein to treat cardiovascular and cerebrovascular diseases. A novel genistein derivative, 7-difluoromethyl-5,4'-dimethoxygenistein (dFMGEN), has shown a better protective effect on vascular endothelial damage in vitro than genistein. In this study, we further evaluated therapeutic effects of dFMGEN on the vascular endothelial wall and atherosclerosis in a rabbit model in vivo. There were 5 groups: the GEN group (genistein 5 mg/kg per day), lovastatin group (lovastatin 5 mg/kg per day), dFMGEN group (dFMGEN 5 mg/kg per day), model control group (the same amount of vehicle solvent), and the normal control group; all feedings administered via intragastric administration. We demonstrated that dFMGEN (1) attenuated the development of atherosclerosis, (2) reduced serum total cholesterol and low-density lipoprotein cholesterol concentrations, (3) decreased lipid peroxidation in the rabbit atherosclerosis model, and (4) increased smooth muscle cell and collagen content in atheroma of thoracic aortas. These results provide an experimental foundation for dFMGEN's potential effects in preventing and treating atherosclerosis, acute coronary syndromes, and potentially ischemia-reperfusion injury during acute myocardial infarction and cerebral infarction.

  11. Hot-gas cleanup system model development. Volume I. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Ushimaru, K.; Bennett, A.; Bekowies, P.J.

    1982-11-01

    This two-volume report summarizes the state of the art in performance modeling of advanced high-temperature, high-pressure (HTHP) gas cleanup devices. Volume I contains the culmination of the research effort carried over the past 12 months and is a summary of research achievements. Volume II is the user's manual for the computer programs developed under the present research project. In this volume, Section 2 presents background information on pressurized, fluidized-bed combustion concepts, a description of the role of the advanced gas cleanup systems, and a list of advanced gas cleanup systems that are currently in development under DOE sponsorship. Section 3 describes the methodology for the software architecture that forms the basis of the well-disciplined and structured computer programs developed under the present project. Section 4 reviews the fundamental theories that are important in analyzing the cleanup performance of HTHP gas filters. Section 5 discusses the effect of alkali agents in HTHP gas cleanup. Section 6 evaluates the advanced HTHP gas cleanup models based on their mathematical integrity, availability of supporting data, and the likelihood of commercialization. As a result of the evaluation procedure detailed in Section 6, five performance models were chosen to be incorporated into the overall system simulation code, ASPEN. These five models (the electrocyclone, ceramic bag filter, moving granular bed filter, electrostatic granular bed filter, and electrostatic precipitator) are described in Section 7. The method of cost projection for these five models is discussed in Section 8. The supporting data and validation of the computer codes are presented in Section 9, and finally the conclusions and recommendations for the HTHP gas cleanup system model development are given in Section 10. 72 references, 19 figures, 25 tables.

  12. 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)

  13. Formal Modeling of mTOR Associated Biological Regulatory Network Reveals Novel Therapeutic Strategy for the Treatment of Cancer

    Directory of Open Access Journals (Sweden)

    Zurah Bibi

    2017-06-01

    Full Text Available Cellular homeostasis is a continuous phenomenon that if compromised can lead to several disorders including cancer. There is a need to understand the dynamics of cellular proliferation to get deeper insights into the prevalence of cancer. Mechanistic Target of Rapamycin (mTOR is implicated as the central regulator of the metabolic pathway involved in growth whereas its two distinct complexes mTORC1 and mTORC2 perform particular functions in cellular propagation. To date, mTORC1 is a well defined therapeutic target to inhibit uncontrolled cell division, while the role of mTORC2 is not well characterized. Therefore, the current study is designed to understand the signaling dynamics of mTOR and its partner proteins such as PI3K, PTEN, mTORC2, PKB (Akt, mTORC1, and FOXO. For this purpose, a qualitative model of mTOR-associated Biological Regulatory Network (BRN is constructed to predict its regulatory behaviors which may not be predictable otherwise. The depleted expression of PTEN and FOXO along with the overexpression of PI3K, mTORC2, mTORC1 and Akt is predicted as a stable steady state which is in accordance with their observed expression levels in the progression of various cancers. The qualitative model also predicts the homeostasis of all the entities in the form of qualitative cycles. The significant qualitative (discrete cycle is identified by analyzing betweenness centralities of the qualitative (discrete states. This cycle is further refined as a linear hybrid automaton model with the production (activation and degradation (inhibition time delays in order to analyze the real-time constraints for its existence. The analysis of the hybrid model provides a formal proof that during homeostasis the inhibition time delay of Akt is less than the inhibition time delay of mTORC2. In conclusion, our observations characterize that in homeostasis Akt is degraded with a faster rate than mTORC2 which suggests that the inhibition of Akt along with the

  14. Therapeutic Effectiveness of Anti-RAGE Antibody Administration in a Rat Model of Crush Injury.

    Science.gov (United States)

    Matsumoto, Hisatake; Matsumoto, Naoya; Shimazaki, Junya; Nakagawa, Junichiro; Imamura, Yukio; Yamakawa, Kazuma; Yamada, Tomoki; Ikeda, Mitsunori; Hiraike, Hiroko; Ogura, Hiroshi; Shimazu, Takeshi

    2017-09-25

    Crush injury patients often have systemic inflammatory response syndrome that leads to multiple organ failure. Receptor for advanced glycation endproducts (RAGE) functions as a pattern recognition receptor that regulates inflammation. We evaluated the effects of anti-RAGE antibody in a crush injury model. Pressure was applied to both hindlimbs of rats for 6 h by 3.0-kg blocks and then released. Animals were randomly divided into the sham (RAGE-Sh) group, crush (RAGE-Ctrl) group or anti-RAGE antibody-treated crush (RAGE-Tx) group. Samples were collected at 3, 6 and 24 h after releasing pressure. In the RAGE-Ctrl group, fluorescent immunostaining in the lung showed upregulated RAGE expression at 3 h. The serum soluble RAGE (sRAGE) level, which reflects the amount of RAGE expression in systemic tissue, increased at 6 h. Serum interleukin 6 (IL-6; systemic inflammation marker) increased immediately at 3 h. Histological analysis revealed lung injury at 6 and 24 h. Administration of anti-RAGE antibody before releasing compression inhibited upregulated RAGE expression in the lung alveoli, suppressed RAGE-associated mediators sRAGE and IL6, attenuated the lung damage and improved the 7-day survival rate. Collectively, our results indicated that the use of anti-RAGE antibody before releasing compression is associated with a favourable prognosis following crush injury.

  15. 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...

  16. The Fold Variant BM4 Is Beneficial in a Therapeutic Bet v 1 Mouse Model

    Directory of Open Access Journals (Sweden)

    Ulrike Pichler

    2013-01-01

    Full Text Available Background. Specific immunotherapy using recombinant allergens is clinically effective; still wild-type allergens can provoke treatment-induced side effects and often show poor immunogenicity in vivo. Thus, we tested the low IgE-binding, highly immunogenic fold variant BM4 in a Bet v 1 mouse model. Methods. Recombinant BM4 was used as active vaccine ingredient to treat mice sensitized to Bet v 1. As controls, mice were treated with either Bet v 1 or sham, and the humoral as well as cellular immune response was monitored. Moreover, lung function and lung inflammation were analysed. Results. BM4 was more effective than wild-type Bet v 1 in inducing Bet v 1-specific blocking antibodies as well as IFN-γ and IL-10 producing T cells. Further, birch pollen induced lung inflammation could be ameliorated significantly by BM4 treatment as demonstrated by a reduction of airway hyperresponsiveness and drastically decreased eosinophil counts in bronchoalveolar lavage fluids. Conclusion. The study outlines the high potential of BM4 as vaccine candidate for the treatment of Bet v 1-mediated birch pollen allergies.

  17. Boron neutron capture therapy (BNCT) for liver metastasis: therapeutic efficacy in an experimental model.

    Science.gov (United States)

    Pozzi, Emiliano C C; Cardoso, Jorge E; Colombo, Lucas L; Thorp, Silvia; Monti Hughes, Andrea; Molinari, Ana J; Garabalino, Marcela A; Heber, Elisa M; Miller, Marcelo; Itoiz, Maria E; Aromando, Romina F; Nigg, David W; Quintana, Jorge; Trivillin, Verónica A; Schwint, Amanda E

    2012-08-01

    Boron neutron capture therapy (BNCT) was proposed for untreatable colorectal liver metastases. The present study evaluates tumor control and potential radiotoxicity of BNCT in an experimental model of liver metastasis. BDIX rats were inoculated with syngeneic colon cancer cells DHD/K12/TRb. Tumor-bearing animals were divided into three groups: BPA-BNCT, boronophenylalanine (BPA) + neutron irradiation; Beam only, neutron irradiation; Sham, matched manipulation. The total absorbed dose administered with BPA-BNCT was 13 ± 3 Gy in tumor and 9 ± 2 Gy in healthy liver. Three weeks post-treatment, the tumor surface area post-treatment/pre-treatment ratio was 0.46 ± 0.20 for BPA-BNCT, 2.7 ± 1.8 for Beam only and 4.5 ± 3.1 for Sham. The pre-treatment tumor nodule mass of 48 ± 19 mg fell significantly to 19 ± 16 mg for BPA-BNCT, but rose significantly to 140 ± 106 mg for Beam only and to 346 ± 302 mg for Sham. For both end points, the differences between the BPA-BNCT group and each of the other groups were statistically significant (ANOVA). No clinical, macroscopic or histological normal liver radiotoxicity was observed. It is concluded that BPA-BNCT induced a significant remission of experimental colorectal tumor nodules in liver with no contributory liver toxicity.

  18. Boron neutron capture therapy (BNCT) for liver metastasis: therapeutic efficacy in an experimental model

    Energy Technology Data Exchange (ETDEWEB)

    David W. Nigg

    2012-08-01

    Boron neutron capture therapy (BNCT) was proposed for untreatable colorectal liver metastases. The present study evaluates tumor control and potential radiotoxicity of BNCT in an experimental model of liver metastasis. BDIX rats were inoculated with syngeneic colon cancer cells DHD/K12/TRb. Tumor-bearing animals were divided into three groups: BPA–BNCT, boronophenylalanine (BPA) ? neutron irradiation; Beam only, neutron irradiation; Sham, matched manipulation. The total absorbed dose administered with BPA–BNCT was 13 ± 3 Gy in tumor and 9 ± 2 Gy in healthy liver. Three weeks posttreatment, the tumor surface area post-treatment/pre-treatment ratio was 0.46 ± 0.20 for BPA–BNCT, 2.7 ± 1.8 for Beam only and 4.5 ± 3.1 for Sham. The pre-treatment tumor nodule mass of 48 ± 19 mgfell significantly to 19 ± 16 mg for BPA–BNCT, but rose significantly to 140 ± 106 mg for Beam only and to 346 ± 302 mg for Sham. For both end points, the differences between the BPA–BNCT group and each of the other groups were statistically significant (ANOVA). No clinical, macroscopic or histological normal liver radiotoxicity was observed. It is concluded that BPA– BNCT induced a significant remission of experimental colorectal tumor nodules in liver with no contributory liver toxicity.

  19. 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.

  20. 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 BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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

  1. MEMFIS - Measuring, modelling and forecasting ice loads on structures - Final report

    Energy Technology Data Exchange (ETDEWEB)

    Dierer, S.; Cattin, R.

    2010-05-15

    This illustrated final report for the Swiss Federal Office of Energy (SFOE) takes a look at the icing-up of structures such as overhead power lines, wind turbines and aerial cableways in mountainous or arctic areas. The measurement of icing at three locations in Switzerland, in the high Alps, the alpine foothills and the Jura mountains using a vertical freely-rotating cylinder is described. Problems encountered during the measurement campaigns are described and discussed. The development of a simulation system in parallel to the measurement campaign is also discussed. A comparison of measured and simulated data calculated with the WRF and COSMO models was made difficult as a result of the problems encountered with the apparatus used. The basic effects causing icing-up are discussed and the measurement apparatus used is examined.

  2. 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)

  3. 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.

  4. FInal Report: First Principles Modeling of Mechanisms Underlying Scintillator Non-Proportionality

    Energy Technology Data Exchange (ETDEWEB)

    Aberg, Daniel [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Sadigh, Babak [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Zhou, Fei [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

    2015-01-01

    This final report presents work carried out on the project “First Principles Modeling of Mechanisms Underlying Scintillator Non-Proportionality” at Lawrence Livermore National Laboratory during 2013-2015. The scope of the work was to further the physical understanding of the microscopic mechanisms behind scintillator nonproportionality that effectively limits the achievable detector resolution. Thereby, crucial quantitative data for these processes as input to large-scale simulation codes has been provided. In particular, this project was divided into three tasks: (i) Quantum mechanical rates of non-radiative quenching, (ii) The thermodynamics of point defects and dopants, and (iii) Formation and migration of self-trapped polarons. The progress and results of each of these subtasks are detailed.

  5. RVX-297, a BET Bromodomain Inhibitor, Has Therapeutic Effects in Preclinical Models of Acute Inflammation and Autoimmune Disease.

    Science.gov (United States)

    Jahagirdar, Ravi; Attwell, Sarah; Marusic, Suzana; Bendele, Alison; Shenoy, Narmada; McLure, Kevin G; Gilham, Dean; Norek, Karen; Hansen, Henrik C; Yu, Raymond; Tobin, Jennifer; Wagner, Gregory S; Young, Peter R; Wong, Norman C W; Kulikowski, Ewelina

    2017-12-01

    Bromodomain (BD) and extra-terminal domain containing proteins (BET) are chromatin adapters that bind acetylated histone marks via two tandem BDs, BD1 and BD2, to regulate gene transcription. BET proteins are involved in transcriptional reprogramming in response to inflammatory stimuli. BET BD inhibitors (BETis) that are nonselective for BD1 or BD2 have recognized anti-inflammatory properties in vitro and counter pathology in models of inflammation or autoimmune disease. Although both BD1 and BD2 bind acetylated histone residues, they may independently regulate the expression of BET-sensitive genes. Here we characterized the ability of RVX-297, a novel orally active BETi with selectivity for BD2, to modulate inflammatory processes in vitro, in vivo, and ex vivo. RVX-297 suppressed inflammatory gene expression in multiple immune cell types in culture. Mechanistically, RVX-297 displaced BET proteins from the promoters of sensitive genes and disrupted recruitment of active RNA polymerase II, a property shared with pan-BETis that nonselectively bind BET BDs. In the lipopolysaccharide model of inflammation, RVX-297 reduced proinflammatory mediators assessed in splenic gene expression and serum proteins. RVX-297 also countered pathology in three rodent models of polyarthritis: rat and mouse collagen-induced arthritis, and mouse collagen antibody-induced arthritis. Further, RVX-297 prevented murine experimental autoimmune encephalomyelitis (a model of human multiple sclerosis) disease development when administered prophylactically and reduced hallmarks of pathology when administered therapeutically. We show for the first time that a BD2-selective BETi maintains anti-inflammatory properties and is effective in preclinical models of acute inflammation and autoimmunity. Copyright © 2017 The Author(s).

  6. Cost effectiveness of community-based therapeutic care for children with severe acute malnutrition in Zambia: decision tree model

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    Bachmann Max O

    2009-01-01

    Full Text Available Abstract Background Children aged under five years with severe acute malnutrition (SAM in Africa and Asia have high mortality rates without effective treatment. Primary care-based treatment of SAM can have good outcomes but its cost effectiveness is largely unknown. Method This study estimated the cost effectiveness of community-based therapeutic care (CTC for children with severe acute malnutrition in government primary health care centres in Lusaka, Zambia, compared to no care. A decision tree model compared the costs (in year 2008 international dollars and outcomes of CTC to a hypothetical 'do-nothing' alternative. The primary outcomes were mortality within one year, and disability adjusted life years (DALYs after surviving one year. Outcomes and health service costs of CTC were obtained from the CTC programme, local health services and World Health Organization (WHO estimates of unit costs. Outcomes of doing nothing were estimated from published African cohort studies. Probabilistic and deterministic sensitivity analyses were done. Results The mean cost of CTC per child was $203 (95% confidence interval (CI $139–$274, of which ready to use therapeutic food (RUTF cost 36%, health centre visits cost 13%, hospital admissions cost 17% and technical support while establishing the programme cost 34%. Expected death rates within one year of presentation were 9.2% with CTC and 20.8% with no treatment (risk difference 11.5% (95% CI 0.4–23.0%. CTC cost $1760 (95% CI $592–$10142 per life saved and $ 53 (95% CI $18–$306 per DALY gained. CTC was at least 80% likely to be cost effective if society was willing to pay at least $88 per DALY gained. Analyses were most sensitive to assumptions about mortality rates with no treatment, weeks of CTC per child and costs of purchasing RUTF. Conclusion CTC is relatively cost effective compared to other priority health care interventions in developing countries, for a wide range of assumptions.

  7. Targeting of histone deacetylases to reactivate tumour suppressor genes and its therapeutic potential in a human cervical cancer xenograft model.

    Directory of Open Access Journals (Sweden)

    Dingqing Feng

    Full Text Available Aberrant histone acetylation plays an essential role in the neoplastic process via the epigenetic silencing of tumour suppressor genes (TSGs; therefore, the inhibition of histone deacetylases (HDAC has become a promising target in cancer therapeutics. To investigate the correlation of histone acetylation with clinicopathological features and TSG expression, we examined the expression of acetylated H3 (AcH3, RARβ2, E-cadherin, and β-catenin by immunohistochemistry in 65 cervical squamous cell carcinoma patients. The results revealed that the absence of AcH3 was directly associated with poor histological differentiation and nodal metastasis as well as reduced/negative expression of RARβ2, E-cadherin, and β-catenin in clinical tumour samples. We further demonstrated that the clinically available HDAC inhibitors valproic acid (VPA and suberoylanilide hydroxamic acid (SAHA, in combination with all-trans retinoic acid (ATRA, can overcome the epigenetic barriers to transcription of RARβ2 in human cervical cancer cells. Chromatin immunoprecipitation analysis showed that the combination treatment increased the enrichment of acetylated histone in the RARβ2-RARE promoter region. In view of these findings, we evaluated the antitumor effects induced by combined VPA and ATRA treatment in a xenograft model implanted with poorly differentiated human squamous cell carcinoma. Notably, VPA restored RARβ2 expression via epigenetic modulation. Additive antitumour effects were produced in tumour xenografts by combining VPA with ATRA treatment. Mechanistically, the combination treatment reactivated the expression of TSGs RARβ2, E-cadherin, P21 (CIP1 , and P53 and reduced the level of p-Stat3. Sequentially, upregulation of involucrin and loricrin, which indicate terminal differentiation, strongly contributed to tumour growth inhibition along with partial apoptosis. In conclusion, targeted therapy with HDAC inhibitors and RARβ2 agonists may represent a novel

  8. A large animal neuropathic pain model in sheep: a strategy for improving the predictability of preclinical models for therapeutic development

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    Wilkes D

    2012-10-01

    Full Text Available Denise Wilkes,1 Guangwen Li,2 Carmina F Angeles,3 Joel T Patterson,4 Li-Yen Mae Huang21Department of Anesthesiology, 2Department of Neuroscience and Cell Biology, 3Department of Neurosurgery University of Texas Medical Branch, Galveston, TX, USA; 4Neurospine Institute, Eugene, OR, USABackground: Evaluation of analgesics in large animals is a necessary step in the development of better pain medications or gene therapy prior to clinical trials. However, chronic neuropathic pain models in large animals are limited. To address this deficiency, we developed a neuropathic pain model in sheep, which shares many anatomical similarities in spine dimensions and cerebrospinal fluid volume as humans.Methods: A neuropathic pain state was induced in sheep by tight ligation and axotomy of the common peroneal nerve. The analgesic effect of intrathecal (IT morphine was investigated. Interspecies comparison was conducted by analyzing the ceiling doses of IT morphine for humans, sheep, and rats.Results: Peroneal nerve injury (PNI produced an 86% decrease in von-Frey filament-evoked withdrawal threshold on postsurgery day 3 and the decrease lasted for the 8-week test period. Compared to the pre-injury, sham, and contralateral hindlimb, the IT morphine dose that produces 50% of maximum analgesia (ED50 for injured PNI hindlimb was 1.8-fold larger and Emax, the dose that produces maximal analgesia, was 6.1-fold lower. The sheep model closely predicts human IT morphine ceiling dose by allometric scaling. This is in contrast to the approximately 10-fold lower morphine ceiling dose predicted by the rat spinal nerve ligated or spared nerve injury models.Conclusion: PNI sheep model has a fast onset and shows stable and long-lasting pain behavioral characteristics. Since the antinociceptive properties of IT morphine are similar to those observed in humans, the PNI sheep model will be a useful tool for the development of analgesics. Its large size and consistent chronic pain

  9. [Therapeutic effect of a natural squamosamide derivative FLZ on Parkinson's disease model mice induced by LPS plus MPTP].

    Science.gov (United States)

    Yu, Ling-Hong; Wei, Huai-Ling; Bao, Xiu-Qi; Zhang, Dan; Sun, Hua

    2013-10-01

    The aim of this study is to investigate the protective effect of N-[2-(4-hydroxyphenyl)ethyl]-2-(2, 5-dimethoxyphenyl)-3-(3-methoxy-4-hydroxyphenyl)acrylamide (FLZ), a novel synthetic squamosamide cyclic derivative, against Parkinson's disease (PD) model mice induced by the inflammatory bacterial endotoxin, lipopolysaccharides (LPS) and the neurotoxin 1-methy-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP). C57/BL mice were ip injected LPS (5 mg x kg(-1)) once. One week following the LPS injection, mice received a subcutaneous injection of MPTP (25 mg x kg(-1)) once daily for 2 days. Eight weeks later, FLZ (25, 50 and 75 mg x kg(-1)) was orally administered to mice once daily for 60 days. The motor ability of the mice was evaluated by rod climbing test and footprint test. The dopamine (DA) levels in mouse striatum were determined by high performance liquid chromatography system. The tyrosine hydroxylase (TH)-positive cells were showed by immunohistochemical analysis. FLZ treatment significantly improved motor dysfunction of mice challenged by LPS plus MPTP. The increase of TH-positive cell numbers and elevation of DA levels may be contributed to the beneficial effects of FLZ on motor behavior. This study showed FLZ has significant therapeutic effect on LPS plus MPTP induced chronic PD model, which indicates its potential as a new candidate drug to treat PD.

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

    Science.gov (United States)

    Lee, Jee Bum; Li, Ying; Choi, Ji Suk; Lee, Hyo Seok

    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 extracts improved clinical signs, decreased inflammation, and ameliorated oxidative stress marker and ROS production on the ocular surface of the EDE model mice. PMID:27313829

  11. Human Organ Chip Models Recapitulate Orthotopic Lung Cancer Growth, Therapeutic Responses, and Tumor Dormancy In Vitro

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    Bryan A. Hassell

    2017-10-01

    Full Text Available Here, we show that microfluidic organ-on-a-chip (organ chip cell culture technology can be used to create in vitro human orthotopic models of non-small-cell lung cancer (NSCLC that recapitulate organ microenvironment-specific cancer growth, tumor dormancy, and responses to tyrosine kinase inhibitor (TKI therapy observed in human patients in vivo. Use of the mechanical actuation functionalities of this technology revealed a previously unknown sensitivity of lung cancer cell growth, invasion, and TKI therapeutic responses to physical cues associated with breathing motions, which appear to be mediated by changes in signaling through epidermal growth factor receptor (EGFR and MET protein kinase. These findings might help to explain the high level of resistance to therapy in cancer patients with minimal residual disease in regions of the lung that remain functionally aerated and mobile, in addition to providing an experimental model to study cancer persister cells and mechanisms of tumor dormancy in vitro.

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

    Science.gov (United States)

    Bae, Min-Jung; See, Hye-Jeong; Choi, Gyeyoung; Kang, Chang-Yuil; Shon, Dong-Hwa; Shin, Hee Soon

    2016-01-01

    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.

  13. Client and therapist therapeutic alliance, session evaluation, and client reliable change: a moderated actor-partner interdependence model.

    Science.gov (United States)

    Kivlighan, Dennis M; Marmarosh, Cheri L; Hilsenroth, Mark J

    2014-01-01

    Actor-partner interdependence modeling (APIM; Kashy & Kenny, 2000) was used to study the early therapeutic alliance in 74 clients being treated by 29 therapists to explore the relationship between the alliance and treatment progress, while prioritizing the dyadic nature of the alliance. The APIM examines collaboration/influence by modeling the impact of one dyad member's alliance ratings on the other member's session impact rating (partner effects). In terms of the alliance, the results revealed significant client-actor effects for client ratings of session depth and positivity as well as significant therapist-actor effects for therapist ratings of session smoothness and positivity. For client-rated alliance, there were also significant client-partner effects for therapist ratings of session depth. For clients who made a reliable change in treatment, an increase in client-reported alliance was related to therapist reporting more arousal in the 3rd session. For clients who did not make a reliable change in treatment, client-reported alliance was not related to therapist arousal. Limitations of the study and implications of the findings are discussed. (PsycINFO Database Record (c) 2014 APA, all rights reserved).

  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. 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

  16. The subchronic phencyclidine rat model: relevance for the assessment of novel therapeutics for cognitive impairment associated with schizophrenia.

    Science.gov (United States)

    Janhunen, Sanna K; Svärd, Heta; Talpos, John; Kumar, Gaurav; Steckler, Thomas; Plath, Niels; Lerdrup, Linda; Ruby, Trine; Haman, Marie; Wyler, Roger; Ballard, Theresa M

    2015-11-01

    Current treatments for schizophrenia have modest, if any, efficacy on cognitive dysfunction, creating a need for novel therapies. Their development requires predictive animal models. The N-methyl-D-aspartate (NMDA) hypothesis of schizophrenia indicates the use of NMDA antagonists, like subchronic phencyclidine (scPCP) to model cognitive dysfunction in adult animals. The objective of this study was to assess the scPCP model by (1) reviewing published findings of scPCP-induced neurochemical changes and effects on cognitive tasks in adult rats and (2) comparing findings from a multi-site study to determine scPCP effects on standard and touchscreen cognitive tasks. Across four research sites, the effects of scPCP (typically 5 mg/kg twice daily for 7 days, followed by at least 7-day washout) in adult male Lister Hooded rats were studied on novel object recognition (NOR) with 1-h delay, acquisition and reversal learning in Morris water maze and touchscreen-based visual discrimination. Literature findings showed that scPCP impaired attentional set-shifting (ASST) and NOR in several labs and induced a variety of neurochemical changes across different labs. In the multi-site study, scPCP impaired NOR, but not acquisition or reversal learning in touchscreen or water maze. Yet, this treatment regimen induced locomotor hypersensitivity to acute PCP until 13-week post-cessation. The multi-site study confirmed that scPCP impaired NOR and ASST only and demonstrated the reproducibility and usefulness of the touchscreen approach. Our recommendation, prior to testing novel therapeutics in the scPCP model, is to be aware that further work is required to understand the neurochemical changes and specificity of the cognitive deficits.

  17. Thalidomide Effects in Patients with Hereditary Hemorrhagic Telangiectasia During Therapeutic Treatment and in Fli-EGFP Transgenic Zebrafish Model.

    Science.gov (United States)

    Peng, Hong-Ling; Yi, Yi-Fang; Zhou, Shun-Ke; Xie, Si-Si; Zhang, Guang-Sen

    2015-11-20

    Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease characterized by recurrent epistaxis, mucocutaneous telangiectasia, and arteriovenous malformations. The efficacy of traditional treatments for HHT is very limited. The aim of this study was to investigate the therapeutic role of thalidomide in HHT patients and the effect in FLI-EGFP transgenic zebrafish model. HHT was diagnosed according to Shovlin criteria. Five HHT patients were treated with thalidomide (100 mg/d). The Epistaxis Severity Score (ESS), telangiectasia spots, and hepatic computed tomography angiography (CTA) were used to assess the clinical efficacy of thalidomide. The Fli-EGFP zebrafish model was investigated for the effect of thalidomide on angiogenesis. Dynamic real-time polymerase chain reaction assay, ELISA and Western blotting from patient's peripheral blood mononuclear cells and plasma were used to detect the expression of transforming growth factor beta 3 (TGF-β3) messenger RNA (mRNA) and vascular endothelial growth factor (VEGF) protein before and after 6 months of thalidomide treatment. The average ESS before and after thalidomide were 6.966 ± 3.093 and 1.799 ± 0.627, respectively (P = 0.009). The "telangiectatic spot" on the tongue almost vanished; CTA examination of case 2 indicated a smaller proximal hepatic artery and decreased or ceased hepatic artery collateral circulation. The Fli-EGFP zebrafish model manifested discontinuous vessel development and vascular occlusion (7 of 10 fishes), and the TGF-β3 mRNA expression of five patients was lower after thalidomide therapy. The plasma VEGF protein expression was down-regulated in HHT patients. Thalidomide reverses telangiectasia and controls nosebleeds by down-regulating the expression of TGF-β3 and VEGF in HHT patients. It also leads to vascular remodeling in the zebrafish model.

  18. Mouse models of neuronal ceroid lipofuscinoses: useful pre-clinical tools to delineate disease pathophysiology and validate therapeutics.

    Science.gov (United States)

    Shacka, John J

    2012-05-01

    The neuronal ceroid lipofuscinoses (NCL, also known as Batten disease) is a devastating neurodegenerative diseases caused by mutations in either soluble enzymes or membrane-associated structural proteins that result in lysosome dysfunction. Different forms of NCL were defined initially by age of onset, affected population and/or type of storage material but collectively represent the most prevalent pediatric hereditary neurovisceral storage disorder. Specific gene mutations are now known for each subclass of NCL in humans that now largely define the disease: cathepsin D (CTSD) for congenital (CLN10 form); palmitoyl protein thioesterase 1 (PPT1) for infantile (CLN1 form); tripeptidyl peptidase 1 (TPP1) for classic late infantile (CLN2 form); variant late infantile-CLN5, CLN6 or CLN8 for variant late infantile forms; and CLN3 for juvenile (CLN3 form). Several mouse models of NCL have been developed, or in some cases exist sporadically, that exhibit mutations producing a progressive neurodegenerative phenotype similar to that observed in human NCL. The study of these mouse models of NCL has dramatically advanced our knowledge of NCL pathophysiology and in some cases has helped delineate the function of proteins mutated in human NCL. In addition, NCL mutant mice have been tested for several different therapeutic approaches and as such they have become important pre-clinical models for validating treatment options. In this review we will assess the current state of mouse models of NCL with regards to their unique pathophysiology and how these mice have helped investigators achieve a better understanding of human NCL disease and therapy. Published by Elsevier Inc.

  19. 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.

  20. 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.

  1. 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).

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

    Science.gov (United States)

    Liu, Zhen; Wang, Cunfu; Wang, Xiao; Xu, Shunliang

    2015-01-01

    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. 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. 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. Overexpression of as-miR-937 in MSCs may substantially improve the therapeutic effects of MSCs on AD, possibly through augmenting Brn

  3. Therapeutic potency of IL2-caspase 3 targeted treatment in a murine experimental model of inflammatory bowel disease.

    Science.gov (United States)

    Shteingart, S; Rapoport, M; Grodzovski, I; Sabag, O; Lichtenstein, M; Eavri, R; Lorberboum-Galski, H

    2009-06-01

    Inflammatory bowel disease (IBD) comprises primarily the two disorders - ulcerative colitis and Crohn's disease - that involve deregulated T cell responses. The ever-increasing incidence rate of Crohn's disease and ulcerative colitis during recent decades, combined with the limited efficacy and potential adverse effects of current treatments, explain the real need for seeking more specific and selective methods for treating these diseases. To investigate the ability of interleukin 2 (IL2)-caspase 3 chimeric protein, designed to target activated T lymphocytes that express the high-affinity IL2 receptor, to ameliorate the clinical symptoms of acute murine experimental colitis, using a mouse model of dextran sodium sulfate (DSS)-induced colitis. Mice with DSS-induced colitis were treated with IL2-caspase 3 for 7 days and disease severity was assessed in parallel to control, non-treated mice, receiving only daily injections of phosphate-buffered saline. IL2-caspase 3 was tested both for its ability to prevent the development of colitis, and for its therapeutic potential to cure on-going, active acute disease. In addition, colon tissue samples were used for myeloperoxidase assays and RNA isolation followed by polymerase chain reaction to determine mRNA expression levels of specific genes. Treatment with IL2-caspase 3 dose-dependently ameliorated the disease activity index (DAI) of mice colitis. We achieved up to 78% improvement in DAI with intravenous injections of 15 microg/mouse/day. Furthermore, IL2-caspase 3 decreased neutrophil and macrophage infiltration to the inflamed tissue by up to 57%. IL2-caspase 3 was proven as a therapeutic reagent in another model, where treatment begins only after disease onset. Here we demonstrated a 70% decrease in DAI when compared to non-treated sick mice. A reduction in mRNA expression levels of both IL1 beta and tumour necrosis factor alpha was found in lysates of total colon tissue of treated mice, as compared to sick, untreated

  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. 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.

  6. 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

  7. 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.

  8. Immunization with an HPV-16 L1-based chimeric virus-like particle containing HPV-16 E6 and E7 epitopes elicits long-lasting prophylactic and therapeutic efficacy in an HPV-16 tumor mice model.

    Science.gov (United States)

    Monroy-García, Alberto; Gómez-Lim, Miguel Angel; Weiss-Steider, Benny; Hernández-Montes, Jorge; Huerta-Yepez, Sara; Rangel-Santiago, Jesús F; Santiago-Osorio, Edelmiro; Mora García, María de Lourdes

    2014-02-01

    HPV L1-based virus-like particles vaccines (VLPs) efficiently induce temporary prophylactic activity through the induction of neutralizing antibodies; however, VLPs that can provide prophylactic as well as therapeutic properties for longer periods of time are needed. For this purpose, we generated a novel HPV 16 L1-based chimeric virus-like particle (cVLP) produced in plants that contains a string of T-cell epitopes from HPV 16 E6 and E7 fused to its C-terminus. In the present study, we analyzed the persistence of specific IgG antibodies with neutralizing activity induced by immunization with these cVLPs, as well as their therapeutic potential in a tumor model of C57BL/6 mice. We observed that these cVLPs induced persistent IgG antibodies for over 12 months, with reactivity and neutralizing activity for VLPs composed of only the HPV-16 L1 protein. Efficient protection for long periods of time and inhibition of tumor growth induced by TC-1 tumor cells expressing HPV-16 E6/E7 oncoproteins, as well as significant tumor reduction (57 %), were observed in mice immunized with these cVLPs. Finally, we discuss the possibility that chimeric particles of the type described in this work may be the basis for developing HPV prophylactic and therapeutic vaccines with high efficacy.

  9. Glass Furnace Model (GFM) development and technology transfer program final report.

    Energy Technology Data Exchange (ETDEWEB)

    Lottes, S. A.; Petrick, M.; Energy Systems

    2007-12-04

    indices into the simulation to facilitate optimization studies with regard to productivity, energy use and emissions. Midway through the Part II program, however, at the urging of the industrial consortium members, the decision was made to refocus limited resources on transfer of the existing GFM 2.0 software to the industry to speed up commercialization of the technology. This decision, in turn, necessitated a de-emphasis of the development of the planned final version of the GFM software that had full multiphase capability, GFM 3.0. As a result, version 3.0 was not completed; considerable progress, however, was made before the effort was terminated. The objectives of the Technology Transfer program were to transfer the Glass Furnace Model (GFM) to the glass industry and to promote its widespread use by providing the requisite technical support to allow effective use of the software. GFM Version 2.0 was offered at no cost on a trial, six-month basis to expedite its introduction to and use by the industry. The trial licenses were issued to generate a much more thorough user beta test of the software than the relatively small amount completed by the consortium members prior to the release of version 2.0.

  10. Modeling Laser Effects on the Final Optics in Simulated IFE Environments

    Energy Technology Data Exchange (ETDEWEB)

    Nasr Ghoniem

    2004-08-14

    When laser light interacts with a material's surface, photons rapidly heat the electronic system, resulting in very fast energy transfer to the underlying atomic crystal structure. The intense rate of energy deposition in the shallow sub-surface layer creates atomic defects, which alter the optical characteristics of the surface itself. In addition, the small fraction of energy absorbed in the mirror leads to its global deformation by thermal and gravity loads (especially for large surface area mirrors). The aim of this research was to model the deformation of mirror surfaces at multiple length and time scales for applications in advanced Inertial Fusion Energy (IFE) systems. The goal is to control micro- and macro-deformations by material system and structural design. A parallel experimental program at UCSD has been set up to validate the modeling efforts. The main objective of the research program was to develop computer models and simulations for Laser-Induced Damage (LID) in reflective and transmissive final optical elements in IFE laser-based systems. A range of materials and material concepts were investigated and verified by experiments at UCSD. Four different classes of materials were considered: (1) High-reflectivity FCC metals (e.g. Cu, Au, Ag, and Al), (2) BCC metals (e.g. Mo, Ta and W), (3) Advanced material concepts (e.g. functionally graded material systems, amorphous coatings, and layered structures), and (4) Transmissive dielectrics (e.g. fused SiO2). In this report, we give a summary of the three-year project, followed by details in three areas: (1) Characterization of laser-induced damage; (2) Theory development for LIDT; and (3) Design of IFE reflective laser mirrors.

  11. 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.

  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. Therapeutic efficacy for hepatocellular carcinoma by boric acid-mediated boron neutron capture therapy in a rat model.

    Science.gov (United States)

    Lin, Sy-Yu; Lin, Chen-Jou; Liao, Jiunn-Wang; Peir, Jinn-Jer; Chen, Wei-Lin; Chi, Chin-Wen; Lin, Yung-Chang; Liu, Yu-Ming; Chou, Fong-In

    2013-11-01

    Hepatocellular carcinoma (HCC) is a common malignant tumor with poor prognosis. Boron neutron capture therapy (BNCT) may provide an alternative therapy for HCC. This study investigated the therapeutic efficacy of boric acid (BA)-mediated BNCT for HCC in a rat model. The pharmacokinetic and biodistribution of BA in N1S1 tumor-bearing rats were analyzed. Rats were injected with 25 mg B/kg body weight via tail veins before neutron irradiation at the Tsing Hua Open-pool Reactor, and the efficacy of BNCT was evaluated from the tumor size, tumor blood flow, and biochemical analyses. HCC-bearing rats administered BNCT showed reductions in tumor size on ultrasound imaging, as well as an obvious reduction in the distribution of tumor blood flow. The lesion located in livers had disappeared on the 80th day after BNCT; a recovery of values to normal levels was also recorded. BA-mediated BNCT is a promising alternative for liver cancer therapy since the present study demonstrated the feasibility of curing a liver tumor and restoring liver function in rats. Efforts are underway to investigate the histopathological features and the detailed mechanisms of BA-mediated BNCT.

  15. Evaluations of therapeutic efficacy of intravitreal injected polylactic-glycolic acid microspheres loaded with triamcinolone acetonide on a rabbit model of uveitis.

    Science.gov (United States)

    Li, Wenchang; He, Bing; Dai, Wenbing; Zhang, Qiang; Liu, Yuling

    2014-06-01

    Conventional treatments of uveitis are not ideal because of the short period of therapeutic efficacy. In the present study, biodegradable polylactic-glycolic acid microspheres loaded with triamcinolone acetonide (TA) were prepared to achieve sustained drug release and their therapeutic efficacy was investigated on a rabbit model of uveitis. TA-loaded microspheres (TA-MS) were prepared by the solvent evaporation method and characterized for encapsulation efficiency, particle size, morphology and in vitro release. The therapeutic efficacy was studied on the rabbit experimental uveitis model based on scoring of the inflammation, aqueous leukocyte counting, aqueous protein determination and histological examination. The TA-MS exhibited smooth and intact surfaces with an average diameter of 50.87 μm. The drug-loading coefficient and encapsulation efficiency were 15.2 ± 0.6 % and 91.24 ± 3.77 %, respectively. The drug release from TA-MS lasted up to 87 days, but only 46 days for TA suspension. The change in surface morphology also showed sustained drug release from TA-MS. TA-MS exhibited improved therapeutic efficacy in lipopolysaccharide -induced uveitis compared to TA suspension, especially in regard to the inhibition of inflammation. The TA-MS had a longer-term therapeutic effect on intraocular inflammation in LPS-induced uveitis in rabbits compared to TA suspension. The results suggested that TA-MS can be developed as a potential sustained-release system for the treatment of uveitis.

  16. ENFERMEDAD DE HUNTINGTON: MODELOS EXPERIMENTALES Y PERSPECTIVAS TERAPÉUTICAS Huntington'disease: Experimentals Models and Therapeutic Perspectives

    Directory of Open Access Journals (Sweden)

    TERESA SERRANO SÁNCHEZ

    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 t 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 appropiate to reproduce the neuropathologic characteristic of the disease, an genetic models contributing with more evidence to the knowledge of the disease ethiology. 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.

  17. [Efficacy of the therapeutic community model in the treatment of drug use-related problems: a systematic review].

    Science.gov (United States)

    Fiestas, Fabián; Ponce, Javier

    2012-03-01

    To summarize the scientific evidence about the efficacy of therapeutic communities (TC) to reduce substance use and related problems among people with substance use disorders. This systematic review builds from the work performed by Smith et al. (2006). We searched MEDLINE, EMBASE, Web of Science, Scielo, and LILACS for randomized trials that compare a TC with no treatment, a different type of treatment or another type of TC published from March 2004 to May 2011. 5 publications from 4 randomized trials were identified. All the studies had serious methodological limitations according to the CONSORT. The heterogeneity among studies did not allow for metaanalytic analysis to calculate pooled estimates. The primary analysis showed that, in prison, certain models of TC might be marginally superior to other types of treatments regarding levels of alcohol use, days in prison and re-incarceration rates. Also, evidence from a community setting (i.e., not in-prison) suggests that a community-based TC is not superior to an outpatient treatment model regarding levels of substance use, crime and unemployment at the 12-month follow-up. In general, there is no evidence to support superiority of TC over other more accessible and less costly types of treatment for drug use. However, in a prison context, TC might be of more benefit than other types of treatment. More research with solid experimental methodology is needed to add to the still weak body of evidence that supports the use of TC over other more affordable types of treatment for drug use disorders.

  18. The 3-hydroxy-3-methylglutaryl coenzyme-A reductases from fungi: a proposal as a therapeutic target and as a study model.

    Science.gov (United States)

    Andrade-Pavón, Dulce; Sánchez-Sandoval, Eugenia; Rosales-Acosta, Blanca; Ibarra, José Antonio; Tamariz, Joaquín; Hernández-Rodríguez, César; Villa-Tanaca, Lourdes

    2014-01-01

    The enzyme 3-hydroxy-3-methylglutaryl coenzyme-A reductase (HMGR) catalyzes the conversion of HMG-Co-A into mevalonate. This step is the limiting point for the synthesis of cholesterol in mammals and ergosterol in fungi. We describe in this article the genome organization of HMGR coding genes and those deduced from different fungi, recount the evidence showing statins as HMGR inhibitors for ergosterol synthesis and its effect in yeast viability, and propose fungal HMGR (HMGRf) as a model to study the use of pharmaceutical compounds to inhibit cholesterol and ergosterol synthesis. Bibliographical search and bioinformatic analyses were performed and discussed. HMGRfs belong to the class I with a high homology in the catalytic region. The sterol biosynthetic pathway in humans and fungi share many enzymes in the initial steps (such as the HMGR enzyme), but in the last steps enzymes are different rendering the two final products: cholesterol in mammals and ergosterol in fungi. With regards to inhibitors such as statins and other compounds, these affect also fungal viability. Since HMGR from Schizosaccharomyces pombe and Ustilago maydis are very similar to the human HMGR in the catalytic regions, we propose that fungal enzymes can be used to test inhibitors for a potential use in humans. We consider that HMGRf is a good therapeutic target to design and test new antifungal compounds. This manuscript is part of the series of works presented at the "V International Workshop: Molecular genetic approaches to the study of human pathogenic fungi" (Oaxaca, Mexico, 2012). Copyright © 2013 Revista Iberoamericana de Micología. Published by Elsevier Espana. All rights reserved.

  19. 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

  20. 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

  1. 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

  2. Ultrasound and Microbubble Mediated Doxil Delivery in a Murine Breast Cancer Model: Therapeutic Efficacy Dependence on Tumor Growth Rate

    NARCIS (Netherlands)

    Seip, R.; Leyvi, E.; Raju, B.I.; Shi, W.T.; Bohmer, M.R.; Chlon, C.H.T.; Sio, C.F.; Reibling, K.; Swanson, T.

    2011-01-01

    Background, Motivation and Objective: Localized drug delivery couldimprove the therapeutic efficacy for treatment of pathological lesions and reduce toxic exposure to healthy organs and tissues. The objective is to develop image-guided, ultrasound-activated tumor chemotherapy with intravenously

  3. Antiamoebic and toxicity studies of a carbamic acid derivative and its therapeutic effect in a hamster model of hepatic amoebiasis.

    Science.gov (United States)

    Ordaz-Pichardo, Cynthia; Shibayama, Mineko; Villa-Treviño, Saúl; Arriaga-Alba, Myriam; Angeles, Enrique; de la Garza, Mireya

    2005-03-01

    Amoebiasis is an important public health problem in developing countries. Entamoeba histolytica, the causative agent of amoebiasis, may develop resistance to nitroimidazoles, a group of drugs considered to be the most effective against this parasitic disease. Therefore, research on new drugs for the treatment of this common infection still constitutes an important therapeutic demand. In the present study we determined the effects of a carbamate derivative, ethyl 4-chlorophenylcarbamate (C4), on trophozoites of E. histolytica strain HM-1:IMSS. C4 was subject to various toxicity tests, including the determination of mutagenicity for bacterial DNA and changes in the enzymatic activities of eukaryotic cells. Genotoxicity studies were performed by the mutagenicity Ames test (plate incorporation and preincubation methods) with Salmonella enterica serovar Typhimurium, with or without metabolic activation produced by the S9 fraction of rat liver. C4 toxicity studies were performed by measuring enzymatic activity in eukaryotic cells by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide-formazan test with Fischer 344 rat hepatocytes. C4 did not induce either frame-shift mutations in S. enterica serovar Typhimurium TA97 or TA98 or base pair substitutions in strains TA100 and TA102. The compound was not toxic for cultured rat hepatic cells. Trophozoites treated with 100 microg of C4 per ml were inhibited 97.88% at 48 h of culture; moreover, damage to the amoebae was also confirmed by electron microscopy. The antiamoebic activity of C4 was evaluated by using an in vivo model of amoebic liver abscess in hamsters. Doses of 75 and 100 mg/100 g of body weight reduced the extent of the amoebic liver abscess by 84 and 94%, respectively. These results justify further studies to clearly validate whether C4 is a new suitable antiamoebic drug.

  4. Therapeutic hypothermia activates the endothelin and nitric oxide systems after cardiac arrest in a pig model of cardiopulmonary resuscitation.

    Directory of Open Access Journals (Sweden)

    Frank Zoerner

    Full Text Available Post-cardiac arrest myocardial dysfunction is a major cause of mortality in patients receiving successful cardiopulmonary resuscitation (CPR. Mild therapeutic hypothermia (MTH is the recommended treatment after resuscitation from cardiac arrest (CA and is known to exert neuroprotective effects and improve short-term survival. Yet its cytoprotective mechanisms are not fully understood. In this study, our aim was to determine the possible effect of MTH on vasoactive mediators belonging to the endothelin/nitric oxide axis in our porcine model of CA and CPR. Pigs underwent either untreated CA or CA with subsequent CPR. After state-of-the-art resuscitation, the animals were either left untreated, cooled between 32-34 °C after ROSC or treated with a bolus injection of S-PBN (sodium 4-[(tert-butylimino methyl]benzene-3-sulfonate N-oxide until 180 min after ROSC, respectively. The expression of endothelin 1 (ET-1, endothelin converting enzyme 1 (ECE-1, and endothelin A and B receptors (ETAR and ETBR transcripts were measured using quantitative real-time PCR while protein levels for the ETAR, ETBR and nitric oxide synthases (NOS were assessed using immunohistochemistry and Western Blot. Our results indicated that the endothelin system was not upregulated at 30, 60 and 180 min after ROSC in untreated postcardiac arrest syndrome. Post-resuscitative 3 hour-long treatments either with MTH or S-PBN stimulated ET-1, ECE-1, ETAR and ETBR as well as neuronal NOS and endothelial NOS in left ventricular cardiomyocytes. Our data suggests that the endothelin and nitric oxide pathways are activated by MTH in the heart.

  5. Therapeutic drug monitoring, electronic health records, and pharmacokinetic modeling to evaluate sirolimus drug exposure-response relationships in renal transplant patients

    Science.gov (United States)

    Zimmerman, Kanecia O.; Wu, Huali; Greenberg, Rachel; Hill, Kevin; Patel, Uptal D.; Ku, Lawrence; Gonzalez, Daniel; Hornik, Christoph; Jiang, Wenlei; Zheng, Nan; Melloni, Chiara; Cohen-Wolkowiez, Michael

    2016-01-01

    Background Sirolimus, an immunosuppressant agent used in renal transplantation, can prevent allograft rejection. Identification of the therapeutic index (ratio of minimum toxic concentration to minimum therapeutic concentration) for immunosuppresants is necessary to optimize the care of patients and set standards for bioequivalence evaluation of sirolimus products. However, the therapeutic index for sirolimus has been inconsistently defined, potentially due to inconsistencies in sirolimus exposure-response relationships. Methods The authors used retrospective therapeutic drug monitoring data from the electronic health records of patients treated in a tertiary healthcare system from 2008 to 2014, to: 1) develop a population pharmacokinetic model, 2) use the model to simulate sirolimus concentrations, and 3) characterize the exposure-response relationship. Using Wilcoxon rank-sum and Fisher’s exact tests, the authors determined relationships between sirolimus exposure and adverse events (anemia, leukopenia, thrombocytopenia, hyperlipidemia, decline in renal function) and the composite efficacy endpoint of graft loss or rejection. Results The developed 2-compartment population pharmacokinetic model showed appropriate goodness of fit. In a late-phase (>12 months), post-renal transplant population of 27 inpatients, the authors identified statistically significant relationships between 83 simulated peak and trough sirolimus concentrations and outcomes: graft loss or rejection (p=0.018), and decline in renal function (p=0.006), respectively. Conclusions Use of therapeutic drug monitoring results and pharmacokinetic modeling permitted correlation of sirolimus concentrations with graft loss or rejection, and decline in renal function. However, the method was limited in its assessment of other adverse events. To better evaluate sirolimus exposure-response relationships, the method should be applied to a larger sample of newly-transplanted patients with a higher propensity

  6. Preclinical modeling highlights the therapeutic potential of hematopoietic stem cell gene editing for correction of SCID-X1.

    Science.gov (United States)

    Schiroli, Giulia; Ferrari, Samuele; Conway, Anthony; Jacob, Aurelien; Capo, Valentina; Albano, Luisa; Plati, Tiziana; Castiello, Maria C; Sanvito, Francesca; Gennery, Andrew R; Bovolenta, Chiara; Palchaudhuri, Rahul; Scadden, David T; Holmes, Michael C; Villa, Anna; Sitia, Giovanni; Lombardo, Angelo; Genovese, Pietro; Naldini, Luigi

    2017-10-11

    Targeted genome editing in hematopoietic stem/progenitor cells (HSPCs) is an attractive strategy for treating immunohematological diseases. However, the limited efficiency of homology-directed editing in primitive HSPCs constrains the yield of corrected cells and might affect the feasibility and safety of clinical translation. These concerns need to be addressed in stringent preclinical models and overcome by developing more efficient editing methods. We generated a humanized X-linked severe combined immunodeficiency (SCID-X1) mouse model and evaluated the efficacy and safety of hematopoietic reconstitution from limited input of functional HSPCs, establishing thresholds for full correction upon different types of conditioning. Unexpectedly, conditioning before HSPC infusion was required to protect the mice from lymphoma developing when transplanting small numbers of progenitors. We then designed a one-size-fits-all IL2RG (interleukin-2 receptor common γ-chain) gene correction strategy and, using the same reagents suitable for correction of human HSPC, validated the edited human gene in the disease model in vivo, providing evidence of targeted gene editing in mouse HSPCs and demonstrating the functionality of the IL2RG-edited lymphoid progeny. Finally, we optimized editing reagents and protocol for human HSPCs and attained the threshold of IL2RG editing in long-term repopulating cells predicted to safely rescue the disease, using clinically relevant HSPC sources and highly specific zinc finger nucleases or CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR-associated protein 9). Overall, our work establishes the rationale and guiding principles for clinical translation of SCID-X1 gene editing and provides a framework for developing gene correction for other diseases. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

  7. 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.

  8. 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).

  9. Iron Reduction and Radionuclide Immobilization: Kinetic, Thermodynamic and Hydrologic controls & Reaction-Based Modeling - Final Report

    Energy Technology Data Exchange (ETDEWEB)

    William D. Burgos

    2004-06-18

    et al, 2003). We have demonstrated the use of a reaction-based reactive transport model (HYDROGEOCHEM) for the simulation of biological iron reduction in natural sediment columns (Burgos and Yeh, unpublished results). Finally, we have developed a preliminary reaction-based model of coupled Fe(III) oxide/U(VI) reduction that has been employed in numerical simulations of U(VI) bioreduction in bench-scale (Roden, 2003d) and field-scale (Roden and Scheibe, 2003;Roden, 2003c) systems.

  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. The Infant Care Project: A Mother-Child Intervention Model Directed at Cocaine Use during Pregnancy. Final Report.

    Science.gov (United States)

    O'Donnell, Karen J.; And Others

    This final report discusses the outcomes of the federally funded Infant Care Project (ICP) that provided comprehensive and continuous services to 99 women who had used cocaine during pregnancy and their infants. The ICP model combined high risk obstetric care, infant and child development services, and substance abuse services on site in the…

  12. Neurotrophin-3 Is a Novel Angiogenic Factor Capable of Therapeutic Neovascularization in a Mouse Model of Limb Ischemia

    Science.gov (United States)

    Cristofaro, Brunella; Stone, Oliver A.; Caporali, Andrea; Dawbarn, David; Ieronimakis, Nicholas; Reyes, Morayma; Madeddu, Paolo; Bates, David O.; Emanueli, Costanza

    2010-01-01

    Objective To investigate the novel hypothesis that neurotrophin-3 (NT-3), an established neurotrophic factor that participates in embryonic heart development, promotes blood vessel growth. Methods and Results We evaluated the proangiogenic capacity of recombinant NT-3 in vitro and of NT-3 gene transfer in vivo (rat mesenteric angiogenesis assay and mouse normoperfused adductor muscle). Then, we studied whether either transgenic or endogenous NT-3 mediates postischemic neovascularization in a mouse model of limb ischemia. In vitro, NT-3 stimulated endothelial cell survival, proliferation, migration, and network formation on the basement membrane matrix Matrigel. In the mesenteric assay, NT-3 increased the number and size of functional vessels, including vessels covered with mural cells. Consistently, NT-3 overexpression increased muscular capillary and arteriolar densities in either the absence or the presence of ischemia and improved postischemic blood flow recovery in mouse hind limbs. NT-3–induced microvascular responses were accompanied by tropomyosin receptor kinase C (an NT-3 high-affinity receptor) phosphorylation and involved the phosphatidylinositol 3-kinase–Akt kinase–endothelial nitric oxide synthase pathway. Finally, endogenous NT-3 was shown to be essential in native postischemic neovascularization, as demonstrated by using a soluble tropomyosin receptor kinase C receptor domain that neutralizes NT-3. Conclusion Our results provide the first insight into the proangiogenic capacity of NT-3 and propose NT-3 as a novel potential agent for the treatment of ischemic disease. PMID:20360537

  13. 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.

  14. Final Progress Report for the NASA Inductrack Model Rocket Launcher at the Lawrence Livermore National Laboratory

    Energy Technology Data Exchange (ETDEWEB)

    Tung, L S; Post, R F; Martinez-Frias, J

    2001-06-27

    The Inductrack magnetic levitation system, developed at the Lawrence Livermore National Laboratory, was studied for its possible use for launching rockets. Under NASA sponsorship, a small model system was constructed at the Laboratory to pursue key technical aspects of this proposed application. The Inductrack is a passive magnetic levitation system employing special arrays of high-field permanent magnets (Halbach arrays) on the levitating cradle, moving above a ''track'' consisting of a close-packed array of shorted coils with which are interleaved with special drive coils. Halbach arrays produce a strong spatially periodic magnetic field on the front surface of the arrays, while canceling the field on their back surface. Relative motion between the Halbach arrays and the track coils induces currents in those coils. These currents levitate the cradle by interacting with the horizontal component of the magnetic field. Pulsed currents in the drive coils, synchronized with the motion of the carrier, interact with the vertical component of the magnetic field to provide acceleration forces. Motional stability, including resistance to both vertical and lateral aerodynamic forces, is provided by having Halbach arrays that interact with both the upper and the lower sides of the track coils. At present, a 7.8 meter track composed of drive and levitation coils has been built and the electronic drive circuitry performs as designed. A 9 kg cradle that carries the Halbach array of permanent magnets has been built. A mechanical launcher is nearly complete which will provide an initial cradle velocity of 9 m/s into the electronic drive section. We have found that the drag forces from the levitation coils were higher than in our original design. However, measurements of drag force at velocities less than 1 m/s are exactly as predicted by theory. Provided here are recommended design changes to improve the track's performance so that a final velocity of 40

  15. 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.

  16. [Therapeutic effects and related mechanisms of erythropoietin sustained-release gelatin hydrogel microspheres on a murine model of hindlimb ischemia].

    Science.gov (United States)

    Xiao, J W; Li, L H; Hong, B Z; Xiao, J Q; Wei, D M; Jin, Z

    2016-06-24

    To investigate the therapeutic effects of erythropoietin sustained-release gelatin hydrogel microspheres (EPO-GHM) on a murine model of hindlimb ischemia and related mechanisms. Fifty two ten weeks old male C57BL/6J mice were assigned to 5 groups: sham-operated group (the right femoral artery suture was passed through the right femoral artery but not tied, n=8); saline group (right femoral artery ligation and intramuscular injection of saline at a dose of 4 ml/kg into the right hind limb, n=12); EPO group(right femoral artery ligation and intramuscular injection of EPO at a dose of 5 000 IU/kg into the right hind limb, n=12), empty GHM group (right femoral artery ligation and intramuscular injection of empty GHM at a dose of 4 ml/kg into the right hind limb, n=8); EPO-GHM group(right femoral artery ligation and intramuscular injection of EPO-GHM at a dose of 5 000 IU/kg into the right hind limb, n=12). The blood flow ratio of ischemic limb (right)/nonischemic limb (left) was measured using a laser Doppler perfusion imager. After 8 weeks, immunohistochemical analysis were used to evaluate the vessel density (vessel density of CD31 positive), arteriole density(vessel density of α-smooth muscle actin(α-SMA) positive) and muscle area(HHF35 positive area). The proliferating index of vessels was evaluated by double immunofluorescent labeling to evaluate effect of EPO-GHM on angiogenesis of ischemia limb. Western blot was used to evaluate the protein expression of EPO receptor, protein kinase B(AKT), p-AKT, endothelial nitric oxide synthase(eNOS), p-eNOS and matrix metalloproteinase 2(MMP-2). (1) Eight weeks later, the blood flow ratio of ischemic limb/nonischemic limb was significantly higher in the EPO-GHM group compared with other groups(0.810±0.080, 0.563±0.051, 0.570±0.056 and 0.561±0.052 respectively, all P0.05). (4)The proliferating index of vessels was higher in the EPO-GHM group compared with other groups(P0.05). RESULTS from present study suggest EPO

  17. Modeling of fluidized-bed combustion of coal: Phase II, final reports. Volume II. Detailed description of the model

    Energy Technology Data Exchange (ETDEWEB)

    Louis, J.F.; Tung, S.E.

    1980-10-01

    This document is the second of a seven volume series of our Phase II Final Report. This volume deals with detailed descriptions of the structure of each program member (subroutines and functions), the interrelation between the members of a submodel, and the interrelation between the various submodels as such. The systems model for fluidized bed combustors (FBC-II) consists of a systematic combination of the following interrelated areas: fluid mechanics and bubble growth, char combustion and associated kinetics for particle burnout, sulfur capture, NO/sub x/ formation and reduction, freeboard reactions, and heat transfer. Program outline is shown in Figure 1.1. Input variables (supplied by the user are inspected to check that they lie inside the allowed range of values and are input to the various routines as needed. The necessary physical and fluid mechanical properties are calculated and utilized in estimating char combustion and sulfur capture in the bed and the freeboard. NO/sub x/ and CO emissions are estimated by taking into account all relevant chemical reactions. A material and energy balance is made over the bed. Figure 1.1 shows a block diagram of the systems program. In this diagram, the overall structure of the FBC program is illustrated in terms of the various submodels that together constitute the systems program. A more detailed outline of the systems program is shown in Figure 1.2. In this figure, all important subroutine members of the FBC program are shown, and their linkage to each other, as well as to the main program is indicated. A description of the exact sequence in which these various routines are called at time of program execution is provided in Chapter 8 under the executive routine MAIN.

  18. Therapeutic advantage of inhaled tacrolimus-bound albumin nanoparticles in a bleomycin-induced pulmonary fibrosis mouse model.

    Science.gov (United States)

    Seo, Jisoo; Lee, Changkyu; Hwang, Ha Shin; Kim, Bomi; Thao, Le Quang; Lee, Eun Seong; Oh, Kyung Taek; Lim, Jong-Lae; Choi, Han-Gon; Youn, Yu Seok

    2016-02-01

    Tacrolimus (Tac) is an immunosuppressant that inhibits translocation of nuclear factor of activated T cells and has therapeutic potential for pulmonary fibrosis. Here, we investigated the therapeutic efficacy of a sustained-release type inhaled Tac formulation for treating bleomycin-induced pulmonary fibrosis. Inhalation has many meaningful advantages over injections, such as improved patient compliance, safety, and therapeutic effect. To this end, we fabricated inhalable albumin nanoparticles with bound Tac (Tac Alb-NPs) at a daily therapeutic dose (60 μg/mouse) using a high-pressure homogenizer via nanoparticle albumin-bound technology. The Tac Alb-NPs were spherical, ∼ 182.1 ± 28.5 nm in size, with a zeta potential of -34.5 ± 0.3 mV, and the Tac incorporation efficiency was as high as ∼ 85.3%. The bound tacrolimus was released gradually from Tac Alb-NPs for ∼ 24 h, which was sufficient time for pulmonary delivery. Most of all, the inhaled Tac Alb-NPs displayed remarkable anti-fibrotic efficacy in mice with bleomycin-induced pulmonary fibrosis, which was much better than the efficacy resulting from intraperitoneal administration of Tac (60 μg/mouse) based on histopathological results (hematoxylin and eosin and Masson's trichrome staining). Furthermore, the inhaled Cy5.5-labelled Tac Alb-NPs were visualized throughout the lungs of mice for ∼ 48 h, indicating direct exposure to fibrotic tissues in lung lesions. In conclusion, Tac Alb-NPs offer great potential as an inhalation delivery formulation for treating pulmonary fibrosis. Additionally, these NPs would be particularly useful as an effective and safe prototype for delivering practically insoluble therapeutic agents into the lungs. Copyright © 2016 Elsevier Ltd. All rights reserved.

  19. Development of weekend travel demand and mode choice models : final report, June 2009.

    Science.gov (United States)

    2010-06-30

    Travel demand models are widely used for forecasting and analyzing policies for automobile and transit travel. However, these models are typically developed for average weekday travel when regular activities are routine. The weekday models focus prim...

  20. Rett syndrome: genes, synapses, circuits and therapeutics

    Directory of Open Access Journals (Sweden)

    Abhishek eBanerjee

    2012-05-01

    Full Text Available Development of the nervous system proceeds through a set of complex checkpoints which arise from a combination of sequential gene expression and early neural activity sculpted by the environment. Genetic and environmental insults lead to neurodevelopmental disorders which encompass a large group of diseases that result from anatomical and physiological abnormalities during maturation and development of brain circuits. Rett syndrome (RTT is a postnatal neurological disorder of genetic origin, caused by mutations in the X-linked gene MECP2. It features neuropsychiatric abnormalities like motor dysfunctions and mild to severe cognitive impairment. This review discusses several key questions and attempts to evaluate recently developed animal models, cell-type specific function of MeCP2, defects in neural circuit plasticity and possible therapeutic strategies. Finally, we also discuss how genes, proteins and overlapping signaling pathways affect the molecular etiology of apparently unrelated neuropsychiatric disorders, an understanding of which can offer novel therapeutic strategies.

  1. A Realistic View of Aging: A Model for Teaching Future Generations. Final Report.

    Science.gov (United States)

    Lucchino, Ronald

    This final project report examines how to successfully develop a national approach for the infusion of aging content into the K-12 grade curricula. As the U.S. society is "graying," the students in schools should be exposed to aging information on the increasing responsibilities for the care of aging family members with a realistic view of their…

  2. Effects of prophylactic and therapeutic teriflunomide in transcranial magnetic stimulation-induced motor-evoked potentials in the dark agouti rat model of experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Iglesias-Bregna, Deborah; Hanak, Susan; Ji, Zhongqi; Petty, Margaret; Liu, Li; Zhang, Donghui; McMonagle-Strucko, Kathleen

    2013-10-01

    Teriflunomide is a once-daily oral immunomodulatory agent recently approved in the United States for the treatment of relapsing multiple sclerosis (RMS). This study investigated neurophysiological deficits in descending spinal cord motor tracts during experimental autoimmune encephalomyelitis (EAE; a model of multiple sclerosis) and the functional effectiveness of prophylactic or therapeutic teriflunomide treatment in preventing the debilitating paralysis observed in this model. Relapsing-remitting EAE was induced in Dark Agouti rats using rat spinal cord homogenate. Animals were treated with oral teriflunomide (10 mg/kg daily) prophylactically, therapeutically, or with vehicle (control). Transcranial magnetic motor-evoked potentials were measured throughout the disease to provide quantitative assessment of the neurophysiological status of descending motor tracts. Axonal damage was quantified histologically by silver staining. Both prophylactic and therapeutic teriflunomide treatment significantly reduced maximum EAE disease scores (P teriflunomide treatment regimens prevented a delay in wave-form latency and a decrease in wave-form amplitude compared with that observed in vehicle-treated animals. A significant reduction in axonal loss was observed with both teriflunomide treatment regimens compared with vehicle (P teriflunomide can prevent the deficits observed in this animal model in descending spinal cord motor tracts. The mechanism behind reduced axonal loss and improved motor function may be primarily the reduced inflammation and consequent demyelination observed in these animals through the known effects of teriflunomide on impairing proliferation of stimulated T cells. These findings may have significant implications for patients with RMS.

  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. Reporting therapeutic discourse in a therapeutic community.

    Science.gov (United States)

    Chapman, G E

    1988-03-01

    Research in nurses' communications has concentrated on nurse to patient interactions. Those few studies which focus on nurse to nurse communications seem to be generated by a pragmatic and normative concern with effective information sharing. In this paper, which describes one aspect of a larger case study of a hospital-based therapeutic community, the description and analysis of nurses' reports flows not from a normative model of professional practice, but rather an exploration of how professional practice is articulated as discourse in nurses' written accounts. Foucault's ideas about therapeutic discourse inform the theoretical framework of the research. Ethnomethodological concerns with the importance of documentary analysis provide the methodological rationale for examining nurses' 24-hour report documents, as official discourse, reflecting therapeutic practice in this setting. A content analysis of nurses' reports, collected over a period of 4 months, demonstrated the importance of domesticity and ordinary everyday activities in nurses' accounts of hospital life. Disruption to the 'life as usual' domesticity in the community seemed to be associated with admission to and discharge from the hospital when interpersonal and interactional changes between patients occur. It is suggested that nurses in general hospital wards and more orthodox psychiatric settings might usefully consider the impact of admissions and discharges on the group of patients they manage, and make this a discursive focus of their work.

  5. Therapeutic approaches to cellulite.

    Science.gov (United States)

    Green, Jeremy B; Cohen, Joel L; Kaufman, Joely; Metelitsa, Andrei I; Kaminer, Michael S

    2015-09-01

    Cellulite is a condition that affects the vast majority of women. Although it is of no danger to one's overall health, cellulite can be psychosocially debilitating. Consequently, much research has been devoted to understanding cellulite and its etiopathogenesis. With additional insights into the underlying causes of its clinical presentation, therapeutic modalities have been developed that offer hope to cellulite sufferers. This review examines evidence for topical treatments, noninvasive energy-based devices, and recently developed minimally invasive interventions that may finally provide a solution. ©2015 Frontline Medical Communications.

  6. Analysis and synthesis of models for effects of climate change on agricultural systems. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Geng, S.; Plant, R.; Loomis, R.

    1992-07-27

    Our objectives are to develop a new integrative physiological-morphological model of the wheat crop that will behave realistically in high-CO{sub 2} environments, and to update the ALFALFA model to match the wheat model`s photosynthetic structures and microclimates.

  7. Digital Avionics Information System (DAIS): Reliability and Maintainability Model. Final Report.

    Science.gov (United States)

    Czuchry, Andrew J.; And Others

    The reliability and maintainability (R&M) model described in this report represents an important portion of a larger effort called the Digital Avionics Information System (DAIS) Life Cycle Cost (LCC) Study. The R&M model is the first of three models that comprise a modeling system for use in LCC analysis of avionics systems. The total…

  8. Modeling, Analysis and Simulation of Multiscale Preferential Flow - 8/05-8/10 - Final Report

    Energy Technology Data Exchange (ETDEWEB)

    Ralph Showalter; Malgorzata Peszynska

    2012-07-03

    The research agenda of this project are: (1) Modeling of preferential transport from mesoscale to macroscale; (2) Modeling of fast flow in narrow fractures in porous media; (3) Pseudo-parabolic Models of Dynamic Capillary Pressure; (4) Adaptive computational upscaling of flow with inertia from porescale to mesoscale; (5) Adaptive modeling of nonlinear coupled systems; and (6) Adaptive modeling and a-posteriori estimators for coupled systems with heterogeneous data.

  9. Therapeutic validity and effectiveness of preoperative exercise on functional recovery after joint replacement: a systematic review and meta-analysis.

    Science.gov (United States)

    Hoogeboom, Thomas J; Oosting, Ellen; Vriezekolk, Johanna E; Veenhof, Cindy; Siemonsma, Petra C; de Bie, Rob A; van den Ende, Cornelia H M; van Meeteren, Nico L U

    2012-01-01

    Our aim was to develop a rating scale to assess the therapeutic validity of therapeutic exercise programmes. By use of this rating scale we investigated the therapeutic validity of therapeutic exercise in patients awaiting primary total joint replacement (TJR). Finally, we studied the association between therapeutic validity of preoperative therapeutic exercise and its effectiveness in terms of postoperative functional recovery. (Quasi) randomised clinical trials on preoperative therapeutic exercise in adults awaiting TJR on postoperative recovery of functioning within three months after surgery were identified through database and reference screening. Two reviewers extracted data and assessed the risk of bias and therapeutic validity. Therapeutic validity of the interventions was assessed with a nine-itemed, expert-based rating scale (scores range from 0 to 9; score ≥6 reflecting therapeutic validity), developed in a four-round Delphi study. Effects were pooled using a random-effects model and meta-regression was used to study the influence of therapeutic validity. Of the 7,492 articles retrieved, 12 studies (737 patients) were included. None of the included studies demonstrated therapeutic validity and two demonstrated low risk of bias. Therapeutic exercise was not associated with 1) observed functional recovery during the hospital stay (Standardised Mean Difference [SMD]: -1.19; 95%-confidence interval [CI], -2.46 to 0.08); 2) observed recovery within three months of surgery (SMD: -0.15; 95%-CI, -0.42 to 0.12); and 3) self-reported recovery within three months of surgery (SMD -0.07; 95%-CI, -0.35 to 0.21) compared with control participants. Meta-regression showed no statistically significant relationship between therapeutic validity and pooled-effects. Preoperative therapeutic exercise for TJR did not demonstrate beneficial effects on postoperative functional recovery. However, poor therapeutic validity of the therapeutic exercise programmes may have hampered

  10. Preclinical Models Provide Scientific Justification and Translational Relevance for Moving Novel Therapeutics into Clinical Trials for Pediatric Cancer.

    Science.gov (United States)

    Langenau, David M; Sweet-Cordero, Alejandro; Wechsler-Reya, Robert; Dyer, Michael A

    2015-12-15

    Despite improvements in survival rates for children with cancer since the 1960s, progress for many pediatric malignancies has slowed over the past two decades. With the recent advances in our understanding of the genomic landscape of pediatric cancer, there is now enthusiasm for individualized cancer therapy based on genomic profiling of patients' tumors. However, several obstacles to effective personalized cancer therapy remain. For example, relatively little data from prospective clinical trials demonstrate the selective efficacy of molecular-targeted therapeutics based on somatic mutations in the patient's tumor. In this commentary, we discuss recent advances in preclinical testing for pediatric cancer and provide recommendations for providing scientific justification and translational relevance for novel therapeutic combinations for childhood cancer. Establishing rigorous criteria for defining and validating druggable mutations will be essential for the success of ongoing and future clinical genomic trials for pediatric malignancies. ©2015 American Association for Cancer Research.

  11. 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.

  12. 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.

  13. Finite element modeling of reinforced concrete structures strengthened with FRP laminates : final report.

    Science.gov (United States)

    2001-05-01

    Linear and non-linear finite element method models were developed for a reinforced concrete bridge that had been strengthened with fiber reinforced polymer composites. ANSYS and SAP2000 modeling software were used; however, most of the development ef...

  14. Surface transportation security and reliability information system model deployment : iFlorida final concept of operations

    Science.gov (United States)

    2003-09-03

    FDOT began design of a Surface Transportation Security and Reliability Information System Model Deployment in May 2003. This model deployment focuses on enhancing the security and reliability of the surface transportation system through the widesprea...

  15. 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(ε-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.

  16. Pressure Model for the Vacuum System for the Electron Gun and Injector for LCLS Final Design Report

    Energy Technology Data Exchange (ETDEWEB)

    Tung, L S; Eriksson, L

    2006-04-28

    The vacuum system of the injector for the Linac Coherent Light Source (LCLS) has been analyzed and configured by the Lawrence Livermore National Laboratory's New Technologies Engineering Division (NTED) as requested by the SLAC/LCLS program. The vacuum system layout and detailed analyses for the injector are presented in this final design report. The vacuum system was analyzed and optimized using a coupled gas load balance model of sub-volumes of the components to be evacuated.

  17. 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

    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......Immunotherapy against cancer has shown increased overall survival of metastatic cancer patients and is a promising new vaccine target. For this to succeed, appropriate tailoring of vaccine formulations to mount in vivo cytotoxic T cell (CTL) responses towards co-delivered cancer antigens...... 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...

  18. 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.

  19. An improved switching converter model. Ph.D. Thesis. Final Report

    Science.gov (United States)

    Shortt, D. J.

    1982-01-01

    The nonlinear modeling and analysis of dc-dc converters in the continuous mode and discontinuous mode was done by averaging and discrete sampling techniques. A model was developed by combining these two techniques. This model, the discrete average model, accurately predicts the envelope of the output voltage and is easy to implement in circuit and state variable forms. The proposed model is shown to be dependent on the type of duty cycle control. The proper selection of the power stage model, between average and discrete average, is largely a function of the error processor in the feedback loop. The accuracy of the measurement data taken by a conventional technique is affected by the conditions at which the data is collected.

  20. 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.

  1. 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.

  2. 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.

  3. A Model for Evaluating Programs in Vocational Education for the Handicapped. Final Report.

    Science.gov (United States)

    Bekker, Gerald; Christiansen, James E.

    An evaluation model was developed to measure the effectiveness of pilot programs in vocational education for handicapped persons in selected State schools and State hospitals in Texas. The model was field-tested by conducting evaluations of 16 pilot programs in vocational education for the handicapped located in seven State schools/hospitals. Data…

  4. Learning and enhanced climate representation in integrated assessment models. Final report, September 1994--May 1997

    Energy Technology Data Exchange (ETDEWEB)

    Kolstad, C.D.

    1997-12-31

    The objective of the project is to enhance capabilities for integrated-assessment modeling in two major areas: learning/R and D/information acquisition and the nexus between climate dynamics and climate impacts. In the first of these areas, the author`s objective is to improve the way in which economic models deal with learning (endogenous and/or exogenous) within an economy. This would obviously include the R and D process, whereby knowledge about climate change (and many other things) is acquired over time and influences regulatory actions. The work in climate dynamics is focused in part on incorporating the regional climate-change results from equilibrium and transient general circulation model (GCM) simulations in the simplified integrated-assessment model. While the work is generic and therefore applicable to any integrated-assessment model, it is done in the context of a standard Ramsey growth model. Thus, the work involves theoretical conceptualization, empirical implementation in an integrated-assessment model, and analysis using that model.

  5. A Model Distributive Education Competency Based Learning Laboratory. Final Report. Research Series No. 25.

    Science.gov (United States)

    Strate, James W.; Brorson, Bruce

    The research project focused on the utilization of the model-school store as a distributive education learning laboratory. Objectives were to: (1) Determine the competencies required of teacher-coordinators, (2) determine the instructional materials and equipment needed, (3) develop a model-school store curriculum for secondary education, and (4)…

  6. Predicting Coupled Ocean-Atmosphere Modes with a Climate Modeling Hierarchy -- Final Report

    Energy Technology Data Exchange (ETDEWEB)

    Michael Ghil, UCLA; Andrew W. Robertson, IRI, Columbia Univ.; Sergey Kravtsov, U. of Wisconsin, Milwaukee; Padhraic Smyth, UC Irvine

    2006-08-04

    The goal of the project was to determine midlatitude climate predictability associated with tropical-extratropical interactions on interannual-to-interdecadal time scales. Our strategy was to develop and test a hierarchy of climate models, bringing together large GCM-based climate models with simple fluid-dynamical coupled ocean-ice-atmosphere models, through the use of advanced probabilistic network (PN) models. PN models were used to develop a new diagnostic methodology for analyzing coupled ocean-atmosphere interactions in large climate simulations made with the NCAR Parallel Climate Model (PCM), and to make these tools user-friendly and available to other researchers. We focused on interactions between the tropics and extratropics through atmospheric teleconnections (the Hadley cell, Rossby waves and nonlinear circulation regimes) over both the North Atlantic and North Pacific, and the ocean’s thermohaline circulation (THC) in the Atlantic. We tested the hypothesis that variations in the strength of the THC alter sea surface temperatures in the tropical Atlantic, and that the latter influence the atmosphere in high latitudes through an atmospheric teleconnection, feeding back onto the THC. The PN model framework was used to mediate between the understanding gained with simplified primitive equations models and multi-century simulations made with the PCM. The project team is interdisciplinary and built on an existing synergy between atmospheric and ocean scientists at UCLA, computer scientists at UCI, and climate researchers at the IRI.

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

    Energy Technology Data Exchange (ETDEWEB)

    Hobbs, D.T. [Westinghouse Savannah River Co., Aiken, SC (United States); Prasad, S.; Farell, A.E.; Weidner, J.W.; White, R.E. [South Carolina Univ., Columbia, SC (United States). Dept. of Chemical Engineering

    1995-12-31

    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.

  8. Architectural considerations for agent-based national scale policy models : LDRD final report.

    Energy Technology Data Exchange (ETDEWEB)

    Backus, George A.; Strip, David R.

    2007-09-01

    The need to anticipate the consequences of policy decisions becomes ever more important as the magnitude of the potential consequences grows. The multiplicity of connections between the components of society and the economy makes intuitive assessments extremely unreliable. Agent-based modeling has the potential to be a powerful tool in modeling policy impacts. The direct mapping between agents and elements of society and the economy simplify the mapping of real world functions into the world of computation assessment. Our modeling initiative is motivated by the desire to facilitate informed public debate on alternative policies for how we, as a nation, provide healthcare to our population. We explore the implications of this motivation on the design and implementation of a model. We discuss the choice of an agent-based modeling approach and contrast it to micro-simulation and systems dynamics approaches.

  9. Evaluation of the Chinese Medicinal Herb, Graptopetalum paraguayense, as a Therapeutic Treatment for Liver Damage in Rat Models

    Directory of Open Access Journals (Sweden)

    Li-Jen Su

    2012-01-01

    Full Text Available The incidence of cirrhosis is rising due to the widespread occurrence of chronic hepatitis, as well as the evident lack of an established therapy for hepatic fibrosis. In the search for hepatoprotective therapeutic agents, Graptopetalum paraguayense (GP showed greater cytotoxicity toward hepatic stellate cells than other tested herbal medicines. Histopathological and biochemical analyses suggest that GP treatment significantly prevented DMN-induced hepatic inflammation and fibrosis in rats. Microarray profiling indicated that expression of most of metabolism- and cell growth and/or maintenance-related genes recovered to near normal levels following GP treatment as classified by gene ontology and LSM analysis, was observed. ANOVA showed that expression of 64% of 256 liver damage-related genes recovered significantly after GP treatment. By examining rat liver samples with Q-RT-PCR, five liver damage-related genes were identified. Among them, Egr1 and Nrg1 may serve as necroinflammatory markers, and Btg2 may serve as a fibrosis marker. Oldr1 and Hmgcs1 were up- and down-regulated markers, respectively. A publicly accessible website has been established to provide access to these data Identification of 44 necroinflammation-related and 62 fibrosis-related genes provides useful insight into the molecular mechanisms underlying liver damage and provides potential targets for the rational development of therapeutic drugs such as GP.

  10. 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

  11. Hot-gas cleanup system model development. Volume II. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Ushimaru, K.; Bennett, A.; Bekowies, P.J.

    1982-11-01

    Under Contract to the Department of Energy (DOE) through the Morgantown Energy Technology Center (METC), Flow Industries, Inc., has developed computer models to simulate the physical performance of five hot-gas cleanup devices for pressurized, fluidized-bed combustion (PFBC), combined-cycle power plants. Separate cost models have also been developed to estimate the cost of each device. The work leading to the development of these models is described in Volume I of this report. This volume contains the user's manuals for both the physical and cost models. The manuals for the physical models are given first followed by those for the cost models. Each manual is a complete and separate document. The model names and devices and their respective subroutine names are: (1) Moving Granular Bed Filter by Combustion Power Company, USRCGB, QFCOST; (2) Ceramic Bag Filter by Acurex, USRACB, QDCOST; (3) Electrostatic Granular Bed Filter by General Electric, USRGGB, QACOST; (4) Electrostatic Precipitator by Research Cottrell, USRCEP, QECOST; and (5) Electrocyclone by General Electric, USRGCY, QBCOST.

  12. Fractal modeling of natural fracture networks. Final report, June 1994--June 1995

    Energy Technology Data Exchange (ETDEWEB)

    Ferer, M.V.; Dean, B.H.; Mick, C.

    1996-04-01

    Recovery from naturally fractured, tight-gas reservoirs is controlled by the fracture network. Reliable characterization of the actual fracture network in the reservoir is severely limited. The location and orientation of fractures intersecting the borehole can be determined, but the length of these fractures cannot be unambiguously determined. Fracture networks can be determined for outcrops, but there is little reason to believe that the network in the reservoir should be identical because of the differences in stresses and history. Because of the lack of detailed information about the actual fracture network, modeling methods must represent the porosity and permeability associated with the fracture network, as accurately as possible with very little apriori information. Three rather different types of approaches have been used: (1) dual porosity simulations; (2) `stochastic` modeling of fracture networks, and (3) fractal modeling of fracture networks. Stochastic models which assume a variety of probability distributions of fracture characteristics have been used with some success in modeling fracture networks. The advantage of these stochastic models over the dual porosity simulations is that real fracture heterogeneities are included in the modeling process. In the sections provided in this paper the authors will present fractal analysis of the MWX site, using the box-counting procedure; (2) review evidence testing the fractal nature of fracture distributions and discuss the advantages of using their fractal analysis over a stochastic analysis; (3) present an efficient algorithm for producing a self-similar fracture networks which mimic the real MWX outcrop fracture network.

  13. Thermodynamic model for calorimetric and phase coexistence properties of coal derived fluids. Final technical report

    Energy Technology Data Exchange (ETDEWEB)

    Kabadi, V.N.

    1992-10-01

    The work on this project was initiated on September 1, 1989. The project consisted of three different tasks. 1. A thermodynamic model to predict VLE and calorimetric properties of coal liquids. 2. VLE measurements at high temperature and high pressure for coal model compounds and 3. Chromatographic characterization of coal liquids for distribution of heteroatoms. The thermodynamic model developed is an extension of the previous model developed for VLE of coal derived fluids (DOE Grant no. FG22-86PC90541). The model uses the modified UNIFAC correlation for the liquid phase. Some unavailable UNIFAC interactions parameters have been regressed from experimental VLE and excess enthalpy data. The model is successful in predicting binary VLE and excess enthalpy data. Further refinements of the model are suggested. An apparatus for the high pressure high temperature VLE data measurements has been built and tested. Tetralin-Quinoline is the first binary system selected for data measurements. The equipment was tested by measuring 325{degree}C isotherm for this system and comparing it with literature data. Additional isotherms at 350{degree}C and 370{degree}C have been measured. The framework for a characterization procedure for coal derived liquids has been developed. A coal liquid is defined by a true molecular weight distribution and distribution of heteroatoms as a function of molecular weights. Size exclusions liquid chromatography, elemental analysis and FTIR spectroscopy methods are used to obtain the molecular weight and hetroatom distributions. Further work in this area should include refinements of the characterization procedure, high temperature high pressure VLE data measurements for selective model compound binary systems, and improvement of the thermodynamic model using the new measured data and consistent with the developments in the characterization procedure.

  14. Aspartate-β-semialdeyhyde dehydrogenase as a potential therapeutic target of Mycobacterium tuberculosis H37Rv: Evidence from in-silico elementary mode analysis of biological network model.

    Science.gov (United States)

    Khan, Saif; Somvanshi, Pallavi; Bhardwaj, Tulika; Mandal, Raju K; Dar, Sajad A; Wahid, Mohd; Jawed, Arshad; Lohani, Mohtashim; Khan, Mahvish; Areeshi, Mohammed Y; Haque, Shafiul

    2017-10-25

    The emergence of multi-drug resistant strains and co-occurrence of tuberculosis with HIV creates a major burden to the human health globally. Failure of primary antibacterial therapy necessitates the identification of new mycobacterial drugs. In this study, a comprehensive analysis involving bottom-up systems biology approach was applied wherein we have identified potential therapeutic targets of Mycobacterium tuberculosis infections. Our study prioritized M. tuberculosis therapeutic targets [aspartate-β-semialdeyhde dehydrogenase (ASD), dihydrodipicolinate reductase and diaminopimelate decarboxylase] based on flux and elementary mode analysis using direct mathematical modeling of the relevant metabolic pathways. Molecular docking and simulation studies of the priority target (i.e., ASD) revealed the therapeutic potential of the selected natural products (Huperzine A, Rosmarinic acid and Curcumin) based ASD inhibitors. The study highlights the crucial role of systems biology in conjunction with molecular interaction (docking) for probing novel leads against an increasingly resistant pathogen, M. tuberculousis. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  15. 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.

  16. Final technical report for DOE Computational Nanoscience Project: Integrated Multiscale Modeling of Molecular Computing Devices

    Energy Technology Data Exchange (ETDEWEB)

    Cummings, P. T.

    2010-02-08

    This document reports the outcomes of the Computational Nanoscience Project, "Integrated Multiscale Modeling of Molecular Computing Devices". It includes a list of participants and publications arising from the research supported.

  17. Validation of Model Simulations of Anvil Cirrus Properties During TWP-ICE: Final Report

    Energy Technology Data Exchange (ETDEWEB)

    Zipser, Edward J. [University of Utah

    2013-05-20

    This 3-year grant, with two extensions, resulted in a successful 5-year effort, led by Ph.D. student Adam Varble, to compare cloud resolving model (CRM) simulations with the excellent database obtained during the TWP-ICE field campaign. The objective, largely achieved, is to undertake these comparisons comprehensively and quantitatively, informing the community in ways that goes beyond pointing out errors in the models, but points out ways to improve both cloud dynamics and microphysics parameterizations in future modeling efforts. Under DOE support, Adam Varble, with considerable assistance from Dr. Ann Fridlind and others, entrained scientists who ran some 10 different CRMs and 4 different limited area models (LAMs) using a variety of microphysics parameterizations, to ensure that the conclusions of the study will have considerable generality.

  18. ATHENA calculation model for the ITER-FEAT divertor cooling system. Final report with updates

    Energy Technology Data Exchange (ETDEWEB)

    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.

  19. Second International Symposium on the Biogeochemistry of Model Estuaries: Estuarine processes in global change. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Windom, H.L.

    1991-12-31

    This report summarizes estuary events discussed at the symposium on biogeochemistry. Topics include; sedimentation, salinity, inputs and outputs of the estuary, effects of global change, and the need for effective sampling and modeling of estuaries.

  20. 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

  1. 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.

  2. 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.

  3. 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.

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

    Science.gov (United States)

    Niu, Yi-Nong; Wang, Kai; Jin, Song; Fan, Dong-Dong; Wang, Ming-Shuai; Xing, Nian-Zeng; Xia, Shu-Jie

    2016-01-01

    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.

  5. 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.

  6. 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.

  7. 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.).

  8. 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

    avoidance response behaviour in rodents, correlate with clinically relevant plasma exposure for the classical antipsychotic drug haloperidol and four second generation antipsychotics: sertindole, clozapine, risperidone and olanzapine, including selected metabolites. In order to confirm the validity...... receptor occupancy required to suppress conditioned avoidance response behaviour according to EC50 measurements to be sertindole (+dehydrosertindole)=dehydrosertindole=paliperidone (the metabolite of risperidone)=haloperidol=olanzapine>risperidone>clozapine. Overall, a good agreement was observed between...... 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...

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

    Energy Technology Data Exchange (ETDEWEB)

    Coderre, J.A.; Micca, P.L.; Nawrocky, M.M.; Fisher, C.D.; Bywaters, A. [Brookhaven National Lab., Upton, NY (United States); Morris, G.M.; Hopewell, J.W. [Univ. of Oxford (United Kingdom). CRC Normal Tissue Radiobiological Research Group

    1996-10-01

    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 {sup 10}B(n,{alpha}){sup 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 {sup 10}B(n,{alpha}){sup 7}Li reaction. To distinguish these differences from true RBEs we have used the term {open_quotes}compound biological effectiveness{close_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 factor{close_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).

  10. 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.

  11. 'Get in Early'; Biofilm and Wax Moth (Galleria mellonella) Models Reveal New Insights into the Therapeutic Potential of Clostridium difficile Bacteriophages.

    Science.gov (United States)

    Nale, Janet Y; Chutia, Mahananda; Carr, Philippa; Hickenbotham, Peter T; Clokie, Martha R J

    2016-01-01

    Clostridium difficile infection (CDI) is a global health threat associated with high rates of morbidity and mortality. Conventional antibiotic CDI therapy can result in treatment failure and recurrent infection. C. difficile produces biofilms which contribute to its virulence and impair antimicrobial activity. Some bacteriophages (phages) can penetrate biofilms and thus could be developed to either replace or supplement antibiotics. Here, we determined the impact of a previously optimized 4-phage cocktail on C. difficile ribotype 014/020 biofilms, and additionally as adjunct to vancomycin treatment in Galleria mellonella larva CDI model. The phages were applied before or after biofilm establishment in vitro, and the impact was analyzed according to turbidity, viability counts and topography as observed using scanning electron and confocal microscopy. The infectivity profiles and efficacies of orally administered phages and/or vancomycin were ascertained by monitoring colonization levels and larval survival rates. Phages prevented biofilm formation, and penetrated established biofilms. A single phage application reduced colonization causing extended longevity in the remedial treatment and prevented disease in the prophylaxis group. Multiple phage doses significantly improved the larval remedial regimen, and this treatment is comparable to vancomycin and the combined treatments. Taken together, our data suggest that the phages significantly reduce C. difficile biofilms, and prevent colonization in the G. mellonella model when used alone or in combination with vancomycin. The phages appear to be highly promising therapeutics in the targeted eradication of CDI and the use of these models has revealed that prophylactic use could be a propitious therapeutic option.

  12. Transposon-mediated Generation of Cellular and Mouse Models of Splicing Mutations to Assess the Efficacy of snRNA-based Therapeutics

    Directory of Open Access Journals (Sweden)

    Elena Barbon

    2016-01-01

    Full Text Available Disease-causing splicing mutations can be rescued by variants of the U1 small nuclear RNA (U1snRNAs. However, the evaluation of the efficacy and safety of modified U1snRNAs as therapeutic tools is limited by the availability of cellular and animal models specific for a given mutation. Hence, we exploited the hyperactive Sleeping Beauty transposon system (SB100X to integrate human factor IX (hFIX minigenes into genomic DNA in vitro and in vivo. We generated stable HEK293 cell lines and C57BL/6 mice harboring splicing-competent hFIX minigenes either wild type (SChFIX-wt or mutated (SChFIXex5-2C. In both models the SChFIXex5-2C variant, found in patients affected by Hemophilia B, displayed an aberrant splicing pattern characterized by exon 5 skipping. This allowed us to test, for the first time in a genomic DNA context, the efficacy of the snRNA U1-fix9, delivered with an adeno-associated virus (AAV vector. With this approach, we showed rescue of the correct splicing pattern of hFIX mRNA, leading to hFIX protein expression. These data validate the SB100X as a versatile tool to quickly generate models of human genetic mutations, to study their effect in a stable DNA context and to assess mutation-targeted therapeutic strategies.

  13. [Therapeutic community model in short psychiatric hospitalization. Descriptive study on the dynamic psychiatric inpatient unit of the Italian hospital of Buenos Aires].

    Science.gov (United States)

    Matusevich, Daniel; Ruiz, Martín; Vairo, María; Girard, Paula; Rozadilla, Gustavo; Castagnola, Guido; Job, Alfredo; Pinto, Inés; Finkelsztein, Carlos

    2006-01-01

    the aim of this paper is to communicate a project of short term psychiatric hospitalization, based on a therapeutic community model, considering qualitative and quantitative aspects in the present socio - cultural context. this psychiatric hospitalization model that embraces psychodynamic and pharmacological interventions is focused in the intensity of interactions between members of the therapeutic community and integrated to the administrative structure of a general hospital; this will be the key to consider patient's return to the community and to move forward over the prejudices that inpatients suffer. quantitative, prospective, observational and transversal study on a Dynamic Psychiatric Inpatient Unit. 605 patients were included. mean length of stay was 16.34 days; principal causes of admission were depression (19.4%), suicide ideas (17.7%), suicide attempt (17.6%), substance abuse or dependence (14.3%), psychosis (13.8%), behavioral and psychological symptoms of dementia (6%). There were 75 readmissions. 14.88% patients were physically restrained. Principal Axis I diagnosis were depression (32.1%), substance dependence (13.2%), bipolar disorder (10.2%), dementia (7.6%), schizophrenia (7.5%), and psychotic disorder (5.8). Axis II diagnosis were borderline personality disorder (27.3%), narcissistic personality disorder (8.9%), histrionic personality disorder (5.3%). this kind of approach shows a structural model that allows possible and persistent favorable changes for psychiatric inpatients.

  14. 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.

  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 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.

  17. 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

  18. Reduced order models for thermal analysis : final report : LDRD Project No. 137807.

    Energy Technology Data Exchange (ETDEWEB)

    Hogan, Roy E., Jr.; Gartling, David K.

    2010-09-01

    This LDRD Senior's Council Project is focused on the development, implementation and evaluation of Reduced Order Models (ROM) for application in the thermal analysis of complex engineering problems. Two basic approaches to developing a ROM for combined thermal conduction and enclosure radiation problems are considered. As a prerequisite to a ROM a fully coupled solution method for conduction/radiation models is required; a parallel implementation is explored for this class of problems. High-fidelity models of large, complex systems are now used routinely to verify design and performance. However, there are applications where the high-fidelity model is too large to be used repetitively in a design mode. One such application is the design of a control system that oversees the functioning of the complex, high-fidelity model. Examples include control systems for manufacturing processes such as brazing and annealing furnaces as well as control systems for the thermal management of optical systems. A reduced order model (ROM) seeks to reduce the number of degrees of freedom needed to represent the overall behavior of the large system without a significant loss in accuracy. The reduction in the number of degrees of freedom of the ROM leads to immediate increases in computational efficiency and allows many design parameters and perturbations to be quickly and effectively evaluated. Reduced order models are routinely used in solid mechanics where techniques such as modal analysis have reached a high state of refinement. Similar techniques have recently been applied in standard thermal conduction problems e.g. though the general use of ROM for heat transfer is not yet widespread. One major difficulty with the development of ROM for general thermal analysis is the need to include the very nonlinear effects of enclosure radiation in many applications. Many ROM methods have considered only linear or mildly nonlinear problems. In the present study a reduced order model is

  19. 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...

  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. Final Report on Hierarchical Coupled Modeling and Prediction of Regional Climate Change in the Atlantic Sector

    Energy Technology Data Exchange (ETDEWEB)

    Saravanan, Ramalingam [Texas A& M University

    2011-10-30

    During the course of this project, we have accomplished the following: a) Carried out studies of climate changes in the past using a hierarchy of intermediate coupled models (Chang et al., 2008; Wan et al 2009; Wen et al., 2010a,b) b) Completed the development of a Coupled Regional Climate Model (CRCM; Patricola et al., 2011a,b) c) Carried out studies testing hypotheses testing the origin of systematic errors in the CRCM (Patricola et al., 2011a,b) d) Carried out studies of the impact of air-sea interaction on hurricanes, in the context of barrier layer interactions (Balaguru et al)

  4. A web-based portfolio model as the students' final assignment: Dealing with the development of higher education trend

    Science.gov (United States)

    Utanto, Yuli; Widhanarto, Ghanis Putra; Maretta, Yoris Adi

    2017-03-01

    This study aims to develop a web-based portfolio model. The model developed in this study could reveal the effectiveness of the new model in experiments conducted at research respondents in the department of curriculum and educational technology FIP Unnes. In particular, the further research objectives to be achieved through this development of research, namely: (1) Describing the process of implementing a portfolio in a web-based model; (2) Assessing the effectiveness of web-based portfolio model for the final task, especially in Web-Based Learning courses. This type of research is the development of research Borg and Gall (2008: 589) says "educational research and development (R & D) is a process used to develop and validate educational production". The series of research and development carried out starting with exploration and conceptual studies, followed by testing and evaluation, and also implementation. For the data analysis, the technique used is simple descriptive analysis, analysis of learning completeness, which then followed by prerequisite test for normality and homogeneity to do T - test. Based on the data analysis, it was concluded that: (1) a web-based portfolio model can be applied to learning process in higher education; (2) The effectiveness of web-based portfolio model with field data from the respondents of large group trial participants (field trial), the number of respondents who reached mastery learning (a score of 60 and above) were 24 people (92.3%) in which it indicates that the web-based portfolio model is effective. The conclusion of this study is that a web-based portfolio model is effective. The implications of the research development of this model, the next researcher is expected to be able to use the guideline of the development model based on the research that has already been conducted to be developed on other subjects.

  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. Design of Training Systems, Phase II-A Report. An Educational Technology Assessment Model. Final Report.

    Science.gov (United States)

    Miller, Robert B.; Duffy, Larry R.

    Study results and design for an Educational Technology Assessment Model (ETAM) are outlined, and conclusions and recommendations of the study are summarized. An eight-task procedure is provided to guide the assessor of a training innovation through the required data collection and analysis steps leading to a decision to accept, reject, or continue…

  7. Final Report for Enhancing the MPI Programming Model for PetaScale Systems

    Energy Technology Data Exchange (ETDEWEB)

    Gropp, William Douglas [University of Illinois at Urbana-Champaign

    2013-07-22

    This project performed research into enhancing the MPI programming model in two ways: developing improved algorithms and implementation strategies, tested and realized in the MPICH implementation, and exploring extensions to the MPI standard to better support PetaScale and ExaScale systems.

  8. Black liquor combustion validated recovery boiler modeling: Final year report. Volume 4 (Appendix IV)

    Energy Technology Data Exchange (ETDEWEB)

    Grace, T.M.; Frederick, W.J.; Salcudean, M.; Wessel, R.A.

    1998-08-01

    This project was initiated in October 1990, with the objective of developing and validating a new computer model of a recovery boiler furnace using a computational fluid dynamics (CFD) code specifically tailored to the requirements for solving recovery boiler flows, and using improved submodels for black liquor combustion based on continued laboratory fundamental studies. The key tasks to be accomplished were as follows: (1) Complete the development of enhanced furnace models that have the capability to accurately predict carryover, emissions behavior, dust concentrations, gas temperatures, and wall heat fluxes. (2) Validate the enhanced furnace models, so that users can have confidence in the predicted results. (3) Obtain fundamental information on aerosol formation, deposition, and hardening so as to develop the knowledge base needed to relate furnace model outputs to plugging and fouling in the convective sections of the boiler. (4) Facilitate the transfer of codes, black liquid submodels, and fundamental knowledge to the US kraft pulp industry. Volume 4 contains the following appendix sections: Radiative heat transfer properties for black liquor combustion -- Facilities and techniques and Spectral absorbance and emittance data; and Radiate heat transfer determination of the optical constants of ash samples from kraft recovery boilers -- Calculation procedure; Computation program; Density determination; Particle diameter determination; Optical constant data; and Uncertainty analysis.

  9. 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…

  10. Analysis of safety impacts of access management alternatives using the surrogate safety assessment model : final report.

    Science.gov (United States)

    2017-06-01

    The purpose of this study was to evaluate if the Surrogate Safety Assessment Model (SSAM) could be used to assess the safety of a highway segment or an intersection in terms of the number and type of conflicts and to compare the safety effects of mul...

  11. The Materosion project, a sediment cascade modeling for torrential sediment transfers: final results and perspectives

    Science.gov (United States)

    Rudaz, Benjamin; Loye, Alexandre; Mazotti, Benoit; Bardou, Eric; Jaboyedoff, Michel

    2013-04-01

    The Materosion project, conducted between the swiss canton of Valais (CREALP) and University of Lausanne (CRET) aims at forecasting sediment transfer in alpine torrents using the sediment cascade concept. The study site is the high Anniviers valley, around the village of Zinal (Valais). The torrents are divided in homogeneous reaches, to and from which sediments are transported by debris flows and bedload transport events. The model runs simulations of 100 years, with a 1-month time step, each with a given a random meteorological event ranging from no activity up to high magnitude debris flows. These events are calibrated using local rain data and observed corresponding debris flow frequencies. The model is applied to ten torrent systems with variable geological context, watershed geometries and sediment supplies. Given the high number of possible event scenarios, 10'000 simulations per torrent are performed, giving a statistical distribution of cumulated volumes and an event size distribution. A way to visualize the complex results data is proposed, and a back-analysis of the internal sediment cascade dynamic is performed. The back-analysis shows that the results' distribution stabilize after ~5'000 simulations. The model results, especially the range of debris flow volumes are crucial to maintain mitigation measures such as retention dams, and give clues for future sediment cascade modeling.

  12. 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.

  13. Financial constraints in capacity planning: a national utility regulatory model (NUREG). Volume I of III: methodology. Final report

    Energy Technology Data Exchange (ETDEWEB)

    1981-10-29

    This report develops and demonstrates the methodology for the National Utility Regulatory (NUREG) Model developed under contract number DEAC-01-79EI-10579. It is accompanied by two supporting volumes. Volume II is a user's guide for operation of the NUREG software. This includes description of the flow of software and data, as well as the formats of all user data files. Finally, Volume III is a software description guide. It briefly describes, and gives a listing of, each program used in NUREG.

  14. 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.

  15. Rare four-leptonic B-decays with light leptons in the final state in the Standard Model

    Science.gov (United States)

    Danilina, Anna; Nikitin, Nikolai

    2017-10-01

    We present predictions for the four-leptonic decays of B--mesons with three light charged leptons and one neutrino in the final states. We obtain the branching ratio for decay at the level 1.3 × 10-7 taking into account the photon emission from the u- and b- valence quarks of B- -meson and the Bremsstrahlung. The contribution of the virtual photon was calculated using the Vector Meson Dominance model (VMD). As a next step we present prediction for branching ratio of the decay and the estimation for .

  16. Final Progress Report: FRACTURE AND SUBCRITICAL DEBONDING IN THIN LAYERED STRUCTURES: EXPERIMENTS AND MULTI-SCALE MODELING

    Energy Technology Data Exchange (ETDEWEB)

    Reinhold H. Dauskardt

    2005-08-30

    Final technical report detailing unique experimental and multi-scale computational modeling capabilities developed to study fracture and subcritical cracking in thin-film structures. Our program to date at Stanford has studied the mechanisms of fracture and fatigue crack-growth in structural ceramics at high temperature, bulk and thin-film glasses in selected moist environments where we demonstrated the presence of a true mechanical fatigue effect in some glass compositions. We also reported on the effects of complex environments and fatigue loading on subcritical cracking that effects the reliability of MEMS and other micro-devices using novel micro-machined silicon specimens and nanomaterial layers.

  17. Human umbilical cord mesenchymal stem cells and derived hepatocyte-like cells exhibit similar therapeutic effects on an acute liver failure mouse model.

    Directory of Open Access Journals (Sweden)

    Ruiping Zhou

    Full Text Available Mesenchymal stem cells (MSCs have exhibited therapeutic effects in multiple animal models so that are promising liver substitute for transplantation treatment of end-stage liver diseases. However, it has been shown that over-manipulation of these cells increased their tumorigenic potential, and that reducing the in vitro culture time could minimize the risk. In this study, we used a D-galactosamine plus lipopolysaccharide (Gal/LPS-induced acute liver failure mouse model, which caused death of about 50% of the mice with necrosis of more than 50% hepatocytes, to compare the therapeutic effects of human umbilical cord MSCs (hUCMSCs before and after induction of differentiation into hepatocyte (i-Heps. Induction of hUCMSCs to become i-Heps was achieved by treatment of the cells with a group of growth factors within 4 weeks. The resulted i-Heps exhibited a panel of human hepatocyte biomarkers including cytokeratin (hCK-18, α-fetoprotein (hAFP, albumin (hALB, and hepatocyte-specific functions glycogen storage and urea metabolism. We demonstrated that transplantation of both cell types through tail vein injection rescued almost all of the Gal/LPS-intoxicated mice. Although both cell types exhibited similar ability in homing at the mouse livers, the populations of the hUCMSCs-derived cells, as judged by expressing hAFP, hCK-18 and human hepatocyte growth factor (hHGF, were small. These observations let us to conclude that the hUCMSCs was as effective as the i-Heps in treatment of the mouse acute liver failure, and that the therapeutic effects of hUCMSCs were mediated largely via stimulation of host hepatocyte regeneration, and that delivery of the cells through intravenous injection was effective.

  18. 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.

  19. Modeling a material from packing, through sintering and to the final microstructural properties

    DEFF Research Database (Denmark)

    Bjørk, Rasmus; Nielsen, Kaspar Kirstein

    and magnetism known as the magnetocaloric effect. We present a 3-dimensional time-dependent numerical model that spatially resolves samples down to the grain size, and includes the demagnetizing field, chemical inhomogeneity realized as a spatial variation of Curie temperature across the sample, local...... hysteresis and heat transfer. We can thus model how particle size, packing, sintering and chemical inhomogeneity affect the observed properties of magnetocaloric samples. For example, we show that even a modest distribution in Curie temperature (TC) across the sample results in a significant broadening...... and lowering of the total entropy change of the sample around TC. We discuss how clustering of grains with similar values of TC across the sample influences the results....

  20. Coupled models in low-frequency electromagnetic simulation LDRD Final Report 94-ERI-004

    Energy Technology Data Exchange (ETDEWEB)

    Hewett, D.W.; Bateson, D.; Gibbons, M.; Lambert, M.; Tung, L.; Rodrique, G.

    1997-02-03

    Responding to a need to include realistic chemistry and ionization in the driven plasmas in plasma-aided manufacture, we became convinced that existing computational tools were not able to fulfill our requirements. In response to this, we invented an entirely new approach to such problems. Our approach is to generalize the capabilities of existing methods: Particle-In-Cell (PIC) contains the required details of the distributions but becomes overwhelming expensive when applied to realistic, multidimensional problems. The common alternative, the hydrodynamic model, has simply lost the ability to model this science because of the simple fluid assumption. Our solution, GAPH (for Grid and Particle Hydrodynamics), retains the kinetic capabilities of PIC while using fluid concepts within each particle to control the incredible expense. The coupling of these two methods has resulted in a very powerful new algorithm that is now being applied to a range of programmatic problems throughout LLNL that now far outstrips the initial applications area.

  1. Modeling of Cation Binding in Hydrated 2:1 Clay Minerals - Final Report

    Energy Technology Data Exchange (ETDEWEB)

    Smith, David E.

    2000-09-14

    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.

  2. Scalable Entity-Based Modeling of Population-Based Systems, Final LDRD Report

    Energy Technology Data Exchange (ETDEWEB)

    Cleary, A J; Smith, S G; Vassilevska, T K; Jefferson, D R

    2005-01-27

    The goal of this project has been to develop tools, capabilities and expertise in the modeling of complex population-based systems via scalable entity-based modeling (EBM). Our initial focal application domain has been the dynamics of large populations exposed to disease-causing agents, a topic of interest to the Department of Homeland Security in the context of bioterrorism. In the academic community, discrete simulation technology based on individual entities has shown initial success, but the technology has not been scaled to the problem sizes or computational resources of LLNL. Our developmental emphasis has been on the extension of this technology to parallel computers and maturation of the technology from an academic to a lab setting.

  3. Thermal layer development modeling. Final report 1 December 1975--20 June 1977

    Energy Technology Data Exchange (ETDEWEB)

    Knasel, T.M.; Versteegen, P.L.; Powers, J.A.

    1977-06-01

    Thermal layers which may develop during the employment of nuclear weapons have been investigated theoretically. If such a layer forms, non-ideal shock wave propagation results. This in turn modifies the potential damage levels, adding risk and uncertainty to the sure-kill and sure-safe areas around the burst point. The study calculates the effective thermal layer temperature for a series of atmospheric nuclear explosions. By reinterpretation of previous evidence, good agreement between layer temperature and shock propagation behavior is evident. From additional data on soil response to strong thermal radiation, a semi-empirical model of thermal layer temperature distributions and dust generation was constructed based on first principles. This model agrees with the known values of thermal layer parameters including those of layer temperature.

  4. FINAL REPORT: Mechanistically-Base Field Scale Models of Uranium Biogeochemistry from Upscaling Pore-Scale Experiments and Models

    Energy Technology Data Exchange (ETDEWEB)

    Wood, Brian D. [Oregon State Univ., Corvallis, OR (United States)

    2013-11-04

    Biogeochemical reactive transport processes in the subsurface environment are important to many contemporary environmental issues of significance to DOE. Quantification of risks and impacts associated with environmental management options, and design of remediation systems where needed, require that we have at our disposal reliable predictive tools (usually in the form of numerical simulation models). However, it is well known that even the most sophisticated reactive transport models available today have poor predictive power, particularly when applied at the field scale. Although the lack of predictive ability is associated in part with our inability to characterize the subsurface and limitations in computational power, significant advances have been made in both of these areas in recent decades and can be expected to continue. In this research, we examined the upscaling (pore to Darcy and Darcy to field) the problem of bioremediation via biofilms in porous media. The principle idea was to start with a conceptual description of the bioremediation process at the pore scale, and apply upscaling methods to formally develop the appropriate upscaled model at the so-called Darcy scale. The purpose was to determine (1) what forms the upscaled models would take, and (2) how one might parameterize such upscaled models for applications to bioremediation in the field. We were able to effectively upscale the bioremediation process to explain how the pore-scale phenomena were linked to the field scale. The end product of this research was to produce a set of upscaled models that could be used to help predict field-scale bioremediation. These models were mechanistic, in the sense that they directly incorporated pore-scale information, but upscaled so that only the essential features of the process were needed to predict the effective parameters that appear in the model. In this way, a direct link between the microscale and the field scale was made, but the upscaling process

  5. 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.

  6. Lens modelling Abell 370: crowning the final frontier field with MUSE

    Science.gov (United States)

    Lagattuta, David J.; Richard, Johan; Clément, Benjamin; Mahler, Guillaume; Patrício, Vera; Pelló, Roser; Soucail, Geneviève; Schmidt, Kasper B.; Wisotzki, Lutz; Martinez, Johany; Bina, David

    2017-08-01

    We present a strong lensing analysis on the massive cluster Abell 370 (A370; z = 0.375), using a combination of deep multiband Hubble Space Telescope (HST) imaging and Multi-Unit Spectroscopic Explorer (MUSE) spectroscopy. From only 2 h of the MUSE data, we are able to measure 120 redshifts in the southern BCG area, including several multiply imaged lens systems. In total, we increase the number of multiply imaged systems with a secure redshift from 4 to 15, nine of which are newly discovered. Of these, eight are located at z > 3, greatly extending the redshift range of spectroscopically confirmed systems over previous work. Using these systems as constraints, we update a parametric lens model of A370, probing the mass distribution from cluster to galaxy scales. Overall, we find that a model with only two cluster-scale dark matter haloes (one for each BCG) does a poor job of fitting these new image constraints. Instead, two additional mass clumps - a central `bar' of mass located between the BCGs, and another clump located within a `crown' of galaxies in the northern part of the cluster field - provide significant improvements to the fit. Additional physical evidence suggests these clumps are indeed real features of the system, but with relatively few image constraints in the crown region, this claim is difficult to evaluate from a modelling perspective. Additional MUSE observations of A370 covering the entire strong-lensing region will greatly help these efforts, further improving our understanding of this intriguing cluster.

  7. Modeling of fluidized-bed combustion of coal: Phase II, final reports. Volume IV. FBC-Model-II manual

    Energy Technology Data Exchange (ETDEWEB)

    Louis, J.F.; Tung, S.E.

    1980-10-01

    This document is the fourth of the seven volume series of our Phase II Final Report. The purpose of this manual is to describe how to access and use M.I.T.'s Fluidized Bed Combustor (FBC) System Program. Presently, the FBC program is stored in a Honeywell Computer System and can be accessed using the Multics interactive system. The intention in writing this manual is to answer the questions that may arise regarding the mechanics of operating the system program, as well as warn the user of possible pitfalls and mistakes that could be made. No attempt is made here to describe the internals of the systems program. The manual describes the procedures an individual would follow to become an active user of the system program. It then explains the various options available for reaching the Multics interactive system on Honeywell 6180 computer on which the program runs. For users outside the Metropolitan Boston area, a public network for data communications is described which is relatively inexpensive. As the system program is approached through Multics using a special command facility TPSA, a separate introduction is provided for Multics TPSA. This facility allows commands appropriate for testing the program and carrying out parametric studies to be executed in a convenient way. Multics TPSA was formulated to meet the needs of the FBC project in particular. Finally, some sample sessions are presented which illustrate the login and logout procedures, the command language, and the data manipulation features of the FBC program. The use of commands helpful in debugging the program is also illustrated.

  8. Foundation Heat Exchanger Final Report: Demonstration, Measured Performance, and Validated Model and Design Tool

    Energy Technology Data Exchange (ETDEWEB)

    Hughes, Patrick [Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States); Im, Piljae [Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)

    2012-01-01

    (FHX) has been coined to refer exclusively to ground heat exchangers installed in the overcut around the basement walls. The primary technical challenge undertaken by this project was the development and validation of energy performance models and design tools for FHX. In terms of performance modeling and design, ground heat exchangers in other construction excavations (e.g., utility trenches) are no different from conventional HGHX, and models and design tools for HGHX already exist. This project successfully developed and validated energy performance models and design tools so that FHX or hybrid FHX/HGHX systems can be engineered with confidence, enabling this technology to be applied in residential and light commercial buildings. The validated energy performance model also addresses and solves another problem, the longstanding inadequacy in the way ground-building thermal interaction is represented in building energy models, whether or not there is a ground heat exchanger nearby. Two side-by-side, three-level, unoccupied research houses with walkout basements, identical 3,700 ft{sup 2} floor plans, and hybrid FHX/HGHX systems were constructed to provide validation data sets for the energy performance model and design tool. The envelopes of both houses are very energy efficient and airtight, and the HERS ratings of the homes are 44 and 45 respectively. Both houses are mechanically ventilated with energy recovery ventilators, with space conditioning provided by water-to-air heat pumps with 2 ton nominal capacities. Separate water-to-water heat pumps with 1.5 ton nominal capacities were used for water heating. In these unoccupied research houses, human impact on energy use (hot water draw, etc.) is simulated to match the national average. At House 1 the hybrid FHX/HGHX system was installed in 300 linear feet of excavation, and 60% of that was construction excavation (needed to construct the home). At House 2 the hybrid FHX/HGHX system was installed in 360 feet of

  9. Foundation Heat Exchanger Final Report: Demonstration, Measured Performance, and Validated Model and Design Tool

    Energy Technology Data Exchange (ETDEWEB)

    Hughes, Patrick [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Im, Piljae [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

    2012-04-01

    (FHX) has been coined to refer exclusively to ground heat exchangers installed in the overcut around the basement walls. The primary technical challenge undertaken by this project was the development and validation of energy performance models and design tools for FHX. In terms of performance modeling and design, ground heat exchangers in other construction excavations (e.g., utility trenches) are no different from conventional HGHX, and models and design tools for HGHX already exist. This project successfully developed and validated energy performance models and design tools so that FHX or hybrid FHX/HGHX systems can be engineered with confidence, enabling this technology to be applied in residential and light commercial buildings. The validated energy performance model also addresses and solves another problem, the longstanding inadequacy in the way ground-building thermal interaction is represented in building energy models, whether or not there is a ground heat exchanger nearby. Two side-by-side, three-level, unoccupied research houses with walkout basements, identical 3,700 ft{sup 2} floor plans, and hybrid FHX/HGHX systems were constructed to provide validation data sets for the energy performance model and design tool. The envelopes of both houses are very energy efficient and airtight, and the HERS ratings of the homes are 44 and 45 respectively. Both houses are mechanically ventilated with energy recovery ventilators, with space conditioning provided by water-to-air heat pumps with 2 ton nominal capacities. Separate water-to-water heat pumps with 1.5 ton nominal capacities were used for water heating. In these unoccupied research houses, human impact on energy use (hot water draw, etc.) is simulated to match the national average. At House 1 the hybrid FHX/HGHX system was installed in 300 linear feet of excavation, and 60% of that was construction excavation (needed to construct the home). At House 2 the hybrid FHX/HGHX system was installed in 360 feet of

  10. Evaluation of carbonic anhydrase IX as a therapeutic target for inhibition of breast cancer invasion and metastasis using a series of in vitro breast cancer models.

    Science.gov (United States)

    Ward, Carol; Meehan, James; Mullen, Peter; Supuran, Claudiu; Dixon, J Michael; Thomas, Jeremy S; Winum, Jean-Yves; Lambin, Philippe; Dubois, Ludwig; Pavathaneni, Nanda-Kumar; Jarman, Edward J; Renshaw, Lorna; Um, In Hwa; Kay, Charlene; Harrison, David J; Kunkler, Ian H; Langdon, Simon P

    2015-09-22

    Triple negative, resistant or metastatic disease are major factors in breast cancer mortality, warranting novel approaches. Carbonic anhydrase IX (CAIX) is implicated in survival, migration and invasion of breast cancer cells and inhibition provides an innovative therapeutic strategy. The efficacy of 5 novel ureido-substituted sulfamate CAIX inhibitors were assessed in increasingly complex breast cancer models, including cell lines in normoxia and hypoxia, 3D spheroids and an ex-vivo explant model utilizing fresh biopsy tissue from different breast cancer subtypes. CAIX expression was evaluated in a tissue microarray (TMA) of 92 paired lymph node and primary breast cancers and 2 inhibitors were appraised in vivo using MDA-MB-231 xenografts. FC11409B, FC9398A, FC9403, FC9396A and S4 decreased cell proliferation and migration and inhibited 3D spheroid invasion. S4, FC9398A and FC9403A inhibited or prevented invasion into collagen. FC9403A significantly reversed established invasion whilst FC9398A and DTP348 reduced xenograft growth. TMA analysis showed increased CAIX expression in triple negative cancers. These data establish CAIX inhibition as a relevant therapeutic goal in breast cancer, targeting the migratory, invasive, and metastatic potential of this disease. The use of biopsy tissue suggests efficacy against breast cancer subtypes, and should provide a useful tool in drug testing against invasive cancers.

  11. Therapeutic effect of BDNF-overexpressing human neural stem cells (HB1.F3.BDNF) in a rodent model of middle cerebral artery occlusion.

    Science.gov (United States)

    Chang, Da-Jeong; Lee, Nayeon; Choi, Chunggab; Jeon, Iksoo; Oh, Seung-Hun; Shin, Dong Ah; Hwang, Tae-Sun; Lee, Hong J; Kim, Seung U; Moon, Hyeyoung; Hong, Kwan Soo; Kang, Kyung-Sun; Song, Jihwan

    2013-01-01

    Ischemic stroke mainly caused by middle cerebral artery occlusion (MCAo) represents the major type of stroke; however, there are still very limited therapeutic options for the stroke-damaged patients. In this study, we evaluated the neurogenic and therapeutic potentials of human neural stem cells (NSCs) overexpressing brain-derived neurotrophic factor (HB1.F3.BDNF) following transplantation into a rodent model of MCAo. F3.BDNF human NSCs (F3.BDNF) were transplanted into the contralateral side of striatum at 7 days after MCAo, and the transplanted animals were monitored up to 8 weeks using animal MRI and various behavioral tests before they were sacrificed for immunohistochemical analysis. Interestingly, animal MRI results indicate that the majority of contralaterally transplanted neural stem cells were migrated to the peri-infarct area, showing a pathotropism. Transplanted animals exhibited significant behavioral improvements in stepping, rotarod, and modified neurological severity score (mNSS) tests. We also found that the transplanted human cells were colocalized with nestin, DCX, MAP2, DARPP-32, TH, GAD65/67-positive cells, of which results can be correlated with neural regeneration and behavioral recovery in the transplanted animals. More importantly, we were able to detect high levels of human BDNF protein expression, presumably derived from the transplanted F3.BDNF. Taken together, these results provide strong evidence that human neural stem cells (F3.BDNF) are effective in treating stroke animal models.

  12. Therapeutic Effects of Korean Red Ginseng Extract in a Murine Model of Atopic Dermatitis: Anti-pruritic and Anti-inflammatory Mechanism.

    Science.gov (United States)

    Lee, Hyun Joo; Cho, Sang Hyun

    2017-04-01

    Korean red ginseng (KRG) and ginsenosides exhibit diverse biological effects, including anti-inflammatory and anti-allergic. We aimed to investigate the therapeutic effect of KRG in a murine model of atopic dermatitis (AD) is mediated whether by diminishing the pruritus or by suppressing the inflammation. Thirty NC/Nga mice were randomly divided to 5 groups. AD-like skin lesions were induced by percutaneous challenge with 2,4,6-trinitro-1-chrolobenzene (TNCB) on the ears and backs of NC/Nga mice. KRG extract, evening primrose oil, cyclosporine, and phosphate-buffered saline were administered orally by a gastric tube. Each study group was also divided into scratching-permitted and scratching-restricted subgroups to evaluate the impact of scratching behavior on AD. The effects of KRG and the other agents were assessed by measuring the clinical severity score, ear thickness, extent of transepidermal water loss (TEWL), number of scratching movements, total systemic immunoglobulin E (IgE) and interleukin (IL)-31 levels, histologic changes of cutaneous lesions, and mRNA expression levels of tumor necrosis factor (TNF)-α, interferon (IFN)-γ, thymic stromal lymphopoietin (TSLP), and IL-31. KRG exerts therapeutic effects against AD by inhibiting the T helper 2 (Th2) mediated inflammation as well as by diminishing the itching sensation. Moreover, restricting scratching behavior suppresses the vicious cycle of itching and scratching, thus reducing clinical and systemic inflammation in our murine model of AD. © 2017 The Korean Academy of Medical Sciences.

  13. 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.

  14. Evaluation of follistatin as a therapeutic in models of skeletal muscle atrophy associated with denervation and tenotomy.

    Science.gov (United States)

    Sepulveda, Patricio V; Lamon, Séverine; Hagg, Adam; Thomson, Rachel E; Winbanks, Catherine E; Qian, Hongwei; Bruce, Clinton R; Russell, Aaron P; Gregorevic, Paul

    2015-12-11

    Follistatin is an inhibitor of TGF-β superfamily ligands that repress skeletal muscle growth and promote muscle wasting. Accordingly, follistatin has emerged as a potential therapeutic to ameliorate the deleterious effects of muscle atrophy. However, it remains unclear whether the anabolic effects of follistatin are conserved across different modes of non-degenerative muscle wasting. In this study, the delivery of a recombinant adeno-associated viral vector expressing follistatin (rAAV:Fst) to the hind-limb musculature of mice two weeks prior to denervation or tenotomy promoted muscle hypertrophy that was sufficient to preserve muscle mass comparable to that of untreated sham-operated muscles. However, administration of rAAV:Fst to muscles at the time of denervation or tenotomy did not prevent subsequent muscle wasting. Administration of rAAV:Fst to innervated or denervated muscles increased protein synthesis, but markedly reduced protein degradation only in innervated muscles. Phosphorylation of the signalling proteins mTOR and S6RP, which are associated with protein synthesis, was increased in innervated muscles administered rAAV:Fst, but not in treated denervated muscles. These results demonstrate that the anabolic effects of follistatin are influenced by the interaction between muscle fibres and motor nerves. These findings have important implications for understanding the potential efficacy of follistatin-based therapies for non-degenerative muscle wasting.

  15. Therapeutic attenuation of neuroinflammation and apoptosis by black tea theaflavin in chronic MPTP/probenecid model of Parkinson's disease.

    Science.gov (United States)

    Anandhan, Annadurai; Essa, Musthafa Mohamed; Manivasagam, Thamilarasan

    2013-02-01

    Neuroinflammation and apoptosis in the dopaminergic neurons of substantia nigra play an important role in the pathogenesis of experimental and clinical Parkinson's disease (PD). This study focused on the possible anti-inflammatory and anti-apoptotic effects of theaflavin (TF), a black tea polyphenol against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in mice. C57BL/6 male mice were treated with 10 doses of MPTP (25 mg/kg, s.c.) and probenecid (250 mg/kg, i.p.) for 3.5 days interval. TF (10 mg/kg) was administered 1 h prior to the administration of MPTP for 35 days of experimental period. MPTP/p treatment upregulates the release of interleukin-1beta, IL-6, tumor necrosis factor-alpha, IL-10, glial fibrillary acidic protein and Bax, and downregulates anti-apoptotic marker Bcl-2. Oral treatment of black tea polyphenol TF significantly attenuates MPTP-induced neuroinflammation as well as apoptosis. Behavioral studies (catalepsy and akinesia) were carried out to confirm these molecular studies. The results demonstrate that TF mediated its neuroprotection against chronic MPTP-induced toxicity through the involvement of multiple molecular events. It was concluded that TF may provide a precious therapeutic strategy for the treatment of progressive neurodegenerative disease such as PD in future.

  16. Timing of therapeutic intervention determines functional and survival outcomes in a mouse model of late infantile batten disease.

    Science.gov (United States)

    Cabrera-Salazar, Mario A; Roskelley, Eric M; Bu, Jie; Hodges, Bradley L; Yew, Nelson; Dodge, James C; Shihabuddin, Lamya S; Sohar, Istvan; Sleat, David E; Scheule, Ronald K; Davidson, Beverly L; Cheng, Seng H; Lobel, Peter; Passini, Marco A

    2007-10-01

    Classical late infantile neuronal ceroid lipofuscinosis (cLINCL) is a monogenic disorder caused by the loss of tripeptidyl peptidase 1 (TPP1) activity as a result of mutations in CLN2. Absence of TPP1 results in lysosomal storage with an accompanying axonal degeneration throughout the central nervous system (CNS), which leads to progressive neurodegeneration and early death. In this study, we compared the efficacies of pre- and post-symptomatic injections of recombinant adeno-associated virus (AAV) for treating the cellular and functional abnormalities of CLN2 mutant mice. Intracranial injection of AAV1-hCLN2 resulted in widespread human TPP1 (hTPP1) activity in the brain that was 10-100-fold above wild-type levels. Injections before disease onset prevented storage and spared neurons from axonal degeneration, reflected by the preservation of motor function. Furthermore, the majority of CLN2 mutant mice treated pre-symptomatically lived for at least 330 days, compared with a median survival of 151 days in untreated CLN2 mutant controls. In contrast, although injection after disease onset ameliorated lysosomal storage, there was evidence of axonal degeneration, motor function showed limited recovery, and the animals had a median lifespan of 216 days. These data illustrate the importance of early intervention for enhanced therapeutic benefit, which may provide guidance in designing novel treatment strategies for cLINCL patients.

  17. 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.

  18. 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.

  19. Kinetic modeling of petroleum formation in the Maracaibo Basin: Final report, Annex 12

    Energy Technology Data Exchange (ETDEWEB)

    Burnham, A.K.; Braun, R.L.; Sweeney, J.J.; Reynolds, J.G. [Lawrence Livermore National Lab., CA (United States); Vallejos, C.; Talukdar, S. [INTEVEP, Filial de Petroleos de Venezuela, SA, Caracas (Venezuela)

    1992-07-01

    The purpose of this project is to develop and test improved kinetic models of petroleum generation and cracking, pore pressure buildup, and fluid expulsion. The work was performed jointly between Lawrence Livermore National Laboratory and Research Organization of the Venezuelan National Petroleum Company under Annex 12 of an agreement between DOE and the Venezuelan Ministry of Energy and Mines. Laboratory experiments were conducted at both LLNL and INTEVEP to obtain the reaction rate and product composition information needed to develop chemical kinetic models. Experiments at INTEVEP included hydrous pyrolysis and characterization of oils by gas and liquid chromatography. Experiments at LLNL included programmed pyrolysis in open and self-purging reactors, sometimes including on-line gas analysis by tandem mass spectrometry, and characterization of oils by gas chromatography and nuclear magnetic resonance. The PMOD code was used to develop a detailed pyrolysis mechanism from the extensive laboratory data. This mechanism is able to predict yield of bitumen, oil, and gas as a function of time and temperature for such diverse laboratory conditions as hydrous pyrolysis and rapid, programmed, open pyrolysis. PMOD calculations were compared to geologic observations for 22 wells in the Maracaibo basin. When permeability parameters are chosen to match calculated pore pressures with measured present day values, the PMOD calculations indicate that organic maturation reactions contribute a significant fraction of the overpressure during oil generation and early oil cracking. Calculations agreed with observed geochemical maturity parameters of the source rock. 37 refs., 64 figs., 20 tabs.

  20. 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.

  1. Final report on "Modeling Diurnal Variations of California Land Biosphere CO2 Fluxes"

    Energy Technology Data Exchange (ETDEWEB)

    Fung, Inez

    2014-07-28

    In Mediterranean climates, the season of water availability (winter) is out of phase with the season of light availability and atmospheric demand for moisture (summer). Multi-year half-hourly observations of sap flow velocities in 26 evergreen trees in a small watershed in Northern California show that different species of evergreen trees have different seasonalities of transpiration: Douglas-firs respond immediately to the first winter rain, while Pacific madrones have peak transpiration in the dry summer. Using these observations, we have derived species-specific parameterization of normalized sap flow velocities in terms of insolation, vapor pressure deficit and near-surface soil moisture. A simple 1-D boundary layer model showed that afternoon temperatures may be higher by 1 degree Celsius in an area with Douglas-firs than with Pacific madrones. The results point to the need to develop a new representation of subsurface moisture, in particular pools beneath the organic soil mantle and the vadose zone. Our ongoing and future work includes coupling our new parameterization of transpiration with new representation of sub-surface moisture in saprolite and weathered bedrock. The results will be implemented in a regional climate model to explore vegetation-climate feedbacks, especially in the dry season.

  2. Engineering model of future motor vehicles. Final report Jul 75-Jun 76

    Energy Technology Data Exchange (ETDEWEB)

    Danckert, H.; Grove, H.W.; Schmidt, R.

    1977-02-01

    The objective of the work performed was to develop a comprehensive engineering model of future motor vehicles which will provide a realistic and uniform basis for developing safety requirements and assessing their future effects. To achieve the objectives a data base handled by a computer program was developed which consists of identified and projected design and performance data related to safety and other areas affecting safety (such as fuel economy requirements). This data base contains pertinent information on current and previous makes and models of the U.S. passenger car population back to 1965. A comprehensive statistical program package such as multiple regression, frequency and distribution functions, etc. was incorporated into the computer program for data evaluation and can be used to determine interdependencies between the variables contained in the data base. A weight-weight interdependency program makes it possible to project vehicle weight caused by planned alterations of certain substructures in order to increase vehicle safety. Using a set of assumptions the data base permits the projection of possible tendencies of future motor vehicles development.

  3. 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.

  4. 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.

  5. 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

  6. 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.

  7. The network model of depression as a basis for new therapeutic strategies for treating major depressive disorder in Parkinson’s disease

    Directory of Open Access Journals (Sweden)

    Kevin eD'Ostilio

    2016-04-01

    Full Text Available The high prevalence of major depressive disorder in people with Parkinson's disease, 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 Parkinson's disease within the framework of the network model of depression. According to this model, major depressive disorder reflects maladaptive neuronal plasticity. Non-invasive brain stimulation using high frequency repetitive transcranial magnetic stimulation 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 non-invasive brain stimulation together with cognitive and behavioral interventions.

  8. 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

  9. 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

  10. 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.

  11. 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.

  12. Toluene model for hydrocarbon risk assessment. Final report, 1 January-31 December 1989

    Energy Technology Data Exchange (ETDEWEB)

    Morre, J.

    1990-05-29

    This project was for continuation of research to investigate the molecular mode of action of a membrane-active hydrocarbon, toluene, potentially present in the Air Force environment as a flight fuel component or from other sources and to serve as a model for other membrane-active molecules in the environment. Two important target sites were identified where rapid dose-dependent but reversible changes in the membrane organization occurred at low dose levels. One of these was at the plasma membrane where the ability of the membrane to form protuberances was severely compromised. The other concerned a failure to form protuberances by membranes involved in internal trafficking between the endoplasmic reticulum and the Golgi apparatus. This step was reproduced in a cell-free system making detailed studies possible. The toluene inhibited step was identified as dependent on ATP hydrolysis. The involved ATPase activity was characterized, solubilized and partially purified.

  13. 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.

  14. Demonstration of an advanced circulation fludized bed coal combustor phase 1: Cold model study. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Govind, R. [Cincinnati Univ., OH (United States). Dept. of Chemical Engineering

    1993-03-20

    It was found that there was a strong dependence of the density profile on the secondary air injection location and that there was a pronounced solid separation from the conveying gas, due to the swirl motion. Furthermore, the swirl motion generated strong internal circulation patterns and higher slip velocities than in the case of nonswirl motion as in an ordinary circulating fluidized bed. Radial solids flux profiles were measured at different axial locations. The general radial profile in a swirling circulating fluidized bed indicated an increased downward flow of solids near the bed walls, and strong variations in radial profiles along the axial height. For swirl numbers less than 0.9, which is typical for swirling circulating fluidized beds, there is no significant increase in erosion due to swirl motion inside the bed. Pending further investigation of swirl motion with combustion, at least from our cold model studies, no disadvantages due to the introduction of swirl motion were discovered.

  15. 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.

  16. MULTIRESOLUTION FEATURE ANALYSIS AND OTHER TECHNIQUES FOR UNDERSTANDING AND MODELING TURBULENCE IN STABLE ATMOSPHERES Final Report

    Energy Technology Data Exchange (ETDEWEB)

    R. L. Street; F. L. Ludwig; Y. Chen

    2005-04-11

    Our DOE project is one of the efforts comprising the Vertical Transport and Mixing Program of the Environmental Sciences Division of the Office of Biological and Environmental Research in Department of Energy. We used ARPS to simulate flow in the Salt Lake Valley. We simulated the physical processes more accurately so that we can better understand the physics of flow in complex terrain and its effects at larger scales. The simulations provided evidence that atmospheric forcing interacts with the Jordan Narrows, the Traverse Range and other complex mountain terrain at the south end of the Salt Lake Valley to produce lee rotors, hydraulic jumps and other effects. While we have successfully used ARPS to simulate VTMX 2000 flows, we have also used observed data to test the model and identify some of its weaknesses. Those are being addressed in a continuation project supported by DOE.

  17. 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)

  18. 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)

  19. Processes and parameters involved in modeling radionuclide transport from bedded salt repositories. Final report. Technical memorandum

    Energy Technology Data Exchange (ETDEWEB)

    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.

  20. Development of a model and computer code to describe solar grade silicon production processes. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Gould, R K; Srivastava, R

    1979-12-01

    Models and computer codes which may be used to describe flow reactors in which high purity, solar grade silicon is produced via reduction of gaseous silicon halides are described. A prominent example of the type of process which may be studied using the codes developed in this program is the SiCl/sub 4//Na reactor currently being developed by the Westinghouse Electric Corp. During this program two large computer codes were developed. The first is the CHEMPART code, an axisymmetric, marching code which treats two-phase flows with models describing detailed gas-phase chemical kinetics, particle formation, and particle growth. This code, based on the AeroChem LAPP (Low Altitude Plume Program) code can be used to describe flow reactors in which reactants mix, react, and form a particulate phase. Detailed radial gas-phase composition, temperature, velocity, and particle size distribution profiles are computed. Also, depositon of heat, momentum, and mass (either particulate or vapor) on reactor walls is described. The second code is a modified version of the GENMIX boundary layer code which is used to compute rates of heat, momentum, and mass transfer to the reactor walls. This code lacks the detailed chemical kinetics and particle handling features of the CHEMPART code but has the virtue of running much more rapidly than CHEMPART, while treating the phenomena occurring in the boundary layer in more detail than can be afforded using CHEMPART. These two codes have been used in this program to predict particle formation characteristics and wall collection efficiencies for SiCl/sub 4//Na flow reactors. Results are described.

  1. 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

  2. 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.

  3. [Therapeutic effects of histone deacetylase inhibitor givinostat on air inflammation and high airway resistance in a murine asthma model].

    Science.gov (United States)

    Su, X M; Ren, Y; Kong, L F; Kang, J

    2017-02-01

    Objective: To investigate the therapeutic effects of givinostat, a histone deacetylase inhibitor (HDACI), on the development of chronic asthma with airway inflammation, airway remodeling and airway hyperresponsiveness (AHR). Methods: BALB/C mice were randomly divided into control group, asthma group, dexamethasone group and givinostat group (n=12 per group). AHR was assessed. Total cell numbers and differential counts, interleukin-4(IL-4), interleukin-5(IL-5) and interferon-γ (IFNγ) levels in the bronchoalveolar lavage fluid (BALF) were measured in the above 4 groups. The pathology of lung tissue was evaluated. Immunohistochemical (IHC) staining and Western blot were used to detect α smooth muscle actin(α-SMA) and transforming growth factor-β1(TGFβ1). Results: Compared with the asthma only group, givinostat treatment relieved airway resistance (2.96±1.01 vs 6.50±0.79, P0.05] was enhanced in BALF. Inflammatory cell infiltration around the airway was reduced, with decreased inflammatory cell score[(1.60±0.69)points vs (3.40±0.68) points, P<0.01] and inflammatory cell number (111.65±31.41 vs 601.25±186.85, P<0.01). The goblet cell metaplasia [(26.36±2.33)% vs (57.21±11.56)%] and collagen deposition area [(52.77±7.58)μm(2)/μm vs (111.81±12.40)μm(2)/μm] were obviously reduced (P<0.01). The expressions of α-SMA and TGFβ1 in the lung tissue were both significantly decreased (P<0.01). Conclusion: Givinostat treatment can reduce airway inflammation, airway remodeling and airway hyperresponsiveness in chronic asthma. Its effect is comparable to that of glucocorticoid hormone treatment.

  4. Therapeutic Antibodies Targeting CSF1 Impede Macrophage Recruitment in a Xenograft Model of Tenosynovial Giant Cell Tumor

    Directory of Open Access Journals (Sweden)

    Hongwei Cheng

    2010-01-01

    Full Text Available Tenosynovial giant cell tumor is a neoplastic disease of joints that can cause severe morbidity. Recurrences are common following local therapy, and no effective medical therapy currently exists. Recent work has demonstrated that all cases overexpress macrophage colony-stimulating factor (CSF1, usually as a consequence of an activating gene translocation, resulting in an influx of macrophages that form the bulk of the tumor. New anti-CSF1 drugs have been developed; however there are no preclinical models suitable for evaluation of drug benefits in this disease. In this paper, we describe a novel renal subcapsular xenograft model of tenosynovial giant cell tumor. Using this model, we demonstrate that an anti-CSF1 monoclonal antibody significantly inhibits host macrophage infiltration into this tumor. The results from this model support clinical trials of equivalent humanized agents and anti-CSF1R small molecule drugs in cases of tenosynovial giant cell tumor refractory to conventional local therapy.

  5. A model of fracture risk used to examine the link between bone mineral density and the impact of different therapeutic mechanisms on fracture outcomes in patients with osteoporosis.

    Science.gov (United States)

    Eudy-Byrne, Rena J; Gillespie, William; Riggs, Matthew M; Gastonguay, Marc R

    2017-12-01

    A hazard model of fracture was developed using individual patient data (IPD) from the NHANES (2005-2008) database and summary-level data from an aggregate dataset (AD). The AD was built by performing a comprehensive and systematic literature search of clinical studies published from 1995 to 2015, recording fracture rate and bone mineral density (BMD) for both treatment and placebo arms. The search resulted in a metadata set comprised of 21 studies investigating the effects of various bisphosphonates, teriparatide, denosumab, and raloxifene in 65,254 patients over a cumulative 56.75 years of study. The IPD was used to augment an AD in a model-based meta-analysis (MBMA) hierarchical modeling approach. The resulting model predicts the probability of fracture events in patients with osteoporosis. The object of model building using this approach was to promote understanding of the impact of therapeutic drug effects on the probability of fracture together with, or independent of their effects on BMD. Candidate models were evaluated by deviance information criteria and posterior predictive check. The model with covariates for lumbar spine BMD with interaction with a drug effect on BMD, and patient body mass index, years post-menopause, fracture measure method (clinical or radiological) and an additional drug effect outperformed those models without interaction and without additional drug effects. The model quantitatively supports the widely held notion that changes in bone microarchitecture, which cannot be measured by areal BMD elicited by therapy contribute in a significant way to a reduction in fracture. Furthermore, this model can be used to simulate fracture risk in a clinical cohort similar to those contained in the MBMA.

  6. 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.

  7. 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

  8. Therapeutic hypothermia can be induced and maintained using either commercial water bottles or a "phase changing material" mattress in a newborn piglet model.

    Science.gov (United States)

    Iwata, S; Iwata, O; Olson, L; Kapetanakis, A; Kato, T; Evans, S; Araki, Y; Kakuma, T; Matsuishi, T; Setterwall, F; Lagercrantz, H; Robertson, N J

    2009-05-01

    Therapeutic hypothermia, a safe and effective treatment for neonatal encephalopathy in an intensive care setting, is not available in low-resource settings. Aims/ To assess two low-tech, low-cost cooling devices for use in low-resource settings: (i) commercially available water bottles filled with tepid water (25 degrees C); (ii) a mattress made of phase changing material (PCM) with a melting point of 32 degrees C (PCM works as a heat buffer at this temperature). Eleven anaesthetised newborn piglets were studied following transient hypoxia-ischaemia. The cooling device was applied 2-26 h after hypoxia-ischaemia with a target rectal temperature (T(rectal)) of 33-34 degrees C. T(rectal) undershoot was adjusted using cotton blankets; the cooling device was renewed when T(rectal) rose above 35 degrees C. T(rectal) data during cooling were dichotomised (within or without target) to assess: (a) the total period within the target T(rectal) range; (b) the stability and fluctuation of T(rectal) during cooling. Therapeutic hypothermia was achieved with both water bottles (n = 5) and the PCM mattress (n = 6). The mean (SD) time to reach target T(rectal) was 1.8 (0.5) h with water bottles and 1.9 (0.3) h with PCM. PCM cooling led to a longer period within the target T(rectal) range (pWater bottle cooling required device renewal (in four out of five piglets). Simple, low-tech cooling devices can induce and maintain therapeutic hypothermia effectively in a porcine model of neonatal encephalopathy, although frequent fine tuning by adjusting the number of blankets insulating the piglet was required to maintain a stable temperature. PCM may induce more stable cooling compared with water bottles.

  9. 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).

  10. Search for the Standard Model Higgs boson in final states with $b$ quarks at the Tevatron

    Energy Technology Data Exchange (ETDEWEB)

    Potamianos, Karolos

    2011-11-01

    We present the result of searches for a low mass Standard Model Higgs boson produced in association with a W or a Z boson at a center-of-mass energy of {radical}s = 1.96 TeV with the CDF and D0 detectors at the Fermilab Tevatron collider. The search is performed in events containing one or two b tagged jets in association with either two leptons, or one lepton and an imbalance in transverse energy, or simply a large imbalance in transverse energy. Datasets corresponding to up to 8.5 fb{sup -1} of integrated luminosity are considered in the analyses. These are the most powerful channels in the search for a low mass Higgs boson at the Tevatron. Recent sensitivity improvements are discussed. For a Higgs mass of 115 GeV/c{sup 2}, the expected sensitivity for the most sensitive individual analyses reaches 2.3 times the SM prediction at 95% confidence level (C.L.), with all limits below 5 times the SM. Additionally, a WZ/ZZ cross-section measurement is performed to validate the analysis techniques deployed for searching for the Higgs.

  11. Technology and Cost of the Model Year (MY) 2007 Toyota Camry HEV Final Report

    Energy Technology Data Exchange (ETDEWEB)

    None

    2007-09-30

    The Oak Ridge National Laboratory (ORNL) provides research and development (R&D) support to the Department of Energy on issues related to the cost and performance of hybrid vehicles. ORNL frequently benchmarks its own research against commercially available hybrid components currently used in the market. In 2005 we completed a detailed review of the cost of the second generation Prius hybrid. This study examines the new 2007 Camry hybrid model for changes in technology and cost relative to the Prius. The work effort involved a detailed review of the Camry hybrid and the system control strategy to identify the hybrid components used in the drive train. Section 2 provides this review while Section 3 presents our detailed evaluation of the specific drive train components and their cost estimates. Section 3 also provides a summary of the total electrical drive train cost for the Camry hybrid vehicle and contrasts these estimates to the costs for the second generation Prius that we estimated in 2005. Most of the information on cost and performance were derived from meetings with the technical staff of Toyota, Nissan, and some key Tier I suppliers like Hitachi and Panasonic Electric Vehicle Energy (PEVE) and we thank these companies for their kind cooperation.

  12. 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.

  13. 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.

  14. 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.

  15. The New Global Digital Elevation Model : TanDEM-X DEM and its Final Performance

    Science.gov (United States)

    Gonzalez, Carolina; Rizzoli, Paola; Martone, Michele; Wecklich, Christopher; Borla Tridon, Daniela; Bachmann, Markus; Fritz, Thomas; Wessel, Birgit; Krieger, Gerhard; Zink, Manfred

    2017-04-01

    Digital elevation models (DEMs) have become widely used in many scientific and commercial applications and there are several local products have been developed in the last years. They provide a representation of the topographic features of the landscape. The importance of them is known and valued in every geoscience field, but they have also vast use in navigation and in other commercial areas. The main goal of the TanDEM-X (TerraSARX add-on for Digital Elevation Measurements) mission is the generation of a global DEM, homogeneous in quality with unprecedented global accuracy and resolution, which has been completed in mid-2016. For over four years, the almost identical satellites TerraSAR-X and TanDEM-X acquired single-pass interferometric SAR image pairs, from which is it possible to derive the topographic height by unwrapping the interferometric phase, unaffected by temporal decorrelation. Both satellites have been flying in close formation with a flexible geometric configuration. An optimized acquisition strategy aimed at achieving an absolute vertical accuracy much better than 10 meters and a relative vertical accuracy of 2 m and 4 m for flat and steep terrain, respectively, within a horizontal raster of 12 m x 12 m, which slightly varies depending on the geographic latitude. In this paper, we assess the performance of the global Tandem-X DEM, characterized in terms of relative and absolute vertical accuracy. The coverage statistics are also discussed in comparison to the previous almost global but with lower resolution DEM provided by the Shuttle Radar Topography Mission (SRTM). The exceptional quality of the global DEM is confirmed by the obtained results and the global TanDEM-X DEM is now ready to be distributed to the scientific and commercial community.

  16. 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.

  17. 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

  18. 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.

  19. Pathogenetic and therapeutic perspectives on neurocognitive models in psychiatry: A synthesis of behavioral, brain imaging, and biological studies.

    Science.gov (United States)

    Rao, Naren P

    2012-07-01

    Neurocognitive assessments are useful to determine the locus of insult as well as functional capacities of patients on treatment. In psychiatry, neurocognitive assessment is useful in the identification of brain lesions, evaluation of cognitive deterioration over time, and advancement of theories regarding the neuroanatomical localization of symptoms. Neurocognitive models provide a bridging link between brain pathology and phenomenology. They provide a useful framework to understand the pathogenesis of psychiatric disorders, bringing together isolated findings in behavioral, neuroimaging, and other neurobiological studies. This review will discuss neurocognitive model of three disorders - schizophrenia, bipolar disorder, and obsessive compulsive disorder - by incorporating findings from neurocognitive, neuroimaging, and other biological studies.

  20. Co-culturing of Fungal Strains Against Botrytis cinerea as a Model for the Induction of Chemical Diversity and Therapeutic Agents

    Science.gov (United States)

    Serrano, Rachel; González-Menéndez, Víctor; Rodríguez, Lorena; Martín, Jesús; Tormo, José R.; Genilloud, Olga

    2017-01-01

    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. PMID:28469610

  1. Prophylactic and therapeutic intranasal administration with an immunomodulator, Hiltonol® (Poly IC:LC), in a lethal SARS-CoV-infected BALB/c mouse model.

    Science.gov (United States)

    Kumaki, Yohichi; Salazar, Andres M; Wandersee, Miles K; Barnard, Dale L

    2017-03-01

    Hiltonol®, (Poly IC:LC), a potent immunomodulator, is a synthetic, double-stranded polyriboinosinic-polyribocytidylic acid (poly IC) stabilized with Poly-L-lysine and carboxymethyl cellulose (LC). Hiltonol® was tested for efficacy in a lethal SARS-CoV-infected BALB/c mouse model. Hiltonol® at 5, 1, 0.5 or 0.25 mg/kg/day by intranasal (i.n.) route resulted in significant survival benefit when administered at selected times 24 h prior to challenge with a lethal dose of mouse-adapted severe acute respiratory syndrome coronavirus (SARS-CoV). The infected BALB/c mice receiving the Hiltonol® treatments were also significantly effective in protecting mice against weight loss due to infection (p SARS-CoV infection in mice leads to substantial prophylactic and therapeutic effects and could be used for treatment of other virus disease such as those caused by MERS-CoV a related coronavirus. These properties might be therapeutically advantageous if Hiltonol® is considered for possible clinical use. Published by Elsevier B.V.

  2. Prophylactic and therapeutic effect of ginko biloba extract (Egb761 on mortality of intestinal deep ischemia-reperfusion model in rats

    Directory of Open Access Journals (Sweden)

    Mustafa Ateş

    2010-09-01

    Full Text Available Objectives: Ginkgo biloba extract (EGb761 is a standardized form of Ginkgo Biloba plant leaves which have been used by Chines nearly 5000 years and Its’ antioxidant activity is known. In this study we aimed to investigate effect use of EGb761 on mortality in Megison'un deep ischemia reperfusion model of rats.Materials and Methods: 138 male Spraque-Dawley rats were used in this study. The rats were divided into 4 groups: Group I (control group, Group II (deep ischemia-reperfusion group, Group III (Group of prophylaxis and treatment of deep ischemia-reperfusion with EGb 761, Group IV (group of treatment with EGb 761 during deep ischemia. Deep ischemia was applied 30 minutes. Rats were followed-up one week after laparotomy. Differences between numbers of mortality in groups during one week follow-up were compared.Results: Number of died rats in Group I, II, III, and IV during one week follow-up were 2 (7.7%, 22 (61.1%, 6 (13.6%, and 11 (34.3% respectively. Mortality rate decreased statistically significant with use of EGb761 with pro-phylactic and therapeutic purposes (p<0.001, p<0.028.Conclusion: EGb761's prophylactic and therapeutic benefit on intestinal ischemia reperfusion injury was observed. However, these results should be supported with further biochemical and histopathological studies.

  3. 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.

  4. 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

  5. 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.

  6. Modeling of Filtration Processes-Microfiltration and Depth Filtration for Harvest of a Therapeutic Protein Expressed in Pichia pastoris at Constant Pressure.

    Science.gov (United States)

    Sampath, Muthukumar; Shukla, Anupam; Rathore, Anurag S

    2014-12-08

    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.

  7. ‘Get in early’; biofilm and wax moth (Galleria mellonella models reveal new insights into the therapeutic potential of Clostridium difficile bacteriophages

    Directory of Open Access Journals (Sweden)

    Janet Yakubu Nale

    2016-08-01

    Full Text Available Clostridium difficile infection (CDI is a global health threat associated with high rates of morbidity and mortality. Conventional antibiotic CDI therapy can result in treatment failure and recurrent infection. C. difficile produces biofilms which contribute to its virulence and impair antimicrobial activity. Some bacteriophages (phages can penetrate biofilms and thus could be developed to either replace or supplement antibiotics. Here, we determined the impact of a previously optimized 4-phage cocktail on C. difficile ribotype 014/020 biofilms, and additionally as adjunct to vancomycin treatment in Galleria mellonella larva CDI model. The phages were applied before or after biofilm establishment in vitro, and the impact was analyzed according to turbidity, viability counts and topography as observed using scanning electron and confocal microscopy. The infectivity profiles and efficacies of orally administered phages and/or vancomycin were ascertained by monitoring colonization levels and larval survival rates. Phages prevented biofilm formation, and penetrated established biofilms. A single phage application reduced colonization causing extended longevity in the remedial treatment and prevented disease in the prophylaxis group. Multiple phage doses significantly improved the larval remedial regimen, and this treatment is comparable to vancomycin and the combined treatments. Taken together, our data suggest that the phages significantly reduce C. difficile biofilms, and prevent colonization in the G. mellonella model when used alone or in combination with vancomycin. The phages appear to be highly promising therapeutics in the targeted eradication of CDI and the use of these models has revealed that prophylactic use could be a propitious therapeutic option.

  8. Final Report. DOE Computational Nanoscience Project DE-FG02-03ER46096: Integrated Multiscale Modeling of Molecular Computing Devices

    Energy Technology Data Exchange (ETDEWEB)

    Cummings, Peter [Vanderbilt University

    2009-11-15

    The document is the final report of the DOE Computational Nanoscience Project DE-FG02-03ER46096: Integrated Multiscale Modeling of Molecular Computing Devices. It included references to 62 publications that were supported by the grant.

  9. 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

  10. 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

  11. Optimization and characterization of a murine lung infection model for the evaluation of novel therapeutics against Burkholderia cenocepacia.

    Science.gov (United States)

    Vanhoutte, Bieke; Cappoen, Davie; Maira, Bidart de Macedo; Cools, Freya; Torfs, Eveline; Coenye, Tom; Martinet, Wim; Caljon, Guy; Maes, Louis; Delputte, Peter; Cos, Paul

    2017-08-01

    Several B. cenocepacia mouse models are available to study the pulmonary infection by this Burkholderia cepacia complex (BCC) species. However, a characterized B. cenocepacia mouse model to evaluate the efficacy of potential new antibacterial therapies is not yet described. Therefore, we optimized and validated the course of infection (i.e. bacterial proliferation in lung, liver and spleen) and the efficacy of a reference antibiotic, tobramycin (TOB), in a mouse lung infection model. Furthermore, the local immune response and histological changes in lung tissue were studied during infection and treatment. A reproducible lung infection was observed when immunosuppressed BALB/c mice were infected with B. cenocepacia LMG 16656. Approximately 50 to 60% of mice infected with this BCC species demonstrated a dissemination to liver and spleen. TOB treatment resulted in a two log reduction in lung burden, prevented dissemination of B. cenocepacia to liver and spleen and significantly reduced levels of proinflammatory cytokines. As this mouse model is characterized by a reproducible course of infection and efficacy of TOB, it can be used as a tool for the in vivo evaluation of new antibacterial therapies. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. The pros and cons of vertebrate animal models for functional and therapeutic research on inherited retinal dystrophies

    NARCIS (Netherlands)

    Slijkerman, R.W.; Song, F.; Astuti, G.D.; Huijnen, M.A.; WIjk, E.; Stieger, K.; Collin, R.W.

    2015-01-01

    Over the last decade, huge progress has been made in the understanding of the molecular mechanisms underlying inherited retinal dystrophy (IRD), as well as in the development and implementation of novel therapies, especially in the field of gene therapy. The use of mutant animal models, either

  13. Therapeutic Issues and the Relationship to the Deceased: Working Clinically with the Two-Track Model of Bereavement

    Science.gov (United States)

    Malkinson, Ruth; Rubin, Simon Shimshon; Witztum, Eliezer

    2006-01-01

    Psychological intervention with the bereaved can provide critical assistance to individuals, families, and communities contending with the loss of significant others. In the organizational paradigm of the Two-Track Model of Bereavement, the outcome of both successful and problematic mourning are manifest along two distinct but interrelated tracks…

  14. Collaborative Visualization for Large-Scale Accelerator Electromagnetic Modeling (Final Report)

    Energy Technology Data Exchange (ETDEWEB)

    William J. Schroeder

    2011-11-13

    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 proposed address the typical problems faced by geographicallyand organizationally-separated research and engineering teams, who produce large data (either through simulation or experimental measurement) and wish to work together to analyze and understand their data. Because the data is large, we expect that it cannot be easily transported to each team member's work site, and that the visualization server must reside near the data. Further, we also expect that each work site has heterogeneous resources: some with large computing clients, tiled (or large) displays and high bandwidth; others sites as simple as a team member on a laptop computer. Our solution is based on the open-source, widely used ParaView large-data visualization application. We extended this tool to support multiple collaborative clients who may locally visualize data, and then periodically rejoin and synchronize with the group to discuss their findings. Options for managing session control, adding annotation, and defining the visualization pipeline, among others, were incorporated. We also developed and deployed a Web visualization framework based on ParaView that enables the Web browser to act as a participating client in a collaborative session. The ParaView Web Visualization framework leverages various Web technologies including WebGL, JavaScript, Java and Flash to enable interactive 3D visualization over the web using ParaView as the visualization server. We steered the development of this technology by teaming with the SLAC National Accelerator Laboratory. SLAC has a computationally

  15. Final Report - Epigenetics of low dose radiation effects in an animal model

    Energy Technology Data Exchange (ETDEWEB)

    Kovalchuk, Olga

    2014-10-22

    This project sought mechanistic understanding of the epigenetic response of tissues as well as the consequences of those responses, when induced by low dose irradiation in a well-established model system (mouse). Based on solid and extensive preliminary data we investigated the molecular epigenetic mechanisms of in vivo radiation responses, particularly – effects of low, occupationally relevant radiation exposures on the genome stability and adaptive response in mammalian tissues and organisms. We accumulated evidence that low dose irradiation altered epigenetic profiles and impacted radiation target organs of the exposed animals. The main long-term goal was to dissect the epigenetic basis of induction of the low dose radiation-induced genome instability and adaptive response and the specific fundamental roles of epigenetic changes (i.e. DNA methylation, histone modifications and miRNAs) in their generation. We hypothesized that changes in global and regional DNA methylation, global histone modifications and regulatory microRNAs played pivotal roles in the generation and maintenance low-dose radiation-induced genome instability and adaptive response. We predicted that epigenetic changes influenced the levels of genetic rearrangements (transposone reactivation). We hypothesized that epigenetic responses from low dose irradiation were dependent on exposure regimes, and would be greatest when organisms are exposed in a protracted/fractionated manner: fractionated exposures > acute exposures. We anticipated that the epigenetic responses were correlated with the gene expression levels. Our immediate objectives were: • To investigate the exact nature of the global and locus-specific DNA methylation changes in the LDR exposed cells and tissues and dissect their roles in adaptive response • To investigate the roles of histone modifications in the low dose radiation effects and adaptive response • To dissect the roles of regulatory microRNAs and their targets in low

  16. Development of Mouse Models of Ovarian Cancer for Studying Tumor Biology and Testing Novel Molecularly Targeted Therapeutic Strategies

    Science.gov (United States)

    2011-09-01

    Fonseca BD, Sonenberg N. Dissecting the role of mTOR: lessons from mTOR inhibitors. Biochim Biophys Acta 2010;1804:433–9. 22. Chen XG, Liu F, Song XF...FROM THE RESEARCH EFFORT: Kathleen R. Cho (Initiating PI) Yali Zhai (Research Investigator, Cho Laboratory) Rong Wu (Research Assistant Professor...Clin Cancer Res Rong Wu, Tom C. Hu, Alnawaz Rehemtulla, et al. Mouse Model of Ovarian Endometrioid Adenocarcinoma Preclinical Testing of PI3K/AKT

  17. A GAA repeat expansion reporter model of Friedreich's ataxia recapitulates the genomic context and allows rapid screening of therapeutic compounds.

    Science.gov (United States)

    Lufino, Michele M P; Silva, Ana M; Németh, Andrea H; Alegre-Abarrategui, Javier; Russell, Angela J; Wade-Martins, Richard

    2013-12-20

    Friedreich's ataxia (FRDA) is caused by large GAA expansions in intron 1 of the frataxin gene (FXN), which lead to reduced FXN expression through a mechanism not fully understood. Understanding such mechanism is essential for the identification of novel therapies for FRDA and this can be accelerated by the development of cell models which recapitulate the genomic context of the FXN locus and allow direct comparison of normal and expanded FXN loci with rapid detection of frataxin levels. Here we describe the development of the first GAA-expanded FXN genomic DNA reporter model of FRDA. We modified BAC vectors carrying the whole FXN genomic DNA locus by inserting the luciferase gene in exon 5a of the FXN gene (pBAC-FXN-Luc) and replacing the six GAA repeats present in the vector with an ∼310 GAA repeat expansion (pBAC-FXN-GAA-Luc). We generated human clonal cell lines carrying the two vectors using site-specific integration to allow direct comparison of normal and expanded FXN loci. We demonstrate that the presence of expanded GAA repeats recapitulates the epigenetic modifications and repression of gene expression seen in FRDA. We applied the GAA-expanded reporter model to the screening of a library of novel small molecules and identified one molecule which up-regulates FXN expression in FRDA patient primary cells and restores normal histone acetylation around the GAA repeats. These results suggest the potential use of genomic reporter cell models for the study of FRDA and the identification of novel therapies, combining physiologically relevant expression with the advantages of quantitative reporter gene expression.

  18. Pathogenetic and therapeutic perspectives on neurocognitive models in psychiatry: A synthesis of behavioral, brain imaging, and biological studies

    OpenAIRE

    Rao, Naren P.

    2012-01-01

    Neurocognitive assessments are useful to determine the locus of insult as well as functional capacities of patients on treatment. In psychiatry, neurocognitive assessment is useful in the identification of brain lesions, evaluation of cognitive deterioration over time, and advancement of theories regarding the neuroanatomical localization of symptoms. Neurocognitive models provide a bridging link between brain pathology and phenomenology. They provide a useful framework to understand the path...

  19. 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.

  20. A Bayesian Model of the Uncanny Valley Effect for Explaining the Effects of Therapeutic Robots in Autism Spectrum Disorder.

    Science.gov (United States)

    Ueyama, Yuki

    2015-01-01

    One of the core features of autism spectrum disorder (ASD) is impaired reciprocal social interaction, especially in processing emotional information. Social robots are used to encourage children with ASD to take the initiative and to interact with the robotic tools to stimulate emotional responses. However, the existing evidence is limited by poor trial designs. The purpose of this study was to provide computational evidence in support of robot-assisted therapy for children with ASD. We thus propose an emotional model of ASD that adapts a Bayesian model of the uncanny valley effect, which holds that a human-looking robot can provoke repulsion and sensations of eeriness. Based on the unique emotional responses of children with ASD to the robots, we postulate that ASD induces a unique emotional response curve, more like a cliff than a valley. Thus, we performed numerical simulations of robot-assisted therapy to evaluate its effects. The results showed that, although a stimulus fell into the uncanny valley in the typical condition, it was effective at avoiding the uncanny cliff in the ASD condition. Consequently, individuals with ASD may find it more comfortable, and may modify their emotional response, if the robots look like deformed humans, even if they appear "creepy" to typical individuals. Therefore, we suggest that our model explains the effects of robot-assisted therapy in children with ASD and that human-looking robots may have potential advantages for improving social interactions in ASD.

  1. Homology modeling and molecular docking studies of Bacillomycin and Iturin synthetases with novel ligands for the production of therapeutic lipopeptides.

    Science.gov (United States)

    Eswari, Jujjavarapu Satya; Dhagat, Swasti; Kaser, Shubham; Tiwari, Anoop

    2017-08-15

    Lipopeptide synthetases play an important role in the production of lipopeptides. Lipopeptides are molecules made up of peptides and fatty acid moieties and have shown to have a broad range of antimicrobial activity. As infectious diseases have caused severe health problems mainly resulting from the development of antibiotic resistant strains of disease causing microorganisms there is a need of alternatives to antibiotics. The lipopeptide synthetase of the corresponding lipopeptides can be used as templates to design these as drugs using computational techniques. The objective of this study was homology modeling and molecular docking of two lipopeptide synthetases, bacillomycin D synthetase and iturin A synthetase, with their ligands as a means of drug design. Schrödinger software was used for homology modeling and molecular docking. After the identification of ligands, molecular docking of these ligands with the lipopeptide (bacillomycin and iturin) synthetases was performed. The docking was tested on the parameters of docking score and glide energy. 5 out of 21 ligands were found to dock with bacillomycin D synthetase whereas 8 out of 20 ligands docked with the iturin A synthetase. The knowledge of the docking sites and docking characteristics of the lipopeptide synthetases mentioned in the paper with the ligands can provide advantages of high speed and reliability, reduced costs on chemicals and experiments and the ethical issues concerned with the use of animal models for screening of drug toxicity. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  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

    are derived from CFD results and applied to examine if the process is operated in an efficient and economic manner. It has been found that the displacement time can be predicted from the inner pipe diameter and the mean flow velocity using a power law relationship. Changing flow velocities does......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...... for optimizing the rinse steps with lower water consumption based on the above observations. A case of rinsing a 24 m long straight pipe describes the promising application of the CFD study. The recovery of cleaning agent can be up to 89.3% of the volume and the saving of intermediate rinsing water can...

  3. 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.

  4. Study of metastatic kinetics in metastatic melanoma treated with B-RAF inhibitors: Introducing mathematical modelling of kinetics into the therapeutic decision.

    Directory of Open Access Journals (Sweden)

    Niklas Hartung

    Full Text Available Evolution of metastatic melanoma (MM under B-RAF inhibitors (BRAFi is unpredictable, but anticipation is crucial for therapeutic decision. Kinetics changes in metastatic growth are driven by molecular and immune events, and thus we hypothesized that they convey relevant information for decision making.We used a retrospective cohort of 37 MM patients treated by BRAFi only with at least 2 close CT-scans available before BRAFi, as a model to study kinetics of metastatic growth before, under and after BRAFi. All metastases (mets were individually measured at each CT-scan. From these measurements, different measures of growth kinetics of each met and total tumor volume were computed at different time points. A historical cohort permitted to build a reference model for the expected spontaneous disease kinetics without BRAFi. All variables were included in Cox and multistate regression models for survival, to select best candidates for predicting overall survival.Before starting BRAFi, fast kinetics and moreover a wide range of kinetics (fast and slow growing mets in a same patient were pejorative markers. At the first assessment after BRAFi introduction, high heterogeneity of kinetics predicted short survival, and added independent information over RECIST progression in multivariate analysis. Metastatic growth rates after BRAFi discontinuation was usually not faster than before BRAFi introduction, but they were often more heterogeneous than before.Monitoring kinetics of different mets before and under BRAFi by repeated CT-scan provides information for predictive mathematical modelling. Disease kinetics deserves more interest.

  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. Final Report for Award #DE-SC3956 Separating Algorithm and Implementation via programming Model Injection (SAIMI)

    Energy Technology Data Exchange (ETDEWEB)

    Strout, Michelle [Colorado State Univ., Fort Collins, CO (United States)

    2015-08-15

    Programming parallel machines is fraught with difficulties: the obfuscation of algorithms due to implementation details such as communication and synchronization, the need for transparency between language constructs and performance, the difficulty of performing program analysis to enable automatic parallelization techniques, and the existence of important "dusty deck" codes. The SAIMI project developed abstractions that enable the orthogonal specification of algorithms and implementation details within the context of existing DOE applications. The main idea is to enable the injection of small programming models such as expressions involving transcendental functions, polyhedral iteration spaces with sparse constraints, and task graphs into full programs through the use of pragmas. These smaller, more restricted programming models enable orthogonal specification of many implementation details such as how to map the computation on to parallel processors, how to schedule the computation, and how to allocation storage for the computation. At the same time, these small programming models enable the expression of the most computationally intense and communication heavy portions in many scientific simulations. The ability to orthogonally manipulate the implementation for such computations will significantly ease performance programming efforts and expose transformation possibilities and parameter to automated approaches such as autotuning. At Colorado State University, the SAIMI project was supported through DOE grant DE-SC3956 from April 2010 through August 2015. The SAIMI project has contributed a number of important results to programming abstractions that enable the orthogonal specification of implementation details in scientific codes. This final report summarizes the research that was funded by the SAIMI project.

  7. Therapeutic benefit derived from RNAi-mediated ablation of IMPDH1 transcripts in a murine model of autosomal dominant retinitis pigmentosa (RP10).

    Science.gov (United States)

    Tam, Lawrence C S; Kiang, Anna-Sophia; Kennan, Avril; Kenna, Paul F; Chadderton, Naomi; Ader, Marius; Palfi, Arpad; Aherne, Aileen; Ayuso, Carmen; Campbell, Matthew; Reynolds, Alison; McKee, Alex; Humphries, Marian M; Farrar, G Jane; Humphries, Pete

    2008-07-15

    Mutations within the inosine 5'-monophosphate dehydrogenase 1 (IMPDH1) gene cause the RP10 form of autosomal dominant retinitis pigmentosa (adRP), an early-onset retinopathy resulting in extensive visual handicap owing to progressive death of photoreceptors. Apart from the prevalence of RP10, estimated to account for 5-10% of cases of adRP in United States and Europe, two observations render this form of RP an attractive target for gene therapy. First, we show that while recombinant adeno-associated viral (AAV)-mediated expression of mutant human IMPDH1 protein in the mouse retina results in an aggressive retinopathy modelling the human counterpart, expression of a normal human IMPDH1 gene under similar conditions has no observable pathological effect on retinal function, indicating that over-expression of a therapeutic replacement gene may be relatively well tolerated. Secondly, complete absence of IMPDH1 protein in mice with a targeted disruption of the gene results in relatively mild retinal dysfunction, suggesting that significant therapeutic benefit may be derived even from the suppression-only component of an RNAi-based gene therapy. We show that AAV-mediated co-expression in the murine retina of a mutant human IMPDH1 gene together with short hairpin RNAs (shRNA) validated in vitro and in vivo, targeting both human and mouse IMPDH1, substantially suppresses the negative pathological effects of mutant IMPDH1, at a point where, in the absence of shRNA, expression of mutant protein in the RP10 model essentially ablates all photoreceptors in transfected areas of the retina. These data strongly suggest that an RNAi-mediated approach to therapy for RP10 holds considerable promise for human subjects.

  8. Evaluation of the therapeutic potential of bone marrow-derived myeloid suppressor cell (MDSC adoptive transfer in mouse models of autoimmunity and allograft rejection.

    Directory of Open Access Journals (Sweden)

    Lucile Drujont

    Fu