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Sample records for pathways model apm

  1. A Methodology for Phased Array Radar Threshold Modeling Using the Advanced Propagation Model (APM)

    Science.gov (United States)

    2017-10-01

    There are exact equations to determine a Pd given SNR, but the inverse cannot be expressed analytically (Shnidman, 2002). However, Shnidman developed a...each mode. Therefore, to determine the overall radar performance at any azimuth for both modes simultaneously , only eight executions of the APM are...same azimuth for multiple waveforms improves the overall efficiency in determining radar performance for all operational scan modes simultaneously

  2. HLA class I antigen processing machinery (APM) component expression and PD-1:PD-L1 pathway activation in HIV-infected head and neck cancers.

    Science.gov (United States)

    Pai, Sara I; Jack Lee, J; Carey, Thomas E; Westra, William H; Ferrone, Soldano; Moore, Charles; Mosunjac, Marina B; Shin, Dong M; Ferris, Robert L

    2018-02-01

    Human immunodeficiency virus (HIV)-infected individuals are at increased risk for developing several non-AIDS related malignancies and are often excluded from cancer immunotherapy regimens. To evaluate the immune competence of this cancer patient population, we evaluated HLA class I antigen presenting machinery (APM) component expression and PD-1:PD-L1 pathway upregulation in HIV(+) and HIV(-) head and neck cancers (HNCs). Sixty-two HIV(+) and 44 matched HIV(-) controls diagnosed with HNC between 1991 and 2011 from five tertiary care referral centers in the United States were identified. HLA class I APM component, PD-1, and PD-L1 expression were analyzed by immunohistochemical staining with monoclonal antibodies (mAbs). Clinical data was abstracted from the medical records. There was no significant difference between the cases and controls in LMP2, TAP1, HLA-A and HLA-B/C, as well as PD-1 and PD-L1 expression. Overall, 62% of all subjects had high PD-1 expression and 82% of the subjects expressed PD-L1 within the tumor microenvironment. LMP2, HLA-A and HLA-B/C expression were significantly associated with moderate to high PD-1 expression in the HIV(+) HNC cases (p = .004, p = .026, and p = .006, respectively) but not in the HIV(-) controls. In addition, HLA-A expression was significantly associated with PD-L1 expression in the HIV(+) HNC cases only (p = .029). HIV-infected individuals diagnosed with HNC do not have any detectable defects in HLA class I APM component expression and in PD-1:PD-L1 pathway activation. Given the current successes of HAART therapy in maintaining immune cell counts, HIV(+) patients diagnosed with cancer may benefit from the recently FDA-approved immune checkpoint blockade therapy. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Aquatic pathways model to predict the fate of phenolic compounds

    Energy Technology Data Exchange (ETDEWEB)

    Aaberg, R.L.; Peloquin, R.A.; Strenge, D.L.; Mellinger, P.J.

    1983-04-01

    Organic materials released from energy-related activities could affect human health and the environment. To better assess possible impacts, we developed a model to predict the fate of spills or discharges of pollutants into flowing or static bodies of fresh water. A computer code, Aquatic Pathways Model (APM), was written to implement the model. The computer programs use compartmental analysis to simulate aquatic ecosystems. The APM estimates the concentrations of chemicals in fish tissue, water and sediment, and is therefore useful for assessing exposure to humans through aquatic pathways. The APM will consider any aquatic pathway for which the user has transport data. Additionally, APM will estimate transport rates from physical and chemical properties of chemicals between several key compartments. The major pathways considered are biodegradation, fish and sediment uptake, photolysis, and evaporation. The model has been implemented with parameters for distribution of phenols, an important class of compounds found in the water-soluble fractions of coal liquids. Current modeling efforts show that, in comparison with many pesticides and polyaromatic hydrocarbons (PAH), the lighter phenolics (the cresols) are not persistent in the environment. The properties of heavier molecular weight phenolics (indanols, naphthols) are not well enough understood at this time to make similar judgements. For the twelve phenolics studied, biodegradation appears to be the major pathway for elimination from aquatic environments. A pond system simulation (using APM) of a spill of solvent refined coal (SRC-II) materials indicates that phenol, cresols, and other single cyclic phenolics are degraded to 16 to 25 percent of their original concentrations within 30 hours. Adsorption of these compounds into sediments and accumulation by fish was minor.

  4. APME launches common method

    International Nuclear Information System (INIS)

    Anon.

    1993-01-01

    A common approach for carrying out ecological balances for commodity thermoplastics is due to be launched by the Association of Plastics Manufacturers in Europe (APME; Brussels) and its affiliate, The European Centre for Plastics in the Environment (PWMI) this week. The methodology report is the latest stage of a program started in 1990 that aims to describe all operations up to the production of polymer powder or granules at the plant gate. Information gathered will be made freely available to companies considering the use of polymers. An industry task force, headed by PWMI executive director Vince Matthews, has gathered information on the plastics production processes from oil to granule, and an independent panel of specialists, chaired by Ian Boustead of the U.K.'s Open University, devised the methodology and analysis. The methodology report stresses the need to define the system being analyzed and discusses how complex chemical processes can be analyzed in terms of consumption of fuels, energy, and raw materials, as well as solid, liquid, and gaseous emissions

  5. Medicare Program; Merit-Based Incentive Payment System (MIPS) and Alternative Payment Model (APM) Incentive Under the Physician Fee Schedule, and Criteria for Physician-Focused Payment Models. Final rule with comment period.

    Science.gov (United States)

    2016-11-04

    The Medicare Access and CHIP Reauthorization Act of 2015 (MACRA) repeals the Medicare sustainable growth rate (SGR) methodology for updates to the physician fee schedule (PFS) and replaces it with a new approach to payment called the Quality Payment Program that rewards the delivery of high-quality patient care through two avenues: Advanced Alternative Payment Models (Advanced APMs) and the Merit-based Incentive Payment System (MIPS) for eligible clinicians or groups under the PFS. This final rule with comment period establishes incentives for participation in certain alternative payment models (APMs) and includes the criteria for use by the Physician-Focused Payment Model Technical Advisory Committee (PTAC) in making comments and recommendations on physician-focused payment models (PFPMs). Alternative Payment Models are payment approaches, developed in partnership with the clinician community, that provide added incentives to deliver high-quality and cost-efficient care. APMs can apply to a specific clinical condition, a care episode, or a population. This final rule with comment period also establishes the MIPS, a new program for certain Medicare-enrolled practitioners. MIPS will consolidate components of three existing programs, the Physician Quality Reporting System (PQRS), the Physician Value-based Payment Modifier (VM), and the Medicare Electronic Health Record (EHR) Incentive Program for Eligible Professionals (EPs), and will continue the focus on quality, cost, and use of certified EHR technology (CEHRT) in a cohesive program that avoids redundancies. In this final rule with comment period we have rebranded key terminology based on feedback from stakeholders, with the goal of selecting terms that will be more easily identified and understood by our stakeholders.

  6. APM Best Practices Realizing Application Performance Management

    CERN Document Server

    Sydor, Michael J

    2011-01-01

    The objective of APM Best Practices: Realizing Application Performance Management is to establish reliable application performance management (APM) practices - to demonstrate value, to do it quickly, and to adapt to the client circumstances. It's important to balance long-term goals with short-term deliverables, but without compromising usefulness or correctness. The successful strategy is to establish a few reasonable goals, achieve them quickly, and then iterate over the same topics two more times, with each successive iteration expanding the skills and capabilities of the APM team. This str

  7. Future considerations for clinical dermatology in the setting of 21st century American policy reform: The Medicare Access and Children's Health Insurance Program Reauthorization Act and Alternative Payment Models in dermatology.

    Science.gov (United States)

    Barbieri, John S; Miller, Jeffrey J; Nguyen, Harrison P; Forman, Howard P; Bolognia, Jean L; VanBeek, Marta J

    2017-06-01

    With the introduction of the Medicare Access and Children's Health Insurance Program Reauthorization Act, clinicians who are not eligible for an exemption must choose to participate in 1 of 2 new reimbursement models: the Merit-based Incentive Payment System or Alternative Payment Models (APMs). Although most dermatologists are expected to default into the Merit-based Incentive Payment System, some may have an interest in exploring APMs, which have associated financial incentives. However, for dermatologists interested in the APM pathway, there are currently no options other than joining a qualifying Accountable Care Organization, which make up only a small subset of Accountable Care Organizations overall. As a result, additional APMs relevant to dermatologists are needed to allow those interested in the APMs to explore this pathway. Fortunately, the Medicare Access and Children's Health Insurance Program Reauthorization Act establishes a process for new APMs to be approved and the creation of bundled payments for skin diseases may represent an opportunity to increase the number of APMs available to dermatologists. In this article, we will provide a detailed review of APMs under the Medicare Access and Children's Health Insurance Program Reauthorization Act and discuss the development and introduction of APMs as they pertain to dermatology. Copyright © 2017 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

  8. Implementing adaptive phased management (APM) for Canada's used nuclear fuel

    International Nuclear Information System (INIS)

    King, F.

    2008-01-01

    This paper discusses the implementation of Adaptive Phased Management (APM) for Canada's used nuclear fuel. APM is a combination of technology and management system. The technology involves centralized containment and isolation in deep geological repository in a suitable rock formation, as well as shallow storage where used fuel remains retrievable. In both cases there is continuous monitoring. The management system consists of public engagement, phased decision-making, continuous learning and adaption, open and inclusive. Finally, it involves seeking an in formed willing host community

  9. Colchicine and amiprophos-methyl (APM) in polyploidy induction in ...

    African Journals Online (AJOL)

    Jane

    2011-10-12

    Oct 12, 2011 ... The objective was to assess the colchicine and amiprophos-methyl (APM) concentration and exposure period in the chromosome duplication of breed banana plants diploids. Banana stem tips were used from the following genotypes: breed diploids (1304-04 [Malaccensis x Madang (Musa acuminata spp.

  10. Colchicine and amiprophos-methyl (APM) in polyploidy induction in ...

    African Journals Online (AJOL)

    The objective was to assess the colchicine and amiprophos-methyl (APM) concentration and exposure period in the chromosome duplication of breed banana plants diploids. Banana stem tips were used from the following genotypes: breed diploids (1304-04 [Malaccensis x Madang (Musa acuminata spp. banksii)] and ...

  11. APMS: An Integrated Set of Tools for Measuring Safety

    Science.gov (United States)

    Statler, Irving C.; Reynard, William D. (Technical Monitor)

    1996-01-01

    This is a report of work in progress. In it, I summarize the status of the research and development of the Aviation Performance Measuring System (APMS) for managing, processing, and analyzing digital flight-recorded data. The objectives of the NASA-FAA APMS research project are to establish a sound scientific and technological basis for flight-data analysis, to define an open and flexible architecture for flight-data-analysis systems, and to articulate guidelines for a standardized database structure on which to continue to build future flight-data-analysis extensions. APMS will offer to the air transport community an open, voluntary standard for flight-data-analysis software, a standard that will help to ensure suitable functionality, and data interchangeability, among competing software programs. APMS will develop and document the methodologies, algorithms, and procedures for data management and analyses to enable users to easily interpret the implications regarding safety and efficiency of operations. APMS does not entail the implementation of a nationwide flight-data-collection system. It is intended to provide technical tools to ease the large-scale implementation of flight-data analyses at both the air-carrier and the national-airspace levels in support of their Flight Operations and Quality Assurance (FOQA) Programs and Advanced Qualifications Programs (AQP). APMS cannot meet its objectives unless it develops tools that go substantially beyond the capabilities of the current commercially available software and supporting analytic methods that are mainly designed to count special events. These existing capabilities, while of proven value, were created primarily with the needs of air crews in mind. APMS tools must serve the needs of the government and air carriers, as well as air crews, to fully support the FOQA and AQP programs. They must be able to derive knowledge not only through the analysis of single flights (special-event detection), but through

  12. ATR performance modeling concepts

    Science.gov (United States)

    Ross, Timothy D.; Baker, Hyatt B.; Nolan, Adam R.; McGinnis, Ryan E.; Paulson, Christopher R.

    2016-05-01

    Performance models are needed for automatic target recognition (ATR) development and use. ATRs consume sensor data and produce decisions about the scene observed. ATR performance models (APMs) on the other hand consume operating conditions (OCs) and produce probabilities about what the ATR will produce. APMs are needed for many modeling roles of many kinds of ATRs (each with different sensing modality and exploitation functionality combinations); moreover, there are different approaches to constructing the APMs. Therefore, although many APMs have been developed, there is rarely one that fits a particular need. Clarified APM concepts may allow us to recognize new uses of existing APMs and identify new APM technologies and components that better support coverage of the needed APMs. The concepts begin with thinking of ATRs as mapping OCs of the real scene (including the sensor data) to reports. An APM is then a mapping from explicit quantized OCs (represented with less resolution than the real OCs) and latent OC distributions to report distributions. The roles of APMs can be distinguished by the explicit OCs they consume. APMs used in simulations consume the true state that the ATR is attempting to report. APMs used online with the exploitation consume the sensor signal and derivatives, such as match scores. APMs used in sensor management consume neither of those, but estimate performance from other OCs. This paper will summarize the major building blocks for APMs, including knowledge sources, OC models, look-up tables, analytical and learned mappings, and tools for signal synthesis and exploitation.

  13. Nutrition pathways in consequence modeling

    International Nuclear Information System (INIS)

    Tveten, U.

    1982-01-01

    During 1979-1980 calculations of risk from waste transportation by truck (fire following collision) and fire in temporary storage for waste were performed. A modified version of the consequence model of WASH-1400 (CRAC) was used. Two exposure pathways dominated the results: external exposure from material on the ground and exposure via nutrition. Many of the parameters entering into the nutrition calculations will depend upon local conditions, like soil composition, crop yield, etc. It was decided to collect detailed comments upon the CRAC nutritions model and parameter values from radioecologists in the four Nordic countries. Four alternate sets of parameter values were derived from these comments, and new risk calculations were performed

  14. APM for a Constellation Intersatellite Link - EM Qualification and Lessons Learned

    Science.gov (United States)

    Hartel, Frank; Kozilek, Horst

    2016-01-01

    For an Intersatellite Link (ISL) of a future constellation program, a study phase was initiated by ESA to design a mechanism for Radio Frequency communication. Airbus DS Friedrichshafen (ADSF) proposed a design based on the Antenna Pointing Mechanism (APM) family with modifications that met the stated needs of the constellation. A qualification program was started beginning in September 2015 to verify the launch and thermal loads and the equipment performance (Radio Frequency, Pointing, Microvibration and Magnetic Moment). Technical challenges identified with the Engineering Model will be discussed within this paper.

  15. Constraining omega and bias from the Stromlo-APM survey

    International Nuclear Information System (INIS)

    Loveday, J.

    1995-05-01

    Galaxy redshift surveys provide a distorted picture of the universe due to the non-Hubble component of galaxy motions. By measuring such distortions in the linear regime one can constrain the quantity β = Ω 0.6 where Ω is the cosmological density parameter and b is the (linear) bias factor for optically-selected galaxies. In this paper we estimate β from the Stromlo-APM redshift survey by comparing the amplitude of the direction-averaged redshift space correlation function to the real space correlation function. We find a 95% confidence upper limit of β = 0.75, with a 'best estimate' of β ∼ 0.48. A bias parameter b ∼ 2 is thus required if Ω ≡ 1. However, higher-order correlations measured from the APM galaxy survey indicate a low value for the bias parameter b ∼ 1, requiring that Q approx-lt 0.6

  16. DISCOVERY OF WATER VAPOR IN THE HIGH-REDSHIFT QUASAR APM 08279+5255 AT z = 3.91

    International Nuclear Information System (INIS)

    Lis, D. C.; Phillips, T. G.; Neufeld, D. A.; Gerin, M.; Neri, R.

    2011-01-01

    We report a detection of the excited 2 20 -2 11 rotational transition of para-H 2 O in APM 08279+5255 using the IRAM Plateau de Bure Interferometer. At z = 3.91, this is the highest-redshift detection of interstellar water to date. From large velocity gradient modeling, we conclude that this transition is predominantly radiatively pumped and on its own does not provide a good estimate of the water abundance. However, additional water transitions are predicted to be detectable in this source, which would lead to an improved excitation model. We also present a sensitive upper limit for the hydrogen fluoride (HF) J = 1-0 absorption toward APM 08279+5255. While the face-on geometry of this source is not favorable for absorption studies, the lack of HF absorption is still puzzling and may be indicative of a lower fluorine abundance at z = 3.91 compared with the Galactic interstellar medium.

  17. The fastest disk wind in APM 08279+5255 and its acceleration mechanism

    Science.gov (United States)

    Hagino, K.; Done, C.; Odaka, H.; Watanabe, S.; Takahashi, T.

    2017-10-01

    The luminous high-z quasar APM 08279+5255 has the most powerful ultra-fast outflow (UFO), which is claimed as the fastest disk wind with velocity of 0.7c. This extreme velocity is very important for constraining the physical mechanism to launch the UFOs because only magnetic driving mechanism can accelerate the winds up to velocities above 0.3c, at which radiation drag effects prevent radiation driving. We reanalyze all the observed data of this source with our spectral model of highly ionized disk winds constructed by 3D Monte Carlo radiation transfer simulation. This was applied to an archetypal disk wind in PDS 456, and successfully reproduced all the spectra observed with Suzaku in spite of their strong spectral variability. By applying our spectral model to APM 08279+5255, all the spectra observed with XMM-Newton, Chandra and Suzaku are explained with less extreme outflow velocities of 0.1-0.2c. In our analysis, the high energy absorption features, which were previously interpreted as absorption lines with extremely fast velocities, are produced by iron-K absorption edges from moderately ionized clumps embedded in the highly ionized wind. We also investigate the broadband SED, and find that it is X-ray weak and UV bright, which prefers the radiation driving.

  18. An optimization model for metabolic pathways.

    Science.gov (United States)

    Planes, F J; Beasley, J E

    2009-10-15

    Different mathematical methods have emerged in the post-genomic era to determine metabolic pathways. These methods can be divided into stoichiometric methods and path finding methods. In this paper we detail a novel optimization model, based upon integer linear programming, to determine metabolic pathways. Our model links reaction stoichiometry with path finding in a single approach. We test the ability of our model to determine 40 annotated Escherichia coli metabolic pathways. We show that our model is able to determine 36 of these 40 pathways in a computationally effective manner.

  19. APMS 3.0 Flight Analyst Guide: Aviation Performance Measuring System

    Science.gov (United States)

    Jay, Griff; Prothero, Gary; Romanowski, Timothy; Lynch, Robert; Lawrence, Robert; Rosenthal, Loren

    2004-01-01

    The Aviation Performance Measuring System (APMS) is a method-embodied in software-that uses mathematical algorithms and related procedures to analyze digital flight data extracted from aircraft flight data recorders. APMS consists of an integrated set of tools used to perform two primary functions: a) Flight Data Importation b) Flight Data Analysis.

  20. Wound care clinical pathway: a conceptual model.

    Science.gov (United States)

    Barr, J E; Cuzzell, J

    1996-08-01

    A clinical pathway is a written sequence of clinical processes or events that guides a patient with a defined problem toward an expected outcome. Clinical pathways are tools to assist with the cost-effective management of clinical outcomes related to specific problems or disease processes. The primary obstacles to developing clinical pathways for wound care are the chronic natures of some wounds and the many variables that can delay healing. The pathway introduced in this article was modeled upon the three phases of tissue repair: inflammatory, proliferative, and maturation. This physiology-based model allows clinicians to identify and monitor outcomes based on observable and measurable clinical parameters. The pathway design, which also includes educational and behavioral outcomes, allows the clinician to individualize the expected timeframe for outcome achievement based on individual patient criteria and expert judgement. Integral to the pathway are the "4P's" which help standardize the clinical processes by wound type: Protocols, Policies, Procedures, and Patient education tools. Four categories into which variances are categorized based on the cause of the deviation from the norm are patient, process/system, practitioner, and planning/discharge. Additional research is warranted to support the value of this clinical pathway in the clinical arena.

  1. Radiation hardening and irradiation testing of in-cell electronics for MA23/APM

    International Nuclear Information System (INIS)

    Friant, A.

    1988-09-01

    We relate briefly the radiation hardening method used to guarantee a gamma resistance of 10 Mrad for the whole electronic equipment associated with the slave arm of MA23 M servomanipulator which will be set up in cell 404 in Marcoule (APM). We describe the radiation testing of electronic devices and of the various subsystems designed by the D. LETI groups involved in the MA23/APM project

  2. Pappas and Tepe's Pathways to Knowledge Model.

    Science.gov (United States)

    Zimmerman, Nancy P.; Pappas, Marjorie L.; Tepe, Ann E.

    2002-01-01

    Describes the Pathways to Knowledge model for helping students achieve information literacy in library media programs. Discusses the searcher's thinking, information search or seeking, and instructional strategies; information skills; the six stages in the model, including appreciation, presearch, search, interpretation, communication, and…

  3. Modelling and Decision Support of Clinical Pathways

    Science.gov (United States)

    Gabriel, Roland; Lux, Thomas

    The German health care market is under a rapid rate of change, forcing especially hospitals to provide high-quality services at low costs. Appropriate measures for more effective and efficient service provision are process orientation and decision support by information technology of clinical pathway of a patient. The essential requirements are adequate modelling of clinical pathways as well as usage of adequate systems, which are capable of assisting the complete path of a patient within a hospital, and preferably also outside of it, in a digital way. To fulfil these specifications the authors present a suitable concept, which meets the challenges of well-structured clinical pathways as well as rather poorly structured diagnostic and therapeutic decisions, by interplay of process-oriented and knowledge-based hospital information systems.

  4. Serpentinization reaction pathways: implications for modeling approach

    Energy Technology Data Exchange (ETDEWEB)

    Janecky, D.R.

    1986-01-01

    Experimental seawater-peridotite reaction pathways to form serpentinites at 300/sup 0/C, 500 bars, can be accurately modeled using the EQ3/6 codes in conjunction with thermodynamic and kinetic data from the literature and unpublished compilations. These models provide both confirmation of experimental interpretations and more detailed insight into hydrothermal reaction processes within the oceanic crust. The accuracy of these models depends on careful evaluation of the aqueous speciation model, use of mineral compositions that closely reproduce compositions in the experiments, and definition of realistic reactive components in terms of composition, thermodynamic data, and reaction rates.

  5. Mathematical modeling of the Phoenix Rising pathway.

    Directory of Open Access Journals (Sweden)

    Chad Liu

    2014-02-01

    Full Text Available Apoptosis is a tightly controlled process in mammalian cells. It is important for embryogenesis, tissue homoeostasis, and cancer treatment. Apoptosis not only induces cell death, but also leads to the release of signals that promote rapid proliferation of surrounding cells through the Phoenix Rising (PR pathway. To quantitatively understand the kinetics of interactions of different molecules in this pathway, we developed a mathematical model to simulate the effects of various changes in the PR pathway on the secretion of prostaglandin E2 (PGE2, a key factor for promoting cell proliferation. These changes include activation of caspase 3 (C3, caspase 7 (C7, and nuclear factor κB (NFκB. In addition, we simulated the effects of cyclooxygenase-2 (COX2 inhibition and C3 knockout on the level of secreted PGE2. The model predictions on PGE2 in MEF and 4T1 cells at 48 hours after 10-Gray radiation were quantitatively consistent with the experimental data in the literature. Compared to C7, the model predicted that C3 activation was more critical for PGE2 production. The model also predicted that PGE2 production could be significantly reduced when COX2 expression was blocked via either NFκB inactivation or treatment of cells with exogenous COX2 inhibitors, which led to a decrease in the rate of conversion from arachidonic acid to prostaglandin H2 in the PR pathway. In conclusion, the mathematical model developed in this study yielded new insights into the process of tissue regrowth stimulated by signals from apoptotic cells. In future studies, the model can be used for experimental data analysis and assisting development of novel strategies/drugs for improving cancer treatment or normal tissue regeneration.

  6. Ontology modeling for generation of clinical pathways

    Directory of Open Access Journals (Sweden)

    Jasmine Tehrani

    2012-12-01

    Full Text Available Purpose: Increasing costs of health care, fuelled by demand for high quality, cost-effective healthcare has drove hospitals to streamline their patient care delivery systems. One such systematic approach is the adaptation of Clinical Pathways (CP as a tool to increase the quality of healthcare delivery. However, most organizations still rely on are paper-based pathway guidelines or specifications, which have limitations in process management and as a result can influence patient safety outcomes. In this paper, we present a method for generating clinical pathways based on organizational semiotics by capturing knowledge from syntactic, semantic and pragmatic to social level. Design/methodology/approach: The proposed modeling approach to generation of CPs adopts organizational semiotics and enables the generation of semantically rich representation of CP knowledge. Semantic Analysis Method (SAM is applied to explicitly represent the semantics of the concepts, their relationships and patterns of behavior in terms of an ontology chart. Norm Analysis Method (NAM is adopted to identify and formally specify patterns of behavior and rules that govern the actions identified on the ontology chart. Information collected during semantic and norm analysis is integrated to guide the generation of CPs using best practice represented in BPMN thus enabling the automation of CP. Findings: This research confirms the necessity of taking into consideration social aspects in designing information systems and automating CP. The complexity of healthcare processes can be best tackled by analyzing stakeholders, which we treat as social agents, their goals and patterns of action within the agent network. Originality/value: The current modeling methods describe CPs from a structural aspect comprising activities, properties and interrelationships. However, these methods lack a mechanism to describe possible patterns of human behavior and the conditions under which the

  7. 77 FR 51518 - Alternative Personnel Management System (APMS) at the National Institute of Standards and Technology

    Science.gov (United States)

    2012-08-24

    ... through automation. Since implementing the APMS in 1987, according to findings in the Office of Personnel..., provides agencies with the authority to appoint candidates directly to jobs for which OPM determines that... advertises the availability of job opportunities in direct-hire occupations by posting on the OPM USAJOBS Web...

  8. Carmen de Burgos, la APM y aquellas admirables chicas del 98

    Directory of Open Access Journals (Sweden)

    Hernando, Bernardino M.

    2010-06-01

    Full Text Available It enters the five women journalists pertaining to the Association of the Press of Madrid (APM was the writer, professor, lecturer and hardened travelling Carmen de Burgos, Colombine call. It and the other four, Jesusa Granda, participant in the foundation of the APM in 1895, Atocha Ossorio and Gallardo, Salomé Núñez de Topete and Consuelo Álvarez Pool trained a made an effort group of admirable women fighters by the culture and the human rights. Identified with the advanced to “generation of 98” if this nonhuibera be as chauvinistic as was almost everything then.

    Entre las cinco primeras mujeres periodistas pertenecientes a la Asociación de la Prensa de Madrid (APM estaba la escritora, profesora, conferenciante y empedernida viajera Carmen de Burgos, llamada Colombine. Ella y las otras cuatro, Jesusa Granda, participante en la fundación de la APM en 1895, Atocha Ossorio y Gallardo, Salomé Núñez de Topete y Consuelo Álvarez Pool formaban un grupo esforzado de admirables mujeres luchadoras por la cultura y los derechos humanos. Identificadas con los ideales sociales más avanzados podrían haber pertenecido a la “generación del 98” si esta no hubiera sido tan machista como era casi todo en aquella época.

  9. Modeling biological pathway dynamics with timed automata.

    Science.gov (United States)

    Schivo, Stefano; Scholma, Jetse; Wanders, Brend; Urquidi Camacho, Ricardo A; van der Vet, Paul E; Karperien, Marcel; Langerak, Rom; van de Pol, Jaco; Post, Janine N

    2014-05-01

    Living cells are constantly subjected to a plethora of environmental stimuli that require integration into an appropriate cellular response. This integration takes place through signal transduction events that form tightly interconnected networks. The understanding of these networks requires capturing their dynamics through computational support and models. ANIMO (analysis of Networks with Interactive Modeling) is a tool that enables the construction and exploration of executable models of biological networks, helping to derive hypotheses and to plan wet-lab experiments. The tool is based on the formalism of Timed Automata, which can be analyzed via the UPPAAL model checker. Thanks to Timed Automata, we can provide a formal semantics for the domain-specific language used to represent signaling networks. This enforces precision and uniformity in the definition of signaling pathways, contributing to the integration of isolated signaling events into complex network models. We propose an approach to discretization of reaction kinetics that allows us to efficiently use UPPAAL as the computational engine to explore the dynamic behavior of the network of interest. A user-friendly interface hides the use of Timed Automata from the user, while keeping the expressive power intact. Abstraction to single-parameter kinetics speeds up construction of models that remain faithful enough to provide meaningful insight. The resulting dynamic behavior of the network components is displayed graphically, allowing for an intuitive and interactive modeling experience.

  10. APMS: An Integrated Suite of Tools for Measuring Performance and Safety

    Science.gov (United States)

    Statler, Irving C.; Lynch, Robert E.; Connors, Mary M. (Technical Monitor)

    1997-01-01

    This is a report of work in progress. In it, I summarize the status of the research and development of the Aviation Performance Measuring System (APMS) for managing, processing, and analyzing digital flight-recorded data. The objectives of the NASA-FAA APMS research project are to establish a sound scientific and technological basis for flight-data analysis, to define an open and flexible architecture for flight-data-analysis systems, and to articulate guidelines for a standardized database structure on which to continue to build future flight-data-analysis extensions. APMS will offer to the air transport community an open, voluntary standard for flight-data-analysis software, a standard that will help to ensure suitable functionality, and data interchangeability, among competing software programs. APMS will develop and document the methodologies, algorithms, and procedures for data management and analyses to enable users to easily interpret the implications regarding safety and efficiency of operations. APMS does not entail the implementation of a nationwide flight-data-collection system. It is intended to provide technical tools to ease the large-scale implementation of flight-data analyses at both the air-carrier and the national-airspace levels in support of their Flight Operations and Quality Assurance (FOQA) Programs and Advanced Qualifications Programs (AQP). APMS cannot meet its objectives unless it develops tools that go substantially beyond the capabilities of the current commercially available software and supporting analytic methods that are mainly designed to count special events. These existing capabilities, while of proven value, were created primarily with the needs of air crews in mind. APMS tools must serve the needs of the government and air carriers, as well as air crews, to fully support the FOQA and AQP programs. They must be able to derive knowledge not only through the analysis of single flights (special-event detection), but through

  11. The Aviation Performance Measuring System (APMS): An Integrated Suite of Tools for Measuring Performance and Safety

    Science.gov (United States)

    Statler, Irving C.; Connor, Mary M. (Technical Monitor)

    1998-01-01

    This is a report of work in progress. In it, I summarize the status of the research and development of the Aviation Performance Measuring System (APMS) for managing, processing, and analyzing digital flight-recorded data, The objectives of the NASA-FAA APMS research project are to establish a sound scientific and technological basis for flight-data analysis, to define an open and flexible architecture for flight-data analysis systems, and to articulate guidelines for a standardized database structure on which to continue to build future flight-data-analysis extensions. APMS offers to the air transport community an open, voluntary standard for flight-data-analysis software; a standard that will help to ensure suitable functionality and data interchangeability among competing software programs. APMS will develop and document the methodologies, algorithms, and procedures for data management and analyses to enable users to easily interpret the implications regarding safety and efficiency of operations. APMS does not entail the implementation of a nationwide flight-data-collection system. It is intended to provide technical tools to ease the large-scale implementation of flight-data analyses at both the air-carrier and the national-airspace levels in support of their Flight Operations and Quality Assurance (FOQA) Programs and Advanced Qualifications Programs (AQP). APMS cannot meet its objectives unless it develops tools that go substantially beyond the capabilities of the current commercially available software and supporting analytic methods that are mainly designed to count special events. These existing capabilities, while of proven value, were created primarily with the needs-of aircrews in mind. APMS tools must serve the needs of the government and air carriers, as well as aircrews, to fully support the FOQA and AQP programs. They must be able to derive knowledge not only through the analysis of single flights (special-event detection), but also through

  12. Stochastic modeling of virus capsid assembly pathways

    Science.gov (United States)

    Schwartz, Russell

    2009-03-01

    Virus capsids have become a key model system for understanding self-assembly due to their high complexity, robust and efficient assembly processes, and experimental tractability. Our ability to directly examine and manipulate capsid assembly kinetics in detail nonetheless remains limited, creating a need for computer models that can infer experimentally inaccessible features of the assembly process and explore the effects of hypothetical manipulations on assembly trajectories. We have developed novel algorithms for stochastic simulation of capsid assembly [1,2] that allow us to model capsid assembly over broad parameter spaces [3]. We apply these methods to study the nature of assembly pathway control in virus capsids as well as their sensitivity to assembly conditions and possible experimental interventions. [4pt] [1] F. Jamalyaria, R. Rohlfs, and R. Schwartz. J Comp Phys 204, 100 (2005). [0pt] [2] N. Misra and R. Schwartz. J Chem Phys 129, in press (2008). [0pt] [3] B. Sweeney, T. Zhang, and R. Schwartz. Biophys J 94, 772 (2008).

  13. Optimal time points sampling in pathway modelling.

    Science.gov (United States)

    Hu, Shiyan

    2004-01-01

    Modelling cellular dynamics based on experimental data is at the heart of system biology. Considerable progress has been made to dynamic pathway modelling as well as the related parameter estimation. However, few of them gives consideration for the issue of optimal sampling time selection for parameter estimation. Time course experiments in molecular biology rarely produce large and accurate data sets and the experiments involved are usually time consuming and expensive. Therefore, to approximate parameters for models with only few available sampling data is of significant practical value. For signal transduction, the sampling intervals are usually not evenly distributed and are based on heuristics. In the paper, we investigate an approach to guide the process of selecting time points in an optimal way to minimize the variance of parameter estimates. In the method, we first formulate the problem to a nonlinear constrained optimization problem by maximum likelihood estimation. We then modify and apply a quantum-inspired evolutionary algorithm, which combines the advantages of both quantum computing and evolutionary computing, to solve the optimization problem. The new algorithm does not suffer from the morass of selecting good initial values and being stuck into local optimum as usually accompanied with the conventional numerical optimization techniques. The simulation results indicate the soundness of the new method.

  14. Evaluating between-pathway models with expression data.

    Science.gov (United States)

    Hescott, B J; Leiserson, M D M; Cowen, L J; Slonim, D K

    2010-03-01

    Between-pathway models (BPMs) are network motifs consisting of pairs of putative redundant pathways. In this article, we show how adding another source of high-throughput data--microarray gene expression data from knockout experiments--allows us to identify a compensatory functional relationship between genes from the two BPM pathways. We evaluate the quality of the BPMs from four different studies, and we describe how our methods might be extended to refine pathways.

  15. How alternative payment models in emergency medicine can benefit physicians, payers, and patients.

    Science.gov (United States)

    Harish, Nir J; Miller, Harold D; Pines, Jesse M; Zane, Richard D; Wiler, Jennifer L

    2017-06-01

    While there has been considerable effort devoted to developing alternative payment models (APMs) for primary care physicians and for episodes of care beginning with inpatient admissions, there has been relatively little attention by payers to developing APMs for specialty ambulatory care, and no efforts to develop APMs that explicitly focus on emergency care. In order to ensure that emergency care is appropriately integrated and valued in future payment models, emergency physicians (EPs) must engage with the stakeholders within the broader health care system. In this article, we describe a framework for the development of APMs for emergency medicine and present four examples of APMs that may be applicable in emergency medicine. A better understanding of how APMs can work in emergency medicine will help EPs develop new APMs that improve the cost and quality of care, and leverage the value that emergency care brings to the system. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Uji Angka Paling Mungkin (APM) Coliform pada Teh Kering Dalam Kemasan

    OpenAIRE

    Gaol, Patma Lumban

    2017-01-01

    142410054 Teh kering dalam kemasan adalah produk teh kering tunggal atau campuran dari teh hitam, teh hijau, teh putih dan atau teh beraroma lain yang harus memenuhi ketentuan Standar Nasional Indonesia (SNI). Pengujian ini bertujuan untuk memeriksa adanya bakteri coliform pada teh kering dalam kemasan dengan persyaratan SNI yang berlaku. Pengujian bakteri coliform dilakukan dengan metode Angka Paling Mungkin (APM) Coliform menggunakan metode tiga tabung berdasarkan metode MA Supp 69/MIK/0...

  17. The Impact of Alternative Payment Models on Oncology Innovation and Patient Care.

    Science.gov (United States)

    Miller, Amy M; Omenn, Gilbert S; Kean, Marcia A

    2016-05-15

    Oncology care is in a time of major transformation. Scientific discovery is driving breakthroughs in prevention, diagnostics, and treatment, resulting in tremendous gains for patients as the number of cancer survivors continues to grow on an annual basis. At the same time, there is mounting pressure across the healthcare system to contain costs while improving the quality of cancer care. In response to this pressure, private and government payers are increasingly turning to tools such as alternative payment models (APM) and clinical pathways to improve the efficiency of care, inform coverage decisions, and support shared decision-making. As APMs, clinical pathways and other tools are utilized more broadly, it will be critical that these models support the evidence-based use of innovative biomedical advances, including personalized medicine, and deliver patient-centered, high-value care. Clin Cancer Res; 22(10); 2335-41. ©2016 AACR. ©2016 American Association for Cancer Research.

  18. APM_GUI: analyzing particle movement on the cell membrane and determining confinement.

    Science.gov (United States)

    Menchón, Silvia A; Martín, Mauricio G; Dotti, Carlos G

    2012-02-20

    Single-particle tracking is a powerful tool for tracking individual particles with high precision. It provides useful information that allows the study of diffusion properties as well as the dynamics of movement. Changes in particle movement behavior, such as transitions between Brownian motion and temporary confinement, can reveal interesting biophysical interactions. Although useful applications exist to determine the paths of individual particles, only a few software implementations are available to analyze these data, and these implementations are generally not user-friendly and do not have a graphical interface,. Here, we present APM_GUI (Analyzing Particle Movement), which is a MatLab-implemented application with a Graphical User Interface. This user-friendly application detects confined movement considering non-random confinement when a particle remains in a region longer than a Brownian diffusant would remain. In addition, APM_GUI exports the results, which allows users to analyze this information using software that they are familiar with. APM_GUI provides an open-source tool that quantifies diffusion coefficients and determines whether trajectories have non-random confinements. It also offers a simple and user-friendly tool that can be used by individuals without programming skills.

  19. APM_GUI: analyzing particle movement on the cell membrane and determining confinement

    Directory of Open Access Journals (Sweden)

    Menchón Silvia A

    2012-02-01

    Full Text Available Abstract Background Single-particle tracking is a powerful tool for tracking individual particles with high precision. It provides useful information that allows the study of diffusion properties as well as the dynamics of movement. Changes in particle movement behavior, such as transitions between Brownian motion and temporary confinement, can reveal interesting biophysical interactions. Although useful applications exist to determine the paths of individual particles, only a few software implementations are available to analyze these data, and these implementations are generally not user-friendly and do not have a graphical interface,. Results Here, we present APM_GUI (Analyzing Particle Movement, which is a MatLab-implemented application with a Graphical User Interface. This user-friendly application detects confined movement considering non-random confinement when a particle remains in a region longer than a Brownian diffusant would remain. In addition, APM_GUI exports the results, which allows users to analyze this information using software that they are familiar with. Conclusions APM_GUI provides an open-source tool that quantifies diffusion coefficients and determines whether trajectories have non-random confinements. It also offers a simple and user-friendly tool that can be used by individuals without programming skills.

  20. Novel personalized pathway-based metabolomics models reveal key metabolic pathways for breast cancer diagnosis

    DEFF Research Database (Denmark)

    Huang, Sijia; Chong, Nicole; Lewis, Nathan

    2016-01-01

    diagnosis. We applied this method to predict breast cancer occurrence, in combination with correlation feature selection (CFS) and classification methods. Results: The resulting all-stage and early-stage diagnosis models are highly accurate in two sets of testing blood samples, with average AUCs (Area Under.......993. Moreover, important metabolic pathways, such as taurine and hypotaurine metabolism and the alanine, aspartate, and glutamate pathway, are revealed as critical biological pathways for early diagnosis of breast cancer. Conclusions: We have successfully developed a new type of pathway-based model to study...... metabolomics data for disease diagnosis. Applying this method to blood-based breast cancer metabolomics data, we have discovered crucial metabolic pathway signatures for breast cancer diagnosis, especially early diagnosis. Further, this modeling approach may be generalized to other omics data types for disease...

  1. Building executable biological pathway models automatically from BioPAX

    NARCIS (Netherlands)

    Willemsen, Timo; Feenstra, Anton; Groth, Paul

    2013-01-01

    The amount of biological data exposed in semantic formats is steadily increasing. In particular, pathway information (a model of how molecules interact within a cell) from databases such as KEGG and WikiPathways are available in a standard RDF-based format BioPAX. However, these models are

  2. Precise generation of systems biology models from KEGG pathways.

    Science.gov (United States)

    Wrzodek, Clemens; Büchel, Finja; Ruff, Manuel; Dräger, Andreas; Zell, Andreas

    2013-02-21

    The KEGG PATHWAY database provides a plethora of pathways for a diversity of organisms. All pathway components are directly linked to other KEGG databases, such as KEGG COMPOUND or KEGG REACTION. Therefore, the pathways can be extended with an enormous amount of information and provide a foundation for initial structural modeling approaches. As a drawback, KGML-formatted KEGG pathways are primarily designed for visualization purposes and often omit important details for the sake of a clear arrangement of its entries. Thus, a direct conversion into systems biology models would produce incomplete and erroneous models. Here, we present a precise method for processing and converting KEGG pathways into initial metabolic and signaling models encoded in the standardized community pathway formats SBML (Levels 2 and 3) and BioPAX (Levels 2 and 3). This method involves correcting invalid or incomplete KGML content, creating complete and valid stoichiometric reactions, translating relations to signaling models and augmenting the pathway content with various information, such as cross-references to Entrez Gene, OMIM, UniProt ChEBI, and many more.Finally, we compare several existing conversion tools for KEGG pathways and show that the conversion from KEGG to BioPAX does not involve a loss of information, whilst lossless translations to SBML can only be performed using SBML Level 3, including its recently proposed qualitative models and groups extension packages. Building correct BioPAX and SBML signaling models from the KEGG database is a unique characteristic of the proposed method. Further, there is no other approach that is able to appropriately construct metabolic models from KEGG pathways, including correct reactions with stoichiometry. The resulting initial models, which contain valid and comprehensive SBML or BioPAX code and a multitude of cross-references, lay the foundation to facilitate further modeling steps.

  3. Chemical Transformation Motifs --- Modelling Pathways as Integer Hyperflows

    DEFF Research Database (Denmark)

    Andersen, Jakob L.; Flamm, Christoph; Merkle, Daniel

    2018-01-01

    analysis are discussed in detail. To demonstrate the applicability of the mathematical framework to real-life problems we first explore the design space of possible non-oxidative glycolysis pathways and show that recent manually designed pathways can be further optimised. We then use a model of sugar...... chemistry to investigate pathways in the autocatalytic formose process. A graph transformation-based approach is used to automatically generate the reaction networks of interest....

  4. Designing a Care Pathway Model - A Case Study of the Outpatient Total Hip Arthroplasty Care Pathway.

    Science.gov (United States)

    Oosterholt, Robin I; Simonse, Lianne Wl; Boess, Stella U; Vehmeijer, Stephan Bw

    2017-03-09

    Although the clinical attributes of total hip arthroplasty (THA) care pathways have been thoroughly researched, a detailed understanding of the equally important organisational attributes is still lacking. The aim of this article is to contribute with a model of the outpatient THA care pathway that depicts how the care team should be organised to enable patient discharge on the day of surgery. The outpatient THA care pathway enables patients to be discharged on the day of surgery, shortening the length of stay and intensifying the provision and organisation of care. We utilise visual care modelling to construct a visual design of the organisation of the care pathway. An embedded case study was conducted of the outpatient THA care pathway at a teaching hospital in the Netherlands. The data were collected using a visual care modelling toolkit in 16 semi-structured interviews. Problems and inefficiencies in the care pathway were identified and addressed in the iterative design process. The results are two visual models of the most critical phases of the outpatient THA care pathway: diagnosis & preparation (1) and mobilisation & discharge (4). The results show the care team composition, critical value exchanges, and sequence that enable patient discharge on the day of surgery. The design addressed existing problems and is an optimisation of the case hospital's pathway. The network of actors consists of the patient (1), radiologist (1), anaesthetist (1), nurse specialist (1), pharmacist (1), orthopaedic surgeon (1,4), physiotherapist (1,4), nurse (4), doctor (4) and patient application (1,4). The critical value exchanges include patient preparation (mental and practical), patient education, aligned care team, efficient sequence of value exchanges, early patient mobilisation, flexible availability of the physiotherapist, functional discharge criteria, joint decision making and availability of the care team.

  5. Version control of pathway models using XML patches.

    Science.gov (United States)

    Saffrey, Peter; Orton, Richard

    2009-03-17

    Computational modelling has become an important tool in understanding biological systems such as signalling pathways. With an increase in size complexity of models comes a need for techniques to manage model versions and their relationship to one another. Model version control for pathway models shares some of the features of software version control but has a number of differences that warrant a specific solution. We present a model version control method, along with a prototype implementation, based on XML patches. We show its application to the EGF/RAS/RAF pathway. Our method allows quick and convenient storage of a wide range of model variations and enables a thorough explanation of these variations. Trying to produce these results without such methods results in slow and cumbersome development that is prone to frustration and human error.

  6. A kinetic model for the penicillin biosynthetic pathway in

    DEFF Research Database (Denmark)

    Nielsen, Jens; Jørgensen, Henrik

    1996-01-01

    A kinetic model for the first two steps in the penicillin biosynthetic pathway, i.e. the ACV synthetase (ACVS) and the isopenicillin N synthetase (IPNS) is proposed. The model is based on Michaelis-Menten type kinetics with non-competitive inhibition of the ACVS by ACV, and competitive inhibition...... of the IPNS by glutathione. The model predicted flux through the pathway corresponds well with the measured rate of penicillin biosynthesis. From the kinetic model the elasticity coefficients and the flux control coefficients are calculated throughout a fed-batch cultivation, and it is found...

  7. Computational Modeling of Biological Systems From Molecules to Pathways

    CERN Document Server

    2012-01-01

    Computational modeling is emerging as a powerful new approach for studying and manipulating biological systems. Many diverse methods have been developed to model, visualize, and rationally alter these systems at various length scales, from atomic resolution to the level of cellular pathways. Processes taking place at larger time and length scales, such as molecular evolution, have also greatly benefited from new breeds of computational approaches. Computational Modeling of Biological Systems: From Molecules to Pathways provides an overview of established computational methods for the modeling of biologically and medically relevant systems. It is suitable for researchers and professionals working in the fields of biophysics, computational biology, systems biology, and molecular medicine.

  8. Modelling and Analysis of Biochemical Signalling Pathway Cross-talk

    Directory of Open Access Journals (Sweden)

    Robin Donaldson

    2010-02-01

    Full Text Available Signalling pathways are abstractions that help life scientists structure the coordination of cellular activity. Cross-talk between pathways accounts for many of the complex behaviours exhibited by signalling pathways and is often critical in producing the correct signal-response relationship. Formal models of signalling pathways and cross-talk in particular can aid understanding and drive experimentation. We define an approach to modelling based on the concept that a pathway is the (synchronising parallel composition of instances of generic modules (with internal and external labels. Pathways are then composed by (synchronising parallel composition and renaming; different types of cross-talk result from different combinations of synchronisation and renaming. We define a number of generic modules in PRISM and five types of cross-talk: signal flow, substrate availability, receptor function, gene expression and intracellular communication. We show that Continuous Stochastic Logic properties can both detect and distinguish the types of cross-talk. The approach is illustrated with small examples and an analysis of the cross-talk between the TGF-b/BMP, WNT and MAPK pathways.

  9. Genetic pathways to Neurodegeneration Models and mechanisms ...

    Indian Academy of Sciences (India)

    Paige Rudich

    Models and mechanisms of repeat expansion disorders: a worm's eye view ..... retardation 1 gene FMR1 gives rise to a spectrum of neurological disorders (Saul and Tarleton ... autism. Shorter repeat expansion lengths from 55-200 cause the.

  10. How Does Attention Relate to the Ability-Specific and Position-Specific Components of Reasoning Measured by APM?

    Science.gov (United States)

    Ren, Xuezhu; Goldhammer, Frank; Moosbrugger, Helfried; Schweizer, Karl

    2012-01-01

    The aim of the present study was to clarify the nature of the ability-specific and position-specific components of Raven's Advanced Progressive Matrices (APM) by relating them to a number of types of attention. The ability-specific component represents the constant part of cognitive performance whereas the position-specific component reflects the…

  11. Construction and completion of flux balance models from pathway databases.

    Science.gov (United States)

    Latendresse, Mario; Krummenacker, Markus; Trupp, Miles; Karp, Peter D

    2012-02-01

    Flux balance analysis (FBA) is a well-known technique for genome-scale modeling of metabolic flux. Typically, an FBA formulation requires the accurate specification of four sets: biochemical reactions, biomass metabolites, nutrients and secreted metabolites. The development of FBA models can be time consuming and tedious because of the difficulty in assembling completely accurate descriptions of these sets, and in identifying errors in the composition of these sets. For example, the presence of a single non-producible metabolite in the biomass will make the entire model infeasible. Other difficulties in FBA modeling are that model distributions, and predicted fluxes, can be cryptic and difficult to understand. We present a multiple gap-filling method to accelerate the development of FBA models using a new tool, called MetaFlux, based on mixed integer linear programming (MILP). The method suggests corrections to the sets of reactions, biomass metabolites, nutrients and secretions. The method generates FBA models directly from Pathway/Genome Databases. Thus, FBA models developed in this framework are easily queried and visualized using the Pathway Tools software. Predicted fluxes are more easily comprehended by visualizing them on diagrams of individual metabolic pathways or of metabolic maps. MetaFlux can also remove redundant high-flux loops, solve FBA models once they are generated and model the effects of gene knockouts. MetaFlux has been validated through construction of FBA models for Escherichia coli and Homo sapiens. Pathway Tools with MetaFlux is freely available to academic users, and for a fee to commercial users. Download from: biocyc.org/download.shtml. mario.latendresse@sri.com Supplementary data are available at Bioinformatics online.

  12. MACRA, Alternative Payment Models, and the Physician-Focused Payment Model: Implications for Radiology.

    Science.gov (United States)

    Rosenkrantz, Andrew B; Nicola, Gregory N; Allen, Bibb; Hughes, Danny R; Hirsch, Joshua A

    2017-06-01

    The Medicare Access and CHIP Reauthorization Act (MACRA) of 2015 describes alternative payment models (APMs) as new approaches to health care payment that incentivize higher quality and value. MACRA incentivizes increasing APM participation by all physician specialties over the coming years. Some APMs will be deemed Advanced APMs; clinicians who are a Qualifying Participant in an Advanced APM will receive substantial benefits under MACRA including an automatic 5% payment bonus, regardless of their performance and savings within the APM, and a larger payment rate increase beginning in 2026. Existing APMs are most relevant to primary care physicians, and opportunities for radiologists to participate in Advanced APMs fulfilling Qualified Participant requirements are limited. Physician-Focused Payment Models (PFPMs), as described in MACRA, are APMs that target physicians' Medicare payments based on quality and cost of physician services. PFPMs must address a new issue or specialty compared with existing APMs and will thus foster a more diverse range of APMs encompassing a wider range of specialties. The PFPM Technical Advisory Committee is a new independent agency that will review proposals for new PFPMs and provide recommendations to CMS regarding their approval. The PFPM Technical Advisory Committee comprises largely primary care physicians and health policy experts and is not required to consult clinical experts when reviewing new specialist-proposed PFPMs. As PFPMs provide a compelling opportunity for radiologists to demonstrate and be rewarded for their unique contributions toward patient care, radiologists should embrace this new model and actively partner with other stakeholders in developing radiology-relevant PFPMs. Copyright © 2016 American College of Radiology. Published by Elsevier Inc. All rights reserved.

  13. On the study of ricochet and penetration in sand, water and gelatin by spheres, 7.62 mm APM2, and 25 mm projectiles

    Directory of Open Access Journals (Sweden)

    John F. Moxnes

    2016-04-01

    Full Text Available We examine the ricochet and penetration behavior in sand, water and gelatin by steel spheres, 7.62 mm APM2 and 25 mm projectiles. A threshold impact angle (critical angle exists beyond which ricochet cannot occur. The Autodyn simulation code with the smooth particle hydrodynamic (SPH method and Impetus Afea Solver with the corpuscular model are used and the results are compared with experimental and analytical results. The resistance force in sand for spheres was proportional to a term quadratic in velocity plus a term linear in velocity. The drag coefficient for the quadratic term was 0.65. The Autodyn and Impetus Afea codes simulate too large penetration due to the lack of a linear velocity resistance force. Critical ricochet angles were consistent with analytical results in the literature. In ballistic gelatin at velocities of 50–850 m/s a drag coefficient of 0.30 fits the high speed camera recordings if a linear velocity resistance term is included. However, only a quadratic velocity resistance force with drag coefficient that varies with the Reynolds number also fits the measurements. The simulation of a sphere in water with Autodyn showed too large drag coefficient. The 7.62 mm APM2 core simulations in sand fit reasonable well for both codes. The 25 mm projectile ricochet simulations in sand show consistency with the high speed camera recordings. Computer time was reduced by one to two orders of magnitudes when applying the Impetus Afea Solver compared to Autodyn code due to the use of the graphics processing units (GPU.

  14. Development of an Ingestion Pathway Model for AXAIRQ

    Energy Technology Data Exchange (ETDEWEB)

    Simpkins, A.A.

    1999-01-13

    AXAIRQ is a dose mode code used for prospective accident assessment at the Savannah River Site and is primarily used to show regulatory compliance. For completeness of pathway analysis, an ingestion model, AXINGST, has been developed for use with, and incorporation in, AXAIRQ. Currently available ingestion models were referenced as a basis for AXINGST. AXINGST calculates a conservative ingestion dose following an atmospheric release of radionuclides and includes site specific variables where applicable.

  15. A multi-pathway model for photosynthetic reaction center

    International Nuclear Information System (INIS)

    Qin, M.; Shen, H. Z.; Yi, X. X.

    2016-01-01

    Charge separation occurs in a pair of tightly coupled chlorophylls at the heart of photosynthetic reaction centers of both plants and bacteria. Recently it has been shown that quantum coherence can, in principle, enhance the efficiency of a solar cell, working like a quantum heat engine. Here, we propose a biological quantum heat engine (BQHE) motivated by Photosystem II reaction center (PSII RC) to describe the charge separation. Our model mainly considers two charge-separation pathways which is more than that typically considered in the published literature. We explore how these cross-couplings increase the current and power of the charge separation and discuss the effects of multiple pathways in terms of current and power. The robustness of the BQHE against the charge recombination in natural PSII RC and dephasing induced by environments is also explored, and extension from two pathways to multiple pathways is made. These results suggest that noise-induced quantum coherence helps to suppress the influence of acceptor-to-donor charge recombination, and besides, nature-mimicking architectures with engineered multiple pathways for charge separations might be better for artificial solar energy devices considering the influence of environments.

  16. Experience in Using Russian Program Complex «APM Winmachine» for Computing Local Strength of the Umbilical Mast Bearing Construction in the SR “Soyuz-2.1B"

    Directory of Open Access Journals (Sweden)

    V. A. Zverev

    2015-01-01

    Full Text Available The research concerns the computational analyses of local strength of the umbilical mast (UM, which is designed for the prelaunch preparation and launch security of the space rocket (SR "SOYUZ-2" of 1B stage.Based on the finite elements method, modeling and calculation of local strength for the most loaded UM elements are conducted using Russian program complex «APM WINMACHINE». The paper gives a justification for choosing the program complex «APM WINMACHINE, as a program calculation device.In calculating the principles of a local analysis are used. Physical models of the UM particular constructive units are formed to observe them under certain boundary conditions: forces and movements. Parameters of boundary conditions are determined in terms of stress-strain condition of UM simplified model as a whole.As the research results, the paper presents the finite element models of two UM constructive units, namely a joint of the mast farm branches with strengthening of the mast rotating part and an element in the UM bottom rotating part (“the spine”. Besides, there are also the calculated results of the local strength of abovementioned UM rotating part units: a general pattern of the stress distribution with stress values exceeding the allowable ones.The research results allow us to draw conclusions that the units under consideration have performance capability and require their constructive strengthening.The UM developers have taken in consideration recommendations, based on the UM rotating part local strength calculation, making appropriate correction in the project documentation. The experience gained in using the «APM WINMACHINE» allowed us to support the conclusion that it is efficient to solve the tasks of defining stress-strain condition of complicated spatial constructions.

  17. Comparison of Perturbed Pathways in Two Different Cell Models for Parkinson's Disease with Structural Equation Model.

    Science.gov (United States)

    Pepe, Daniele; Do, Jin Hwan

    2015-12-16

    Increasing evidence indicates that different morphological types of cell death coexist in the brain of patients with Parkinson's disease (PD), but the molecular explanation for this is still under investigation. In this study, we identified perturbed pathways in two different cell models for PD through the following procedures: (1) enrichment pathway analysis with differentially expressed genes and the Reactome pathway database, and (2) construction of the shortest path model for the enriched pathway and detection of significant shortest path model with fitting time-course microarray data of each PD cell model to structural equation model. Two PD cell models constructed by the same neurotoxin showed different perturbed pathways. That is, one showed perturbation of three Reactome pathways, including cellular senescence, chromatin modifying enzymes, and chromatin organization, while six modules within metabolism pathway represented perturbation in the other. This suggests that the activation of common upstream cell death pathways in PD may result in various down-stream processes, which might be associated with different morphological types of cell death. In addition, our results might provide molecular clues for coexistence of different morphological types of cell death in PD patients.

  18. BioPlex Display: An Interactive Suite for Large-Scale AP-MS Protein-Protein Interaction Data.

    Science.gov (United States)

    Schweppe, Devin K; Huttlin, Edward L; Harper, J Wade; Gygi, Steven P

    2018-01-05

    The development of large-scale data sets requires a new means to display and disseminate research studies to large audiences. Knowledge of protein-protein interaction (PPI) networks has become a principle interest of many groups within the field of proteomics. At the confluence of technologies, such as cross-linking mass spectrometry, yeast two-hybrid, protein cofractionation, and affinity purification mass spectrometry (AP-MS), detection of PPIs can uncover novel biological inferences at a high-throughput. Thus new platforms to provide community access to large data sets are necessary. To this end, we have developed a web application that enables exploration and dissemination of the growing BioPlex interaction network. BioPlex is a large-scale interactome data set based on AP-MS of baits from the human ORFeome. The latest BioPlex data set release (BioPlex 2.0) contains 56 553 interactions from 5891 AP-MS experiments. To improve community access to this vast compendium of interactions, we developed BioPlex Display, which integrates individual protein querying, access to empirical data, and on-the-fly annotation of networks within an easy-to-use and mobile web application. BioPlex Display enables rapid acquisition of data from BioPlex and development of hypotheses based on protein interactions.

  19. Exploration of the Raven APM-National Adult Reading Test discrepancy as a measure of intellectual decline in older persons.

    Science.gov (United States)

    van den Berg, Esther; Nys, Gudrun M S; Brands, Augustina M A; Ruis, Carla; van Zandvoort, Martine J E; Kessels, Roy P C

    2013-01-01

    Previous studies have shown that the discrepancy between performance on "fluid" and "crystallized" intelligence measures may serve as an indicator for intellectual decline. The validity of this procedure in older persons is unknown. The present study developed a multiple regression equation, to predict the Raven Advanced Progressive Matrices (APM) score from the National Adult Reading Test (NART) score and demographic variables in a large sample of healthy older persons (n = 270). The discrepancy between the predicted and observed Raven APM scores was transformed into a percentile distribution as an indicator of intellectual decline, which can be used in clinical practice. The validity of the procedure was further examined by comparing the proportion of persons with a significant decline (at the -1 and -1.65 SD level) between two older patient samples (87 patients with cerebral stroke and 387 patients with diabetes mellitus) by means of χ(2) tests. There was a significantly higher rate of intellectual decline at the -1 SD ("below average") and -1.65 SD ("impaired") cutoff levels for patients with stroke compared with patients with diabetes (stroke, 34% and 14%; diabetes, 16% and 5%, p Raven APM-NART discrepancy may be a useful measure of intellectual decline in older persons.

  20. k0-INAA for APM samples collected in period of June 2004 - March 2005 and some marine certified reference materials

    International Nuclear Information System (INIS)

    Dung, Ho Manh; Vu, Cao Dong; Y, Truong; Sy, Nguyen Thi

    2006-01-01

    The airborne particulate matter (APM) samples have been collected in 2004 using two types of polycarbonate membrane filter PM 2.5 and PM 2.5-10 at two sites of industrial (Ho Chi Mihn City) and rural (Dateh) regions in south of Vietnam. Three marine certified reference materials have been selected to establish a k0-NAA procedure for marine samples. The concentration of trace multi-element in the samples has been determined by the k 0 -INAA procedure using K o -DALAT software developed in Dalat NRI. About 28 elements in 224 APM samples collected at two areas of Dateh and HCMC of Vietnam in period from June, 2004 to March, 2005 were presented in report. The statistical analysis was applied to the data set to investigate the pollution source at sampling sites. The results proved that the k 0 -NAA on the Dalat research reactor is a reliable and effective analytical technique for characterization of trace multi-element in APM and marine samples for air and marine environmental pollution study in Vietnam. (author)

  1. Selection of Models for Ingestion Pathway and Relocation

    International Nuclear Information System (INIS)

    Blanchard, A.; Thompson, J.M.

    1998-01-01

    The area in which intermediate phase protective actions (such as food interdiction and relocation) may be needed following postulated accidents at three Savannah River Site nonreactor nuclear facilities will be determined by modeling. The criteria used to select dispersion/deposition models are presented. Several models are considered, including ARAC, MACCS, HOTSPOT, WINDS (coupled with PUFF-PLUME), and UFOTRI. Although ARAC and WINDS are expected to provide more accurate modeling of atmospheric transport following an actual release, analyses consistent with regulatory guidance for planning purposes may be accomplished with comparatively simple dispersion models such as HOTSPOT and UFOTRI. A recommendation is made to use HOTSPOT for non-tritium facilities and UFOTRI for tritium facilities. The most recent Food and Drug Administration Derived Intervention Levels (August 1998) are adopted as evaluation guidelines for ingestion pathways

  2. Selection of Models for Ingestion Pathway and Relocation

    International Nuclear Information System (INIS)

    Blanchard, A.; Thompson, J.M.

    1999-01-01

    The area in which intermediate phase protective actions (such as food interdiction and relocation) may be needed following postulated accidents at three Savannah River Site nonreactor nuclear facilities will be determined by modeling. The criteria used to select dispersion/deposition models are presented. Several models are considered, including ARAC, MACCS, HOTSPOT, WINDS (coupled with PUFF-PLUME), and UFOTRI. Although ARAC and WINDS are expected to provide more accurate modeling of atmospheric transport following an actual release, analyses consistent with regulatory guidance for planning purposes may be accomplished with comparatively simple dispersion models such as HOTSPOT and UFOTRI. A recommendation is made to use HOTSPOT for non-tritium facilities and UFOTRI for tritium facilities. The most recent Food and Drug Administration Derived Intervention Levels (August 1998) are adopted as evaluation guidelines for ingestion pathways

  3. Sensitivity and uncertainty analysis of the PATHWAY radionuclide transport model

    International Nuclear Information System (INIS)

    Otis, M.D.

    1983-01-01

    Procedures were developed for the uncertainty and sensitivity analysis of a dynamic model of radionuclide transport through human food chains. Uncertainty in model predictions was estimated by propagation of parameter uncertainties using a Monte Carlo simulation technique. Sensitivity of model predictions to individual parameters was investigated using the partial correlation coefficient of each parameter with model output. Random values produced for the uncertainty analysis were used in the correlation analysis for sensitivity. These procedures were applied to the PATHWAY model which predicts concentrations of radionuclides in foods grown in Nevada and Utah and exposed to fallout during the period of atmospheric nuclear weapons testing in Nevada. Concentrations and time-integrated concentrations of iodine-131, cesium-136, and cesium-137 in milk and other foods were investigated. 9 figs., 13 tabs

  4. Risk methodology for geologic disposal of radioactive waste: model description and user manual for Pathways model

    International Nuclear Information System (INIS)

    Helton, J.C.; Kaestner, P.C.

    1981-03-01

    A model for the environmental movement and human uptake of radionuclides is presented. This model is designated the Pathways-to-Man Model and was developed as part of a project funded by the Nuclear Regulatory Commission to design a methodology to assess the risk associated with the geologic disposal of high-level radioactive waste. The Pathways-to-Man Model is divided into two submodels. One of these, the Environmental Transport Model, represents the long-term distribution and accumulation of radionuclides in the environment. This model is based on a mixed-cell approach and describes radionuclide movement with a system of linear differential equations. The other, the Transport-to-Man Model, represents the movement of radionuclides from the environment to man. This model is based on concentration ratios. General descriptions of these models are provided in this report. Further, documentation is provided for the computer program which implements the Pathways Model

  5. The modelling of external exposure and inhalation pathways in COSYMA

    International Nuclear Information System (INIS)

    Brown, J.; Simmonds, JR.; Ehrhardt, J.; Hasemann, I.

    1991-01-01

    Following an accidental release of radionuclides to atmosphere the major direct exposure pathways of concern are: external irradiation from material in the cloud; internal exposure following inhalation of material in the cloud; external irradiation from material deposited on the ground; and external irradiation due to contamination of skin and clothes. In addition material resuspended from the ground can be inhaled and lead to internal exposure. In this paper the way that these exposure pathways are modelled in COSYMA is described. At present in COSYMA external exposure from deposited material is modelled using a dataset of doses per unit deposit of various radionuclides. This dataset, is based on activity deposited on undisturbed soil. The basic data are for doses outdoors and shielding factors are used to estimate doses for people indoors. Various groups of people spending different amounts of time indoors and out can be considered and shielding factors appropriate to three building types can be adopted. A more complex model has also been developed to predict radiation exposure following deposition to different surfaces in the environment. This model called EXPURT is briefly described in this paper. Using EXPURT, doses as a function of time after a single deposit have been calculated for people living in three types of area. These results are described in the paper and compared with those that are currently used in COSYMA. The paper will also discuss what future work is required in this area and the adequacy of existing models

  6. Model of the pathway of −1 frameshifting: Long pausing

    Directory of Open Access Journals (Sweden)

    Ping Xie

    2016-03-01

    Full Text Available It has been characterized that the programmed ribosomal −1 frameshifting often occurs at the slippery sequence on the presence of a downstream mRNA pseudoknot. In some prokaryotic cases such as the dnaX gene of Escherichia coli, an additional stimulatory signal—an upstream, internal Shine–Dalgarno (SD sequence—is also necessary to stimulate the efficient −1 frameshifting. However, the molecular and physical mechanism of the −1 frameshifting is poorly understood. Here, we propose a model of the pathway of the −1 translational frameshifting during ribosome translation of the dnaX −1 frameshift mRNA. With the model, the single-molecule fluorescence data (Chen et al. (2014 [29] on the dynamics of the shunt either to long pausing or to normal translation, the tRNA transit and sampling dynamics in the long-paused rotated state, the EF-G sampling dynamics, the mean rotated-state lifetimes, etc., are explained quantitatively. Moreover, the model is also consistent with the experimental data (Yan et al. (2015 [30] on translocation excursions and broad branching of frameshifting pathways. In addition, we present some predicted results, which can be easily tested by future optical trapping experiments.

  7. Predictive Modelling Risk Calculators and the Non Dialysis Pathway.

    Science.gov (United States)

    Robins, Jennifer; Katz, Ivor

    2013-04-16

    This guideline will review the current prediction models and survival/mortality scores available for decision making in patients with advanced kidney disease who are being considered for a non-dialysis treatment pathway. Risk prediction is gaining increasing attention with emerging literature suggesting improved patient outcomes through individualised risk prediction (1). Predictive models help inform the nephrologist and the renal palliative care specialists in their discussions with patients and families about suitability or otherwise of dialysis. Clinical decision making in the care of end stage kidney disease (ESKD) patients on a non-dialysis treatment pathway is currently governed by several observational trials (3). Despite the paucity of evidence based medicine in this field, it is becoming evident that the survival advantages associated with renal replacement therapy in these often elderly patients with multiple co-morbidities and limited functional status may be negated by loss of quality of life (7) (6), further functional decline (5, 8), increased complications and hospitalisations. This article is protected by copyright. All rights reserved.

  8. Designing a Care Pathway Model – A Case Study of the Outpatient Total Hip Arthroplasty Care Pathway

    Directory of Open Access Journals (Sweden)

    Robin I. Oosterholt

    2017-03-01

    Full Text Available Introduction: Although the clinical attributes of total hip arthroplasty (THA care pathways have been thoroughly researched, a detailed understanding of the equally important organisational attributes is still lacking. The aim of this article is to contribute with a model of the outpatient THA care pathway that depicts how the care team should be organised to enable patient discharge on the day of surgery. Theory: The outpatient THA care pathway enables patients to be discharged on the day of surgery, short- ening the length of stay and intensifying the provision and organisation of care. We utilise visual care modelling to construct a visual design of the organisation of the care pathway. Methods: An embedded case study was conducted of the outpatient THA care pathway at a teaching hospital in the Netherlands. The data were collected using a visual care modelling toolkit in 16 semi- structured interviews. Problems and inefficiencies in the care pathway were identified and addressed in the iterative design process. Results: The results are two visual models of the most critical phases of the outpatient THA care pathway: diagnosis & preparation (1 and mobilisation & discharge (4. The results show the care team composition, critical value exchanges, and sequence that enable patient discharge on the day of surgery. Conclusion: The design addressed existing problems and is an optimisation of the case hospital’s pathway. The network of actors consists of the patient (1, radiologist (1, anaesthetist (1, nurse specialist (1, pharmacist (1, orthopaedic surgeon (1,4, physiotherapist (1,4, nurse (4, doctor (4 and patient applica- tion (1,4. The critical value exchanges include patient preparation (mental and practical, patient education, aligned care team, efficient sequence of value exchanges, early patient mobilisation, flexible availability of the physiotherapist, functional discharge criteria, joint decision making and availability of the care team.

  9. Deterministic modelling and stochastic simulation of biochemical pathways using MATLAB.

    Science.gov (United States)

    Ullah, M; Schmidt, H; Cho, K H; Wolkenhauer, O

    2006-03-01

    The analysis of complex biochemical networks is conducted in two popular conceptual frameworks for modelling. The deterministic approach requires the solution of ordinary differential equations (ODEs, reaction rate equations) with concentrations as continuous state variables. The stochastic approach involves the simulation of differential-difference equations (chemical master equations, CMEs) with probabilities as variables. This is to generate counts of molecules for chemical species as realisations of random variables drawn from the probability distribution described by the CMEs. Although there are numerous tools available, many of them free, the modelling and simulation environment MATLAB is widely used in the physical and engineering sciences. We describe a collection of MATLAB functions to construct and solve ODEs for deterministic simulation and to implement realisations of CMEs for stochastic simulation using advanced MATLAB coding (Release 14). The program was successfully applied to pathway models from the literature for both cases. The results were compared to implementations using alternative tools for dynamic modelling and simulation of biochemical networks. The aim is to provide a concise set of MATLAB functions that encourage the experimentation with systems biology models. All the script files are available from www.sbi.uni-rostock.de/ publications_matlab-paper.html.

  10. Position-specific isotope modeling of organic micropollutants transformation through different reaction pathways

    DEFF Research Database (Denmark)

    Jin, Biao; Rolle, Massimo

    2016-01-01

    The degradation of organic micropollutants occurs via different reaction pathways. Compound specific isotope analysis is a valuable tool to identify such degradation pathways in different environmental systems. We propose a mechanism-based modeling approach that provides a quantitative framework ...

  11. New Pathways between Group Theory and Model Theory

    CERN Document Server

    Fuchs, László; Goldsmith, Brendan; Strüngmann, Lutz

    2017-01-01

    This volume focuses on group theory and model theory with a particular emphasis on the interplay of the two areas. The survey papers provide an overview of the developments across group, module, and model theory while the research papers present the most recent study in those same areas. With introductory sections that make the topics easily accessible to students, the papers in this volume will appeal to beginning graduate students and experienced researchers alike. As a whole, this book offers a cross-section view of the areas in group, module, and model theory, covering topics such as DP-minimal groups, Abelian groups, countable 1-transitive trees, and module approximations. The papers in this book are the proceedings of the conference “New Pathways between Group Theory and Model Theory,” which took place February 1-4, 2016, in Mülheim an der Ruhr, Germany, in honor of the editors’ colleague Rüdiger Göbel. This publication is dedicated to Professor Göbel, who passed away in 2014. He was one of th...

  12. Hedgehog pathway activity in the LADY prostate tumor model

    Directory of Open Access Journals (Sweden)

    Kasper Susan

    2007-03-01

    Full Text Available Abstract Background Robust Hedgehog (Hh signaling has been implicated as a common feature of human prostate cancer and an important stimulus of tumor growth. The role of Hh signaling has been studied in several xenograft tumor models, however, the role of Hh in tumor development in a transgenic prostate cancer model has never been examined. Results We analyzed expression of Hh pathway components and conserved Hh target genes along with progenitor cell markers and selected markers of epithelial differentiation during tumor development in the LADY transgenic mouse model. Tumor development was associated with a selective increase in Ihh expression. In contrast Shh expression was decreased. Expression of the Hh target Patched (Ptc was significantly decreased while Gli1 expression was not significantly altered. A survey of other relevant genes revealed significant increases in expression of Notch-1 and Nestin together with decreased expression of HNF3a/FoxA1, NPDC-1 and probasin. Conclusion Our study shows no evidence for a generalized increase in Hh signaling during tumor development in the LADY mouse. It does reveal a selective increase in Ihh expression that is associated with increased expression of progenitor cell markers and decreased expression of terminal differentiation markers. These data suggest that Ihh expression may be a feature of a progenitor cell population that is involved in tumor development.

  13. Dynamic colloidal assembly pathways via low dimensional models

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Yuguang; Bevan, Michael A., E-mail: mabevan@jhu.edu [Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland 21218 (United States); Thyagarajan, Raghuram; Ford, David M. [Chemical Engineering, University of Massachusetts, Amherst, Massachusetts 01003 (United States)

    2016-05-28

    Here we construct a low-dimensional Smoluchowski model for electric field mediated colloidal crystallization using Brownian dynamic simulations, which were previously matched to experiments. Diffusion mapping is used to infer dimensionality and confirm the use of two order parameters, one for degree of condensation and one for global crystallinity. Free energy and diffusivity landscapes are obtained as the coefficients of a low-dimensional Smoluchowski equation to capture the thermodynamics and kinetics of microstructure evolution. The resulting low-dimensional model quantitatively captures the dynamics of different assembly pathways between fluid, polycrystal, and single crystals states, in agreement with the full N-dimensional data as characterized by first passage time distributions. Numerical solution of the low-dimensional Smoluchowski equation reveals statistical properties of the dynamic evolution of states vs. applied field amplitude and system size. The low-dimensional Smoluchowski equation and associated landscapes calculated here can serve as models for predictive control of electric field mediated assembly of colloidal ensembles into two-dimensional crystalline objects.

  14. Modular and Stochastic Approaches to Molecular Pathway Models of ATM, TGF beta, and WNT Signaling

    Science.gov (United States)

    Cucinotta, Francis A.; O'Neill, Peter; Ponomarev, Artem; Carra, Claudio; Whalen, Mary; Pluth, Janice M.

    2009-01-01

    Deterministic pathway models that describe the biochemical interactions of a group of related proteins, their complexes, activation through kinase, etc. are often the basis for many systems biology models. Low dose radiation effects present a unique set of challenges to these models including the importance of stochastic effects due to the nature of radiation tracks and small number of molecules activated, and the search for infrequent events that contribute to cancer risks. We have been studying models of the ATM, TGF -Smad and WNT signaling pathways with the goal of applying pathway models to the investigation of low dose radiation cancer risks. Modeling challenges include introduction of stochastic models of radiation tracks, their relationships to more than one substrate species that perturb pathways, and the identification of a representative set of enzymes that act on the dominant substrates. Because several pathways are activated concurrently by radiation the development of modular pathway approach is of interest.

  15. Creating and parameterizing patient-specific deep brain stimulation pathway-activation models using the hyperdirect pathway as an example.

    Science.gov (United States)

    Gunalan, Kabilar; Chaturvedi, Ashutosh; Howell, Bryan; Duchin, Yuval; Lempka, Scott F; Patriat, Remi; Sapiro, Guillermo; Harel, Noam; McIntyre, Cameron C

    2017-01-01

    Deep brain stimulation (DBS) is an established clinical therapy and computational models have played an important role in advancing the technology. Patient-specific DBS models are now common tools in both academic and industrial research, as well as clinical software systems. However, the exact methodology for creating patient-specific DBS models can vary substantially and important technical details are often missing from published reports. Provide a detailed description of the assembly workflow and parameterization of a patient-specific DBS pathway-activation model (PAM) and predict the response of the hyperdirect pathway to clinical stimulation. Integration of multiple software tools (e.g. COMSOL, MATLAB, FSL, NEURON, Python) enables the creation and visualization of a DBS PAM. An example DBS PAM was developed using 7T magnetic resonance imaging data from a single unilaterally implanted patient with Parkinson's disease (PD). This detailed description implements our best computational practices and most elaborate parameterization steps, as defined from over a decade of technical evolution. Pathway recruitment curves and strength-duration relationships highlight the non-linear response of axons to changes in the DBS parameter settings. Parameterization of patient-specific DBS models can be highly detailed and constrained, thereby providing confidence in the simulation predictions, but at the expense of time demanding technical implementation steps. DBS PAMs represent new tools for investigating possible correlations between brain pathway activation patterns and clinical symptom modulation.

  16. Creating and parameterizing patient-specific deep brain stimulation pathway-activation models using the hyperdirect pathway as an example.

    Directory of Open Access Journals (Sweden)

    Kabilar Gunalan

    Full Text Available Deep brain stimulation (DBS is an established clinical therapy and computational models have played an important role in advancing the technology. Patient-specific DBS models are now common tools in both academic and industrial research, as well as clinical software systems. However, the exact methodology for creating patient-specific DBS models can vary substantially and important technical details are often missing from published reports.Provide a detailed description of the assembly workflow and parameterization of a patient-specific DBS pathway-activation model (PAM and predict the response of the hyperdirect pathway to clinical stimulation.Integration of multiple software tools (e.g. COMSOL, MATLAB, FSL, NEURON, Python enables the creation and visualization of a DBS PAM. An example DBS PAM was developed using 7T magnetic resonance imaging data from a single unilaterally implanted patient with Parkinson's disease (PD. This detailed description implements our best computational practices and most elaborate parameterization steps, as defined from over a decade of technical evolution.Pathway recruitment curves and strength-duration relationships highlight the non-linear response of axons to changes in the DBS parameter settings.Parameterization of patient-specific DBS models can be highly detailed and constrained, thereby providing confidence in the simulation predictions, but at the expense of time demanding technical implementation steps. DBS PAMs represent new tools for investigating possible correlations between brain pathway activation patterns and clinical symptom modulation.

  17. Bayesian network model for identification of pathways by integrating protein interaction with genetic interaction data.

    Science.gov (United States)

    Fu, Changhe; Deng, Su; Jin, Guangxu; Wang, Xinxin; Yu, Zu-Guo

    2017-09-21

    Molecular interaction data at proteomic and genetic levels provide physical and functional insights into a molecular biosystem and are helpful for the construction of pathway structures complementarily. Despite advances in inferring biological pathways using genetic interaction data, there still exists weakness in developed models, such as, activity pathway networks (APN), when integrating the data from proteomic and genetic levels. It is necessary to develop new methods to infer pathway structure by both of interaction data. We utilized probabilistic graphical model to develop a new method that integrates genetic interaction and protein interaction data and infers exquisitely detailed pathway structure. We modeled the pathway network as Bayesian network and applied this model to infer pathways for the coherent subsets of the global genetic interaction profiles, and the available data set of endoplasmic reticulum genes. The protein interaction data were derived from the BioGRID database. Our method can accurately reconstruct known cellular pathway structures, including SWR complex, ER-Associated Degradation (ERAD) pathway, N-Glycan biosynthesis pathway, Elongator complex, Retromer complex, and Urmylation pathway. By comparing N-Glycan biosynthesis pathway and Urmylation pathway identified from our approach with that from APN, we found that our method is able to overcome its weakness (certain edges are inexplicable). According to underlying protein interaction network, we defined a simple scoring function that only adopts genetic interaction information to avoid the balance difficulty in the APN. Using the effective stochastic simulation algorithm, the performance of our proposed method is significantly high. We developed a new method based on Bayesian network to infer detailed pathway structures from interaction data at proteomic and genetic levels. The results indicate that the developed method performs better in predicting signaling pathways than previously

  18. Milk distribution and feeding practice data for the PATHWAY model

    International Nuclear Information System (INIS)

    Ward, G.M.; Whicker, F.W.

    1990-01-01

    Milk is a major source for ingestion of several radionuclides, particularly when it is produced from fresh forage. Estimation of radionuclide ingestion via milk from Nevada Test Site fallout events in the 1950s required information on the sources of milk, feeding practices for cows, and elapsed time between milking and consumption for various geographic areas. These data were essential input to the food-chain model, PATHWAY. A data base was compiled from personal interviews. Milk sources included private cows, local dairies, and regional plants that collected from and distributed to wide geographic areas. Estimates of the contribution of each source were made for communities in a nine-state area. Pasture seasons varied from 3 to 6 mo. Pasture use varied from zero to 80% of the cows' diet. Pasture use declined during the 1950s, as did the number of family cows and local dairy plants. Regional distributors captured a larger portion of the market, and improved technologies increased the shelf life of milk. These factors tended to reduce the human intake of fallout radionuclides from milk in the latter part of the 1950s

  19. Cognitive mechanisms underlying third graders' arithmetic skills: Expanding the pathways to mathematics model.

    Science.gov (United States)

    Träff, Ulf; Olsson, Linda; Skagerlund, Kenny; Östergren, Rickard

    2018-03-01

    A modified pathways to mathematics model was used to examine the cognitive mechanisms underlying arithmetic skills in third graders. A total of 269 children were assessed on tasks tapping the four pathways and arithmetic skills. A path analysis showed that symbolic number processing was directly supported by the linguistic and approximate quantitative pathways. The direct contribution from the four pathways to arithmetic proficiency varied; the linguistic pathway supported single-digit arithmetic and word problem solving, whereas the approximate quantitative pathway supported only multi-digit calculation. The spatial processing and verbal working memory pathways supported only arithmetic word problem solving. The notion of hierarchical levels of arithmetic was supported by the results, and the different levels were supported by different constellations of pathways. However, the strongest support to the hierarchical levels of arithmetic were provided by the proximal arithmetic skills. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Personāla atlases un apmācības sistēmas pilnveidošana uzņēmumā "X"

    OpenAIRE

    Strode, Gunta

    2012-01-01

    Bakalaura darbā „Personāla atlases un apmācības sistēmas pilnveidošana uzņēmumā „X” ” tiek izskatīti un analizēti jautājumi par personāla atlases un apmācības procesu. Darbs sastāv no trim daļām. Pirmajā daļā tiek raksturoti personāla atlases mērķi un atlases organizēšanas kārtība. Otrajā daļā tiek raksturota personāla apmācības nozīme un organizēšanas nosacījumi. Trešajā daļā tiek pētīta personāla atlases un apmācības sistēmas pilnveidošana uzņēmumā „X”. Pamatojoties uz veiktajiem ...

  1. An overview of bioinformatics methods for modeling biological pathways in yeast.

    Science.gov (United States)

    Hou, Jie; Acharya, Lipi; Zhu, Dongxiao; Cheng, Jianlin

    2016-03-01

    The advent of high-throughput genomics techniques, along with the completion of genome sequencing projects, identification of protein-protein interactions and reconstruction of genome-scale pathways, has accelerated the development of systems biology research in the yeast organism Saccharomyces cerevisiae In particular, discovery of biological pathways in yeast has become an important forefront in systems biology, which aims to understand the interactions among molecules within a cell leading to certain cellular processes in response to a specific environment. While the existing theoretical and experimental approaches enable the investigation of well-known pathways involved in metabolism, gene regulation and signal transduction, bioinformatics methods offer new insights into computational modeling of biological pathways. A wide range of computational approaches has been proposed in the past for reconstructing biological pathways from high-throughput datasets. Here we review selected bioinformatics approaches for modeling biological pathways inS. cerevisiae, including metabolic pathways, gene-regulatory pathways and signaling pathways. We start with reviewing the research on biological pathways followed by discussing key biological databases. In addition, several representative computational approaches for modeling biological pathways in yeast are discussed. © The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  2. Modelling and performance analysis of clinical pathways using the stochastic process algebra PEPA.

    Science.gov (United States)

    Yang, Xian; Han, Rui; Guo, Yike; Bradley, Jeremy; Cox, Benita; Dickinson, Robert; Kitney, Richard

    2012-01-01

    Hospitals nowadays have to serve numerous patients with limited medical staff and equipment while maintaining healthcare quality. Clinical pathway informatics is regarded as an efficient way to solve a series of hospital challenges. To date, conventional research lacks a mathematical model to describe clinical pathways. Existing vague descriptions cannot fully capture the complexities accurately in clinical pathways and hinders the effective management and further optimization of clinical pathways. Given this motivation, this paper presents a clinical pathway management platform, the Imperial Clinical Pathway Analyzer (ICPA). By extending the stochastic model performance evaluation process algebra (PEPA), ICPA introduces a clinical-pathway-specific model: clinical pathway PEPA (CPP). ICPA can simulate stochastic behaviours of a clinical pathway by extracting information from public clinical databases and other related documents using CPP. Thus, the performance of this clinical pathway, including its throughput, resource utilisation and passage time can be quantitatively analysed. A typical clinical pathway on stroke extracted from a UK hospital is used to illustrate the effectiveness of ICPA. Three application scenarios are tested using ICPA: 1) redundant resources are identified and removed, thus the number of patients being served is maintained with less cost; 2) the patient passage time is estimated, providing the likelihood that patients can leave hospital within a specific period; 3) the maximum number of input patients are found, helping hospitals to decide whether they can serve more patients with the existing resource allocation. ICPA is an effective platform for clinical pathway management: 1) ICPA can describe a variety of components (state, activity, resource and constraints) in a clinical pathway, thus facilitating the proper understanding of complexities involved in it; 2) ICPA supports the performance analysis of clinical pathway, thereby assisting

  3. The dual pathway model of overeating. Replication and extension with actual food consumption

    NARCIS (Netherlands)

    Ouwens, M.A.; Strien, T. van; Leeuwe, J.F.J. van; Staak, C.P.F. van der

    2009-01-01

    van Strien et al. [van Strien, T., Engels, R. C. M. E., van Leeuwe, J., Snoek, H. M. (2005). The Stice model of overeating: tests in clinical and non-clinical samples. Appetite, 45, 205–213] extended the negative affect pathway of Stice's dual pathway model of overeating Stice [Stice, E. (1994).

  4. The dual pathway model of overeating. Replication and extension with actual food consumption

    NARCIS (Netherlands)

    Ouwens, Machteld A; van Strien, T; Leeuwe, J.F.J.; van der Staak, C P F

    van Strien et al. [van Strien, T., Engels, R. C. M. E., van Leeuwe, J., Snoek, H. M. (2005). The Stice model of overeating: tests in clinical and non-clinical samples. Appetite, 45, 205-213] extended the negative affect pathway of Stice's dual pathway model of overeating Stice [Stice, E. (1994).

  5. Cholinergic anti-inflammatory pathway in the non-obese diabetic mouse model

    NARCIS (Netherlands)

    Koopman, F. A.; Vosters, J. L.; Roescher, N.; Broekstra, N.; Tak, P. P.; Vervoordeldonk, M. J.

    2015-01-01

    Activation of the cholinergic anti-inflammatory pathway (CAP) has been shown to reduce inflammation in animal models, while abrogation of the pathway increases inflammation. We investigated whether modulation of CAP influences inflammation in the non-obese diabetic (NOD) mouse model for Sjögren's

  6. Lung cancer, intracellular signaling pathways, and preclinical models

    International Nuclear Information System (INIS)

    Mordant, P.

    2012-01-01

    Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. Activation of phosphatidylinositol-3-kinase (PI3K)-AKT and Kirsten rat sarcoma viral oncogene homologue (KRAS) can induce cellular immortalization, proliferation, and resistance to anticancer therapeutics such as epidermal growth factor receptor inhibitors or chemotherapy. This study assessed the consequences of inhibiting these two pathways in tumor cells with activation of KRAS, PI3K-AKT, or both. We investigated whether the combination of a novel RAF/vascular endothelial growth factor receptor inhibitor, RAF265, with a mammalian target of rapamycin (mTOR) inhibitor, RAD001 (everolimus), could lead to enhanced anti-tumoral effects in vitro and in vivo. To address this question, we used cell lines with different status regarding KRAS, PIK3CA, and BRAF mutations, using immunoblotting to evaluate the inhibitors, and MTT and clonogenic assays for effects on cell viability and proliferation. Subcutaneous xenografts were used to assess the activity of the combination in vivo. RAD001 inhibited mTOR downstream signaling in all cell lines, whereas RAF265 inhibited RAF downstream signaling only in BRAF mutant cells. In vitro, addition of RAF265 to RAD001 led to decreased AKT, S6, and Eukaryotic translation initiation factor 4E binding protein 1 phosphorylation in HCT116 cells. In vitro and in vivo, RAD001 addition enhanced the anti-tumoral effect of RAF265 in HCT116 and H460 cells (both KRAS mut, PIK3CA mut); in contrast, the combination of RAF265 and RAD001 yielded no additional activity in A549 and MDAMB231 cells. The combination of RAF and mTOR inhibitors is effective for enhancing anti-tumoral effects in cells with deregulation of both RAS-RAF and PI3K, possibly through the cross-inhibition of 4E binding protein 1 and S6 protein. We then focus on animal models. Preclinical models of NSCLC require better clinical relevance to study disease mechanisms and innovative

  7. Simplified life cycle assessment models: methodological framework and applications to energy pathways

    International Nuclear Information System (INIS)

    Padey, Pierryves

    2013-01-01

    The energy transition debate is a key issue for today and the coming years. One of the challenges is to limit the environmental impacts of electricity production. Decision support tools, sufficiently accurate, simple to use, accounting for environmental aspects and favoring future energetic choices, must be implemented. However, the environmental assessment of the energy pathways is complex, and it means considering a two levels characterization. The 'energy pathway' is the first level and corresponds to its environmental distribution, to compare overall pathways. The 'system pathway' is the 2. level and compares environmental impacts of systems within each pathway. We have devised a generic methodology covering both necessary characterization levels by estimating the energy pathways environmental profiles while allowing a simple comparison of its systems environmental impacts. This methodology is based on the definition of a parameterized Life Cycle Assessment model and considers, through a Global Sensitivity Analysis, the environmental impacts of a large sample of systems representative of an energy pathway. As a second step, this methodology defines simplified models based on few key parameters identified as inducing the largest variability in the energy pathway environmental impacts. These models assess in a simple way the systems environmental impacts, avoiding any complex LCAs. This reduction methodology has been applied to the onshore wind power energy pathway in Europe and the photovoltaic energy pathway in France. (author)

  8. Modeling position-specific isotope fractionation of organic micropollutants degradation via different reaction pathways

    DEFF Research Database (Denmark)

    Jin, Biao; Rolle, Massimo

    : dichlorobenzamide (BAM), isoproturon (IPU) and diclofenac (DCF). The model successfully reproduces the multi-element isotope data, and precisely captures the dual element isotope trends, characterizing the different degradation pathways. Besides illustrating the model capability of mechanistic evaluation...

  9. Modeling of non-steroidal anti-inflammatory drug effect within signaling pathways and miRNA-regulation pathways.

    Directory of Open Access Journals (Sweden)

    Jian Li

    Full Text Available To date, it is widely recognized that Non-Steroidal Anti-Inflammatory Drugs (NSAIDs can exert considerable anti-tumor effects regarding many types of cancers. The prolonged use of NSAIDs is highly associated with diverse side effects. Therefore, tailoring down the NSAID application onto individual patients has become a necessary and relevant step towards personalized medicine. This study conducts the systemsbiological approach to construct a molecular model (NSAID model containing a cyclooxygenase (COX-pathway and its related signaling pathways. Four cancer hallmarks are integrated into the model to reflect different developmental aspects of tumorigenesis. In addition, a Flux-Comparative-Analysis (FCA based on Petri net is developed to transfer the dynamic properties (including drug responsiveness of individual cellular system into the model. The gene expression profiles of different tumor-types with available drug-response information are applied to validate the predictive ability of the NSAID model. Moreover, two therapeutic developmental strategies, synthetic lethality and microRNA (miRNA biomarker discovery, are investigated based on the COX-pathway. In conclusion, the result of this study demonstrates that the NSAID model involving gene expression, gene regulation, signal transduction, protein interaction and other cellular processes, is able to predict the individual cellular responses for different therapeutic interventions (such as NS-398 and COX-2 specific siRNA inhibition. This strongly indicates that this type of model is able to reflect the physiological, developmental and pathological processes of an individual. The approach of miRNA biomarker discovery is demonstrated for identifying miRNAs with oncogenic and tumor suppressive functions for individual cell lines of breast-, colon- and lung-tumor. The achieved results are in line with different independent studies that investigated miRNA biomarker related to diagnostics of cancer

  10. Environmental Pathway Models-Ground-Water Modeling in Support of Remedial Decision Making at Sites Contaminated with Radioactive Material

    Science.gov (United States)

    The Joint Interagency Environmental Pathway Modeling Working Group wrote this report to promote appropriate and consistent use of mathematical environmental models in the remediation and restoration of sites contaminated by radioactive substances.

  11. Emission pathway modeling to analyze national ambition levels of decarbonization

    International Nuclear Information System (INIS)

    Kainuma, Mikiko; Waisman, Henri

    2015-01-01

    The Deep Decarbonization Pathways Project (DDPP) is a knowledge network comprising 15 Country Research Teams and several Partner Organizations which develop and share methods, assumptions, and findings related to deep decarbonization. It analyzes the technical decarbonization potential, exploring options for deep decarbonization, but also better taking into account existing infrastructure stocks. It shows the possibility to reduce total CO 2 -energy emissions by 45% by 2050, with bottom-up analyses by 15 Country Research Teams

  12. Personality and creativity : The dual pathway to creativity model and a research agenda

    NARCIS (Netherlands)

    Baas, Matthijs; Roskes, Marieke; Sligte, Daniel; Nijstad, Bernard A.; De Dreu, Carsten K W

    2013-01-01

    To better understand the relation between personality traits and creativity, we invoke the Dual-Pathway to Creativity model (DPCM) that identifies two pathways to creative outcomes: (1) flexible processing of information (cognitive flexibility) and (2) persistent probing, and systematically and

  13. Modeling of nitrous oxide production by autotrophic ammonia-oxidizing bacteria with multiple production pathways.

    Science.gov (United States)

    Ni, Bing-Jie; Peng, Lai; Law, Yingyu; Guo, Jianhua; Yuan, Zhiguo

    2014-04-01

    Autotrophic ammonia oxidizing bacteria (AOB) have been recognized as a major contributor to N2O production in wastewater treatment systems. However, so far N2O models have been proposed based on a single N2O production pathway by AOB, and there is still a lack of effective approach for the integration of these models. In this work, an integrated mathematical model that considers multiple production pathways is developed to describe N2O production by AOB. The pathways considered include the nitrifier denitrification pathway (N2O as the final product of AOB denitrification with NO2(-) as the terminal electron acceptor) and the hydroxylamine (NH2OH) pathway (N2O as a byproduct of incomplete oxidation of NH2OH to NO2(-)). In this model, the oxidation and reduction processes are modeled separately, with intracellular electron carriers introduced to link the two types of processes. The model is calibrated and validated using experimental data obtained with two independent nitrifying cultures. The model satisfactorily describes the N2O data from both systems. The model also predicts shifts of the dominating pathway at various dissolved oxygen (DO) and nitrite levels, consistent with previous hypotheses. This unified model is expected to enhance our ability to predict N2O production by AOB in wastewater treatment systems under varying operational conditions.

  14. The Pathway for Oxygen: Tutorial Modelling on Oxygen Transport from Air to Mitochondrion: The Pathway for Oxygen.

    Science.gov (United States)

    Bassingthwaighte, James B; Raymond, Gary M; Dash, Ranjan K; Beard, Daniel A; Nolan, Margaret

    2016-01-01

    The 'Pathway for Oxygen' is captured in a set of models describing quantitative relationships between fluxes and driving forces for the flux of oxygen from the external air source to the mitochondrial sink at cytochrome oxidase. The intervening processes involve convection, membrane permeation, diffusion of free and heme-bound O2 and enzymatic reactions. While this system's basic elements are simple: ventilation, alveolar gas exchange with blood, circulation of the blood, perfusion of an organ, uptake by tissue, and consumption by chemical reaction, integration of these pieces quickly becomes complex. This complexity led us to construct a tutorial on the ideas and principles; these first PathwayO2 models are simple but quantitative and cover: (1) a 'one-alveolus lung' with airway resistance, lung volume compliance, (2) bidirectional transport of solute gasses like O2 and CO2, (3) gas exchange between alveolar air and lung capillary blood, (4) gas solubility in blood, and circulation of blood through the capillary syncytium and back to the lung, and (5) blood-tissue gas exchange in capillaries. These open-source models are at Physiome.org and provide background for the many respiratory models there.

  15. A structured workflow for mapping human Sin3 histone deacetylase complex interactions using Halo-MudPIT AP-MS.

    Science.gov (United States)

    Banks, Charles A S; Thornton, Janet L; Eubanks, Cassandra G; Adams, Mark K; Miah, Sayem; Boanca, Gina; Liu, Xingyu; Katt, Maria; Parmely, Tari; Florens, Laurence A; Washburn, Michael P

    2018-03-29

    Although a variety of affinity purification mass spectrometry (AP-MS) strategies have been used to investigate complex interactions, many of these are susceptible to artifacts due to substantial overexpression of the exogenously expressed bait protein. Here we present a logical and systematic workflow that uses the multifunctional Halo tag to assess the correct localization and behavior of tagged subunits of the Sin3 histone deacetylase complex prior to further AP-MS analysis. Using this workflow, we modified our tagging/expression strategy with 21.7% of the tagged bait proteins that we constructed, allowing us to quickly develop validated reagents. Specifically, we apply the workflow to map interactions between stably expressed versions of the Sin3 subunits SUDS3, SAP30 or SAP30L and other cellular proteins.  Here we show that the SAP30 and SAP30L paralogues strongly associate with the core Sin3 complex, but SAP30L has unique associations with the proteasome and the myelin sheath.  Next, we demonstrate an advancement of the complex NSAF (cNSAF) approach, in which normalization to the scaffold protein SIN3A accounts for variations in the proportion of each bait capturing Sin3 complexes and allows a comparison between different baits capturing the same protein complex. This analysis reveals that although the Sin3 subunit SUDS3 appears to be used in both SIN3A and SIN3B based complexes, the SAP30 subunit is not used in SIN3B based complexes. Intriguingly, we do not detect the Sin3 subunits SAP18 and SAP25 among the 128 high-confidence interactions identified, suggesting that these subunits may not be common to all versions of the Sin3 complex in human cells. This workflow provides the framework for building validated reagents to assemble quantitative interaction networks for chromatin remodeling complexes and provides novel insights into focused protein interaction networks. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.

  16. Recommended Henry’s Law Constants for Non-Groundwater Pathways Models in GoldSim

    Energy Technology Data Exchange (ETDEWEB)

    Dyer, J. [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL)

    2017-06-20

    This memorandum documents the source and numerical value of Henry’s law constants for volatile radionuclides of interest used in the non-groundwater (air and radon) pathways models for the 2018 E-Area Performance Assessment.

  17. Pathway models for analysing and managing the introduction of alien plant pests - an overview and categorization

    NARCIS (Netherlands)

    Douma, J.C.; Pautasso, M.; Venette, R.C.; Robinet, C.; Hemerik, L.; Mourits, M.C.M.; Schans, J.; Werf, van der W.

    2016-01-01

    Alien plant pests are introduced into new areas at unprecedented rates through global trade, transport, tourism and travel, threatening biodiversity and agriculture. Increasingly, the movement and introduction of pests is analysed with pathway models to provide risk managers with quantitative

  18. Constraint-based modeling and kinetic analysis of the Smad dependent TGF-beta signaling pathway.

    Directory of Open Access Journals (Sweden)

    Zhike Zi

    Full Text Available BACKGROUND: Investigation of dynamics and regulation of the TGF-beta signaling pathway is central to the understanding of complex cellular processes such as growth, apoptosis, and differentiation. In this study, we aim at using systems biology approach to provide dynamic analysis on this pathway. METHODOLOGY/PRINCIPAL FINDINGS: We proposed a constraint-based modeling method to build a comprehensive mathematical model for the Smad dependent TGF-beta signaling pathway by fitting the experimental data and incorporating the qualitative constraints from the experimental analysis. The performance of the model generated by constraint-based modeling method is significantly improved compared to the model obtained by only fitting the quantitative data. The model agrees well with the experimental analysis of TGF-beta pathway, such as the time course of nuclear phosphorylated Smad, the subcellular location of Smad and signal response of Smad phosphorylation to different doses of TGF-beta. CONCLUSIONS/SIGNIFICANCE: The simulation results indicate that the signal response to TGF-beta is regulated by the balance between clathrin dependent endocytosis and non-clathrin mediated endocytosis. This model is useful to be built upon as new precise experimental data are emerging. The constraint-based modeling method can also be applied to quantitative modeling of other signaling pathways.

  19. Three molecular pathways model colorectal carcinogenesis in Lynch syndrome.

    Science.gov (United States)

    Ahadova, Aysel; Gallon, Richard; Gebert, Johannes; Ballhausen, Alexej; Endris, Volker; Kirchner, Martina; Stenzinger, Albrecht; Burn, John; von Knebel Doeberitz, Magnus; Bläker, Hendrik; Kloor, Matthias

    2018-07-01

    Lynch syndrome is caused by germline mutations of DNA mismatch repair (MMR) genes. MMR deficiency has long been regarded as a secondary event in the pathogenesis of Lynch syndrome colorectal cancers. Recently, this concept has been challenged by the discovery of MMR-deficient crypt foci in the normal mucosa. We aimed to reconstruct colorectal carcinogenesis in Lynch syndrome by collecting molecular and histology evidence from Lynch syndrome adenomas and carcinomas. We determined the frequency of MMR deficiency in adenomas from Lynch syndrome mutation carriers by immunohistochemistry and by systematic literature analysis. To trace back the pathways of pathogenesis, histological growth patterns and mutational signatures were analyzed in Lynch syndrome colorectal cancers. Literature and immunohistochemistry analysis demonstrated MMR deficiency in 491 (76.7%) out of 640 adenomas (95% CI: 73.3% to 79.8%) from Lynch syndrome mutation carriers. Histologically normal MMR-deficient crypts were found directly adjacent to dysplastic adenoma tissue, proving their role as tumor precursors in Lynch syndrome. Accordingly, mutation signature analysis in Lynch colorectal cancers revealed that KRAS and APC mutations commonly occur after the onset of MMR deficiency. Tumors lacking evidence of polypous growth frequently presented with CTNNB1 and TP53 mutations. Our findings demonstrate that Lynch syndrome colorectal cancers can develop through three pathways, with MMR deficiency commonly representing an early and possibly initiating event. This underlines that targeting MMR-deficient cells by chemoprevention or vaccines against MMR deficiency-induced frameshift peptide neoantigens holds promise for tumor prevention in Lynch syndrome. © 2018 UICC.

  20. Non Linear Programming (NLP) formulation for quantitative modeling of protein signal transduction pathways.

    Science.gov (United States)

    Mitsos, Alexander; Melas, Ioannis N; Morris, Melody K; Saez-Rodriguez, Julio; Lauffenburger, Douglas A; Alexopoulos, Leonidas G

    2012-01-01

    Modeling of signal transduction pathways plays a major role in understanding cells' function and predicting cellular response. Mathematical formalisms based on a logic formalism are relatively simple but can describe how signals propagate from one protein to the next and have led to the construction of models that simulate the cells response to environmental or other perturbations. Constrained fuzzy logic was recently introduced to train models to cell specific data to result in quantitative pathway models of the specific cellular behavior. There are two major issues in this pathway optimization: i) excessive CPU time requirements and ii) loosely constrained optimization problem due to lack of data with respect to large signaling pathways. Herein, we address both issues: the former by reformulating the pathway optimization as a regular nonlinear optimization problem; and the latter by enhanced algorithms to pre/post-process the signaling network to remove parts that cannot be identified given the experimental conditions. As a case study, we tackle the construction of cell type specific pathways in normal and transformed hepatocytes using medium and large-scale functional phosphoproteomic datasets. The proposed Non Linear Programming (NLP) formulation allows for fast optimization of signaling topologies by combining the versatile nature of logic modeling with state of the art optimization algorithms.

  1. Non Linear Programming (NLP formulation for quantitative modeling of protein signal transduction pathways.

    Directory of Open Access Journals (Sweden)

    Alexander Mitsos

    Full Text Available Modeling of signal transduction pathways plays a major role in understanding cells' function and predicting cellular response. Mathematical formalisms based on a logic formalism are relatively simple but can describe how signals propagate from one protein to the next and have led to the construction of models that simulate the cells response to environmental or other perturbations. Constrained fuzzy logic was recently introduced to train models to cell specific data to result in quantitative pathway models of the specific cellular behavior. There are two major issues in this pathway optimization: i excessive CPU time requirements and ii loosely constrained optimization problem due to lack of data with respect to large signaling pathways. Herein, we address both issues: the former by reformulating the pathway optimization as a regular nonlinear optimization problem; and the latter by enhanced algorithms to pre/post-process the signaling network to remove parts that cannot be identified given the experimental conditions. As a case study, we tackle the construction of cell type specific pathways in normal and transformed hepatocytes using medium and large-scale functional phosphoproteomic datasets. The proposed Non Linear Programming (NLP formulation allows for fast optimization of signaling topologies by combining the versatile nature of logic modeling with state of the art optimization algorithms.

  2. Static analysis of a Model of the LDL degradation pathway

    DEFF Research Database (Denmark)

    Pilegaard, Henrik; Nielson, Flemming; Nielson, Hanne Riis

    2005-01-01

    BioAmbients is a derivative of mobile ambients that has shown promise of describing interesting features of the behaviour of biological systems. As for other ambient calculi static program analysis can be used to compute safe approximations of the behavior of modelled systems. We use these tools ...... to model and analyse the production of cholesterol in living cells and show that we are able to pinpoint the difference in behaviour between models of healthy systems and models of mutated systems giving rise to known diseases....

  3. RAMS Model for Terrestrial Pathways Version 3. 0 (for microcomputers). Model-Simulation

    Energy Technology Data Exchange (ETDEWEB)

    Niebla, E.

    1989-01-01

    The RAMS Model for Terrestrial Pathways is a computer program for calculation of numeric criteria for land application and distribution and marketing of sludges under the sewage-sludge regulations at 40 CFR Part 503. The risk-assessment models covered assume that municipal sludge with specified characteristics is spread across a defined area of ground at a known rate once each year for a given number of years. Risks associated with direct land application of sludge applied after distribution and marketing are both calculated. The computer program calculates the maximum annual loading of contaminants that can be land applied and still meet the risk criteria specified as input. Software Description: The program is written in the Turbo/Basic programming language for implementation on IBM PC/AT or compatible machines using DOS 3.0 or higher operating system. Minimum core storage is 512K.

  4. Selection of Models for Ingestion Pathway and Relocation Radii Determination

    International Nuclear Information System (INIS)

    Blanchard, A.

    1998-01-01

    The distance at which intermediate phase protective actions (such as food interdiction and relocation) may be needed following postulated accidents at three Savannah River Site nonreactor nuclear facilities will be determined by modeling. The criteria used to select dispersion/deposition models are presented. Several models were considered, including ARAC, MACCS, HOTSPOT, WINDS (coupled with PUFF-PLUME), and UFOTRI. Although ARAC and WINDS are expected to provide more accurate modeling of atmospheric transport following an actual release, analyses consistent with regulatory guidance for planning purposes may be accomplished with comparatively simple dispersion models such as HOTSPOT and UFOTRI. A recommendation is made to use HOTSPOT for non-tritium facilities and UFOTRI for tritium facilities

  5. Petroleum migration pathways and charge concentration: A three-dimensional model

    Energy Technology Data Exchange (ETDEWEB)

    Hindle, A.D. [Anadarko Algeria Corp., Middlesex (United Kingdom)

    1997-09-01

    Petroleum migration pathways through a basin are determined by the three-dimensional distribution of discontinuous sealing surfaces, which are usually parallel to bedding. The petroleum migrates below the sealing surface, taking the structurally most advantageous route. The three-dimensional distribution of migration pathways within the petroleum system can be modeled on a personal computer using a program based on the parameters discussed in this paper. Application of the model to the Paris and Williston basins demonstrates that a good correlation between predicted pathways and discovered accumulations can be made using simple models. Pathways form a dense network overlying generating areas in the central parts of basins. Toward the basin margins these routes commonly become increasingly focused into discrete pathways by the sealing-surface morphologies. Eventually, these pathways may reach the surface as seepages. It is important to integrate surface outcrops of migration routes (surface seepages) into migration modeling. Deflection of the pathways from the structurally most advantageous route below the sealing surface may be caused by lateral sealing barriers due to faces variation in the carrier rock below the seal, fault juxtaposition, or cross-formational seals such as salt intrusions. Deflection of pathways also occurs where there are hydrodynamic conditions in response to topography-driven groundwater flow. Zones of vertical migration are associated with facies changes along the horizon of the sealing surface into a nonsealing facies, or juxtaposition to nonsealing strata by faults. Vertical migration from either normally or abnormally pressured strata is most likely to occur into normally or lesser pressured strata at intrabasinal highs where hydrocarbons can be stored and transferred at times of temporary seal rupture.

  6. IntPath--an integrated pathway gene relationship database for model organisms and important pathogens.

    Science.gov (United States)

    Zhou, Hufeng; Jin, Jingjing; Zhang, Haojun; Yi, Bo; Wozniak, Michal; Wong, Limsoon

    2012-01-01

    Pathway data are important for understanding the relationship between genes, proteins and many other molecules in living organisms. Pathway gene relationships are crucial information for guidance, prediction, reference and assessment in biochemistry, computational biology, and medicine. Many well-established databases--e.g., KEGG, WikiPathways, and BioCyc--are dedicated to collecting pathway data for public access. However, the effectiveness of these databases is hindered by issues such as incompatible data formats, inconsistent molecular representations, inconsistent molecular relationship representations, inconsistent referrals to pathway names, and incomprehensive data from different databases. In this paper, we overcome these issues through extraction, normalization and integration of pathway data from several major public databases (KEGG, WikiPathways, BioCyc, etc). We build a database that not only hosts our integrated pathway gene relationship data for public access but also maintains the necessary updates in the long run. This public repository is named IntPath (Integrated Pathway gene relationship database for model organisms and important pathogens). Four organisms--S. cerevisiae, M. tuberculosis H37Rv, H. Sapiens and M. musculus--are included in this version (V2.0) of IntPath. IntPath uses the "full unification" approach to ensure no deletion and no introduced noise in this process. Therefore, IntPath contains much richer pathway-gene and pathway-gene pair relationships and much larger number of non-redundant genes and gene pairs than any of the single-source databases. The gene relationships of each gene (measured by average node degree) per pathway are significantly richer. The gene relationships in each pathway (measured by average number of gene pairs per pathway) are also considerably richer in the integrated pathways. Moderate manual curation are involved to get rid of errors and noises from source data (e.g., the gene ID errors in WikiPathways and

  7. Sustainable BECCS pathways evaluated by an integrated assessment model

    Science.gov (United States)

    Kato, E.

    2017-12-01

    Negative emissions technologies, particularly Bioenergy with Carbon Capture and Storage (BECCS), are key components of mitigation strategies in ambitious future socioeconomic scenarios analysed by integrated assessment models. Generally, scenarios aiming to keep mean global temperature rise below 2°C above pre-industrial would require net negative carbon emissions in the end of the 21st century. Also, in the context of Paris agreement which acknowledges "a balance between anthropogenic emissions by sources and removals by sinks of greenhouse gases in the second half of this century", RD&D for the negative emissions technologies in this decade has a crucial role for the possibility of early deployment of the technology. Because of the requirement of potentially extensive use of land and water for producing the bioenergy feedstock to get the anticipated level of gross negative emissions, researches on how to develop sustainable scenarios of BECCS is needed. Here, we present BECCS deployment scenarios that consider economically viable flow of bioenergy system including power generation and conversion process to liquid and gaseous fuels for transportation and heat with consideration of sustainable global biomass use. In the modelling process, detailed bioenergy representations, i.e. various feedstock and conversion technologies with and without CCS, are implemented in an integrated assessment (IA) model GRAPE (Global Relationship Assessment to Protect the Environment). Also, to overcome a general discrepancy about assumed future agricultural yield between 'top-down' IA models and 'bottom-up' estimates, which would crucially affect the land-use pattern, we applied yields change of food and energy crops consistent with process-based biophysical crop models in consideration of changing climate conditions. Using the framework, economically viable strategy for implementing sustainable bioenergy and BECCS flow are evaluated in the scenarios targeting to keep global average

  8. Observed and Modeled Pathways of the Iceland Scotland Overflow Water in the eastern North Atlantic

    Science.gov (United States)

    Zou, Sijia; Lozier, Susan; Zenk, Walter; Bower, Amy; Johns, William

    2017-04-01

    The Iceland Scotland Overflow Water (ISOW), one of the major components of the lower limb of the Atlantic Meridional Overturning Circulation (AMOC), is formed in the Nordic Seas and enters the eastern North Atlantic subpolar gyre via the Iceland-Scotland sill. After entraining the ambient waters, the relatively homogeneous ISOW spreads southward into the North Atlantic. An understanding of the distribution and variability of the spreading pathways of the ISOW is fundamental to our understanding of AMOC structure and variability. Three major ISOW pathways have been identified in the eastern North Atlantic by previous studies: 1) across the Reykjanes Ridge via deep gaps, 2) through the Charlie Gibbs Fracture Zone, and 3) southward along the eastern flank of the Mid Atlantic Ridge (MAR). However, most of these studies were conducted using an Eulerian frame with limited observations, especially for the third pathway along the eastern flank of the MAR. In this work, we give a comprehensive description of ISOW pathways in the Eulerian and Lagrangian frames, quantify the relative importance of each pathway and examine the temporal variability of these pathways. Our study distinguishes itself from past studies by using both Eulerian (current meter data) and Lagrangian (eddy-resolving RAFOS float data) observations in combination with modeling output (1/12° FLAME) to describe ISOW spreading pathways and their variability.

  9. Identifying parasitic current pathways in CIGS solar cells by modelling dark J-V response

    NARCIS (Netherlands)

    Williams, B.L.; Smit, S.; Kniknie, B.J.; Bakker, K.J.; Keuning, W.; Kessels, W.M.M.; Schropp, R.E.I.; Creatore, M.

    2015-01-01

    An equivalent circuit model, which allows for the presence of three types of shunting pathways, has been developed to describe the dark J-V characteristics in CIGS solar cells. Excellent agreement between the model and experimental data was apparent throughout a temperature range of 183-323K.

  10. Modeling flow and transport pathways to the potential repository horizon at Yucca Mountain

    International Nuclear Information System (INIS)

    Wolfsberg, A.V.; Roemer, G.J.C.; Fabryka-Martin, J.T.; Robinson, B.A.

    1998-01-01

    The isotopic ratios of 36 Cl/Cl are used in conjunction with geologic interpretation and numerical modeling to evaluate flow and transport pathways, processes, and model parameters in the unsaturated zone at Yucca Mountain. By synthesizing geochemical and geologic data, the numerical model results provide insight into the validity of alternative hydrologic parameter sets, flow and transport processes in and away from fault zones, and the applicability of 36 Cl/Cl ratios for evaluating alternative conceptual models

  11. Economic modelling of diagnostic and treatment pathways in National Institute for Health and Care Excellence clinical guidelines: the Modelling Algorithm Pathways in Guidelines (MAPGuide) project.

    Science.gov (United States)

    Lord, J; Willis, S; Eatock, J; Tappenden, P; Trapero-Bertran, M; Miners, A; Crossan, C; Westby, M; Anagnostou, A; Taylor, S; Mavranezouli, I; Wonderling, D; Alderson, P; Ruiz, F

    2013-12-01

    National Institute for Health and Care Excellence (NICE) clinical guidelines (CGs) make recommendations across large, complex care pathways for broad groups of patients. They rely on cost-effectiveness evidence from the literature and from new analyses for selected high-priority topics. An alternative approach would be to build a model of the full care pathway and to use this as a platform to evaluate the cost-effectiveness of multiple topics across the guideline recommendations. In this project we aimed to test the feasibility of building full guideline models for NICE guidelines and to assess if, and how, such models can be used as a basis for cost-effectiveness analysis (CEA). A 'best evidence' approach was used to inform the model parameters. Data were drawn from the guideline documentation, advice from clinical experts and rapid literature reviews on selected topics. Where possible we relied on good-quality, recent UK systematic reviews and meta-analyses. Two published NICE guidelines were used as case studies: prostate cancer and atrial fibrillation (AF). Discrete event simulation (DES) was used to model the recommended care pathways and to estimate consequent costs and outcomes. For each guideline, researchers not involved in model development collated a shortlist of topics suggested for updating. The modelling teams then attempted to evaluate options related to these topics. Cost-effectiveness results were compared with opinions about the importance of the topics elicited in a survey of stakeholders. The modelling teams developed simulations of the guideline pathways and disease processes. Development took longer and required more analytical time than anticipated. Estimates of cost-effectiveness were produced for six of the nine prostate cancer topics considered, and for five of eight AF topics. The other topics were not evaluated owing to lack of data or time constraints. The modelled results suggested 'economic priorities' for an update that differed from

  12. Kuroshio Pathways in a Climatologically-Forced Model

    Science.gov (United States)

    Douglass, E. M.; Jayne, S. R.; Bryan, F. O.; Peacock, S.; Maltrud, M. E.

    2010-12-01

    A high resolution ocean model forced with an annually repeating atmosphere is used to examine variability of the Kuroshio, the western boundary current in the North Pacific Ocean. A large meander in the path of the Kuroshio south of Japan develops and disappears in a highly bimodal fashion on decadal time scales. This meander is comparable in timing and spatial extent to an observed feature in the region. Various characteristics of the large meander are examined, including shear, transport and velocity. The many similarities between the model and observations indicate that the meander results from intrinsic oceanic variability, which is represented in this climatologically-forced model. Each large meander is preceded by a smaller "trigger" meander that originates at the southern end of Kyushu, moves up the coast, and develops into the large meander. However there are also many meanders very similar in character to the trigger meander that do not develop into large meanders. The mechanism that determines which trigger meanders develop into large meanders is as yet undetermined.

  13. Innovation and entrepreneurship as pathways for new teaching / learning models

    Directory of Open Access Journals (Sweden)

    Helen Kelle dos Santos Costa

    2017-10-01

    Full Text Available Introduction: Modern times demand from society a new attitude, new attitudes, a new way of thinking and seeing the world. It is thus necessary that Education, the foundation for building a society, once again reinvents, innovates and adapts the demands that the process of human development requires. Objective: To emphasize the importance of Innovation and Entrepreneurship as tools for the development of new models of teaching / learning so that there is an education that meets the new social demands. Methodology: The article was structured from a Bibliographic research on theories and models of teaching / learning through an analytical reading, able to identify the characteristics for the effective realization of entrepreneurship in education in an innovative way. Results: The models of education are in constant process of evolution, the adoption of good practices and new resources that can help in teachinglearning as motivating agent of entrepreneurship in education through innovation is a reality to be reviewed by society as a whole. Conclusions: This study is expected to be an important tool for behavioral and / or economic change, with the aim of making the results successful for all parties involved in the attempt to corroborate with the entrepreneurship ecosystem through continuous and increasing multiplication of knowledge.

  14. Physician Reimbursement: From Fee-for-Service to MACRA, MIPS and APMs.

    Science.gov (United States)

    Miller, Phillip; Mosley, Kurt

    2016-01-01

    To a significant degree, "healthcare reform" is a movement to change how both physicians and healthcare facilities are compensated, with value replacing volume as the key compensation metric. The goal of this movement has not yet been accomplished, but the process is accelerating. In this article, we track how the arc of physician compensation is bending, how the Medicare Access and CHIP Reauthorization Act will drive further changes to physician compensation models, and how these changes may affect physician practice patterns and physician staffing in the future.

  15. Review of the chronic exposure pathways models in MACCS [MELCOR Accident Consequence Code System] and several other well-known probabilistic risk assessment models

    International Nuclear Information System (INIS)

    Tveten, U.

    1990-06-01

    The purpose of this report is to document the results of the work performed by the author in connection with the following task, performed for US Nuclear Regulatory Commission, (USNRC) Office of Nuclear Regulatory Research, Division of Systems Research: MACCS Chronic Exposure Pathway Models: Review the chronic exposure pathway models implemented in the MELCOR Accident Consequence Code System (MACCS) and compare those models to the chronic exposure pathway models implemented in similar codes developed in countries that are members of the OECD. The chronic exposures concerned are via: the terrestrial food pathways, the water pathways, the long-term groundshine pathway, and the inhalation of resuspended radionuclides pathway. The USNRC has indicated during discussions of the task that the major effort should be spent on the terrestrial food pathways. There is one chapter for each of the categories of chronic exposure pathways listed above

  16. VISIBIOweb: visualization and layout services for BioPAX pathway models

    Science.gov (United States)

    Dilek, Alptug; Belviranli, Mehmet E.; Dogrusoz, Ugur

    2010-01-01

    With recent advancements in techniques for cellular data acquisition, information on cellular processes has been increasing at a dramatic rate. Visualization is critical to analyzing and interpreting complex information; representing cellular processes or pathways is no exception. VISIBIOweb is a free, open-source, web-based pathway visualization and layout service for pathway models in BioPAX format. With VISIBIOweb, one can obtain well-laid-out views of pathway models using the standard notation of the Systems Biology Graphical Notation (SBGN), and can embed such views within one's web pages as desired. Pathway views may be navigated using zoom and scroll tools; pathway object properties, including any external database references available in the data, may be inspected interactively. The automatic layout component of VISIBIOweb may also be accessed programmatically from other tools using Hypertext Transfer Protocol (HTTP). The web site is free and open to all users and there is no login requirement. It is available at: http://visibioweb.patika.org. PMID:20460470

  17. Modeled exposure assessment via inhalation and dermal pathways to airborne semivolatile organic compounds (SVOCs) in residences.

    Science.gov (United States)

    Shi, Shanshan; Zhao, Bin

    2014-05-20

    Exposure to airborne semivolatile organic compounds (SVOCs) in indoor and outdoor environments of humans may lead to adverse health risks. Thus, we established a model to evaluate exposure to airborne SVOCs. In this model, SVOCs phase-specific concentrations were estimated by a kinetic partition model accounting for particle dynamics. The exposure pathways to airborne SVOCs included inhalation exposure to gas- and particle-phases, dermal exposure by direct gas-to-skin pathway and dermal exposure by direct particle deposition. Exposures of defined "reference people" to two typical classifications of SVOCs, one generated from both indoor and outdoor sources, represented by polycyclic aromatic hydrocarbons (PAHs), and the other generated mainly from only indoor sources, represented by di 2-ethylhexyl phthalate (DEHP), were analyzed as an example application of the model. For PAHs with higher volatility, inhalation exposure to gas-phase, ranging from 6.03 to 16.4 ng/kg/d, accounted for the most of the exposure to the airborne phases. For PAHs with lower volatility, inhalation exposure to particle-phase, ranging from 1.48 to 1.53 ng/kg/d, was the most important exposure pathway. As for DEHP, dermal exposure via direct gas-to-skin pathway was 460 ng/kg/d, which was the most striking exposure pathway when the barrier effect of clothing was neglected.

  18. Mitochondrial pathways governing stress resistance, life, and death in the fungal aging model Podospora anserina.

    Science.gov (United States)

    Osiewacz, Heinz D; Brust, Diana; Hamann, Andrea; Kunstmann, Birgit; Luce, Karin; Müller-Ohldach, Mathis; Scheckhuber, Christian Q; Servos, Jörg; Strobel, Ingmar

    2010-06-01

    Work from more than 50 years of research has unraveled a number of molecular pathways that are involved in controlling aging of the fungal model system Podospora anserina. Early research revealed that wild-type strain aging is linked to gross reorganization of the mitochondrial DNA. Later it was shown that aging of P. anserina does also take place, although at a slower pace, when the wild-type specific mitochondrial DNA rearrangements do not occur. Now it is clear that a network of different pathways is involved in the control of aging. Branches of these pathways appear to be connected and constitute a hierarchical system of responses. Although cross talk between the individual pathways seems to be fundamental in the coordination of the overall system, the precise underlying interactions remain to be unraveled. Such a systematic approach aims at a holistic understanding of the process of biological aging, the ultimate goal of modern systems biology.

  19. A pedagogical walkthrough of computational modeling and simulation of Wnt signaling pathway using static causal models in MATLAB

    OpenAIRE

    Sinha, Shriprakash

    2016-01-01

    Simulation study in systems biology involving computational experiments dealing with Wnt signaling pathways abound in literature but often lack a pedagogical perspective that might ease the understanding of beginner students and researchers in transition, who intend to work on the modeling of the pathway. This paucity might happen due to restrictive business policies which enforce an unwanted embargo on the sharing of important scientific knowledge. A tutorial introduction to computational mo...

  20. A Longitudinal Empirical Investigation of the Pathways Model of Problem Gambling.

    Science.gov (United States)

    Allami, Youssef; Vitaro, Frank; Brendgen, Mara; Carbonneau, René; Lacourse, Éric; Tremblay, Richard E

    2017-12-01

    The pathways model of problem gambling suggests the existence of three developmental pathways to problem gambling, each differentiated by a set of predisposing biopsychosocial characteristics: behaviorally conditioned (BC), emotionally vulnerable (EV), and biologically vulnerable (BV) gamblers. This study examined the empirical validity of the Pathways Model among adolescents followed up to early adulthood. A prospective-longitudinal design was used, thus overcoming limitations of past studies that used concurrent or retrospective designs. Two samples were used: (1) a population sample of French-speaking adolescents (N = 1033) living in low socio-economic status (SES) neighborhoods from the Greater Region of Montreal (Quebec, Canada), and (2) a population sample of adolescents (N = 3017), representative of French-speaking students in Quebec. Only participants with at-risk or problem gambling by mid-adolescence or early adulthood were included in the main analysis (n = 180). Latent Profile Analyses were conducted to identify the optimal number of profiles, in accordance with participants' scores on a set of variables prescribed by the Pathways Model and measured during early adolescence: depression, anxiety, impulsivity, hyperactivity, antisocial/aggressive behavior, and drug problems. A four-profile model fit the data best. Three profiles differed from each other in ways consistent with the Pathways Model (i.e., BC, EV, and BV gamblers). A fourth profile emerged, resembling a combination of EV and BV gamblers. Four profiles of at-risk and problem gamblers were identified. Three of these profiles closely resemble those suggested by the Pathways Model.

  1. APPLICATION OF APM WINMACHINE SOFTWARE FOR DESIGN AND CALCULATIONS IN MECHANICAL ENGINEERING

    Directory of Open Access Journals (Sweden)

    L. O. Neduzha

    2016-04-01

    Full Text Available Purpose.To conduct the research at all stages of design, development, operation, residual operation life determination, namely, preliminary study, action principle choice, design of draft and technical projects, their optimization, preparation of design documentation and control information for automated production, comprehensive engineering analysis, it is required to use the latest computer technologies. Their use can not only present data and information in some way, but also gives the opportunity to effectively and directly interact with the information object that is created or demonstrated. Methodology.To perform engineering calculations associated with the analysis of the strength of machines, mechanisms, constructions one uses both analytical and numerical methods in practice.The most common method for analysing the stress-strain state of object models, obtaining their dynamic and stability characteristics at constant and variable modes of external load is the finite element method, which is implemented in many famous and widespread software products, providing strength calculation of models of machines, mechanisms and structures. Findings.The use of modern software for designing machine parts and various types of their joints and for strength analysis of structures is justified. Colour charts for distribution of stresses, displacement, internal efforts, safety factor and others allow accurate and quick identification of the most dangerous places in the structure. The program also provides an opportunity to «look» inside the elements and see the resulting distribution of internal force factors. Originality.The paper considered the aspects, which are unexplored at present, associated with the current state and prospects of development of industrial production, the use of software package for design and calculations in the mechanical industry. The result of the work is the justification of software application for solving problems that

  2. Development of a pluripotent stem cell derived neuronal model to identify chemically induced pathway perturbations in relation to neurotoxicity: Effects of CREB pathway inhibition

    Energy Technology Data Exchange (ETDEWEB)

    Pistollato, Francesca; Louisse, Jochem; Scelfo, Bibiana; Mennecozzi, Milena [Institute for Health and Consumer Protection (IHCP), JRC, Ispra (Italy); Accordi, Benedetta; Basso, Giuseppe [Oncohematology Laboratory, Department of Woman and Child Health, University of Padova, Padova (Italy); Gaspar, John Antonydas [Center of Physiology and Pathophysiology, Institute of Neurophysiology, University of Cologne, Cologne (Germany); Zagoura, Dimitra; Barilari, Manuela; Palosaari, Taina [Institute for Health and Consumer Protection (IHCP), JRC, Ispra (Italy); Sachinidis, Agapios [Center of Physiology and Pathophysiology, Institute of Neurophysiology, University of Cologne, Cologne (Germany); Bremer-Hoffmann, Susanne, E-mail: susanne.bremer@jrc.ec.europa.eu [Institute for Health and Consumer Protection (IHCP), JRC, Ispra (Italy)

    2014-10-15

    According to the advocated paradigm shift in toxicology, acquisition of knowledge on the mechanisms underlying the toxicity of chemicals, such as perturbations of biological pathways, is of primary interest. Pluripotent stem cells (PSCs), such as human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs), offer a unique opportunity to derive physiologically relevant human cell types to measure molecular and cellular effects of such pathway modulations. Here we compared the neuronal differentiation propensity of hESCs and hiPSCs with the aim to develop novel hiPSC-based tools for measuring pathway perturbation in relation to molecular and cellular effects in vitro. Among other fundamental pathways, also, the cAMP responsive element binding protein (CREB) pathway was activated in our neuronal models and gave us the opportunity to study time-dependent effects elicited by chemical perturbations of the CREB pathway in relation to cellular effects. We show that the inhibition of the CREB pathway, using 2-naphthol-AS-E-phosphate (KG-501), induced an inhibition of neurite outgrowth and synaptogenesis, as well as a decrease of MAP2{sup +} neuronal cells. These data indicate that a CREB pathway inhibition can be related to molecular and cellular effects that may be relevant for neurotoxicity testing, and, thus, qualify the use of our hiPSC-derived neuronal model for studying chemical-induced neurotoxicity resulting from pathway perturbations. - Highlights: • HESCs derived neuronal cells serve as benchmark for iPSC based neuronal toxicity test development. • Comparisons between hESCs and hiPSCs demonstrated variability of the epigenetic state • CREB pathway modulation have been explored in relation to the neurotoxicant exposure KG-501 • hiPSC might be promising tools to translate theoretical AoPs into toxicological in vitro tests.

  3. Ensemble Modeling for Robustness Analysis in engineering non-native metabolic pathways.

    Science.gov (United States)

    Lee, Yun; Lafontaine Rivera, Jimmy G; Liao, James C

    2014-09-01

    Metabolic pathways in cells must be sufficiently robust to tolerate fluctuations in expression levels and changes in environmental conditions. Perturbations in expression levels may lead to system failure due to the disappearance of a stable steady state. Increasing evidence has suggested that biological networks have evolved such that they are intrinsically robust in their network structure. In this article, we presented Ensemble Modeling for Robustness Analysis (EMRA), which combines a continuation method with the Ensemble Modeling approach, for investigating the robustness issue of non-native pathways. EMRA investigates a large ensemble of reference models with different parameters, and determines the effects of parameter drifting until a bifurcation point, beyond which a stable steady state disappears and system failure occurs. A pathway is considered to have high bifurcational robustness if the probability of system failure is low in the ensemble. To demonstrate the utility of EMRA, we investigate the bifurcational robustness of two synthetic central metabolic pathways that achieve carbon conservation: non-oxidative glycolysis and reverse glyoxylate cycle. With EMRA, we determined the probability of system failure of each design and demonstrated that alternative designs of these pathways indeed display varying degrees of bifurcational robustness. Furthermore, we demonstrated that target selection for flux improvement should consider the trade-offs between robustness and performance. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

  4. Pathway Model of the Kinetics of the TGFbeta Antagonist Smad7 and Cross-Talk with the ATM and WNT Pathways

    Science.gov (United States)

    Carra, Claudio; Wang, Minli; Huff, Janice L.; Hada, Megumi; ONeill, Peter; Cucinotta, Francis A.

    2010-01-01

    Signal transduction controls cellular and tissue responses to radiation. Transforming growth factor beta (TGFbeta) is an important regulator of cell growth and differentiation and tissue homeostasis, and is often dis-regulated in tumor formation. Mathematical models of signal transduction pathways can be used to elucidate how signal transduction varies with radiation quality, and dose and dose-rate. Furthermore, modeling of tissue specific responses can be considered through mechanistic based modeling. We developed a mathematical model of the negative feedback regulation by Smad7 in TGFbeta-Smad signaling and are exploring possible connections to the WNT/beta -catenin, and ATM/ATF2 signaling pathways. A pathway model of TGFbeta-Smad signaling that includes Smad7 kinetics based on data in the scientific literature is described. Kinetic terms included are TGFbeta/Smad transcriptional regulation of Smad7 through the Smad3-Smad4 complex, Smad7-Smurf1 translocation from nucleus to cytoplasm, and Smad7 negative feedback regulation of the TGFO receptor through direct binding to the TGFO receptor complex. The negative feedback controls operating in this pathway suggests non-linear responses in signal transduction, which are described mathematically. We then explored possibilities for cross-talk mediated by Smad7 between DNA damage responses mediated by ATM, and with the WNT pathway and consider the design of experiments to test model driven hypothesis. Numerical comparisons of the mathematical model to experiments and representative predictions are described.

  5. Guiding Principles for Data Architecture to Support the Pathways Community HUB Model.

    Science.gov (United States)

    Zeigler, Bernard P; Redding, Sarah; Leath, Brenda A; Carter, Ernest L; Russell, Cynthia

    2016-01-01

    The Pathways Community HUB Model provides a unique strategy to effectively supplement health care services with social services needed to overcome barriers for those most at risk of poor health outcomes. Pathways are standardized measurement tools used to define and track health and social issues from identification through to a measurable completion point. The HUB use Pathways to coordinate agencies and service providers in the community to eliminate the inefficiencies and duplication that exist among them. Experience with the Model has brought out the need for better information technology solutions to support implementation of the Pathways themselves through decision-support tools for care coordinators and other users to track activities and outcomes, and to facilitate reporting. Here we provide a basis for discussing recommendations for such a data infrastructure by developing a conceptual model that formalizes the Pathway concept underlying current implementations. The main contribution is a set of core recommendations as a framework for developing and implementing a data architecture to support implementation of the Pathways Community HUB Model. The objective is to present a tool for communities interested in adopting the Model to learn from and to adapt in their own development and implementation efforts. Experience with the Community Health Access Project (CHAP) data base system (the core implementation of the Model) has identified several issues and remedies that have been developed to address these issues. Based on analysis of issues and remedies, we present several key features for a data architecture meeting the just mentioned recommendations. Presentation of features is followed by a practical guide to their implementation allowing an organization to consider either tailoring off-the-shelf generic systems to meet the requirements or offerings that are specialized for community-based care coordination. Looking to future extensions, we discuss the

  6. Groundwater Pathway Model for the Los Alamos National Laboratory Technical Area 21, Material Disposal Area T

    Energy Technology Data Exchange (ETDEWEB)

    Stauffer, Philip H. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Levitt, Daniel G. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Miller, Terry Ann [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Jordan, Amy [Neptune Inc, Los Alamos, NM (United States); Chu, Shaoping [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Dash, Zora [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2017-02-09

    This report consists of four major sections, including this introductory section. Section 2 provides an overview of previous investigations related to the development of the current sitescale model. The methods and data used to develop the 3-D groundwater model and the techniques used to distill that model into a form suitable for use in the GoldSim models are discussed in Section 3. Section 4 presents the results of the model development effort and discusses some of the uncertainties involved. Three attachments that provide details about the components and data used in this groundwater pathway model are also included with this report.

  7. A compartmental model of the cAMP/PKA/MAPK pathway in Bio-PEPA

    Directory of Open Access Journals (Sweden)

    Federica Ciocchetta

    2009-11-01

    Full Text Available The vast majority of biochemical systems involve the exchange of information between different compartments, either in the form of transportation or via the intervention of membrane proteins which are able to transmit stimuli between bordering compartments. The correct quantitative handling of compartments is, therefore, extremely important when modelling real biochemical systems. The Bio-PEPA process algebra is equipped with the capability of explicitly defining quantitative information such as compartment volumes and membrane surface areas. Furthermore, the recent development of the Bio-PEPA Eclipse Plug-in allows us to perform a correct stochastic simulation of multi-compartmental models. Here we present a Bio-PEPA compartmental model of the cAMP/PKA/MAPK pathway. We analyse the system using the Bio-PEPA Eclipse Plug-in and we show the correctness of our model by comparison with an existing ODE model. Furthermore, we perform computational experiments in order to investigate certain properties of the pathway. Specifically, we focus on the system response to the inhibition and strengthening of feedback loops and to the variation in the activity of key pathway reactions and we observe how these modifications affect the behaviour of the pathway. These experiments are useful to understand the control and regulatory mechanisms of the system.

  8. The fractional diffusion limit of a kinetic model with biochemical pathway

    Science.gov (United States)

    Perthame, Benoît; Sun, Weiran; Tang, Min

    2018-06-01

    Kinetic-transport equations that take into account the intracellular pathways are now considered as the correct description of bacterial chemotaxis by run and tumble. Recent mathematical studies have shown their interest and their relations to more standard models. Macroscopic equations of Keller-Segel type have been derived using parabolic scaling. Due to the randomness of receptor methylation or intracellular chemical reactions, noise occurs in the signaling pathways and affects the tumbling rate. Then comes the question to understand the role of an internal noise on the behavior of the full population. In this paper we consider a kinetic model for chemotaxis which includes biochemical pathway with noises. We show that under proper scaling and conditions on the tumbling frequency as well as the form of noise, fractional diffusion can arise in the macroscopic limits of the kinetic equation. This gives a new mathematical theory about how long jumps can be due to the internal noise of the bacteria.

  9. Acting in solidarity : Testing an extended dual pathway model of collective action by bystander group members

    NARCIS (Netherlands)

    Saab, Rim; Tausch, Nicole; Spears, Russell; Cheung, Wing-Yee

    We examined predictors of collective action among bystander group members in solidarity with a disadvantaged group by extending the dual pathway model of collective action, which proposes one efficacy-based and one emotion-based path to collective action (Van Zomeren, Spears, Fischer, & Leach,

  10. Multi-pathway exposure modelling of chemicals in cosmetics with application to shampoo

    DEFF Research Database (Denmark)

    Ernstoff, Alexi S.; Fantke, Peter; Csiszar, Susan A.

    2016-01-01

    We present a novel multi-pathway, mass balance based, fate and exposure model compatible with life cycle and high-throughput screening assessments of chemicals in cosmetic products. The exposures through product use as well as post-use emissions and environmental media were quantified based...

  11. Multi-pathway exposure modelling of chemicals in cosmetics with application to shampoo

    Science.gov (United States)

    We present a novel multi-pathway, mass balance based, fate and exposure model compatible with life cycle and high-throughput screening assessments of chemicals in cosmetic products. The exposures through product use as well as post-use emissions and environmental media were quant...

  12. Protesters as "passionate economists" : A dynamic dual pathway model of approach coping with collective disadvantage

    NARCIS (Netherlands)

    van Zomeren, Martijn; Leach, Colin Wayne; Spears, Russell

    To explain the psychology behind individuals' motivation to participate in collective action against collective disadvantage (e.g., protest marches), the authors introduce a dynamic dual pathway model of approach coping that integrates many common explanations of collective action (i.e., group

  13. The dual pathway to creativity model: creative ideation as a function of flexibility and persistence

    NARCIS (Netherlands)

    Nijstad, B.A.; de Dreu, C.K.W.; Rietzschel, E.F.; Baas, M.

    2010-01-01

    The dual pathway to creativity model argues that creativity—the generation of original and appropriate ideas—is a function of cognitive flexibility and cognitive persistence, and that dispositional or situational variables may influence creativity either through their effects on flexibility, on

  14. The dual pathway to creativity model : Creative ideation as a function of flexibility and persistence

    NARCIS (Netherlands)

    Nijstad, B.A.; De Dreu, C.K.W.; Rietzschel, E.F.; Baas, M.

    2010-01-01

    The dual pathway to creativity model argues that creativity-the generation of original and appropriate ideas-is a function of cognitive flexibility and cognitive persistence, and that dispositional or situational variables may influence creativity either through their effects on flexibility, on

  15. Ethics. 1983 APME Report.

    Science.gov (United States)

    Associated Press Managing Editors.

    Dealing with a variety of issues related to media ethics and press responsibility, this report presents 12 essays on editorial policy and reporters' responsibility. The essays discuss the following: (1) a reporter who posed as a jail officer to gain entry into a prison to interview an inmate, (2) a journalism professor's opinion as to the ethics…

  16. Position-specific isotope modeling of organic micropollutants transformation through different reaction pathways

    International Nuclear Information System (INIS)

    Jin, Biao; Rolle, Massimo

    2016-01-01

    The degradation of organic micropollutants occurs via different reaction pathways. Compound specific isotope analysis is a valuable tool to identify such degradation pathways in different environmental systems. We propose a mechanism-based modeling approach that provides a quantitative framework to simultaneously evaluate concentration as well as bulk and position-specific multi-element isotope evolution during the transformation of organic micropollutants. The model explicitly simulates position-specific isotopologues for those atoms that experience isotope effects and, thereby, provides a mechanistic description of isotope fractionation occurring at different molecular positions. To demonstrate specific features of the modeling approach, we simulated the degradation of three selected organic micropollutants: dichlorobenzamide (BAM), isoproturon (IPU) and diclofenac (DCF). The model accurately reproduces the multi-element isotope data observed in previous experimental studies. Furthermore, it precisely captures the dual element isotope trends characteristic of different reaction pathways as well as their range of variation consistent with observed bulk isotope fractionation. It was also possible to directly validate the model capability to predict the evolution of position-specific isotope ratios with available experimental data. Therefore, the approach is useful both for a mechanism-based evaluation of experimental results and as a tool to explore transformation pathways in scenarios for which position-specific isotope data are not yet available. - Highlights: • Mechanism-based, position-specific isotope modeling of micropollutants degradation. • Simultaneous description of concentration and primary and secondary isotope effects. • Key features of the model are demonstrated with three illustrative examples. • Model as a tool to explore reaction mechanisms and to design experiments. - We propose a modeling approach incorporating mechanistic information and

  17. The activation of the kynurenine pathway in a rat model with renovascular hypertension.

    Science.gov (United States)

    Bartosiewicz, Jacek; Kaminski, Tomasz; Pawlak, Krystyna; Karbowska, Malgorzata; Tankiewicz-Kwedlo, Anna; Pawlak, Dariusz

    2017-04-01

    Hypertension is a serious condition that can lead to many health problems. The mechanisms underlying this process are still not fully understood. The kynurenine pathway may be involved in the occurrence and progression of hypertension. The purpose of this study was to examine the activity of peripheral kynurenine pathway in rats with renovascular hypertension in Goldblatt 2K1C model. Hypertension was induced in the experimental groups by constricting the renal artery of the left kidney of the rats. Determination of tryptophan (Trp) and kynurenine pathway metabolites was assessed by high-performance liquid chromatography in plasma and tissues obtained at 4, 8, and 16 weeks after the surgical intervention or sham surgery. Levels of Ang II were evaluated using commercial immuno-enzymatic ELISA kits. Surgical treatment led to increased values of mean blood pressure and systolic blood pressure, whereas Trp concentrations were decreased in experimental animals compared to appropriate controls. Simultaneously, the considerable increment of kynurenine pathway components and a significant increase in the activity of tryptophan 2,3-dioxygenase were observed in rats with developed hypertension in comparison with controls. There were no differences between Ang II levels in controls and experimental groups. The inverse relationship was between plasma Trp and both SBP and Ang II values, and Trp independently affected Ang II concentrations in hypertensive rats. In contrast, tryptophan 2,3-dioxygenase activity and plasma kynurenine metabolites positively correlated with blood pressure values as well as with Ang II levels in these animals. Moreover, kynurenine was independently connected with MBP. Renovascular hypertension influences kynurenine pathway and leads to an imbalance in Trp and its metabolite levels. Tryptophan 2,3-dioxygenase and part of the kynurenine metabolites in plasma and tissues positively correlated with blood pressure values and Ang II levels. Although the

  18. Functional Relevance of Different Basal Ganglia Pathways Investigated in a Spiking Model with Reward Dependent Plasticity

    Directory of Open Access Journals (Sweden)

    Pierre Berthet

    2016-07-01

    Full Text Available The brain enables animals to behaviourally adapt in order to survive in a complex and dynamic environment, but how reward-oriented behaviours are achieved and computed by its underlying neural circuitry is an open question. To address this concern, we have developed a spiking model of the basal ganglia (BG that learns to dis-inhibit the action leading to a reward despite ongoing changes in the reward schedule. The architecture of the network features the two pathways commonly described in BG, the direct (denoted D1 and the indirect (denoted D2 pathway, as well as a loop involving striatum and the dopaminergic system. The activity of these dopaminergic neurons conveys the reward prediction error (RPE, which determines the magnitude of synaptic plasticity within the different pathways. All plastic connections implement a versatile four-factor learning rule derived from Bayesian inference that depends upon pre- and postsynaptic activity, receptor type and dopamine level. Synaptic weight updates occur in the D1 or D2 pathways depending on the sign of the RPE, and an efference copy informs upstream nuclei about the action selected. We demonstrate successful performance of the system in a multiple-choice learning task with a transiently changing reward schedule. We simulate lesioning of the various pathways and show that a condition without the D2 pathway fares worse than one without D1. Additionally, we simulate the degeneration observed in Parkinson’s disease (PD by decreasing the number of dopaminergic neurons during learning. The results suggest that the D1 pathway impairment in PD might have been overlooked. Furthermore, an analysis of the alterations in the synaptic weights shows that using the absolute reward value instead of the RPE leads to a larger change in D1.

  19. Hidden Hearing Loss and Computational Models of the Auditory Pathway: Predicting Speech Intelligibility Decline

    Science.gov (United States)

    2016-11-28

    Title: Hidden Hearing Loss and Computational Models of the Auditory Pathway: Predicting Speech Intelligibility Decline Christopher J. Smalt...representation of speech intelligibility in noise. The auditory-periphery model of Zilany et al. (JASA 2009,2014) is used to make predictions of...auditory nerve (AN) responses to speech stimuli under a variety of difficult listening conditions. The resulting cochlear neurogram, a spectrogram

  20. Pathogenesis pathways of idiopathic pulmonary fibrosis in bleomycin-induced lung injury model in mice.

    Science.gov (United States)

    Shi, Keyun; Jiang, Jianzhong; Ma, Tieliang; Xie, Jing; Duan, Lirong; Chen, Ruhua; Song, Ping; Yu, Zhixin; Liu, Chao; Zhu, Qin; Zheng, Jinxu

    2014-01-01

    Our objective was to investigate the pathogenesis pathways of idiopathic pulmonary fibrosis (IPF). Bleomycin (BLM) induced animal models of experimental lung fibrosis were used. CHIP assay was executed to find the link between Smad3 and IL-31, and the expressions of TGF-β1, Smad3, IL-31 and STAT1 were detected to find whether they were similar with each other. We found that in the early injury or inflammation of the animal model, BLM promoted the development of inflammation, leading to severe pulmonary fibrosis. Then the expression of TGF-β1 and Smad3 increased. Activated Smad3 bound to the IL-31 promoter region, followed by the activation of JAK-STAT pathways. The inhibitor of TGF-β1 receptor decreased the IL-31 expression and knocking-down of IL-31 also decreased the STAT1 expression. We conclude that there is a pathway of pathogenesis in BLM-induced mouse model that involves the TGF-β, IL-31 and JAKs/STATs pathway. Copyright © 2013 Elsevier B.V. All rights reserved.

  1. The LUGPA Alternative Payment Model for Initial Therapy of Newly Diagnosed Patients With Organ-confined Prostate Cancer: Rationale and Development.

    Science.gov (United States)

    Kapoor, Deepak A; Shore, Neal D; Kirsh, Gary M; Henderson, Jonathan; Cohen, Todd D; Latino, Kathleen

    2017-01-01

    Over the past several decades, rapid expansion in healthcare expenditures has exposed the utilization incentives inherent in fee-for-service payment models. The passage of Medicare Access and CHIP Reauthorization Act of 2015 heralded a transition toward value-based care, creating incentives for practitioners to accept bidirectional risk linked to outcome and utilization metrics. At present, the limited availability of these vehicles excludes all but a handful of providers from participation in alternative payment models (APMs). The LUGPA APM supports the goals of the triple aim in improving the patient experience, enhancing population health and reducing expenditures. By requiring utilization of certified electronic health record technologies, tying payment to quality metrics, and requiring practices to bear more than nominal risk, the LUGPA APM qualifies as an advanced APM, thereby easing the reporting burden and creating opportunities for participating practices.

  2. The flavonoid pathway in tomato seedlings: transcript abundance and the modeling of metabolite dynamics.

    Directory of Open Access Journals (Sweden)

    Marian Groenenboom

    Full Text Available Flavonoids are secondary metabolites present in all terrestrial plants. The flavonoid pathway has been extensively studied, and many of the involved genes and metabolites have been described in the literature. Despite this extensive knowledge, the functioning of the pathway in vivo is still poorly understood. Here, we study the flavonoid pathway using both experiments and mathematical models. We measured flavonoid metabolite dynamics in two tissues, hypocotyls and cotyledons, during tomato seedling development. Interestingly, the same backbone of interactions leads to very different accumulation patterns in the different tissues. Initially, we developed a mathematical model with constant enzyme concentrations that described the metabolic networks separately in both tissues. This model was unable to fit the measured flavonoid dynamics in the hypocotyls, even if we allowed unrealistic parameter values. This suggested us to investigate the effect of transcript abundance on flavonoid accumulation. We found that the expression of candidate flavonoid genes varies considerably with time. Variation in transcript abundance results in enzymatic variation, which could have a large effect on metabolite accumulation. Candidate transcript abundance was included in the mathematical model as representative for enzyme concentration. We fitted the resulting model to the flavonoid dynamics in the cotyledons, and tested it by applying it to the data from hypocotyls. When transcript abundance is included, we are indeed able to explain flavonoid dynamics in both tissues. Importantly, this is possible under the biologically relevant restriction that the enzymatic properties estimated by the model are conserved between the tissues.

  3. Modelling plant invasion pathways in protected areas under climate change: implication for invasion management

    Directory of Open Access Journals (Sweden)

    C.-J. Wang

    2017-12-01

    Full Text Available Global climate change may enable invasive plant species (IPS to invade protected areas (PAs, but plant invasion on a global scale has not yet been explicitly addressed. Here, we mapped the potential invasion pathways for IPS in PAs across the globe and explored potential factors determining the pathways of plant invasion under climate change. We used species distribution modelling to estimate the suitable habitats of 386 IPS and applied a corridor analysis to compute the potential pathways of IPS in PAs under climate change. Subsequently, we analysed the potential factors affecting the pathways in PAs. According to our results, the main potential pathways of IPS in PAs are in Europe, eastern Australia, New Zealand, southern Africa, and eastern regions of South America and are strongly influenced by changes in temperature and precipitation. Protected areas can play an important role in preventing and controlling the spread of IPS under climate change. This is due to the fact that measures are taken to monitor climate change in detail, to provide effective management near or inside PAs, and to control the introduction of IPS with a high capacity for natural dispersal. A review of conservation policies in PAs is urgently needed.

  4. A residence-time-based transport approach for the groundwater pathway in performance assessment models

    Science.gov (United States)

    Robinson, Bruce A.; Chu, Shaoping

    2013-03-01

    This paper presents the theoretical development and numerical implementation of a new modeling approach for representing the groundwater pathway in risk assessment or performance assessment model of a contaminant transport system. The model developed in the present study, called the Residence Time Distribution (RTD) Mixing Model (RTDMM), allows for an arbitrary distribution of fluid travel times to be represented, to capture the effects on the breakthrough curve of flow processes such as channelized flow and fast pathways and complex three-dimensional dispersion. Mathematical methods for constructing the model for a given RTD are derived directly from the theory of residence time distributions in flowing systems. A simple mixing model is presented, along with the basic equations required to enable an arbitrary RTD to be reproduced using the model. The practical advantages of the RTDMM include easy incorporation into a multi-realization probabilistic simulation; computational burden no more onerous than a one-dimensional model with the same number of grid cells; and straightforward implementation into available flow and transport modeling codes, enabling one to then utilize advanced transport features of that code. For example, in this study we incorporated diffusion into the stagnant fluid in the rock matrix away from the flowing fractures, using a generalized dual porosity model formulation. A suite of example calculations presented herein showed the utility of the RTDMM for the case of a radioactive decay chain, dual porosity transport and sorption.

  5. A first approximation for modeling the liquid diffusion pathway at the greater confinement disposal facilities

    International Nuclear Information System (INIS)

    Olague, N.E.; Price, L.L.

    1991-01-01

    The greater confinement disposal (GCD) project is an ongoing project examining the disposal of orphan wastes in Area 5 of the Nevada Test Site. One of the major tasks for the project is performance assessment. With regard to performance assessment, a preliminary conceptual model for ground-water flow and radionuclide transport to the accessible environment at the GCD facilities has been developed. One of the transport pathways that has been postulated is diffusion of radionuclides in the liquid phase upward to the land surface. This pathway is not usually considered in a performance assessment, but is included in the GCD conceptual model because of relatively low recharge estimates at the GCD site and the proximity of the waste to the land surface. These low recharge estimates indicate that convective flow downward to the water table may be negligible; thus, diffusion upward to the land surface may then become important. As part of a preliminary performance assessment which considered a basecase scenario and a climate-change scenario, a first approximation for modeling the liquid-diffusion pathway was formulated. The model includes an analytical solution that incorporates both diffusion and radioactivity decay. Overall, these results indicate that, despite the configuration of the GCD facilities that establishes the need for considering the liquid-diffusion pathway, the GCD disposal concept appears to be a technically feasible method for disposing of orphan wastes. Future analyses will consist of investigating the underlying assumptions of the liquid-diffusion model, refining the model is necessary, and reducing uncertainty in the input parameters. 11 refs., 6 figs

  6. Aerosol penetration of leak pathways : an examination of the available data and models.

    Energy Technology Data Exchange (ETDEWEB)

    Powers, Dana Auburn

    2009-04-01

    Data and models of aerosol particle deposition in leak pathways are described. Pathways considered include capillaries, orifices, slots and cracks in concrete. The Morewitz-Vaughan criterion for aerosol plugging of leak pathways is shown to be applicable only to a limited range of particle settling velocities and Stokes numbers. More useful are sampling efficiency criteria defined by Davies and by Liu and Agarwal. Deposition of particles can be limited by bounce from surfaces defining leak pathways and by resuspension of particles deposited on these surfaces. A model of the probability of particle bounce is described. Resuspension of deposited particles can be triggered by changes in flow conditions, particle impact on deposits and by shock or vibration of the surfaces. This examination was performed as part of the review of the AP1000 Standard Combined License Technical Report, APP-GW-GLN-12, Revision 0, 'Offsite and Control Room Dose Changes' (TR-112) in support of the USNRC AP1000 Standard Combined License Pre-Application Review.

  7. GEM System: automatic prototyping of cell-wide metabolic pathway models from genomes

    Directory of Open Access Journals (Sweden)

    Nakayama Yoichi

    2006-03-01

    Full Text Available Abstract Background Successful realization of a "systems biology" approach to analyzing cells is a grand challenge for our understanding of life. However, current modeling approaches to cell simulation are labor-intensive, manual affairs, and therefore constitute a major bottleneck in the evolution of computational cell biology. Results We developed the Genome-based Modeling (GEM System for the purpose of automatically prototyping simulation models of cell-wide metabolic pathways from genome sequences and other public biological information. Models generated by the GEM System include an entire Escherichia coli metabolism model comprising 968 reactions of 1195 metabolites, achieving 100% coverage when compared with the KEGG database, 92.38% with the EcoCyc database, and 95.06% with iJR904 genome-scale model. Conclusion The GEM System prototypes qualitative models to reduce the labor-intensive tasks required for systems biology research. Models of over 90 bacterial genomes are available at our web site.

  8. Modeling the effects of a Staphylococcal Enterotoxin B (SEB on the apoptosis pathway

    Directory of Open Access Journals (Sweden)

    Hammamieh Rasha

    2006-05-01

    Full Text Available Abstract Background The lack of detailed understanding of the mechanism of action of many biowarfare agents poses an immediate challenge to biodefense efforts. Many potential bioweapons have been shown to affect the cellular pathways controlling apoptosis 1234. For example, pathogen-produced exotoxins such as Staphylococcal Enterotoxin B (SEB and Anthrax Lethal Factor (LF have been shown to disrupt the Fas-mediated apoptotic pathway 24. To evaluate how these agents affect these pathways it is first necessary to understand the dynamics of a normally functioning apoptosis network. This can then serve as a baseline against which a pathogen perturbed system can be compared. Such comparisons can expose both the proteins most susceptible to alteration by the agent as well as the most critical reaction rates to better instill control on a biological network. Results We explore this through the modeling and simulation of the Fas-mediated apoptotic pathway under normal and SEB influenced conditions. We stimulated human Jurkat cells with an anti-Fas antibody in the presence and absence of SEB and determined the relative levels of seven proteins involved in the core pathway at five time points following exposure. These levels were used to impute relative rate constants and build a quantitative model consisting of a series of ordinary differential equations (ODEs that simulate the network under both normal and pathogen-influenced conditions. Experimental results show that cells exposed to SEB exhibit an increase in the rate of executioner caspase expression (and subsequently apoptosis of 1 hour 43 minutes (± 14 minutes, as compared to cells undergoing normal cell death. Conclusion Our model accurately reflects these results and reveals intervention points that can be altered to restore SEB-influenced system dynamics back to levels within the range of normal conditions.

  9. Observed and modeled pathways of the Iceland Scotland Overflow Water in the eastern North Atlantic

    Science.gov (United States)

    Zou, Sijia; Lozier, Susan; Zenk, Walter; Bower, Amy; Johns, William

    2017-12-01

    The spreading of Iceland Scotland Overflow Water (ISOW) in the eastern North Atlantic has largely been studied in an Eulerian frame using numerical models or with observations limited to a few locations. No study to date has provided a comprehensive description of the ISOW spreading pathways from both Eulerian and Lagrangian perspectives. In this paper, we use a combination of previously unreported current meter data, hydrographic data, RAFOS float data, and a high resolution (1/12°) numerical ocean model to study the spreading pathways of ISOW from both of these perspectives. We identify three ISOW transport cores in the central Iceland Basin (∼59°N), with the major core along the eastern boundary of the Reykjanes Ridge (RR) and the other two in the basin interior. Based on trajectories of observed and/or numerical floats seeded along 59°N, we also describe the ISOW spreading pathways and quantify their relative importance. Within 10 years, 7-11% of ISOW from 59°N escapes into the Irminger Sea via gaps in the RR north of the Charlie Gibbs Fracture Zone (CGFZ); the water that moves through these gaps principally originates from the shallower ISOW layer along the RR eastern boundary. 10-13% travels further southward until the CGFZ, where it crosses westward into the western subpolar gyre. 18-21% of ISOW spreads southward along the eastern flank of the Mid-Atlantic Ridge into the Western European Basin (WEB). Most of the remaining water stays in the Iceland Basin over the 10-year period. A model-based investigation provides a first look at the temporal variability of these ISOW pathways. We find that the fraction of southward water exported into the WEB is anti-correlated with the export through the CGFZ, a result assumed to reflect these pathways' interactions with the North Atlantic Current in magnitude and/or position shift.

  10. Expectancies and Self-Efficacy Mediate the Effects of Impulsivity on Marijuana Use Outcomes: An Application of the Acquired Preparedness Model

    OpenAIRE

    Hayaki, Jumi; Herman, Debra S.; Hagerty, Claire E.; de Dios, Marcel A.; Anderson, Bradley J.; Stein, Michael D.

    2010-01-01

    This study tests the acquired preparedness model (APM) to explain associations among trait impulsivity, social learning principles, and marijuana use outcomes in a community sample of female marijuana users. The APM states that individuals with high-risk dispositions are more likely to acquire certain types of learning that, in turn, instigate problematic substance use behaviors. In this study, three domains of psychosocial learning were tested: positive and negative marijuana use expectancie...

  11. A Computational Model of a Descending Mechanosensory Pathway Involved in Active Tactile Sensing.

    Directory of Open Access Journals (Sweden)

    Jan M Ache

    2015-07-01

    Full Text Available Many animals, including humans, rely on active tactile sensing to explore the environment and negotiate obstacles, especially in the dark. Here, we model a descending neural pathway that mediates short-latency proprioceptive information from a tactile sensor on the head to thoracic neural networks. We studied the nocturnal stick insect Carausius morosus, a model organism for the study of adaptive locomotion, including tactually mediated reaching movements. Like mammals, insects need to move their tactile sensors for probing the environment. Cues about sensor position and motion are therefore crucial for the spatial localization of tactile contacts and the coordination of fast, adaptive motor responses. Our model explains how proprioceptive information about motion and position of the antennae, the main tactile sensors in insects, can be encoded by a single type of mechanosensory afferents. Moreover, it explains how this information is integrated and mediated to thoracic neural networks by a diverse population of descending interneurons (DINs. First, we quantified responses of a DIN population to changes in antennal position, motion and direction of movement. Using principal component (PC analysis, we find that only two PCs account for a large fraction of the variance in the DIN response properties. We call the two-dimensional space spanned by these PCs 'coding-space' because it captures essential features of the entire DIN population. Second, we model the mechanoreceptive input elements of this descending pathway, a population of proprioceptive mechanosensory hairs monitoring deflection of the antennal joints. Finally, we propose a computational framework that can model the response properties of all important DIN types, using the hair field model as its only input. This DIN model is validated by comparison of tuning characteristics, and by mapping the modelled neurons into the two-dimensional coding-space of the real DIN population. This

  12. Adapting Evaluations of Alternative Payment Models to a Changing Environment.

    Science.gov (United States)

    Grannemann, Thomas W; Brown, Randall S

    2018-04-01

    To identify the most robust methods for evaluating alternative payment models (APMs) in the emerging health care delivery system environment. We assess the impact of widespread testing of alternative payment models on the ability to find credible comparison groups. We consider the applicability of factorial research designs for assessing the effects of these models. The widespread adoption of alternative payment models could effectively eliminate the possibility of comparing APM results with a "pure" control or comparison group unaffected by other interventions. In this new environment, factorial experiments have distinct advantages over the single-model experimental or quasi-experimental designs that have been the mainstay of recent tests of Medicare payment and delivery models. The best prospects for producing definitive evidence of the effects of payment incentives for APMs include fractional factorial experiments that systematically vary requirements and payment provisions within a payment model. © Health Research and Educational Trust.

  13. A pedagogical walkthrough of computational modeling and simulation of Wnt signaling pathway using static causal models in MATLAB.

    Science.gov (United States)

    Sinha, Shriprakash

    2016-12-01

    Simulation study in systems biology involving computational experiments dealing with Wnt signaling pathways abound in literature but often lack a pedagogical perspective that might ease the understanding of beginner students and researchers in transition, who intend to work on the modeling of the pathway. This paucity might happen due to restrictive business policies which enforce an unwanted embargo on the sharing of important scientific knowledge. A tutorial introduction to computational modeling of Wnt signaling pathway in a human colorectal cancer dataset using static Bayesian network models is provided. The walkthrough might aid biologists/informaticians in understanding the design of computational experiments that is interleaved with exposition of the Matlab code and causal models from Bayesian network toolbox. The manuscript elucidates the coding contents of the advance article by Sinha (Integr. Biol. 6:1034-1048, 2014) and takes the reader in a step-by-step process of how (a) the collection and the transformation of the available biological information from literature is done, (b) the integration of the heterogeneous data and prior biological knowledge in the network is achieved, (c) the simulation study is designed, (d) the hypothesis regarding a biological phenomena is transformed into computational framework, and (e) results and inferences drawn using d -connectivity/separability are reported. The manuscript finally ends with a programming assignment to help the readers get hands-on experience of a perturbation project. Description of Matlab files is made available under GNU GPL v3 license at the Google code project on https://code.google.com/p/static-bn-for-wnt-signaling-pathway and https: //sites.google.com/site/shriprakashsinha/shriprakashsinha/projects/static-bn-for-wnt-signaling-pathway. Latest updates can be found in the latter website.

  14. Hypospadias surgery in children: improved service model of enhanced recovery pathway and dedicated surgical team.

    Science.gov (United States)

    Wong, Y S; Pang, K K; Tam, Y H

    2018-05-21

    Children in Hong Kong are generally hospitalised for 1 to 2 weeks after hypospadias repairs. In July 2013, we introduced a new service model that featured an enhanced recovery pathway and a dedicated surgical team responsible for all perioperative services. In this study, we investigated the outcomes of hypospadias repair after the introduction of the new service model. We conducted a retrospective study on consecutive children who underwent primary hypospadias repair from January 2006 to August 2016, comparing patients under the old service with those under the new service. Outcome measures included early morbidity, operative success, and completion of enhanced recovery pathway. The old service and new service cohorts comprised 176 and 126 cases, respectively. There was no difference between the two cohorts in types of hypospadias and surgical procedures performed. The median hospital stay was 2 days in the new service cohort compared with 10 days in the old service cohort (Pservice than the old service. Multivariable analysis revealed that the new service significantly reduced the odds of early morbidity (odds ratio=0.35, 95% confidence interval=0.15-0.85; P=0.02) and operative failure (odds ratio=0.32, 95% confidence interval=0.17-0.59; Pservice. Of the new service cohort, 111(88.1%) patients successfully completed the enhanced recovery pathway. The enhanced recovery pathway can be implemented safely and effectively to primary hypospadias repair. A dedicated surgical team may play an important role in successful implementation of the enhanced recovery pathway and optimisation of surgical outcomes.

  15. Savannah River Laboratory DOSTOMAN code: a compartmental pathways computer model of contaminant transport

    International Nuclear Information System (INIS)

    King, C.M.; Wilhite, E.L.; Root, R.W. Jr.

    1985-01-01

    The Savannah River Laboratory DOSTOMAN code has been used since 1978 for environmental pathway analysis of potential migration of radionuclides and hazardous chemicals. The DOSTOMAN work is reviewed including a summary of historical use of compartmental models, the mathematical basis for the DOSTOMAN code, examples of exact analytical solutions for simple matrices, methods for numerical solution of complex matrices, and mathematical validation/calibration of the SRL code. The review includes the methodology for application to nuclear and hazardous chemical waste disposal, examples of use of the model in contaminant transport and pathway analysis, a user's guide for computer implementation, peer review of the code, and use of DOSTOMAN at other Department of Energy sites. 22 refs., 3 figs

  16. Using consensus bayesian network to model the reactive oxygen species regulatory pathway.

    Directory of Open Access Journals (Sweden)

    Liangdong Hu

    Full Text Available Bayesian network is one of the most successful graph models for representing the reactive oxygen species regulatory pathway. With the increasing number of microarray measurements, it is possible to construct the bayesian network from microarray data directly. Although large numbers of bayesian network learning algorithms have been developed, when applying them to learn bayesian networks from microarray data, the accuracies are low due to that the databases they used to learn bayesian networks contain too few microarray data. In this paper, we propose a consensus bayesian network which is constructed by combining bayesian networks from relevant literatures and bayesian networks learned from microarray data. It would have a higher accuracy than the bayesian networks learned from one database. In the experiment, we validated the bayesian network combination algorithm on several classic machine learning databases and used the consensus bayesian network to model the Escherichia coli's ROS pathway.

  17. Catalytic Hydrotreatment of Fast Pyrolysis Oil: Model Studies on Reaction Pathways for the Carbohydrate Fraction

    OpenAIRE

    Wildschut, J.; Arentz, J.; Rasrendra, C. B.; Venderbosch, R. H.; Heeres, H. J.

    2009-01-01

    Fast pyrolysis oil can be upgraded by a catalytic hydrotreatment (250-400 degrees C, 100-200 bar) using heterogeneous catalysts such as Ru/C to hydrocarbon-like products that can serve as liquid transportation fuels. Insight into the complex reaction pathways of the various component fractions during hydrotreatment is desirable to reduce the formation of by-products such as char and gaseous components. This paper deals with the catalytic hydrotreatment of representative model components for t...

  18. Estimation of Anaerobic Debromination Rate Constants of PBDE Pathways Using an Anaerobic Dehalogenation Model.

    Science.gov (United States)

    Karakas, Filiz; Imamoglu, Ipek

    2017-04-01

    This study aims to estimate anaerobic debromination rate constants (k m ) of PBDE pathways using previously reported laboratory soil data. k m values of pathways are estimated by modifying a previously developed model as Anaerobic Dehalogenation Model. Debromination activities published in the literature in terms of bromine substitutions as well as specific microorganisms and their combinations are used for identification of pathways. The range of estimated k m values is between 0.0003 and 0.0241 d -1 . The median and maximum of k m values are found to be comparable to the few available biologically confirmed rate constants published in the literature. The estimated k m values can be used as input to numerical fate and transport models for a better and more detailed investigation of the fate of individual PBDEs in contaminated sediments. Various remediation scenarios such as monitored natural attenuation or bioremediation with bioaugmentation can be handled in a more quantitative manner with the help of k m estimated in this study.

  19. Identification of mutated driver pathways in cancer using a multi-objective optimization model.

    Science.gov (United States)

    Zheng, Chun-Hou; Yang, Wu; Chong, Yan-Wen; Xia, Jun-Feng

    2016-05-01

    New-generation high-throughput technologies, including next-generation sequencing technology, have been extensively applied to solve biological problems. As a result, large cancer genomics projects such as the Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium are producing large amount of rich and diverse data in multiple cancer types. The identification of mutated driver genes and driver pathways from these data is a significant challenge. Genome aberrations in cancer cells can be divided into two types: random 'passenger mutation' and functional 'driver mutation'. In this paper, we introduced a Multi-objective Optimization model based on a Genetic Algorithm (MOGA) to solve the maximum weight submatrix problem, which can be employed to identify driver genes and driver pathways promoting cancer proliferation. The maximum weight submatrix problem defined to find mutated driver pathways is based on two specific properties, i.e., high coverage and high exclusivity. The multi-objective optimization model can adjust the trade-off between high coverage and high exclusivity. We proposed an integrative model by combining gene expression data and mutation data to improve the performance of the MOGA algorithm in a biological context. Copyright © 2016 Elsevier Ltd. All rights reserved.

  20. Modeling reaction histories to study chemical pathways in condensed phase detonation

    International Nuclear Information System (INIS)

    Scott Stewart, D.; Hernández, Alberto; Lee, Kibaek

    2016-01-01

    The estimation of pressure and temperature histories, which are required to understand chemical pathways in condensed phase explosives during detonation, is discussed. We argue that estimates made from continuum models, calibrated by macroscopic experiments, are essential to inform modern, atomistic-based reactive chemistry simulations at detonation pressures and temperatures. We present easy to implement methods for general equation of state and arbitrarily complex chemical reaction schemes that can be used to compute reactive flow histories for the constant volume, the energy process, and the expansion process on the Rayleigh line of a steady Chapman-Jouguet detonation. A brief review of state-of-the-art of two-component reactive flow models is given that highlights the Ignition and Growth model of Lee and Tarver [Phys. Fluids 23, 2362 (1980)] and the Wide-Ranging Equation of State model of Wescott, Stewart, and Davis [J. Appl. Phys. 98, 053514 (2005)]. We discuss evidence from experiments and reactive molecular dynamic simulations that motivate models that have several components, instead of the two that have traditionally been used to describe the results of macroscopic detonation experiments. We present simplified examples of a formulation for a hypothetical explosive that uses simple (ideal) equation of state forms and detailed comparisons. Then, we estimate pathways computed from two-component models of real explosive materials that have been calibrated with macroscopic experiments.

  1. PATH1 self-teaching curriculum: example problems for Pathways-to-Man Model

    International Nuclear Information System (INIS)

    Helton, J.C.; Finley, N.C.

    1982-10-01

    The Pathways-to-Man Model was developed at Sandia National Laboratories to represent the environmental movement and human uptake of radionuclides. This model is implemented by the computer program PATH1. The purpose of this document is to present a sequence of examples of facilitate use of the model and the computer program which implements it. Each example consists of a brief description of the problem under consideration, a discussion of the data cards required to input the problem to PATH1, and the resultant program output. These examples are intended for use in conjunction with the technical report which describes the model and the computer progam which implements it (NUREG/CR-1636, Vol 1; SAND78-1711). In addition, a sequence of appendices provides the following: a description of a surface hydrologic system used in constructing several of the examples, a discussion of mixed-cell models, and a discussion of selected mathematical topics related to the Pathways Model. A copy of the program PATH1 is included with the report

  2. Biosphere modelling for a deep radioactive waste repository: treatment of the groundwater-soil pathway

    International Nuclear Information System (INIS)

    Baeyens, B.; Grogan, H.A.; Dorp, F. van

    1991-07-01

    The effect of radionuclide transfer from near-surface groundwater to the rooting zone soil, via a deep soil layer, is modelled in this report. The possible extent of upward solute movement is evaluated for a region in northern Switzerland. The concentration of 237 Np and 129 I in the deep and top soil, and hence growing crops, are evaluated assuming a constant unit activity concentration in the groundwater. A number of parameter variations are considered, namely variable soil sorption coefficients, reduced infiltration of rain water and decreased groundwater flow. A release to an alternative smaller recipient region in northern Switzerland is also evaluated. For the parameter ranges considered uncertainty in the solid-liquid distribution coefficient has the largest effect on overall uncertainty. These calculations have been presented within the international Biosphere Model Validation Study (BIOMOVS). A description of the test scenario, and the model calculations submitted, have been included in this report for completeness. To place the groundwater-soil-crop-man pathway in context, its contribution to the total dose to man is evaluated for the 237 Np- 233 U- 229 Th decay chain. The results obtained using the two-layer soil model, described in this report, are compared with the single-layer soil model used during Project Gewaehr 1985. The more realistic two-layer soil model indicated an increase in importance of the drinking water pathway. It should be noted, however, that not all the critical pathways have been treated in this study with the same degree of conservatism. (author) 16 figs., 15 tabs., 31 refs

  3. A health economic lifetime treatment pathway model for low back pain in Sweden.

    Science.gov (United States)

    Olafsson, Gylfi; Jonsson, Emma; Fritzell, Peter; Hägg, Olle; Borgström, Fredrik

    2017-12-01

    To develop a health economic model to evaluate the long-term costs and outcomes over the healthcare treatment pathway for patients with low back pain (LBP). A health economic model, consisting of a decision tree structure with a Markov microsimulation model at the end of each branch, was created. Patients were followed from first observed clinical presentation with LBP until the age of 100 years or death. The underlying data to populate the model were based on Swedish national and regional registry data on healthcare resource use and sickness insurance in patients presenting with LBP in the Swedish region Västra Götaland during 2008-2012. Costs (outpatient healthcare visits, inpatient bed days, pharmaceuticals, productivity loss), EUR 2016, and quality-of-life based on EQ-5D data from the registries and published estimates were summarized over the lifetime of the patients with 3% annual discount. A lost quality-adjusted life year (QALY) was valued at €70,000. Mean lifetime total cost was estimated at €47,452/patient, of which indirect costs were 57%. Total lifetime economic burden for all patients coming to clinical presentation in Sweden per year was €8.8bn. The average LBP patient was estimated to face a loss of 2.7 QALYs over their lifetime compared with the general population. For all patients in Sweden coming to clinical presentation in 1 year this gives 505,407 QALYs lost, valued at €35.3bn. Adding the economic burden, the total societal burden amounts to €44.1bn. This pathway model shows that most patients with LBP receive conservative care, and a minority consume high-cost healthcare interventions like surgery. The model could be used to see broad economic effects of different patterns of healthcare provision in sub-groups with LBP and to estimate where it is possible to influence these pathways to increase utility for patients and for society.

  4. Use of critical pathway models and log-normal frequency distributions for siting nuclear facilities

    International Nuclear Information System (INIS)

    Waite, D.A.; Denham, D.H.

    1975-01-01

    The advantages and disadvantages of potential sites for nuclear facilities are evaluated through the use of environmental pathway and log-normal distribution analysis. Environmental considerations of nuclear facility siting are necessarily geared to the identification of media believed to be sifnificant in terms of dose to man or to be potential centres for long-term accumulation of contaminants. To aid in meeting the scope and purpose of this identification, an exposure pathway diagram must be developed. This type of diagram helps to locate pertinent environmental media, points of expected long-term contaminant accumulation, and points of population/contaminant interface for both radioactive and non-radioactive contaminants. Confirmation of facility siting conclusions drawn from pathway considerations must usually be derived from an investigatory environmental surveillance programme. Battelle's experience with environmental surveillance data interpretation using log-normal techniques indicates that this distribution has much to offer in the planning, execution and analysis phases of such a programme. How these basic principles apply to the actual siting of a nuclear facility is demonstrated for a centrifuge-type uranium enrichment facility as an example. A model facility is examined to the extent of available data in terms of potential contaminants and facility general environmental needs. A critical exposure pathway diagram is developed to the point of prescribing the characteristics of an optimum site for such a facility. Possible necessary deviations from climatic constraints are reviewed and reconciled with conclusions drawn from the exposure pathway analysis. Details of log-normal distribution analysis techniques are presented, with examples of environmental surveillance data to illustrate data manipulation techniques and interpretation procedures as they affect the investigatory environmental surveillance programme. Appropriate consideration is given these

  5. Interaction pathways between soft lipid nanodiscs and plasma membranes: A molecular modeling study.

    Science.gov (United States)

    Li, Shixin; Luo, Zhen; Xu, Yan; Ren, Hao; Deng, Li; Zhang, Xianren; Huang, Fang; Yue, Tongtao

    2017-10-01

    Lipid nanodisc, a model membrane platform originally synthesized for study of membrane proteins, has recently been used as the carrier to deliver amphiphilic drugs into target tumor cells. However, the central question of how cells interact with such emerging nanomaterials remains unclear and deserves our research for both improving the delivery efficiency and reducing the side effect. In this work, a binary lipid nanodisc is designed as the minimum model to investigate its interactions with plasma membranes by using the dissipative particle dynamics method. Three typical interaction pathways, including the membrane attachment with lipid domain exchange of nanodiscs, the partial membrane wrapping with nanodisc vesiculation, and the receptor-mediated endocytosis, are discovered. For the first pathway, the boundary normal lipids acting as ligands diffuse along the nanodisc rim to gather at the membrane interface, repelling the central bola lipids to reach a stable membrane attachment. If bola lipids are positioned at the periphery and act as ligands, they diffuse to form a large aggregate being wrapped by the membrane, leaving the normal lipids exposed on the membrane exterior by assembling into a vesicle. Finally, by setting both central normal lipids and boundary bola lipids as ligands, the receptor-mediated endocytosis occurs via both deformation and self-rotation of the nanodiscs. All above pathways for soft lipid nanodiscs are quite different from those for rigid nanoparticles, which may provide useful guidelines for design of soft lipid nanodiscs in widespread biomedical applications. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Protein-phosphotyrosine proteome profiling by superbinder-SH2 domain affinity purification mass spectrometry, sSH2-AP-MS.

    Science.gov (United States)

    Tong, Jiefei; Cao, Biyin; Martyn, Gregory D; Krieger, Jonathan R; Taylor, Paul; Yates, Bradley; Sidhu, Sachdev S; Li, Shawn S C; Mao, Xinliang; Moran, Michael F

    2017-03-01

    Recently, "superbinder" SH2 domain variants with three amino acid substitutions (sSH2) were reported to have 100-fold or greater affinity for protein-phosphotyrosine (pY) than natural SH2 domains. Here we report a protocol in which His-tagged Src sSH2 efficiently captures pY-peptides from protease-digested HeLa cell total protein extracts. Affinity purification of pY-peptides by this method shows little bias for pY-proximal amino acid sequences, comparable to that achieved by using antibodies to pY, but with equal or higher yield. Superbinder-SH2 affinity purification mass spectrometry (sSH2-AP-MS) therefore provides an efficient and economical approach for unbiased pY-directed phospho-proteome profiling without the use of antibodies. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. Reaction pathways of model compounds of biomass-derived oxygenates on Fe/Ni bimetallic surfaces

    Science.gov (United States)

    Yu, Weiting; Chen, Jingguang G.

    2015-10-01

    Controlling the activity and selectivity of converting biomass-derivatives to fuels and valuable chemicals is critical for the utilization of biomass feedstocks. There are primarily three classes of non-food competing biomass, cellulose, hemicellulose and lignin. In the current work, glycolaldehyde, furfural and acetaldehyde are studied as model compounds of the three classes of biomass-derivatives. Monometallic Ni(111) and monolayer (ML) Fe/Ni(111) bimetallic surfaces are studied for the reaction pathways of the three biomass surrogates. The ML Fe/Ni(111) surface is identified as an efficient surface for the conversion of biomass-derivatives from the combined results of density functional theory (DFT) calculations and temperature programmed desorption (TPD) experiments. A correlation is also established between the optimized adsorption geometry and experimental reaction pathways. These results should provide helpful insights in catalyst design for the upgrading and conversion of biomass.

  8. A structural equation modeling approach to understanding pathways that connect socioeconomic status and smoking.

    Science.gov (United States)

    Martinez, Sydney A; Beebe, Laura A; Thompson, David M; Wagener, Theodore L; Terrell, Deirdra R; Campbell, Janis E

    2018-01-01

    The inverse association between socioeconomic status and smoking is well established, yet the mechanisms that drive this relationship are unclear. We developed and tested four theoretical models of the pathways that link socioeconomic status to current smoking prevalence using a structural equation modeling (SEM) approach. Using data from the 2013 National Health Interview Survey, we selected four indicator variables (poverty ratio, personal earnings, educational attainment, and employment status) that we hypothesize underlie a latent variable, socioeconomic status. We measured direct, indirect, and total effects of socioeconomic status on smoking on four pathways through four latent variables representing social cohesion, financial strain, sleep disturbance, and psychological distress. Results of the model indicated that the probability of being a smoker decreased by 26% of a standard deviation for every one standard deviation increase in socioeconomic status. The direct effects of socioeconomic status on smoking accounted for the majority of the total effects, but the overall model also included significant indirect effects. Of the four mediators, sleep disturbance and psychological distress had the largest total effects on current smoking. We explored the use of structural equation modeling in epidemiology to quantify effects of socioeconomic status on smoking through four social and psychological factors to identify potential targets for interventions. A better understanding of the complex relationship between socioeconomic status and smoking is critical as we continue to reduce the burden of tobacco and eliminate health disparities related to smoking.

  9. Determination of heavy metals concentrations in airborne particulates matter (APM) from Manjung district, Perak using energy dispersive X-ray fluorescence (EDXRF) spectrometer

    Science.gov (United States)

    Arshad, Nursyairah; Hamzah, Zaini; Wood, Ab. Khalik; Saat, Ahmad; Alias, Masitah

    2015-04-01

    Airborne particulates trace metals are considered as public health concern as it can enter human lungs through respiratory system. Generally, any substance that has been introduced to the atmosphere that can cause severe effects to living things and the environment is considered air pollution. Manjung, Perak is one of the development districts that is active with industrial activities. There are many industrial activities surrounding Manjung District area such as coal fired power plant, quarries and iron smelting which may contribute to the air pollution into the environment. This study was done to measure the concentrations of Hg, U, Th, K, Cu, Fe, Cr, Zn, As, Se, Pb and Cd in the Airborne Particulate Matter (APM) collected at nine locations in Manjung District area within 15 km radius towards three directions (North, North-East and South-East) in 5 km intervals. The samples were collected using mini volume air sampler with cellulose filter through total suspended particulate (TSP). The sampler was set up for eight hours with the flow rate of 5 L/min. The filter was weighed before and after sample collection using microbalance, to get the amount of APM and kept in desiccator before analyzing. The measurement was done using calibrated Energy Dispersive X-Ray Fluorescence (EDXRF) Spectrometer. The air particulate concentrations were found below the Malaysia Air Quality Guidelines for TSP (260 µg/m3). All of the metals concentrations were also lower than the guidelines set by World Health Organization (WHO), Ontario Ministry of the Environment and Argonne National Laboratory, USA NCRP (1975). From the concentrations, the enrichment factor were calculated.

  10. Creating and analyzing pathway and protein interaction compendia for modelling signal transduction networks

    Directory of Open Access Journals (Sweden)

    Kirouac Daniel C

    2012-05-01

    Full Text Available Abstract Background Understanding the information-processing capabilities of signal transduction networks, how those networks are disrupted in disease, and rationally designing therapies to manipulate diseased states require systematic and accurate reconstruction of network topology. Data on networks central to human physiology, such as the inflammatory signalling networks analyzed here, are found in a multiplicity of on-line resources of pathway and interactome databases (Cancer CellMap, GeneGo, KEGG, NCI-Pathway Interactome Database (NCI-PID, PANTHER, Reactome, I2D, and STRING. We sought to determine whether these databases contain overlapping information and whether they can be used to construct high reliability prior knowledge networks for subsequent modeling of experimental data. Results We have assembled an ensemble network from multiple on-line sources representing a significant portion of all machine-readable and reconcilable human knowledge on proteins and protein interactions involved in inflammation. This ensemble network has many features expected of complex signalling networks assembled from high-throughput data: a power law distribution of both node degree and edge annotations, and topological features of a “bow tie” architecture in which diverse pathways converge on a highly conserved set of enzymatic cascades focused around PI3K/AKT, MAPK/ERK, JAK/STAT, NFκB, and apoptotic signaling. Individual pathways exhibit “fuzzy” modularity that is statistically significant but still involving a majority of “cross-talk” interactions. However, we find that the most widely used pathway databases are highly inconsistent with respect to the actual constituents and interactions in this network. Using a set of growth factor signalling networks as examples (epidermal growth factor, transforming growth factor-beta, tumor necrosis factor, and wingless, we find a multiplicity of network topologies in which receptors couple to downstream

  11. Modelling climate change under no-policy and policy emissions pathways

    International Nuclear Information System (INIS)

    Wigley, T.M.L.

    2003-01-01

    Future emissions under the SRES scenarios are described as examples of no-climate-policy scenarios. The production of policy scenarios is guided by Article 2 of the UN Framework Convention on Climate Change, which requires stabilization of greenhouse-gas concentrations. It is suggested that the choice of stabilization targets should be governed by the need to avoid dangerous interference with the climate system, while the choice of the pathway towards a given target should be determined by some form of cost-benefit analysis. The WRE (Wigley, Richels and Edmonds) concentration profiles are given as examples of stabilization pathways, and an alternative 'overshoot' pathway is introduced. Probabilistic projections (as probability density functions - pdfs) for global-mean temperature under the SRES scenarios are given. The relative importance of different sources of uncertainty is determined by removing individual sources of uncertainty and examining the change in the output temperature pdf. Emissions and climate sensitivity uncertainties dominate, while carbon cycle, aerosol forcing and ocean mixing uncertainties are shown to be small. It is shown that large uncertainties remain even if the emissions are prescribed. Uncertainties in regional climate change are defined by comparing normalized changes (i.e., changes per 1C global-mean warming) across multiple models and using the inter-model standard deviation as an uncertainty metric. Global-mean temperature projections for the policy case are given using the WRE profiles. Different stabilization targets are considered, and the overshoot case for 550ppm stabilization is used to quantify the effects of pathway differences. It is shown that large emissions reductions (from the no-policy to the policy case) will lead to only relatively small reductions in warming over the next 100 years

  12. Groundwater Pathway Model for the Los Alamos National Laboratory Technical Area 54, Area G, Revision 1

    Energy Technology Data Exchange (ETDEWEB)

    Stauffer, Philip H. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Chu, Shaoping [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Miller, Terry A. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Strobridge, Daniel M. [Neptune Inc., Los Alamos, NM (United States); Cole, Gregory L. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Birdsell, Kay H. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Robinson, Bruce Alan [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Gable, Carl Walter [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Broxton, David E. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Springer, Everett P. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Schofield, Tracy [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2017-02-10

    This report consists of four major sections, including this introductory section. Section 2 provides an overview of previous investigations related to the development of the current sitescale model. The methods and data used to develop the 3-D groundwater model and the techniques used to distill that model into a form suitable for use in the GoldSim models are discussed in Section 3. Section 4 presents the results of the model development effort and discusses some of the uncertainties involved. Eight attachments that provide details about the components and data used in this groundwater pathway model are also included with this report. The groundwater modeling effort reported here is a revision of the work that was conducted in 2005 (Stauffer et al., 2005a) in support of the 2008 Area G performance assessment and composite analysis (LANL, 2008). The revision effort was undertaken primarily to incorporate new geologic information that has been collected since 2003 at, and in the vicinity of, Area G. The new data were used to create a more accurate geologic framework model (GFM) that forms the basis of the numerical modeling of the site’s long-term performance. The groundwater modeling uses mean hydrologic properties of the geologic strata underlying Area G; this revision includes an evaluation of the impacts that natural variability in these properties may have on the model projections.

  13. Cellular and molecular modifier pathways in tauopathies: the big picture from screening invertebrate models.

    Science.gov (United States)

    Hannan, Shabab B; Dräger, Nina M; Rasse, Tobias M; Voigt, Aaron; Jahn, Thomas R

    2016-04-01

    Abnormal tau accumulations were observed and documented in post-mortem brains of patients affected by Alzheimer's disease (AD) long before the identification of mutations in the Microtubule-associated protein tau (MAPT) gene, encoding the tau protein, in a different neurodegenerative disease called Frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17). The discovery of mutations in the MAPT gene associated with FTDP-17 highlighted that dysfunctions in tau alone are sufficient to cause neurodegeneration. Invertebrate models have been diligently utilized in investigating tauopathies, contributing to the understanding of cellular and molecular pathways involved in disease etiology. An important discovery came with the demonstration that over-expression of human tau in Drosophila leads to premature mortality and neuronal dysfunction including neurodegeneration, recapitulating some key neuropathological features of the human disease. The simplicity of handling invertebrate models combined with the availability of a diverse range of experimental resources make these models, in particular Drosophila a powerful invertebrate screening tool. Consequently, several large-scale screens have been performed using Drosophila, to identify modifiers of tau toxicity. The screens have revealed not only common cellular and molecular pathways, but in some instances the same modifier has been independently identified in two or more screens suggesting a possible role for these modifiers in regulating tau toxicity. The purpose of this review is to discuss the genetic modifier screens on tauopathies performed in Drosophila and C. elegans models, and to highlight the common cellular and molecular pathways that have emerged from these studies. Here, we summarize results of tau toxicity screens providing mechanistic insights into pathological alterations in tauopathies. Key pathways or modifiers that have been identified are associated with a broad range of processes

  14. Effect of LIPUS on inflammatory factors, cell apoptosis and integrin signaling pathway in osteoarthritis animal models

    Directory of Open Access Journals (Sweden)

    Li-Cai Zhang

    2017-05-01

    Full Text Available Objective: To study the effect of low-intensity pulsed ultrasound (LIPUS on inflammatory factors, cell apoptosis and integrin signaling pathway in osteoarthritis animal models. Methods: Male New Zealand white rabbits were selected as the experimental animals and randomly divided into sham group, osteoarthritis model group (OA group and LIPUS intervention group (LIPUS group, animal models with osteoarthritis in hind limb knee joint were established and then given LIPUS intervention. 6 weeks after the intervention, the articular cartilage was separated to detect the expression of inflammatory factors, cell apoptosis molecules and integrin signaling pathway molecules. Results: OPN, NO, IL-1β, TNF-α, Fas, FasL, LC3-II, Beclin-1, Integrinβ1, FAK, ERK1/2, JNK, p38MAPK, MMP-1 and MMP-3 protein expression in articular cartilage of OA group were significantly higher than those of Sham group while Col-I and Col-II protein expression were significantly lower than those of Sham group; OPN, NO, IL-1β, TNF-α, Fas, FasL, LC3-II, Beclin-1, Integrinβ1, FAK, ERK1/2, JNK, p38MAPK, MMP-1 and MMP-3 protein expression in articular cartilage of LIPUS group were significantly lower than those of OA group while Col-I and Col-II protein expression were significantly higher than those of OA group. Conclusion: LIPUS has inhibiting effect on the inflammation, apoptosis and integrin signaling pathway in articular cartilage of osteoarthritis animal models, and it can promote the repair of articular cartilage.

  15. Construction and Optimization of a Heterologous Pathway for Protocatechuate Catabolism in Escherichia coli Enables Bioconversion of Model Aromatic Compounds.

    Science.gov (United States)

    Clarkson, Sonya M; Giannone, Richard J; Kridelbaugh, Donna M; Elkins, James G; Guss, Adam M; Michener, Joshua K

    2017-09-15

    The production of biofuels from lignocellulose yields a substantial lignin by-product stream that currently has few applications. Biological conversion of lignin-derived compounds into chemicals and fuels has the potential to improve the economics of lignocellulose-derived biofuels, but few microbes are able both to catabolize lignin-derived aromatic compounds and to generate valuable products. While Escherichia coli has been engineered to produce a variety of fuels and chemicals, it is incapable of catabolizing most aromatic compounds. Therefore, we engineered E. coli to catabolize protocatechuate, a common intermediate in lignin degradation, as the sole source of carbon and energy via heterologous expression of a nine-gene pathway from Pseudomonas putida KT2440. We next used experimental evolution to select for mutations that increased growth with protocatechuate more than 2-fold. Increasing the strength of a single ribosome binding site in the heterologous pathway was sufficient to recapitulate the increased growth. After optimization of the core pathway, we extended the pathway to enable catabolism of a second model compound, 4-hydroxybenzoate. These engineered strains will be useful platforms to discover, characterize, and optimize pathways for conversions of lignin-derived aromatics. IMPORTANCE Lignin is a challenging substrate for microbial catabolism due to its polymeric and heterogeneous chemical structure. Therefore, engineering microbes for improved catabolism of lignin-derived aromatic compounds will require the assembly of an entire network of catabolic reactions, including pathways from genetically intractable strains. Constructing defined pathways for aromatic compound degradation in a model host would allow rapid identification, characterization, and optimization of novel pathways. We constructed and optimized one such pathway in E. coli to enable catabolism of a model aromatic compound, protocatechuate, and then extended the pathway to a related

  16. GEP analysis validates high risk MDS and acute myeloid leukemia post MDS mice models and highlights novel dysregulated pathways.

    Science.gov (United States)

    Guerenne, Laura; Beurlet, Stéphanie; Said, Mohamed; Gorombei, Petra; Le Pogam, Carole; Guidez, Fabien; de la Grange, Pierre; Omidvar, Nader; Vanneaux, Valérie; Mills, Ken; Mufti, Ghulam J; Sarda-Mantel, Laure; Noguera, Maria Elena; Pla, Marika; Fenaux, Pierre; Padua, Rose Ann; Chomienne, Christine; Krief, Patricia

    2016-01-27

    In spite of the recent discovery of genetic mutations in most myelodysplasic (MDS) patients, the pathophysiology of these disorders still remains poorly understood, and only few in vivo models are available to help unravel the disease. We performed global specific gene expression profiling and functional pathway analysis in purified Sca1+ cells of two MDS transgenic mouse models that mimic human high-risk MDS (HR-MDS) and acute myeloid leukemia (AML) post MDS, with NRASD12 and BCL2 transgenes under the control of different promoters MRP8NRASD12/tethBCL-2 or MRP8[NRASD12/hBCL-2], respectively. Analysis of dysregulated genes that were unique to the diseased HR-MDS and AML post MDS mice and not their founder mice pointed first to pathways that had previously been reported in MDS patients, including DNA replication/damage/repair, cell cycle, apoptosis, immune responses, and canonical Wnt pathways, further validating these models at the gene expression level. Interestingly, pathways not previously reported in MDS were discovered. These included dysregulated genes of noncanonical Wnt pathways and energy and lipid metabolisms. These dysregulated genes were not only confirmed in a different independent set of BM and spleen Sca1+ cells from the MDS mice but also in MDS CD34+ BM patient samples. These two MDS models may thus provide useful preclinical models to target pathways previously identified in MDS patients and to unravel novel pathways highlighted by this study.

  17. GEP analysis validates high risk MDS and acute myeloid leukemia post MDS mice models and highlights novel dysregulated pathways

    Directory of Open Access Journals (Sweden)

    Laura Guerenne

    2016-01-01

    Full Text Available Abstract Background In spite of the recent discovery of genetic mutations in most myelodysplasic (MDS patients, the pathophysiology of these disorders still remains poorly understood, and only few in vivo models are available to help unravel the disease. Methods We performed global specific gene expression profiling and functional pathway analysis in purified Sca1+ cells of two MDS transgenic mouse models that mimic human high-risk MDS (HR-MDS and acute myeloid leukemia (AML post MDS, with NRASD12 and BCL2 transgenes under the control of different promoters MRP8NRASD12/tethBCL-2 or MRP8[NRASD12/hBCL-2], respectively. Results Analysis of dysregulated genes that were unique to the diseased HR-MDS and AML post MDS mice and not their founder mice pointed first to pathways that had previously been reported in MDS patients, including DNA replication/damage/repair, cell cycle, apoptosis, immune responses, and canonical Wnt pathways, further validating these models at the gene expression level. Interestingly, pathways not previously reported in MDS were discovered. These included dysregulated genes of noncanonical Wnt pathways and energy and lipid metabolisms. These dysregulated genes were not only confirmed in a different independent set of BM and spleen Sca1+ cells from the MDS mice but also in MDS CD34+ BM patient samples. Conclusions These two MDS models may thus provide useful preclinical models to target pathways previously identified in MDS patients and to unravel novel pathways highlighted by this study.

  18. Position-specific isotope modeling of organic micropollutants transformations through different reaction pathways

    Science.gov (United States)

    Jin, Biao; Rolle, Massimo

    2016-04-01

    Organic compounds are produced in vast quantities for industrial and agricultural use, as well as for human and animal healthcare [1]. These chemicals and their metabolites are frequently detected at trace levels in fresh water environments where they undergo degradation via different reaction pathways. Compound specific stable isotope analysis (CSIA) is a valuable tool to identify such degradation pathways in different environmental systems. Recent advances in analytical techniques have promoted the fast development and implementation of multi-element CSIA. However, quantitative frameworks to evaluate multi-element stable isotope data and incorporating mechanistic information on the degradation processes [2,3] are still lacking. In this study we propose a mechanism-based modeling approach to simultaneously evaluate concentration as well as bulk and position-specific multi-element isotope evolution during the transformation of organic micropollutants. The model explicitly simulates position-specific isotopologues for those atoms that experience isotope effects and, thereby, provides a mechanistic description of isotope fractionation occurring at different molecular positions. We validate the proposed approach with the concentration and multi-element isotope data of three selected organic micropollutants: dichlorobenzamide (BAM), isoproturon (IPU) and diclofenac (DCF). The model precisely captures the dual element isotope trends characteristic of different reaction pathways and their range of variation consistent with observed multi-element (C, N) bulk isotope fractionation. The proposed approach can also be used as a tool to explore transformation pathways in scenarios for which position-specific isotope data are not yet available. [1] Schwarzenbach, R.P., Egli, T., Hofstetter, T.B., von Gunten, U., Wehrli, B., 2010. Global Water Pollution and Human Health. Annu. Rev. Environ. Resour. doi:10.1146/annurev-environ-100809-125342. [2] Jin, B., Haderlein, S.B., Rolle, M

  19. Pathway index models for construction of patient-specific risk profiles.

    Science.gov (United States)

    Eng, Kevin H; Wang, Sijian; Bradley, William H; Rader, Janet S; Kendziorski, Christina

    2013-04-30

    Statistical methods for variable selection, prediction, and classification have proven extremely useful in moving personalized genomics medicine forward, in particular, leading to a number of genomic-based assays now in clinical use for predicting cancer recurrence. Although invaluable in individual cases, the information provided by these assays is limited. Most often, a patient is classified into one of very few groups (e.g., recur or not), limiting the potential for truly personalized treatment. Furthermore, although these assays provide information on which individuals are at most risk (e.g., those for which recurrence is predicted), they provide no information on the aberrant biological pathways that give rise to the increased risk. We have developed an approach to address these limitations. The approach models a time-to-event outcome as a function of known biological pathways, identifies important genomic aberrations, and provides pathway-based patient-specific assessments of risk. As we demonstrate in a study of ovarian cancer from The Cancer Genome Atlas project, the patient-specific risk profiles are powerful and efficient characterizations useful in addressing a number of questions related to identifying informative patient subtypes and predicting survival. Copyright © 2012 John Wiley & Sons, Ltd.

  20. Combustion modeling and kinetic rate calculations for a stoichiometric cyclohexane flame. 1. Major reaction pathways.

    Science.gov (United States)

    Zhang, Hongzhi R; Huynh, Lam K; Kungwan, Nawee; Yang, Zhiwei; Zhang, Shaowen

    2007-05-17

    The Utah Surrogate Mechanism was extended in order to model a stoichiometric premixed cyclohexane flame (P = 30 Torr). Generic rates were assigned to reaction classes of hydrogen abstraction, beta scission, and isomerization, and the resulting mechanism was found to be adequate in describing the combustion chemistry of cyclohexane. Satisfactory results were obtained in comparison with the experimental data of oxygen, major products and important intermediates, which include major soot precursors of C2-C5 unsaturated species. Measured concentrations of immediate products of fuel decomposition were also successfully reproduced. For example, the maximum concentrations of benzene and 1,3-butadiene, two major fuel decomposition products via competing pathways, were predicted within 10% of the measured values. Ring-opening reactions compete with those of cascading dehydrogenation for the decomposition of the conjugate cyclohexyl radical. The major ring-opening pathways produce 1-buten-4-yl radical, molecular ethylene, and 1,3-butadiene. The butadiene species is formed via beta scission after a 1-4 internal hydrogen migration of 1-hexen-6-yl radical. Cascading dehydrogenation also makes an important contribution to the fuel decomposition and provides the exclusive formation pathway of benzene. Benzene formation routes via combination of C2-C4 hydrocarbon fragments were found to be insignificant under current flame conditions, inferred by the later concentration peak of fulvene, in comparison with benzene, because the analogous species series for benzene formation via dehydrogenation was found to be precursors with regard to parent species of fulvene.

  1. PumpKin: A tool to find principal pathways in plasma chemical models

    Science.gov (United States)

    Markosyan, A. H.; Luque, A.; Gordillo-Vázquez, F. J.; Ebert, U.

    2014-10-01

    PumpKin is a software package to find all principal pathways, i.e. the dominant reaction sequences, in chemical reaction systems. Although many tools are available to integrate numerically arbitrarily complex chemical reaction systems, few tools exist in order to analyze the results and interpret them in relatively simple terms. In particular, due to the large disparity in the lifetimes of the interacting components, it is often useful to group reactions into pathways that recycle the fastest species. This allows a researcher to focus on the slow chemical dynamics, eliminating the shortest timescales. Based on the algorithm described by Lehmann (2004), PumpKin automates the process of finding such pathways, allowing the user to analyze complex kinetics and to understand the consumption and production of a certain species of interest. We designed PumpKin with an emphasis on plasma chemical systems but it can also be applied to atmospheric modeling and to industrial applications such as plasma medicine and plasma-assisted combustion.

  2. Simulation of biatrial conduction via different pathways during sinus rhythm with a detailed human atrial model

    Institute of Scientific and Technical Information of China (English)

    Dong-dong DENG; Ying-lan GONG; Guo-fa SHOU; Pei-feng JIAO; Heng-gui ZHANG; Xue-song YE; Ling XIA

    2012-01-01

    In order to better understand biatrial conduction,investigate various conduction pathways,and compare the differences between isotropic and anisotropic conductions in human atria,we present a simulation study of biatrial conduction with known/assumed conduction pathways using a recently developed human atrial model.In addition to known pathways:(1) Bachmann's bundle (BB),(2) limbus of fossa ovalis (LFO),and (3) coronary sinus (CS),we also hypothesize that there exist two fast conduction bundles that connect the crista terminalis (CT),LFO,and CS.Our simulation demonstrates that use of these fast conduction bundles results in a conduction pattern consistent with experimental data.The comparison of isotropic and anisotropoic conductions in the BB case showed that the atrial working muscles had small effect on conduction time and conduction speed,although the conductivities assigned in anisotropic conduction were two to four times higher than the isotropic conduction.In conclusion,we suggest that the hypothesized intercaval bundles play a significant role in the biatrial conduction and that myofiber orientation has larger effects on the conduction system than the atrial working muscles.This study presents readers with new insights into human atrial conduction.

  3. A thermodynamic solution model for calcium carbonate: Towards an understanding of multi-equilibria precipitation pathways.

    Science.gov (United States)

    Donnet, Marcel; Bowen, Paul; Lemaître, Jacques

    2009-12-15

    Thermodynamic solubility calculations are normally only related to thermodynamic equilibria in solution. In this paper, we extend the use of such solubility calculations to help elucidate possible precipitation reaction pathways during the entire reaction. We also estimate the interfacial energy of particles using only solubility data by a modification of Mersmann's approach. We have carried this out by considering precipitation reactions as a succession of small quasi-equilibrium states. Thus possible equilibrium precipitation pathways can be evaluated by calculating the evolution of surface charge, particle size and/or interfacial energy during the ongoing reaction. The approach includes the use of the Kelvin's law to express the influence of particle size on the solubility constant of precipitates, the use of Nernst's law to calculate surface potentials from solubility calculations and relate this to experimentally measured zeta potentials. Calcium carbonate precipitation and zeta potential measurements of well characterised high purity calcite have been used as a model system to validate the calculated values. The clarification of the change in zeta potential on titration illustrates the power of this approach as a tool for reaction pathway prediction and hence knowledge based tailoring of precipitation reactions.

  4. Parameter-free methods distinguish Wnt pathway models and guide design of experiments

    KAUST Repository

    MacLean, Adam L.

    2015-02-17

    The canonical Wnt signaling pathway, mediated by β-catenin, is crucially involved in development, adult stem cell tissue maintenance, and a host of diseases including cancer. We analyze existing mathematical models of Wnt and compare them to a new Wnt signaling model that targets spatial localization; our aim is to distinguish between the models and distill biological insight from them. Using Bayesian methods we infer parameters for each model from mammalian Wnt signaling data and find that all models can fit this time course. We appeal to algebraic methods (concepts from chemical reaction network theory and matroid theory) to analyze the models without recourse to specific parameter values. These approaches provide insight into aspects of Wnt regulation: the new model, via control of shuttling and degradation parameters, permits multiple stable steady states corresponding to stem-like vs. committed cell states in the differentiation hierarchy. Our analysis also identifies groups of variables that should be measured to fully characterize and discriminate between competing models, and thus serves as a guide for performing minimal experiments for model comparison.

  5. Uncertainty and sensitivity analysis of food pathway results with the MACCS Reactor Accident Consequence Model

    International Nuclear Information System (INIS)

    Helton, J.C.; Johnson, J.D.; Rollstin, J.A.; Shiver, A.W.; Sprung, J.L.

    1995-01-01

    Uncertainty and sensitivity analysis techniques based on Latin hypercube sampling, partial correlation analysis and stepwise regression analysis are used in an investigation with the MACCS model of the food pathways associated with a severe accident at a nuclear power station. The primary purpose of this study is to provide guidance on the variables to be considered in future review work to reduce the uncertainty in the important variables used in the calculation of reactor accident consequences. The effects of 87 imprecisely-known input variables on the following reactor accident consequences are studied: crop growing season dose, crop long-term dose, milk growing season dose, total food pathways dose, total ingestion pathways dose, total long-term pathways dose, area dependent cost, crop disposal cost, milk disposal cost, condemnation area, crop disposal area and milk disposal area. When the predicted variables are considered collectively, the following input variables were found to be the dominant contributors to uncertainty: fraction of cesium deposition on grain fields that is retained on plant surfaces and transferred directly to grain, maximum allowable ground concentrations of Cs-137 and Sr-90 for production of crops, ground concentrations of Cs-134, Cs-137 and I-131 at which the disposal of milk will be initiated due to accidents that occur during the growing season, ground concentrations of Cs-134, I-131 and Sr-90 at which the disposal of crops will be initiated due to accidents that occur during the growing season, rate of depletion of Cs-137 and Sr-90 from the root zone, transfer of Sr-90 from soil to legumes, transfer of Cs-137 from soil to pasture, transfer of cesium from animal feed to meat, and the transfer of cesium, iodine and strontium from animal feed to milk

  6. Uncertainty and sensitivity analysis of food pathway results with the MACCS reactor accident consequence model

    International Nuclear Information System (INIS)

    Helton, J.C.; Johnson, J.D.; Rollstin, J.A.; Shiver, A.W.; Sprung, J.L.

    1995-01-01

    Uncertainty and sensitivity analysis techniques based on Latin hypercube sampling, partial correlation analysis and stepwise regression analysis are used in an investigation with the MACCS model of the food pathways associated with a severe accident at a nuclear power station. The primary purpose of this study is to provide guidance on the variables to be considered in future review work to reduce the uncertainty in the important variables used in the calculation of reactor accident consequences. The effects of 87 imprecisely-known input variables on the following reactor accident consequences are studied: crop growing-season dose, crop long-term dose, milk growing-season dose, total food pathways dose, total ingestion pathways dose, total long-term pathways dose, area dependent cost, crop disposal cost, milk disposal cost, condemnation area, crop disposal area and milk disposal area. When the predicted variables are considered collectively, the following input variables were found to be the dominant contributors to uncertainty: fraction of cesium deposition on grain fields that is retained on plant surfaces and transferred directly to grain, maximum allowable ground concentrations of Cs-137 and Sr-90 for production of crops, ground concentrations of Cs-134, Cs-137 and I-131 at which the disposal of milk will be initiated due to accidents that occur during the growing season, ground concentrations of Cs-134, I-131 and Sr-90 at which the disposal of crops will be initiated due to accidents that occur during the growing season, rate of depletion of Cs-137 and Sr-90 from the root zone, transfer of Sr-90 from soil to legumes, transfer of Cs-137 from soil to pasture, transfer of cesium from animal feed to meat, and the transfer of cesium, iodine and strontium from animal feed to milk

  7. Mevalonate Pathway Antagonist Suppresses Formation of Serous Tubal Intraepithelial Carcinoma and Ovarian Carcinoma in Mouse Models.

    Science.gov (United States)

    Kobayashi, Yusuke; Kashima, Hiroyasu; Wu, Ren-Chin; Jung, Jin-Gyoung; Kuan, Jen-Chun; Gu, Jinghua; Xuan, Jianhua; Sokoll, Lori; Visvanathan, Kala; Shih, Ie-Ming; Wang, Tian-Li

    2015-10-15

    Statins are among the most frequently prescribed drugs because of their efficacy and low toxicity in treating hypercholesterolemia. Recently, statins have been reported to inhibit the proliferative activity of cancer cells, especially those with TP53 mutations. Because TP53 mutations occur in almost all ovarian high-grade serous carcinoma (HGSC), we determined whether statins suppressed tumor growth in animal models of ovarian cancer. Two ovarian cancer mouse models were used. The first one was a genetically engineered model, mogp-TAg, in which the promoter of oviduct glycoprotein-1 was used to drive the expression of SV40 T-antigen in gynecologic tissues. These mice spontaneously developed serous tubal intraepithelial carcinomas (STICs), which are known as ovarian cancer precursor lesions. The second model was a xenograft tumor model in which human ovarian cancer cells were inoculated into immunocompromised mice. Mice in both models were treated with lovastatin, and effects on tumor growth were monitored. The molecular mechanisms underlying the antitumor effects of lovastatin were also investigated. Lovastatin significantly reduced the development of STICs in mogp-TAg mice and inhibited ovarian tumor growth in the mouse xenograft model. Knockdown of prenylation enzymes in the mevalonate pathway recapitulated the lovastatin-induced antiproliferative phenotype. Transcriptome analysis indicated that lovastatin affected the expression of genes associated with DNA replication, Rho/PLC signaling, glycolysis, and cholesterol biosynthesis pathways, suggesting that statins have pleiotropic effects on tumor cells. The above results suggest that repurposing statin drugs for ovarian cancer may provide a promising strategy to prevent and manage this devastating disease. ©2015 American Association for Cancer Research.

  8. Mevalonate Pathway Antagonist Inhibits Proliferation of Serous Tubal Intraepithelial Carcinoma and Ovarian Carcinoma in Mouse Models

    Science.gov (United States)

    Kobayashi, Yusuke; Kashima, Hiroyasu; Wu, Ren-Chin; Jung, Jin- Gyoung; Kuan, Jen-Chun; Gu, Jinghua; Xuan, Jianhua; Sokoll, Lori; Visvanathan, Kala; Shih, Ie-Ming; Wang, Tian-Li

    2015-01-01

    Purpose Statins are among the most frequently prescribed drugs because of their efficacy and low toxicity in treating hypercholesterolemia. Recently, statins have been reported to inhibit the proliferative activity of cancer cells, especially those with TP53 mutations. Since TP53 mutations occur in almost all of the ovarian high-grade serous carcinoma, we determined if statins suppressed tumor growth in animal models of ovarian cancer. Experimental Design Two ovarian cancer mouse models were employed. The first one was a genetically engineered model, mogp-TAg, in which the promoter of oviduct glycoprotein-1 was used to drive the expression of SV40 T-antigen in gynecologic tissues. These mice spontaneously develop serous tubal intraepithelial carcinomas (STICs), which are known as ovarian cancer precursor lesions. The second model was a xenograft tumor model in which human ovarian cancer cells were inoculated into immunocompromised mice. Mice in both models were treated with lovastatin, and effects on tumor growth were monitored. The molecular mechanisms underlying the anti-tumor effects of lovastatin were also investigated. Results Lovastatin significantly reduced the development of STICs in mogp-TAg mice and inhibited ovarian tumor growth in the mouse xenograft model. Knockdown of prenylation enzymes in the mevalonate pathway recapitulated the lovastatin-induced anti-proliferative phenotype. Transcriptome analysis indicated that lovastatin affected the expression of genes associated with DNA replication, Rho/PLC signaling, glycolysis, and cholesterol biosynthesis pathways, suggesting that statins have pleiotropic effects on tumor cells. Conclusion The above results suggest that repurposing statin drugs for ovarian cancer may provide a promising strategy to prevent and manage this devastating disease. PMID:26109099

  9. Evaluation of additional biogeochemical impacts on mitigation pathways in an energy sytem integrated assessment model.

    Science.gov (United States)

    Dessens, O.

    2017-12-01

    Within the last IPCC AR5 a large and systematic sensitivity study around available technologies and timing of policies applied in IAMs to achieve the 2°C target has been conducted. However the simple climate representations included in IAMs are generally tuned to the results of ensemble means. This may result in hiding within the ensemble mean results possible challenging mitigation pathways for the economy or the technology future scenarios. This work provides new insights on the sensitivity of the socio-economic response to different climate factors under a 2°C climate change target in order to help guide future efforts to reduce uncertainty in the climate mitigation decisions. The main objective is to understand and bring new insights on how future global warming will affect the natural biochemical feedbacks on the climate system and what could be the consequences of these feedbacks on the anthropogenic emission pathways with a specific focus on the energy-economy system. It specifically focuses on three issues of the climate representation affecting the energy system transformation and GHG emissions pathways: 1- Impacts of the climate sensitivity (or TCR); 2- Impacts of warming on the radiative forcing (cloudiness,...); 3- Impacts of warming on the carbon cycle (carbon cycle feedback). We use the integrated assessment model TIAM-UCL to examine the mitigation pathways compatible with the 2C target depending on assumptions regarding the 3 issues of the climate representation introduced above. The following key conclusions drawn from this study are that mitigation to 2°C is still possible under strong climate sensitivity (TCR), strong carbon cycle amplification or positive radiative forcing feedback. However, this level of climate mitigation will require a significant transformation in the way we produce and consume energy. Carbon capture and sequestration on electricity generation, industry and biomass is part of the technology pool needed to achieve this

  10. A Model of an Integrated Immune System Pathway in Homo sapiens and Its Interaction with Superantigen Producing Expression Regulatory Pathway in Staphylococcus aureus: Comparing Behavior of Pathogen Perturbed and Unperturbed Pathway

    Science.gov (United States)

    Tomar, Namrata; De, Rajat K.

    2013-01-01

    Response of an immune system to a pathogen attack depends on the balance between the host immune defense and the virulence of the pathogen. Investigation of molecular interactions between the proteins of a host and a pathogen helps in identifying the pathogenic proteins. It is necessary to understand the dynamics of a normally behaved host system to evaluate the capacity of its immune system upon pathogen attack. In this study, we have compared the behavior of an unperturbed and pathogen perturbed host system. Moreover, we have developed a formalism under Flux Balance Analysis (FBA) for the optimization of conflicting objective functions. We have constructed an integrated pathway system, which includes Staphylococcal Superantigen (SAg) expression regulatory pathway and TCR signaling pathway of Homo sapiens. We have implemented the method on this pathway system and observed the behavior of host signaling molecules upon pathogen attack. The entire study has been divided into six different cases, based on the perturbed/unperturbed conditions. In other words, we have investigated unperturbed and pathogen perturbed human TCR signaling pathway, with different combinations of optimization of concentrations of regulatory and signaling molecules. One of these cases has aimed at finding out whether minimization of the toxin production in a pathogen leads to the change in the concentration levels of the proteins coded by TCR signaling pathway genes in the infected host. Based on the computed results, we have hypothesized that the balance between TCR signaling inhibitory and stimulatory molecules can keep TCR signaling system into resting/stimulating state, depending upon the perturbation. The proposed integrated host-pathogen interaction pathway model has accurately reflected the experimental evidences, which we have used for validation purpose. The significance of this kind of investigation lies in revealing the susceptible interaction points that can take back the

  11. Thymoquinone attenuates brain injury via an antioxidative pathway in a status epilepticus rat model

    Directory of Open Access Journals (Sweden)

    Shao Yi-ye

    2017-03-01

    Full Text Available Status epilepticus (SE results in the generation of reactive oxygen species (ROS, which contribute to seizure-induced brain injury. It is well known that oxidative stress plays a pivotal role in status epilepticus (SE. Thymoquinone (TQ is a bioactive monomer extracted from black cumin (Nigella sativa seed oil that has anti-inflammatory, anti-cancer, and antioxidant activity in various diseases. This study evaluated the protective effects of TQ on brain injury in a lithium-pilocarpine rat model of SE and investigated the underlying mechanism related to antioxidative pathway.

  12. Computing Pathways in Bio-Models Derived from Bio-Science Text Sources

    DEFF Research Database (Denmark)

    Andreasen, Troels; Bulskov, Henrik; Nilsson, Jørgen Fischer

    2015-01-01

    This paper outlines a system, OntoScape, serving to accomplish complex inference tasks on knowledge bases and bio-models derived from life-science text corpora. The system applies so-called natural logic, a form of logic which is readable for humans. This logic affords ontological representations...... of complex terms appearing in the text sources. Along with logical propositions, the system applies a semantic graph representation facilitating calculation of bio-pathways. More generally, the system aords means of query answering appealing to general and domain specic inference rules....

  13. Unprecedented rates of land-use transformation in modeled climate change mitigation pathways

    Science.gov (United States)

    Turner, P. A.; Field, C. B.; Lobell, D. B.; Sanchez, D.; Mach, K. J.

    2017-12-01

    Integrated assessment models (IAMs) generate climate change mitigation scenarios consistent with global temperature targets. To limit warming to 2°, stylized cost-effective mitigation pathways rely on extensive deployments of carbon dioxide (CO2) removal (CDR) technologies, including multi-gigatonne yearly carbon removal from the atmosphere through bioenergy with carbon capture and storage (BECCS) and afforestation/reforestation. These assumed CDR deployments keep ambitious temperature limits in reach, but associated rates of land-use transformation have not been evaluated. For IAM scenarios from the IPCC Fifth Assessment Report, we compare rates of modeled land-use conversion to recent observed commodity crop expansions. In scenarios with a likely chance of limiting warming to 2° in 2100, the rate of energy cropland expansion supporting BECCS exceeds past commodity crop rates by several fold. In some cases, mitigation scenarios include abrupt reversal of deforestation, paired with massive afforestation/reforestation. Specifically, energy cropland in crop. If energy cropland instead increases at rates equal to recent soybean and oil palm expansions, the scale of CO2 removal possible with BECCS is 2.6 to 10-times lower, respectively, than the deployments <2° IAM scenarios rely upon in 2100. IAM mitigation pathways may favor multi-gigatonne biomass-based CDR given undervalued sociopolitical and techno-economic deployment barriers. Heroic modeled rates for land-use transformation imply that large-scale biomass-based CDR is not an easy solution to the climate challenge.

  14. Thymoquinone Attenuates Brain Injury via an Anti-oxidative Pathway in a Status Epilepticus Rat Model.

    Science.gov (United States)

    Shao, Yi-Ye; Li, Bing; Huang, Yong-Mei; Luo, Qiong; Xie, Yang-Mei; Chen, Ying-Hui

    2017-01-01

    Status epilepticus (SE) results in the generation of reactive oxygen species (ROS), which contribute to seizure-induced brain injury. It is well known that oxidative stress plays a pivotal role in status epilepticus (SE). Thymoquinone (TQ) is a bioactive monomer extracted from black cumin (Nigella sativa) seed oil that has anti-inflammatory, anti-cancer, and antioxidant activity in various diseases. This study evaluated the protective effects of TQ on brain injury in a lithium-pilocarpine rat model of SE and investigated the underlying mechanism related to antioxidative pathway. Electroencephalogram and Racine scale were used to value seizure severity. Passive-avoidance test was used to determine learning and memory function. Moreover, anti-oxidative activity of TQ was observed using Western blot and super oxide dismutase (SOD) activity assay. Latency to SE increased in the TQ-pretreated group compared with rats in the model group, while the total power was significantly lower. Seizure severity measured on the Racine scale was significantly lower in the TQ group compared with the model group. Results of behavioral experiments suggest that TQ may also have a protective effect on learning and memory function. Investigation of the protective mechanism of TQ showed that TQ-pretreatment significantly increased the expression of Nrf2, HO-1 proteins and SOD in the hippocampus. These findings showed that TQ attenuated brain injury induced by SE via an anti-oxidative pathway.

  15. Model feasibility study of radioactive pathways from atmosphere to surface water

    International Nuclear Information System (INIS)

    Smith, R.E.; Summer, R.M.; Ferreira, V.A.

    1990-03-01

    A feasibility study of the atmosphere to surface-water radionuclide pathways was performed for small catchments, using a physically-based hydro-ecosystem model, Opus. Detailed time-intensity precipitation records from Arizona and Georgia were used as input to drive the model. Tests of model sensitivity to distribution coefficients, Kd, for Cs-137, Cs-134, and Sr-90 illustrated different vegetation-soil-erosion-runoff pathways, in response to agricultural management practices. Results reflected the fact that low Kd values allow a radionuclide to infiltrate into the soil profile and isolate it from subsequent runoff and erosion. Of the radionuclides and physical settings studied, only the Sr-90, with low Kd values, is sufficiently mobile and long-lived to be removed from the system via percolation below the root zone. Conversely, highly-adsorbed radionuclides were subject to removal by adsorption to sediment particles and subsequent runoff. Comparison of different effective half-lives of I-131 demonstrated the importance of the timing of an erosion-runoff storm event during or immediately after a fallout event. Seasonal timing of a fallout event and crop management also affect the fate of this short-lived radionuclide. Removal by solution to surface-water runoff was negligible for all nuclides studied. 34 refs., 14 figs., 2 tabs

  16. The Kynurenine Pathway Modulates Neurodegeneration in a Drosophila Model of Huntington’s Disease

    Science.gov (United States)

    Campesan, Susanna; Green, Edward W.; Breda, Carlo; Sathyasaikumar, Korrapati V.; Muchowski, Paul J.; Schwarcz, Robert; Kyriacou, Charalambos P.; Giorgini, Flaviano

    2014-01-01

    Summary Neuroactive metabolites of the kynurenine pathway (KP) of tryptophan degradation have been implicated in the pathophysiology of neurodegenerative disorders, including Huntington’s disease (HD) [1]. A central hallmark of HD is neurodegeneration caused by a polyglutamine expansion in the huntingtin (htt) protein [2]. Here we exploit a transgenic Drosophila melanogaster model of HD to interrogate the therapeutic potential of KP manipulation. We observe that genetic and pharmacological inhibition of kynurenine 3-monooxygenase (KMO) increases levels of the neuroprotective metabolite kynurenic acid (KYNA) relative to the neurotoxic metabolite 3-hydroxykynurenine (3-HK) and ameliorates neurodegeneration. We also find that genetic inhibition of tryptophan 2,3-dioxygenase (TDO), the first and rate-limiting step in the pathway, leads to a similar neuroprotective shift toward KYNA synthesis. Importantly, we demonstrate that the feeding of KYNA and 3-HK to HD model flies directly modulates neurodegeneration, underscoring the causative nature of these metabolites. This study provides the first genetic evidence that inhibition of KMO and TDO activity protects against neurodegenerative disease in an animal model, indicating that strategies targeted at two key points within the KP may have therapeutic relevance in HD, and possibly other neurodegenerative disorders. PMID:21636279

  17. A review of models for near-field exposure pathways of chemicals in consumer products

    DEFF Research Database (Denmark)

    Huang, Lei; Ernstoff, Alexi; Fantke, Peter

    2017-01-01

    able to quantify the multiple transfers of chemicals from products used near-field to humans. The present review therefore aims at an in-depth overview of modeling approaches for near-field chemical release and human exposure pathways associated with consumer products. It focuses on lower......-tier, mechanistic models suitable for life cycle assessments (LCA), chemical alternative assessment (CAA) and high-throughput screening risk assessment (HTS). Chemicals in a product enter the near-field via a defined “compartment of entry”, are transformed or transferred to adjacent compartments, and eventually end......Exposure to chemicals in consumer products has been gaining increasing attention, with multiple studies showing that near-field exposures from products is high compared to far-field exposures. Regarding the numerous chemical-product combinations, there is a need for an overarching review of models...

  18. PATHWAY: a simulation model of radionuclide-transport through agricultural food chains

    International Nuclear Information System (INIS)

    Kirchner, T.B.; Whicker, F.W.; Otis, M.D.

    1982-01-01

    PATHWAY simulates the transport of radionuclides from fallout through an agricultural ecosystem. The agro-ecosystem is subdivided into several land management units, each of which is used either for grazing animals, for growing hay, or for growing food crops. The model simulates the transport of radionuclides by both discrete events and continuous, time-dependent processes. The discrete events include tillage of soil, harvest and storage of crops,and deposition of fallout. The continuous processes include the transport of radionuclides due to resuspension, weathering, rain splash, percolation, leaching, adsorption and desorption of radionuclides in the soil, root uptake, foliar absorption, growth and senescence of vegetation, and the ingestion assimilation, and excretion of radionuclides by animals. Preliminary validation studies indicate that the model dynamics and simulated values of radionuclide concentrations in several agricultural products agree well with measured values when the model is driven with site specific data on deposition from world-wide fallout

  19. Multi-pathway model of nuclide transport in fractured media and its application

    International Nuclear Information System (INIS)

    Li Xun; Yang Zeping; Li Jinxuan

    2010-01-01

    In order to know the law of nuclide transport in fracture system, the basic differential equations of nuclide transport in fracture and matrix were obtained based on the dual media theory, and the general analytic solutions of nuclide transport in single fractured media with exponential attenuation source in fracture were deduced by Laplace transform, and one-dimensional multi-pathway model of nuclide transport was proposed based on dual media theory and stochastic distribution of fracture parameters. The transport of Th-229, Cs-135 and Se-79 were simulated with this model, the relative concentration of these nuclides in fracture system were predicted. Further more, it was deduced that aperture and velocity can distinctly influence transport of nuclide by comparing with the results which were simulated by single fracture model. (authors)

  20. Computational Modeling of Fluctuations in Energy and Metabolic Pathways of Methanogenic Archaea

    Energy Technology Data Exchange (ETDEWEB)

    Luthey-Schulten, Zaida [Univ. of Illinois, Urbana-Champaign, IL (United States). Dept. of Chemistry; Carl R. Woese Inst. for Genomic Biology

    2017-01-04

    The methanogenic archaea, anaerobic microbes that convert CO2 and H2 and/or other small organic fermentation products into methane, play an unusually large role in the global carbon cycle. As they perform the final step in the anaerobic breakdown of biomass, methanogens are a biogenic source of an estimated one billion tons methane each year. Depending on the location, produced methane can be considered as either a greenhouse gas (agricultural byproduct), sequestered carbon storage (methane hydrate deposits), or a potential energy source (organic wastewater treatment). These microbes therefore represent an important target for biotechnology applications. Computational models of methanogens with predictive power are useful aids in the adaptation of methanogenic systems, but need to connect processes of wide-ranging time and length scales. In this project, we developed several computational methodologies for modeling the dynamic behavior of entire cells that connects stochastic reaction-diffusion dynamics of individual biochemical pathways with genome-scale modeling of metabolic networks. While each of these techniques were in the realm of well-defined computational methods, here we integrated them to develop several entirely new approaches to systems biology. The first scientific aim of the project was to model how noise in a biochemical pathway propagates into cellular phenotypes. Genetic circuits have been optimized by evolution to regulate molecular processes despite stochastic noise, but the effect of such noise on a cellular biochemical networks is currently unknown. An integrated stochastic/systems model of Escherichia coli species was created to analyze how noise in protein expression gives—and therefore noise in metabolic fluxes—gives rise to multiple cellular phenotype in isogenic population. After the initial work developing and validating methods that allow characterization of the heterogeneity in the model organism E. coli, the project shifted toward

  1. A mouse model of alcoholic liver fibrosis-associated acute kidney injury identifies key molecular pathways

    International Nuclear Information System (INIS)

    Furuya, Shinji; Chappell, Grace A.; Iwata, Yasuhiro; Uehara, Takeki; Kato, Yuki; Kono, Hiroshi; Bataller, Ramon; Rusyn, Ivan

    2016-01-01

    Clinical data strongly indicate that acute kidney injury (AKI) is a critical complication in alcoholic hepatitis, an acute-on-chronic form of liver failure in patients with advanced alcoholic fibrosis. Development of targeted therapies for AKI in this setting is hampered by the lack of an animal model. To enable research into molecular drivers and novel therapies for fibrosis- and alcohol-associated AKI, we aimed to combine carbon tetrachloride (CCl 4 )-induced fibrosis with chronic intra-gastric alcohol feeding. Male C57BL/6J mice were administered a low dose of CCl 4 (0.2 ml/kg 2 × week/6 weeks) followed by alcohol intragastrically (up to 25 g/kg/day for 3 weeks) and with continued CCl 4 . We observed that combined treatment with CCl 4 and alcohol resulted in severe liver injury, more pronounced than using each treatment alone. Importantly, severe kidney injury was evident only in the combined treatment group. This mouse model reproduced distinct pathological features consistent with AKI in human alcoholic hepatitis. Transcriptomic analysis of kidneys revealed profound effects in the combined treatment group, with enrichment for damage-associated pathways, such as apoptosis, inflammation, immune-response and hypoxia. Interestingly, Havcr1 and Lcn2, biomarkers of AKI, were markedly up-regulated. Overall, this study established a novel mouse model of fibrosis- and alcohol-associated AKI and identified key mechanistic pathways. - Highlights: • Acute kidney injury (AKI) is a critical complication in alcoholic hepatitis • We developed a novel mouse model of fibrosis- and alcohol-associated AKI • This model reproduces key molecular and pathological features of human AKI • This animal model can help identify new targeted therapies for alcoholic hepatitis

  2. A mouse model of alcoholic liver fibrosis-associated acute kidney injury identifies key molecular pathways

    Energy Technology Data Exchange (ETDEWEB)

    Furuya, Shinji; Chappell, Grace A.; Iwata, Yasuhiro [Department of Veterinary Integrative Biosciences, Texas A& M University, College Station, TX (United States); Uehara, Takeki; Kato, Yuki [Laboratory of Veterinary Pathology, Osaka Prefecture University, Osaka (Japan); Kono, Hiroshi [First Department of Surgery, University of Yamanashi, Yamanashi (Japan); Bataller, Ramon [Division of Gastroenterology & Hepatology, Department of Medicine, University of North Carolina, Chapel Hill, NC (United States); Rusyn, Ivan, E-mail: irusyn@tamu.edu [Department of Veterinary Integrative Biosciences, Texas A& M University, College Station, TX (United States)

    2016-11-01

    Clinical data strongly indicate that acute kidney injury (AKI) is a critical complication in alcoholic hepatitis, an acute-on-chronic form of liver failure in patients with advanced alcoholic fibrosis. Development of targeted therapies for AKI in this setting is hampered by the lack of an animal model. To enable research into molecular drivers and novel therapies for fibrosis- and alcohol-associated AKI, we aimed to combine carbon tetrachloride (CCl{sub 4})-induced fibrosis with chronic intra-gastric alcohol feeding. Male C57BL/6J mice were administered a low dose of CCl{sub 4} (0.2 ml/kg 2 × week/6 weeks) followed by alcohol intragastrically (up to 25 g/kg/day for 3 weeks) and with continued CCl{sub 4}. We observed that combined treatment with CCl{sub 4} and alcohol resulted in severe liver injury, more pronounced than using each treatment alone. Importantly, severe kidney injury was evident only in the combined treatment group. This mouse model reproduced distinct pathological features consistent with AKI in human alcoholic hepatitis. Transcriptomic analysis of kidneys revealed profound effects in the combined treatment group, with enrichment for damage-associated pathways, such as apoptosis, inflammation, immune-response and hypoxia. Interestingly, Havcr1 and Lcn2, biomarkers of AKI, were markedly up-regulated. Overall, this study established a novel mouse model of fibrosis- and alcohol-associated AKI and identified key mechanistic pathways. - Highlights: • Acute kidney injury (AKI) is a critical complication in alcoholic hepatitis • We developed a novel mouse model of fibrosis- and alcohol-associated AKI • This model reproduces key molecular and pathological features of human AKI • This animal model can help identify new targeted therapies for alcoholic hepatitis.

  3. Modeling of coupled differential equations for cellular chemical signaling pathways: Implications for assay protocols utilized in cellular engineering.

    Science.gov (United States)

    O'Clock, George D

    2016-08-01

    Cellular engineering involves modification and control of cell properties, and requires an understanding of fundamentals and mechanisms of action for cellular derived product development. One of the keys to success in cellular engineering involves the quality and validity of results obtained from cell chemical signaling pathway assays. The accuracy of the assay data cannot be verified or assured if the effect of positive feedback, nonlinearities, and interrelationships between cell chemical signaling pathway elements are not understood, modeled, and simulated. Nonlinearities and positive feedback in the cell chemical signaling pathway can produce significant aberrations in assay data collection. Simulating the pathway can reveal potential instability problems that will affect assay results. A simulation, using an electrical analog for the coupled differential equations representing each segment of the pathway, provides an excellent tool for assay validation purposes. With this approach, voltages represent pathway enzyme concentrations and operational amplifier feedback resistance and input resistance values determine pathway gain and rate constants. The understanding provided by pathway modeling and simulation is strategically important in order to establish experimental controls for assay protocol structure, time frames specified between assays, and assay concentration variation limits; to ensure accuracy and reproducibility of results.

  4. New methods for clinical pathways-Business Process Modeling Notation (BPMN) and Tangible Business Process Modeling (t.BPM).

    Science.gov (United States)

    Scheuerlein, Hubert; Rauchfuss, Falk; Dittmar, Yves; Molle, Rüdiger; Lehmann, Torsten; Pienkos, Nicole; Settmacher, Utz

    2012-06-01

    Clinical pathways (CP) are nowadays used in numerous institutions, but their real impact is still a matter of debate. The optimal design of a clinical pathway remains unclear and is mainly determined by the expectations of the individual institution. The purpose of the here described pilot project was the development of two CP (colon and rectum carcinoma) according to Business Process Modeling Notation (BPMN) and Tangible Business Process Modeling (t.BPM). BPMN is an established standard for business process modelling in industry and economy. It is, in the broadest sense, a computer programme which enables the description and a relatively easy graphical imaging of complex processes. t.BPM is a modular construction system of the BPMN symbols which enables the creation of an outline or raw model, e.g. by placing the symbols on a spread-out paper sheet. The thus created outline can then be transferred to the computer and further modified as required. CP for the treatment of colon and rectal cancer have been developed with support of an external IT coach. The pathway was developed in an interdisciplinary and interprofessional manner (55 man-days over 15 working days). During this time, necessary interviews with medical, nursing and administrative staffs were conducted as well. Both pathways were developed parallel. Subsequent analysis was focussed on feasibility, expenditure, clarity and suitability for daily clinical practice. The familiarization with BPMN was relatively quick and intuitive. The use of t.BPM enabled the pragmatic, effective and results-directed creation of outlines for the CP. The development of both CP was finished from the diagnostic evaluation to the adjuvant/neoadjuvant therapy and rehabilitation phase. The integration of checklists, guidelines and important medical or other documents is easily accomplished. A direct integration into the hospital computer system is currently not possible for technical reasons. BPMN and t.BPM are sufficiently

  5. Modeling The Inhalation Exposure Pathway In Performance Assessment Of Geologic Radioactive Waste Repository At Yucca Mountain

    International Nuclear Information System (INIS)

    M.A. Wasiolek

    2006-01-01

    Inhalation exposure pathway modeling has recently been investigated as one of the tasks of the BIOPROTA Project (BIOPROTA 2005). BIOPROTA was set up to address the key uncertainties in long term assessments of contaminant releases into the environment arising from radioactive waste disposal. Participants of this international Project include national authorities and agencies, both regulators and operators, with responsibility for achieving safe and acceptable radioactive waste management. The objective of the inhalation task was to investigate the calculation of doses arising from inhalation of particles suspended from soils within which long-lived radionuclides, particularly alpha emitters, had accumulated. It was recognized that site-specific conditions influence the choice of conceptual model and input parameter values. Therefore, one of the goals of the task was to identify the circumstances in which different processes included in specific inhalation exposure pathway models were important. This paper discusses evaluation of processes and modeling assumptions specific to the proposed repository at Yucca Mountain as compared to the typical approaches and other models developed for different assessments and project specific contexts. Inhalation of suspended particulates that originate from contaminated soil is an important exposure pathway, particularly for exposure to actinides such as uranium, neptunium and plutonium. Radionuclide accumulation in surface soil arises from irrigation of soil with contaminated water over many years. The level of radionuclide concentration in surface soil depends on the assumed duration of irrigation. Irrigation duration is one of the parameters used on biosphere models and it depends on a specific assessment context. It is one of the parameters addressed in this paper from the point of view of assessment context for the proposed repository at Yucca Mountain. The preferred model for the assessment of inhalation exposure uses

  6. Modeled aerosol nitrate formation pathways during wintertime in the Great Lakes region of North America

    Science.gov (United States)

    Kim, Yoo Jung; Spak, Scott N.; Carmichael, Gregory R.; Riemer, Nicole; Stanier, Charles O.

    2014-11-01

    Episodic wintertime particle pollution by ammonium nitrate is an important air quality concern across the Midwest U.S. Understanding and accurately forecasting PM2.5 episodes are complicated by multiple pathways for aerosol nitrate formation, each with uncertain rate parameters. Here, the Community Multiscale Air Quality model (CMAQ) simulated regional atmospheric nitrate budgets during the 2009 LADCO Winter Nitrate Study, using integrated process rate (IPR) and integrated reaction rate (IRR) tools to quantify relevant processes. Total nitrate production contributing to PM2.5 episodes is a regional phenomenon, with peak production over the Ohio River Valley and southern Great Lakes. Total nitrate production in the lower troposphere is attributed to three pathways, with 57% from heterogeneous conversion of N2O5, 28% from the reaction of OH and NO2, and 15% from homogeneous conversion of N2O5. TNO3 formation rates varied day-to-day and on synoptic timescales. Rate-limited production does not follow urban-rural gradients and NOx emissions due, to counterbalancing of urban enhancement in daytime HNO3 production with nocturnal reductions. Concentrations of HNO3 and N2O5 and nighttime TNO3 formation rates have maxima aloft (100-500 m), leading to net total nitrate vertical flux during episodes, with substantial vertical gradients in nitrate partitioning. Uncertainties in all three pathways are relevant to wintertime aerosol modeling and highlight the importance of interacting transport and chemistry processes during ammonium nitrate episodes, as well as the need for additional constraint on the system through field and laboratory experiments.

  7. Cerebrospinal and interstitial fluid transport via the glymphatic pathway modeled by optimal mass transport.

    Science.gov (United States)

    Ratner, Vadim; Gao, Yi; Lee, Hedok; Elkin, Rena; Nedergaard, Maiken; Benveniste, Helene; Tannenbaum, Allen

    2017-05-15

    The glymphatic pathway is a system which facilitates continuous cerebrospinal fluid (CSF) and interstitial fluid (ISF) exchange and plays a key role in removing waste products from the rodent brain. Dysfunction of the glymphatic pathway may be implicated in the pathophysiology of Alzheimer's disease. Intriguingly, the glymphatic system is most active during deep wave sleep general anesthesia. By using paramagnetic tracers administered into CSF of rodents, we previously showed the utility of MRI in characterizing a macroscopic whole brain view of glymphatic transport but we have yet to define and visualize the specific flow patterns. Here we have applied an alternative mathematical analysis approach to a dynamic time series of MRI images acquired every 4min over ∼3h in anesthetized rats, following administration of a small molecular weight paramagnetic tracer into the CSF reservoir of the cisterna magna. We use Optimal Mass Transport (OMT) to model the glymphatic flow vector field, and then analyze the flow to find the network of CSF-ISF flow channels. We use 3D visualization computational tools to visualize the OMT defined network of CSF-ISF flow channels in relation to anatomical and vascular key landmarks from the live rodent brain. The resulting OMT model of the glymphatic transport network agrees largely with the current understanding of the glymphatic transport patterns defined by dynamic contrast-enhanced MRI revealing key CSF transport pathways along the ventral surface of the brain with a trajectory towards the pineal gland, cerebellum, hypothalamus and olfactory bulb. In addition, the OMT analysis also revealed some interesting previously unnoticed behaviors regarding CSF transport involving parenchymal streamlines moving from ventral reservoirs towards the surface of the brain, olfactory bulb and large central veins. Copyright © 2017. Published by Elsevier Inc.

  8. Computational Model of Antidepressant Response Heterogeneity as Multi-pathway Neuroadaptation

    Directory of Open Access Journals (Sweden)

    Mariam B. Camacho

    2017-12-01

    Full Text Available Current hypotheses cannot fully explain the clinically observed heterogeneity in antidepressant response. The therapeutic latency of antidepressants suggests that therapeutic outcomes are achieved not by the acute effects of the drugs, but rather by the homeostatic changes that occur as the brain adapts to their chronic administration. We present a computational model that represents the known interactions between the monoaminergic neurotransmitter-producing brain regions and associated non-monoaminergic neurotransmitter systems, and use the model to explore the possible ways in which the brain can homeostatically adjust to chronic antidepressant administration. The model also represents the neuron-specific neurotransmitter receptors that are known to adjust their strengths (expressions or sensitivities in response to chronic antidepressant administration, and neuroadaptation in the model occurs through sequential adjustments in these receptor strengths. The main result is that the model can reach similar levels of adaptation to chronic administration of the same antidepressant drug or combination along many different pathways, arriving correspondingly at many different receptor strength configurations, but not all of those adapted configurations are also associated with therapeutic elevations in monoamine levels. When expressed as the percentage of adapted configurations that are also associated with elevations in one or more of the monoamines, our modeling results largely agree with the percentage efficacy rates of antidepressants and antidepressant combinations observed in clinical trials. Our neuroadaptation model provides an explanation for the clinical reports of heterogeneous outcomes among patients chronically administered the same antidepressant drug regimen.

  9. A groundwater mass flux model for screening the groundwater-to-indoor-air exposure pathway

    Energy Technology Data Exchange (ETDEWEB)

    McHugh, T.; Blanc, P.C. de; Connor, J. [Groundwater Services Inc, Houston, TX (United States)

    2003-07-01

    The potential for human exposure via volatilisation of groundwater contaminants into indoor air has been a focus of increasing concern in recent years. At a small number of sites, elevated indoor vapour concentrations have been measured within buildings overlying shallow groundwater contaminated with chlorinated solvents, causing public concern over the potential for similar problems at other corrective action sites. In addition, use of the screening-levelmodel developed by Johnson and Ettinger (1991) for the groundwater-to-indoor-air exposure pathway has suggested that low microgram per litre (ug/L)-range concentrations of either chlorinated or non-chlorinated volatile organic compounds dissolved in groundwater could result in indoor vapour concentrations in excess of applicable risk-based exposure limits. As an alternative screening tool, this paper presents a groundwater mass flux model for evaluation of transport to indoor air. The mass flux model is intended to serve as a highly conservative screening tool that over-predicts groundwater-to-indoor-air mass flux, yet still provides sufficient sensitivity to identify sites for which the groundwater-to-indoor air exposure pathway is not a concern. (orig.)

  10. Acting in solidarity: Testing an extended dual pathway model of collective action by bystander group members.

    Science.gov (United States)

    Saab, Rim; Tausch, Nicole; Spears, Russell; Cheung, Wing-Yee

    2015-09-01

    We examined predictors of collective action among bystander group members in solidarity with a disadvantaged group by extending the dual pathway model of collective action, which proposes one efficacy-based and one emotion-based path to collective action (Van Zomeren, Spears, Fischer, & Leach, 2004). Based on two proposed functions of social identity performance (Klein, Spears, & Reicher, 2007), we distinguished between the efficacy of collective action at consolidating the identity of a protest movement and its efficacy at achieving social change (political efficacy). We expected identity consolidation efficacy to positively predict collective action tendencies directly and indirectly via political efficacy. We also expected collective action tendencies to be positively predicted by moral outrage and by sympathy in response to disadvantaged outgroup's suffering. These hypotheses were supported in two surveys examining intentions to protest for Palestine in Britain (Study 1), and intentions to attend the June 4th vigil in Hong Kong to commemorate the Tiananmen massacre among a sample of Hong Kong citizens (Study 2). The contributions of these findings to research on the dual pathway model of collective action and the different functions of collective action are discussed. © 2014 The British Psychological Society.

  11. Cholinergic anti-inflammatory pathway in the non-obese diabetic mouse model.

    Science.gov (United States)

    Koopman, F A; Vosters, J L; Roescher, N; Broekstra, N; Tak, P P; Vervoordeldonk, M J

    2015-10-01

    Activation of the cholinergic anti-inflammatory pathway (CAP) has been shown to reduce inflammation in animal models, while abrogation of the pathway increases inflammation. We investigated whether modulation of CAP influences inflammation in the non-obese diabetic (NOD) mouse model for Sjögren's syndrome and type 1 diabetes. The alpha-7 nicotinic acetylcholine receptor (α7nAChR) was stimulated with AR-R17779 or nicotine in NOD mice. In a second study, unilateral cervical vagotomy was performed. α7nAChR expression, focus scores, and salivary flow were evaluated in salivary glands (SG) and insulitis score in the pancreas. Cytokines were measured in serum and SG. α7nAChR was expressed on myoepithelial cells in SG. Monocyte chemotactic protein-1 levels were reduced in SG after AR-R17779 treatment and tumor necrosis factor production was increased in the SG of the vagotomy group compared to controls. Focus score and salivary flow were unaffected. NOD mice developed diabetes more rapidly after vagotomy, but at completion of the study there were no statistically significant differences in number of mice that developed diabetes or in insulitis scores. Intervention of the CAP in NOD mice leads to minimal changes in inflammatory cytokines, but did not affect overall inflammation and function of SG or development of diabetes. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  12. Boolean network model for cancer pathways: predicting carcinogenesis and targeted therapy outcomes.

    Directory of Open Access Journals (Sweden)

    Herman F Fumiã

    Full Text Available A Boolean dynamical system integrating the main signaling pathways involved in cancer is constructed based on the currently known protein-protein interaction network. This system exhibits stationary protein activation patterns--attractors--dependent on the cell's microenvironment. These dynamical attractors were determined through simulations and their stabilities against mutations were tested. In a higher hierarchical level, it was possible to group the network attractors into distinct cell phenotypes and determine driver mutations that promote phenotypic transitions. We find that driver nodes are not necessarily central in the network topology, but at least they are direct regulators of central components towards which converge or through which crosstalk distinct cancer signaling pathways. The predicted drivers are in agreement with those pointed out by diverse census of cancer genes recently performed for several human cancers. Furthermore, our results demonstrate that cell phenotypes can evolve towards full malignancy through distinct sequences of accumulated mutations. In particular, the network model supports routes of carcinogenesis known for some tumor types. Finally, the Boolean network model is employed to evaluate the outcome of molecularly targeted cancer therapies. The major find is that monotherapies were additive in their effects and that the association of targeted drugs is necessary for cancer eradication.

  13. Dynamic Modelling Reveals 'Hotspots' on the Pathway to Enzyme-Substrate Complex Formation.

    Directory of Open Access Journals (Sweden)

    Shane E Gordon

    2016-03-01

    Full Text Available Dihydrodipicolinate synthase (DHDPS catalyzes the first committed step in the diaminopimelate pathway of bacteria, yielding amino acids required for cell wall and protein biosyntheses. The essentiality of the enzyme to bacteria, coupled with its absence in humans, validates DHDPS as an antibacterial drug target. Conventional drug design efforts have thus far been unsuccessful in identifying potent DHDPS inhibitors. Here, we make use of contemporary molecular dynamics simulation and Markov state models to explore the interactions between DHDPS from the human pathogen Staphylococcus aureus and its cognate substrate, pyruvate. Our simulations recover the crystallographic DHDPS-pyruvate complex without a priori knowledge of the final bound structure. The highly conserved residue Arg140 was found to have a pivotal role in coordinating the entry of pyruvate into the active site from bulk solvent, consistent with previous kinetic reports, indicating an indirect role for the residue in DHDPS catalysis. A metastable binding intermediate characterized by multiple points of intermolecular interaction between pyruvate and key DHDPS residue Arg140 was found to be a highly conserved feature of the binding trajectory when comparing alternative binding pathways. By means of umbrella sampling we show that these binding intermediates are thermodynamically metastable, consistent with both the available experimental data and the substrate binding model presented in this study. Our results provide insight into an important enzyme-substrate interaction in atomistic detail that offers the potential to be exploited for the discovery of more effective DHDPS inhibitors and, in a broader sense, dynamic protein-drug interactions.

  14. Modeling-independent elucidation of inactivation pathways in recombinant and native A-type Kv channels

    Science.gov (United States)

    Fineberg, Jeffrey D.; Ritter, David M.

    2012-01-01

    A-type voltage-gated K+ (Kv) channels self-regulate their activity by inactivating directly from the open state (open-state inactivation [OSI]) or by inactivating before they open (closed-state inactivation [CSI]). To determine the inactivation pathways, it is often necessary to apply several pulse protocols, pore blockers, single-channel recording, and kinetic modeling. However, intrinsic hurdles may preclude the standardized application of these methods. Here, we implemented a simple method inspired by earlier studies of Na+ channels to analyze macroscopic inactivation and conclusively deduce the pathways of inactivation of recombinant and native A-type Kv channels. We investigated two distinct A-type Kv channels expressed heterologously (Kv3.4 and Kv4.2 with accessory subunits) and their native counterparts in dorsal root ganglion and cerebellar granule neurons. This approach applies two conventional pulse protocols to examine inactivation induced by (a) a simple step (single-pulse inactivation) and (b) a conditioning step (double-pulse inactivation). Consistent with OSI, the rate of Kv3.4 inactivation (i.e., the negative first derivative of double-pulse inactivation) precisely superimposes on the profile of the Kv3.4 current evoked by a single pulse because the channels must open to inactivate. In contrast, the rate of Kv4.2 inactivation is asynchronous, already changing at earlier times relative to the profile of the Kv4.2 current evoked by a single pulse. Thus, Kv4.2 inactivation occurs uncoupled from channel opening, indicating CSI. Furthermore, the inactivation time constant versus voltage relation of Kv3.4 decreases monotonically with depolarization and levels off, whereas that of Kv4.2 exhibits a J-shape profile. We also manipulated the inactivation phenotype by changing the subunit composition and show how CSI and CSI combined with OSI might affect spiking properties in a full computational model of the hippocampal CA1 neuron. This work unambiguously

  15. A probabilistic generative model for quantification of DNA modifications enables analysis of demethylation pathways.

    Science.gov (United States)

    Äijö, Tarmo; Huang, Yun; Mannerström, Henrik; Chavez, Lukas; Tsagaratou, Ageliki; Rao, Anjana; Lähdesmäki, Harri

    2016-03-14

    We present a generative model, Lux, to quantify DNA methylation modifications from any combination of bisulfite sequencing approaches, including reduced, oxidative, TET-assisted, chemical-modification assisted, and methylase-assisted bisulfite sequencing data. Lux models all cytosine modifications (C, 5mC, 5hmC, 5fC, and 5caC) simultaneously together with experimental parameters, including bisulfite conversion and oxidation efficiencies, as well as various chemical labeling and protection steps. We show that Lux improves the quantification and comparison of cytosine modification levels and that Lux can process any oxidized methylcytosine sequencing data sets to quantify all cytosine modifications. Analysis of targeted data from Tet2-knockdown embryonic stem cells and T cells during development demonstrates DNA modification quantification at unprecedented detail, quantifies active demethylation pathways and reveals 5hmC localization in putative regulatory regions.

  16. Modeling effective transmission pathways and control of the world's most successful parasite.

    Science.gov (United States)

    Turner, Matthew; Lenhart, Suzanne; Rosenthal, Benjamin; Zhao, Xiaopeng

    2013-06-01

    Toxoplasma gondii(T. gondii) is a single-celled, intracellular protozoan responsible for the disease toxoplasmosis. The parasite is prevalent worldwide, and it infects all warm-blooded vertebrates. Consumption of meats in which this parasite has encysted confers risk of infection to people and other animals, as does ingestion of water or foods contaminated with environmentally resistant oocysts excreted by cats. Vertical transmission (from mother to offspring) is also possible, leading to disease risk and contributing additional means of ensuring perpetuation of transmission. In this work, we adopt a differential equation model to investigate the effective transmission pathways of T. gondii, as well as potential control mechanisms. Detailed analyses are carried out to examine the significance of transmission routes, virulence, vertical transmission, parasite-induced changes in host behavior, and controls based on vaccination and harvesting. Modeling and analysis efforts may shed insights into understanding the complex life cycle of T. gondii. Copyright © 2013 Elsevier Inc. All rights reserved.

  17. Using logic model methods in systematic review synthesis: describing complex pathways in referral management interventions.

    Science.gov (United States)

    Baxter, Susan K; Blank, Lindsay; Woods, Helen Buckley; Payne, Nick; Rimmer, Melanie; Goyder, Elizabeth

    2014-05-10

    There is increasing interest in innovative methods to carry out systematic reviews of complex interventions. Theory-based approaches, such as logic models, have been suggested as a means of providing additional insights beyond that obtained via conventional review methods. This paper reports the use of an innovative method which combines systematic review processes with logic model techniques to synthesise a broad range of literature. The potential value of the model produced was explored with stakeholders. The review identified 295 papers that met the inclusion criteria. The papers consisted of 141 intervention studies and 154 non-intervention quantitative and qualitative articles. A logic model was systematically built from these studies. The model outlines interventions, short term outcomes, moderating and mediating factors and long term demand management outcomes and impacts. Interventions were grouped into typologies of practitioner education, process change, system change, and patient intervention. Short-term outcomes identified that may result from these interventions were changed physician or patient knowledge, beliefs or attitudes and also interventions related to changed doctor-patient interaction. A range of factors which may influence whether these outcomes lead to long term change were detailed. Demand management outcomes and intended impacts included content of referral, rate of referral, and doctor or patient satisfaction. The logic model details evidence and assumptions underpinning the complex pathway from interventions to demand management impact. The method offers a useful addition to systematic review methodologies. PROSPERO registration number: CRD42013004037.

  18. Using Regularization to Infer Cell Line Specificity in Logical Network Models of Signaling Pathways

    Directory of Open Access Journals (Sweden)

    Sébastien De Landtsheer

    2018-05-01

    Full Text Available Understanding the functional properties of cells of different origins is a long-standing challenge of personalized medicine. Especially in cancer, the high heterogeneity observed in patients slows down the development of effective cures. The molecular differences between cell types or between healthy and diseased cellular states are usually determined by the wiring of regulatory networks. Understanding these molecular and cellular differences at the systems level would improve patient stratification and facilitate the design of rational intervention strategies. Models of cellular regulatory networks frequently make weak assumptions about the distribution of model parameters across cell types or patients. These assumptions are usually expressed in the form of regularization of the objective function of the optimization problem. We propose a new method of regularization for network models of signaling pathways based on the local density of the inferred parameter values within the parameter space. Our method reduces the complexity of models by creating groups of cell line-specific parameters which can then be optimized together. We demonstrate the use of our method by recovering the correct topology and inferring accurate values of the parameters of a small synthetic model. To show the value of our method in a realistic setting, we re-analyze a recently published phosphoproteomic dataset from a panel of 14 colon cancer cell lines. We conclude that our method efficiently reduces model complexity and helps recovering context-specific regulatory information.

  19. How to model mutually exclusive events based on independent causal pathways in Bayesian network models

    OpenAIRE

    Fenton, N.; Neil, M.; Lagnado, D.; Marsh, W.; Yet, B.; Constantinou, A.

    2016-01-01

    We show that existing Bayesian network (BN) modelling techniques cannot capture the correct intuitive reasoning in the important case when a set of mutually exclusive events need to be modelled as separate nodes instead of states of a single node. A previously proposed ‘solution’, which introduces a simple constraint node that enforces mutual exclusivity, fails to preserve the prior probabilities of the events, while other proposed solutions involve major changes to the original model. We pro...

  20. Linking Adverse Outcome Pathways to Dynamic Energy Budgets: A Conceptual Model

    Energy Technology Data Exchange (ETDEWEB)

    Murphy, Cheryl [Michigan State University, East Lansing; Nisbet, Roger [University of California Santa Barbara; Antczak, Philipp [University of Liverpool, UK; Reyero, Natalia [Army Corps of Engineers, Vicksburg; Gergs, Andre [Gaiac; Lika, Dina [University of Crete; Mathews, Teresa J. [ORNL; Muller, Eric [University of California, Santa Barbara; Nacci, Dianne [U.S. Environmental Protection Agency (EPA); Peace, Angela L. [ORNL; Remien, Chris [University of Idaho; Schulz, Irv [Pacific Northwest National Laboratory (PNNL); Watanabe, Karen [Arizona State University

    2018-02-01

    Ecological risk assessment quantifies the likelihood of undesirable impacts of stressors, primarily at high levels of biological organization. Data used to inform ecological risk assessments come primarily from tests on individual organisms or from suborganismal studies, indicating a disconnect between primary data and protection goals. We know how to relate individual responses to population dynamics using individual-based models, and there are emerging ideas on how to make connections to ecosystem services. However, there is no established methodology to connect effects seen at higher levels of biological organization with suborganismal dynamics, despite progress made in identifying Adverse Outcome Pathways (AOPs) that link molecular initiating events to ecologically relevant key events. This chapter is a product of a working group at the National Center for Mathematical and Biological Synthesis (NIMBioS) that assessed the feasibility of using dynamic energy budget (DEB) models of individual organisms as a “pivot” connecting suborganismal processes to higher level ecological processes. AOP models quantify explicit molecular, cellular or organ-level processes, but do not offer a route to linking sub-organismal damage to adverse effects on individual growth, reproduction, and survival, which can be propagated to the population level through individual-based models. DEB models describe these processes, but use abstract variables with undetermined connections to suborganismal biology. We propose linking DEB and quantitative AOP models by interpreting AOP key events as measures of damage-inducing processes in a DEB model. Here, we present a conceptual model for linking AOPs to DEB models and review existing modeling tools available for both AOP and DEB.

  1. Pravastatin Effects on Placental Prosurvival Molecular Pathways in a Mouse Model of Preeclampsia.

    Science.gov (United States)

    Saad, Antonio F; Diken, Zaid M; Kechichian, Talar B; Clark, Shannon M; Olson, Gayle L; Saade, George R; Costantine, Maged M

    2016-11-01

    Using an animal model of preeclampsia induced by overexpression of soluble fms-like tyrosine kinase 1 (sFlt-1), we previously showed that pravastatin prevents the development of a preeclampsia phenotype. Our objective is to determine whether pravastatin treatment may be explained by its effects on apoptotic/survival pathways in the placenta. Pregnant CD1 mice at day 8 of gestation (length of gestation 19 days) were randomly allocated to injection via tail vein with either adenovirus carrying sFlt-1 or adenovirus carrying the murine immunoglobulin G2α Fc fragment (mFc virus control group). Mice from the sFlt group were randomly assigned to receive pravastatin (5 mg/kg/d) in their drinking water from day 9 until killing (sFlt-1 + Pravastatin) or water (sFlt-1). The mFc control received water only. Mice were killed on day 18, and the placentas were collected. Protein mitogen-activated protein kinase (MAPK) pathway substrates were assayed using Bioplex Multiplex Immunoassay (Bio-Rad, Hercules, California). Data are reported as mean  ±  standard error of the mean or median (interquartile range) when appropriate. One-way analysis of variance followed by post hoc analysis was performed. Two-sided P value preeclampsia phenotype may be mediated through pleiotropic mechanisms involving a prosurvival/ antiapoptotic MAPK pathway in the placenta. Our results further support continued research in the role for statins in the prevention of preeclampsia. © The Author(s) 2016.

  2. Focal Solute Trapping and Global Glymphatic Pathway Impairment in a Murine Model of Multiple Microinfarcts.

    Science.gov (United States)

    Wang, Minghuan; Ding, Fengfei; Deng, SaiYue; Guo, Xuequn; Wang, Wei; Iliff, Jeffrey J; Nedergaard, Maiken

    2017-03-15

    Microinfarcts occur commonly in the aging brain as a consequence of diffuse embolic events and are associated with the development of vascular dementia and Alzheimer's disease. However, the manner in which disperse microscopic lesions reduce global cognitive function and increase the risk for Alzheimer's disease is unclear. The glymphatic system, which is a brain-wide perivascular network that supports the recirculation of CSF through the brain parenchyma, facilitates the clearance of interstitial solutes including amyloid β and tau. We investigated whether glymphatic pathway function is impaired in a murine model of multiple microinfarcts induced by intraarterial injection of cholesterol crystals. The analysis showed that multiple microinfarcts markedly impaired global influx of CSF along the glymphatic pathway. Although suppression of global glymphatic function was transient, resolving within 2 weeks of injury, CSF tracers also accumulated within tissue associated with microinfarcts. The effect of diffuse microinfarcts on global glymphatic pathway function was exacerbated in the mice aged 12 months compared with the 2- to 3-month-old mice. These findings indicate that glymphatic function is focally disrupted around microinfarcts and that the aging brain is more vulnerable to this disruption than the young brain. These observations suggest that microlesions may trap proteins and other interstitial solutes within the brain parenchyma, increasing the risk of amyloid plaque formation. SIGNIFICANCE STATEMENT Microinfarcts, small (glymphatic system is a brain-wide network of channels surrounding brain blood vessels that allows CSF to exchange with interstitial fluid, clearing away cellular wastes such as amyloid β. We observed that, in mice, microinfarcts impaired global glymphatic function and solutes from the CSF became trapped in tissue associated with microinfarcts. These data suggest that small, disperse ischemic lesions can impair glymphatic function across the

  3. A model of pathways to artificial superintelligence catastrophe for risk and decision analysis

    Science.gov (United States)

    Barrett, Anthony M.; Baum, Seth D.

    2017-03-01

    An artificial superintelligence (ASI) is an artificial intelligence that is significantly more intelligent than humans in all respects. Whilst ASI does not currently exist, some scholars propose that it could be created sometime in the future, and furthermore that its creation could cause a severe global catastrophe, possibly even resulting in human extinction. Given the high stakes, it is important to analyze ASI risk and factor the risk into decisions related to ASI research and development. This paper presents a graphical model of major pathways to ASI catastrophe, focusing on ASI created via recursive self-improvement. The model uses the established risk and decision analysis modelling paradigms of fault trees and influence diagrams in order to depict combinations of events and conditions that could lead to AI catastrophe, as well as intervention options that could decrease risks. The events and conditions include select aspects of the ASI itself as well as the human process of ASI research, development and management. Model structure is derived from published literature on ASI risk. The model offers a foundation for rigorous quantitative evaluation and decision-making on the long-term risk of ASI catastrophe.

  4. Reconstruction and logical modeling of glucose repression signaling pathways in Saccharomyces cerevisiae

    Directory of Open Access Journals (Sweden)

    Oliveira Ana

    2009-01-01

    Full Text Available Abstract Background In the yeast Saccharomyces cerevisiae, the presence of high levels of glucose leads to an array of down-regulatory effects known as glucose repression. This process is complex due to the presence of feedback loops and crosstalk between different pathways, complicating the use of intuitive approaches to analyze the system. Results We established a logical model of yeast glucose repression, formalized as a hypergraph. The model was constructed based on verified regulatory interactions and it includes 50 gene transcripts, 22 proteins, 5 metabolites and 118 hyperedges. We computed the logical steady states of all nodes in the network in order to simulate wildtype and deletion mutant responses to different sugar availabilities. Evaluation of the model predictive power was achieved by comparing changes in the logical state of gene nodes with transcriptome data. Overall, we observed 71% true predictions, and analyzed sources of errors and discrepancies for the remaining. Conclusion Though the binary nature of logical (Boolean models entails inherent limitations, our model constitutes a primary tool for storing regulatory knowledge, searching for incoherencies in hypotheses and evaluating the effect of deleting regulatory elements involved in glucose repression.

  5. Soil-to-Plant Concentration Ratios for Assessing Food Chain Pathways in Biosphere Models

    Energy Technology Data Exchange (ETDEWEB)

    Napier, Bruce A.; Fellows, Robert J.; Krupka, Kenneth M.

    2007-10-01

    This report describes work performed for the U.S. Nuclear Regulatory Commission’s project Assessment of Food Chain Pathway Parameters in Biosphere Models, which was established to assess and evaluate a number of key parameters used in the food-chain models used in performance assessments of radioactive waste disposal facilities. Section 2 of this report summarizes characteristics of samples of soils and groundwater from three geographical regions of the United States, the Southeast, Northwest, and Southwest, and analyses performed to characterize their physical and chemical properties. Because the uptake and behavior of radionuclides in plant roots, plant leaves, and animal products depends on the chemistry of the water and soil coming in contact with plants and animals, water and soil samples collected from these regions of the United States were used in experiments at Pacific Northwest National Laboratory to determine radionuclide soil-to-plant concentration ratios. Crops and forage used in the experiments were grown in the soils, and long-lived radionuclides introduced into the groundwater provide the contaminated water used to water the grown plants. The radionuclides evaluated include 99Tc, 238Pu, and 241Am. Plant varieties include alfalfa, corn, onion, and potato. The radionuclide uptake results from this research study show how regional variations in water quality and soil chemistry affect radionuclide uptake. Section 3 summarizes the procedures and results of the uptake experiments, and relates the soil-to-plant uptake factors derived. In Section 4, the results found in this study are compared with similar values found in the biosphere modeling literature; the study’s results are generally in line with current literature, but soil- and plant-specific differences are noticeable. This food-chain pathway data may be used by the NRC staff to assess dose to persons in the reference biosphere (e.g., persons who live and work in an area potentially affected by

  6. Modeling the intra- and extracellular cytokine signaling pathway under heat stroke in the liver.

    Directory of Open Access Journals (Sweden)

    Maria Rodriguez-Fernandez

    Full Text Available Heat stroke (HS is a life-threatening illness induced by prolonged exposure to a hot environment that causes central nervous system abnormalities and severe hyperthermia. Current data suggest that the pathophysiological responses to heat stroke may not only be due to the immediate effects of heat exposure per se but also the result of a systemic inflammatory response syndrome (SIRS. The observation that pro- (e.g., IL-1 and anti-inflammatory (e.g., IL-10 cytokines are elevated concomitantly during recovery suggests a complex network of interactions involved in the manifestation of heat-induced SIRS. In this study, we measured a set of circulating cytokine/soluble cytokine receptor proteins and liver cytokine and receptor mRNA accumulation in wild-type and tumor necrosis factor (TNF receptor knockout mice to assess the effect of neutralization of TNF signaling on the SIRS following HS. Using a systems approach, we developed a computational model describing dynamic changes (intra- and extracellular events in the cytokine signaling pathways in response to HS that was fitted to novel genomic (liver mRNA accumulation and proteomic (circulating cytokines and receptors data using global optimization. The model allows integration of relevant biological knowledge and formulation of new hypotheses regarding the molecular mechanisms behind the complex etiology of HS that may serve as future therapeutic targets. Moreover, using our unique modeling framework, we explored cytokine signaling pathways with three in silico experiments (e.g. by simulating different heat insult scenarios and responses in cytokine knockout strains in silico.

  7. Stochastic Modeling of the Clathrin-dependent and -independent Endocytic Pathways

    Science.gov (United States)

    Deng, Hua; Dutta, Prashanta; Liu, Jin

    2017-11-01

    Endocytosis is one of the important processes that bioparticles use to enter the cells. During endocytosis the membrane-bound vesicles are formed by the invagination of plasma membrane as a result of interactions among many proteins and cytoskeletons. The clathrin-mediated endocytosis is one of the most significant form of endocytosis, where the dynamic assembly of clathrin-coated pits play a critical role. While herpes simplex virus-1 has recently shown to infect cell by a novel phagocytosis-like endocytic pathway where actin polymerization may facilitate the viral entry. In this work, we propose a stochastic model for both clathrin-dependent and -independent endocytic pathways based on Monte Carlo simulations. The important roles of clathrin coating and actin cytoskeleton as well as the impact of other biological parameters are studied. Our preliminary results indicate that there exist an intermediate particle size and ligand density that maximize the internalization efficiency. Below a critical size or surface ligand density, it is difficult for the entry of a single particle, which means clustering may needed for more efficient internalization. We also find that lower membrane bending rigidity may help promote the bioparticle entry. Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number R01GM122081.

  8. Quantum optimal control pathways of ozone isomerization dynamics subject to competing dissociation: A two-state one-dimensional model

    International Nuclear Information System (INIS)

    Kurosaki, Yuzuru; Ho, Tak-San; Rabitz, Herschel

    2014-01-01

    We construct a two-state one-dimensional reaction-path model for ozone open → cyclic isomerization dynamics. The model is based on the intrinsic reaction coordinate connecting the cyclic and open isomers with the O 2 + O asymptote on the ground-state 1 A ′ potential energy surface obtained with the high-level ab initio method. Using this two-state model time-dependent wave packet optimal control simulations are carried out. Two possible pathways are identified along with their respective band-limited optimal control fields; for pathway 1 the wave packet initially associated with the open isomer is first pumped into a shallow well on the excited electronic state potential curve and then driven back to the ground electronic state to form the cyclic isomer, whereas for pathway 2 the corresponding wave packet is excited directly to the primary well of the excited state potential curve. The simulations reveal that the optimal field for pathway 1 produces a final yield of nearly 100% with substantially smaller intensity than that obtained in a previous study [Y. Kurosaki, M. Artamonov, T.-S. Ho, and H. Rabitz, J. Chem. Phys. 131, 044306 (2009)] using a single-state one-dimensional model. Pathway 2, due to its strong coupling to the dissociation channel, is less effective than pathway 1. The simulations also show that nonlinear field effects due to molecular polarizability and hyperpolarizability are small for pathway 1 but could become significant for pathway 2 because much higher field intensity is involved in the latter. The results suggest that a practical control may be feasible with the aid of a few lowly excited electronic states for ozone isomerization

  9. Induction of autophagy by ARHI (DIRAS3) alters fundamental metabolic pathways in ovarian cancer models

    International Nuclear Information System (INIS)

    Ornelas, Argentina; McCullough, Christopher R.; Lu, Zhen; Zacharias, Niki M.; Kelderhouse, Lindsay E.; Gray, Joshua; Yang, Hailing; Engel, Brian J.; Wang, Yan; Mao, Weiqun; Sutton, Margie N.; Bhattacharya, Pratip K.; Bast, Robert C. Jr.; Millward, Steven W.

    2016-01-01

    Autophagy is a bulk catabolic process that modulates tumorigenesis, therapeutic resistance, and dormancy. The tumor suppressor ARHI (DIRAS3) is a potent inducer of autophagy and its expression results in necroptotic cell death in vitro and tumor dormancy in vivo. ARHI is down-regulated or lost in over 60 % of primary ovarian tumors yet is dramatically up-regulated in metastatic disease. The metabolic changes that occur during ARHI induction and their role in modulating death and dormancy are unknown. We employed Nuclear Magnetic Resonance (NMR)-based metabolomic strategies to characterize changes in key metabolic pathways in both cell culture and xenograft models of ARHI expression and autophagy. These pathways were further interrogated by cell-based immunofluorescence imaging, tracer uptake studies, targeted metabolic inhibition, and in vivo PET/CT imaging. Induction of ARHI in cell culture models resulted in an autophagy-dependent increase in lactate production along with increased glucose uptake and enhanced sensitivity to glycolytic inhibitors. Increased uptake of glutamine was also dependent on autophagy and dramatically sensitized cultured ARHI-expressing ovarian cancer cell lines to glutaminase inhibition. Induction of ARHI resulted in a reduction in mitochondrial respiration, decreased mitochondrial membrane potential, and decreased Tom20 staining suggesting an ARHI-dependent loss of mitochondrial function. ARHI induction in mouse xenograft models resulted in an increase in free amino acids, a transient increase in [ 18 F]-FDG uptake, and significantly altered choline metabolism. ARHI expression has previously been shown to trigger autophagy-associated necroptosis in cell culture. In this study, we have demonstrated that ARHI expression results in decreased cellular ATP/ADP, increased oxidative stress, and decreased mitochondrial function. While this bioenergetic shock is consistent with programmed necrosis, our data indicates that the accompanying up

  10. Roles of Chaperone/Usher Pathways of Yersinia pestis in a Murine Model of Plague and Adhesion to Host Cells

    Science.gov (United States)

    Hatkoff, Matthew; Runco, Lisa M.; Pujol, Celine; Jayatilaka, Indralatha; Furie, Martha B.; Bliska, James B.

    2012-01-01

    Yersinia pestis and many other Gram-negative pathogenic bacteria use the chaperone/usher (CU) pathway to assemble virulence-associated surface fibers termed pili or fimbriae. Y. pestis has two well-characterized CU pathways: the caf genes coding for the F1 capsule and the psa genes coding for the pH 6 antigen. The Y. pestis genome contains additional CU pathways that are capable of assembling pilus fibers, but the roles of these pathways in the pathogenesis of plague are not understood. We constructed deletion mutations in the usher genes for six of the additional Y. pestis CU pathways. The wild-type (WT) and usher deletion strains were compared in the murine bubonic (subcutaneous) and pneumonic (intranasal) plague infection models. Y. pestis strains containing deletions in CU pathways y0348-0352, y1858-1862, and y1869-1873 were attenuated for virulence compared to the WT strain by the intranasal, but not subcutaneous, routes of infection, suggesting specific roles for these pathways during pneumonic plague. We examined binding of the Y. pestis WT and usher deletion strains to A549 human lung epithelial cells, HEp-2 human cervical epithelial cells, and primary human and murine macrophages. Y. pestis CU pathways y0348-0352 and y1858-1862 were found to contribute to adhesion to all host cells tested, whereas pathway y1869-1873 was specific for binding to macrophages. The correlation between the virulence attenuation and host cell binding phenotypes of the usher deletion mutants identifies three of the additional CU pathways of Y. pestis as mediating interactions with host cells that are important for the pathogenesis of plague. PMID:22851745

  11. Sensitivity analysis on a dose-calculation model for the terrestrial food-chain pathway

    International Nuclear Information System (INIS)

    Abdel-Aal, M.M.

    1994-01-01

    Parameter uncertainty and sensitivity were applied to the U.S. Regulatory Commission's (NRC) Regulatory Guide 1.109 (1977) models for calculating the ingestion dose via a terrestrial food-chain pathway in order to assess the transport of chronically released, low-level effluents from light-water reactors. In the analysis, we used the generation of latin hypercube samples (LHS) and employed a constrained sampling scheme. The generation of these samples is based on information supplied to the LHS program for variables or parameters. The actually sampled values are used to form vectors of variables that are commonly used as inputs to computer models for the purpose of sensitivity and uncertainty analysis. Regulatory models consider the concentrations of radionuclides that are deposited on plant tissues or lead to root uptake of nuclides initially deposited on soil. We also consider concentrations in milk and beef as a consequence of grazing on contaminated pasture or ingestion of contaminated feed by dairy and beef cattle. The radionuclides Sr-90 and Cs-137 were selected for evaluation. The most sensitive input parameters for the model were the ground-dispersion parameter, release rates of radionuclides, and soil-to-plant transfer coefficients of radionuclides. (Author)

  12. Handling uncertainty in dynamic models: the pentose phosphate pathway in Trypanosoma brucei.

    Directory of Open Access Journals (Sweden)

    Eduard J Kerkhoven

    Full Text Available Dynamic models of metabolism can be useful in identifying potential drug targets, especially in unicellular organisms. A model of glycolysis in the causative agent of human African trypanosomiasis, Trypanosoma brucei, has already shown the utility of this approach. Here we add the pentose phosphate pathway (PPP of T. brucei to the glycolytic model. The PPP is localized to both the cytosol and the glycosome and adding it to the glycolytic model without further adjustments leads to a draining of the essential bound-phosphate moiety within the glycosome. This phosphate "leak" must be resolved for the model to be a reasonable representation of parasite physiology. Two main types of theoretical solution to the problem could be identified: (i including additional enzymatic reactions in the glycosome, or (ii adding a mechanism to transfer bound phosphates between cytosol and glycosome. One example of the first type of solution would be the presence of a glycosomal ribokinase to regenerate ATP from ribose 5-phosphate and ADP. Experimental characterization of ribokinase in T. brucei showed that very low enzyme levels are sufficient for parasite survival, indicating that other mechanisms are required in controlling the phosphate leak. Examples of the second type would involve the presence of an ATP:ADP exchanger or recently described permeability pores in the glycosomal membrane, although the current absence of identified genes encoding such molecules impedes experimental testing by genetic manipulation. Confronted with this uncertainty, we present a modeling strategy that identifies robust predictions in the context of incomplete system characterization. We illustrate this strategy by exploring the mechanism underlying the essential function of one of the PPP enzymes, and validate it by confirming the model predictions experimentally.

  13. Cultural models of self and social class disparities at organizational gateways and pathways.

    Science.gov (United States)

    Townsend, Sarah Sm; Truong, Mindy

    2017-12-01

    Attaining a college degree has traditionally been assumed to be key to upward social and professional mobility. However, college graduates from working-class backgrounds achieve less career success in professional, white-collar workplaces compared to those from middle-class backgrounds. Using a cultural models approach, we examine how the independent cultural beliefs and practices promoted by professional organizations disadvantage people from working-class backgrounds, who espouse interdependent beliefs and practices. Our review illustrates how this disadvantage can manifest in two ways. First, despite relative equality in objective qualifications, it can occur at organizational gateways (e.g., interview and hiring decisions). Second, even after people from working-class backgrounds gain access to an organization, it can occur along organizational pathways (e.g., performance evaluations and assignment to high-profile tasks). Copyright © 2017. Published by Elsevier Ltd.

  14. A novel model to combine clinical and pathway-based transcriptomic information for the prognosis prediction of breast cancer.

    Directory of Open Access Journals (Sweden)

    Sijia Huang

    2014-09-01

    Full Text Available Breast cancer is the most common malignancy in women worldwide. With the increasing awareness of heterogeneity in breast cancers, better prediction of breast cancer prognosis is much needed for more personalized treatment and disease management. Towards this goal, we have developed a novel computational model for breast cancer prognosis by combining the Pathway Deregulation Score (PDS based pathifier algorithm, Cox regression and L1-LASSO penalization method. We trained the model on a set of 236 patients with gene expression data and clinical information, and validated the performance on three diversified testing data sets of 606 patients. To evaluate the performance of the model, we conducted survival analysis of the dichotomized groups, and compared the areas under the curve based on the binary classification. The resulting prognosis genomic model is composed of fifteen pathways (e.g., P53 pathway that had previously reported cancer relevance, and it successfully differentiated relapse in the training set (log rank p-value = 6.25e-12 and three testing data sets (log rank p-value < 0.0005. Moreover, the pathway-based genomic models consistently performed better than gene-based models on all four data sets. We also find strong evidence that combining genomic information with clinical information improved the p-values of prognosis prediction by at least three orders of magnitude in comparison to using either genomic or clinical information alone. In summary, we propose a novel prognosis model that harnesses the pathway-based dysregulation as well as valuable clinical information. The selected pathways in our prognosis model are promising targets for therapeutic intervention.

  15. Delineating pathological pathways in a chemically induced mouse model of Gaucher disease.

    Science.gov (United States)

    Vardi, Ayelet; Zigdon, Hila; Meshcheriakova, Anna; Klein, Andrés D; Yaacobi, Chen; Eilam, Raya; Kenwood, Brandon M; Rahim, Ahad A; Massaro, Giulia; Merrill, Alfred H; Vitner, Einat B; Futerman, Anthony H

    2016-08-01

    Great interest has been shown in understanding the pathology of Gaucher disease (GD) due to the recently discovered genetic relationship with Parkinson's disease. For such studies, suitable animal models of GD are required. Chemical induction of GD by inhibition of acid β-glucosidase (GCase) using the irreversible inhibitor conduritol B-epoxide (CBE) is particularly attractive, although few systematic studies examining the effect of CBE on the development of symptoms associated with neurological forms of GD have been performed. We now demonstrate a correlation between the amount of CBE injected into mice and levels of accumulation of the GD substrates, glucosylceramide and glucosylsphingosine, and show that disease pathology, indicated by altered levels of pathological markers, depends on both the levels of accumulated lipids and the time at which their accumulation begins. Gene array analysis shows a remarkable similarity in the gene expression profiles of CBE-treated mice and a genetic GD mouse model, the Gba(flox/flox) ;nestin-Cre mouse, with 120 of the 144 genes up-regulated in CBE-treated mice also up-regulated in Gba(flox/flox) ;nestin-Cre mice. We also demonstrate that various aspects of neuropathology and some behavioural abnormalities can be arrested upon cessation of CBE treatment during a specific time window. Together, our data demonstrate that injection of mice with CBE provides a rapid and relatively easy way to induce symptoms typical of neuronal forms of GD. This is particularly useful when examining the role of specific biochemical pathways in GD pathology, since CBE can be injected into mice defective in components of putative pathological pathways, alleviating the need for time-consuming crossing of mice. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  16. Histological evidence of reproductive activity in lizards from the APM Manso, Chapada dos Guimarães, Mato Grosso State, Brazil =Evidências histológicas da atividade reprodutiva em lagartos da região da APM Manso, Chapada dos Guimarães, Estado do Mato Grosso, Brasil

    Directory of Open Access Journals (Sweden)

    Christine Strüssmann

    2012-07-01

    Full Text Available The construction of dams causes major impacts on fauna by changing or eliminating irreversibly their habitats. The resulting changes lead to deep potential modifications on reproductive biology and population structure of lizards, snakes and amphisbaenas. The reservoir in the Multiple Use Area of Manso (APM-Manso is located near to Chapada dos Guimarães National Park, in Mato Grosso State. We analyzed comparatively the male gonads of Anolis meridionalis, Colobosaura modesta, Cercosaura ocellata, Cnemidophorus ocellifer, Hoplocercus spinosus, Bachia bresslaui, Mabuya frenata, Micrablepharus atticolus and Tropidurus oreadicus, from APM-Manso, aiming to verify possible changes in the reproductive success according to environmental changes. Before the impoundment A. meridionalis, Colobosaura modesta, Cercosaura ocellata, M. atticolus and T. oreadicus showed up reproductive. However, during the impoundment period they presented changes in seminiferous tubules, evidenced by the absence of spermatids and spermatozoids. B. bresslaui and M. frenata had no differences in the seminiferous tubules before and after the impoundment, being reproductive in both moments. The damming and the formation of the lake of Manso reservoir may have interfered on the reproduction of some lizards species, especially if the reproductive cycle is regulated by the rainfall of the habitat.A construção de barragens tem ocasionado grandes impactos sobre a fauna ao alterar ou eliminar seus habitats de forma irreversível. Alterações decorrentes exercem profundas modificações potenciais na biologia reprodutiva e na estrutura populacional de lagartos, serpentes e anfisbenas. O reservatório da Área de Aproveitamento Múltiplo de Manso (APM-Manso localiza-se próximo ao Parque Nacional da Chapada dos Guimarães, em Mato Grosso. Foram analisadas comparativamente as gônadas masculinas de Anolis meridionalis, Colobosaura modesta, Cercosaura ocellata, Cnemidophorus ocellifer

  17. Numerical modeling of the radionuclide water pathway with HYDRUS and comparison with the IAEA model of SR 44.

    Science.gov (United States)

    Merk, Rainer

    2012-02-01

    This study depicts a theoretical experiment in which the radionuclide transport through the porous material of a landfill consisting of concrete rubble (e.g., from the decommissioning of nuclear power plants) and the subsequent migration through the vadose zone and aquifer to a model well is calculated by means of the software HYDRUS-1D (Simunek et al., 2008). The radionuclides originally contained within the rubble become dissolved due to leaching caused by infiltrated rainwater. The resulting well-water contamination (in Bq/L) is calculated numerically as a function of time and location and compared with the outcome of a simplified analytic model for the groundwater pathway published by the IAEA (2005). Identical model parameters are considered. The main objective of the present work is to evaluate the predictive capacity of the more simple IAEA model using HYDRUS-1D as a reference. For most of the radionuclides considered (e.g., ¹²⁹I, and ²³⁹Pu), results from applying the IAEA model were found to be comparable to results from the more elaborate HYDRUS modeling, provided the underlying parameter values are comparable. However, the IAEA model appears to underestimate the effects resulting from, for example, high nuclide mobility, short half-life, or short-term variations in the water infiltration. The present results indicate that the IAEA model is suited for screening calculations and general recommendation purposes. However, the analysis of a specific site should be accompanied by detailed HYDRUS computer simulations. In all models considered, the calculation outcome largely depends on the choice of the sorption parameter K(d). Copyright © 2011 Elsevier Ltd. All rights reserved.

  18. Well-to-wheels analysis of fast pyrolysis pathways with the GREET model.

    Energy Technology Data Exchange (ETDEWEB)

    Han, J.; Elgowainy, A.; Palou-Rivera, I.; Dunn, J.B.; Wang, M.Q. (Energy Systems)

    2011-12-01

    The pyrolysis of biomass can help produce liquid transportation fuels with properties similar to those of petroleum gasoline and diesel fuel. Argonne National Laboratory conducted a life-cycle (i.e., well-to-wheels [WTW]) analysis of various pyrolysis pathways by expanding and employing the Greenhouse Gases, Regulated Emissions, and Energy Use in Transportation (GREET) model. The WTW energy use and greenhouse gas (GHG) emissions from the pyrolysis pathways were compared with those from the baseline petroleum gasoline and diesel pathways. Various pyrolysis pathway scenarios with a wide variety of possible hydrogen sources, liquid fuel yields, and co-product application and treatment methods were considered. At one extreme, when hydrogen is produced from natural gas and when bio-char is used for process energy needs, the pyrolysis-based liquid fuel yield is high (32% of the dry mass of biomass input). The reductions in WTW fossil energy use and GHG emissions relative to those that occur when baseline petroleum fuels are used, however, is modest, at 50% and 51%, respectively, on a per unit of fuel energy basis. At the other extreme, when hydrogen is produced internally via reforming of pyrolysis oil and when bio-char is sequestered in soil applications, the pyrolysis-based liquid fuel yield is low (15% of the dry mass of biomass input), but the reductions in WTW fossil energy use and GHG emissions are large, at 79% and 96%, respectively, relative to those that occur when baseline petroleum fuels are used. The petroleum energy use in all scenarios was restricted to biomass collection and transportation activities, which resulted in a reduction in WTW petroleum energy use of 92-95% relative to that found when baseline petroleum fuels are used. Internal hydrogen production (i.e., via reforming of pyrolysis oil) significantly reduces fossil fuel use and GHG emissions because the hydrogen from fuel gas or pyrolysis oil (renewable sources) displaces that from fossil fuel

  19. Construction and Optimization of a Heterologous Pathway for Protocatechuate Catabolism in Escherichia coli Enables Bioconversion of Model Aromatic Compounds

    Energy Technology Data Exchange (ETDEWEB)

    Clarkson, Sonya M. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Biosciences Division; Giannone, Richard J. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Chemical Sciences Division; Kridelbaugh, Donna M. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Biosciences Division; Elkins, James G. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Biosciences Division; Guss, Adam M. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Biosciences Division; Michener, Joshua K. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Biosciences Division, BioEnergy Science Center; Vieille, Claire [Michigan State Univ., East Lansing, MI (United States)

    2017-07-21

    The production of biofuels from lignocellulose yields a substantial lignin by-product stream that currently has few applications. Biological conversion of lignin-derived compounds into chemicals and fuels has the potential to improve the economics of lignocellulose-derived biofuels, but few microbes are able both to catabolize lignin-derived aromatic compounds and to generate valuable products. WhileEscherichia colihas been engineered to produce a variety of fuels and chemicals, it is incapable of catabolizing most aromatic compounds. Therefore, we engineeredE. colito catabolize protocatechuate, a common intermediate in lignin degradation, as the sole source of carbon and energy via heterologous expression of a nine-gene pathway fromPseudomonas putidaKT2440. Then, we used experimental evolution to select for mutations that increased growth with protocatechuate more than 2-fold. Increasing the strength of a single ribosome binding site in the heterologous pathway was sufficient to recapitulate the increased growth. After optimization of the core pathway, we extended the pathway to enable catabolism of a second model compound, 4-hydroxybenzoate. These engineered strains will be useful platforms to discover, characterize, and optimize pathways for conversions of lignin-derived aromatics.

    IMPORTANCELignin is a challenging substrate for microbial catabolism due to its polymeric and heterogeneous chemical structure. Therefore, engineering microbes for improved catabolism of lignin-derived aromatic compounds will require the assembly of an entire network of catabolic reactions, including pathways from genetically intractable strains. By constructing defined pathways for aromatic compound degradation in a model host would allow rapid

  20. A model for genetic and epigenetic regulatory networks identifies rare pathways for transcription factor induced pluripotency

    Science.gov (United States)

    Artyomov, Maxim; Meissner, Alex; Chakraborty, Arup

    2010-03-01

    Most cells in an organism have the same DNA. Yet, different cell types express different proteins and carry out different functions. This is because of epigenetic differences; i.e., DNA in different cell types is packaged distinctly, making it hard to express certain genes while facilitating the expression of others. During development, upon receipt of appropriate cues, pluripotent embryonic stem cells differentiate into diverse cell types that make up the organism (e.g., a human). There has long been an effort to make this process go backward -- i.e., reprogram a differentiated cell (e.g., a skin cell) to pluripotent status. Recently, this has been achieved by transfecting certain transcription factors into differentiated cells. This method does not use embryonic material and promises the development of patient-specific regenerative medicine, but it is inefficient. The mechanisms that make reprogramming rare, or even possible, are poorly understood. We have developed the first computational model of transcription factor-induced reprogramming. Results obtained from the model are consistent with diverse observations, and identify the rare pathways that allow reprogramming to occur. If validated, our model could be further developed to design optimal strategies for reprogramming and shed light on basic questions in biology.

  1. A workflow for mathematical modeling of subcellular metabolic pathways in leaf metabolism of Arabidopsis thaliana

    Directory of Open Access Journals (Sweden)

    Thomas eNägele

    2013-12-01

    Full Text Available During the last decade genome sequencing has experienced a rapid technological development resulting in numerous sequencing projects and applications in life science. In plant molecular biology, the availability of sequence data on whole genomes has enabled the reconstruction of metabolic networks. Enzymatic reactions are predicted by the sequence information. Pathways arise due to the participation of chemical compounds as substrates and products in these reactions. Although several of these comprehensive networks have been reconstructed for the genetic model plant Arabidopsis thaliana, the integration of experimental data is still challenging. Particularly the analysis of subcellular organization of plant cells limits the understanding of regulatory instances in these metabolic networks in vivo. In this study, we develop an approach for the functional integration of experimental high-throughput data into such large-scale networks. We present a subcellular metabolic network model comprising 524 metabolic intermediates and 548 metabolic interactions derived from a total of 2769 reactions. We demonstrate how to link the metabolite covariance matrix of different Arabidopsis thaliana accessions with the subcellular metabolic network model for the inverse calculation of the biochemical Jacobian, finally resulting in the calculation of a matrix which satisfies a Lyaponov equation involving a covariance matrix. In this way, differential strategies of metabolite compartmentation and involved reactions were identified in the accessions when exposed to low temperature.

  2. Electrophilic properties of patulin. Adduct structures and reaction pathways with 4-bromothiophenol and other model nucleophiles.

    Science.gov (United States)

    Fliege, R; Metzler, M

    2000-05-01

    The mycotoxin patulin (PAT) is believed to exert its cytotoxic and chromosome-damaging effects by forming covalent adducts with essential cellular thiols. Since the chemical structures of such adducts are unknown to date, we have studied the reaction of PAT and its O-acetylated derivative with the monofunctional thiol model compound 4-bromothiophenol (BTP), which was chosen due to analytical advantages. By means of analytical and preparative high-performance liquid chromatography, 16 adducts of PAT and 3 adducts of acetyl-PAT were isolated and their chemical structures elucidated by (1)H and (13)C NMR, IR, and UV spectroscopy. Time course studies and analysis of daughter product formation from isolated intermediate adducts led to a detailed scheme for the reaction of PAT with BTP. The structures of adducts of PAT formed with other model nucleophiles, e. g., the aliphatic thiol 2-mercaptoethanol and the aromatic amine 4-bromoaniline, were also elucidated and found to corroborate the reaction scheme. In addition, one further reaction pathway was observed with 2-mercaptoethanol, which appears to be independent from those found for BTP. Our study with model nucleophiles provides insights into the electrophilic reactivity of PAT and proved to be useful for the structure elucidation of PAT adducts with biological nucleophiles of toxicological relevance, as will be reported by Fliege and Metzler [(2000) Chem. Res. Toxicol. 13, 373-381].

  3. The effect of genistein on TGF-β signal, dysregulation of apoptosis, cyclooxygenase-2 pathway, and NF-kB pathway in mice peritoneum of endometriosis model

    Directory of Open Access Journals (Sweden)

    Sutrisno Sutrisno

    2017-12-01

    Full Text Available This research aimed to investigate the effect of genistein on TGF-β, dysregulation of apoptosis, NF-κB pathway, COX-2 pathway in mice of endometriosis model. Twenty-eight female mice (Mus musculus were divided into seven groups (n = 4, involving control (normal non-treated group; endometriosis group; the endometriosis group treated with various genistein dosages (0.78; 1.04; 1.3 mg/day for 15 days, and endometriosis group treated with standard drug, namely leuprolide acetate (0.00975 mg each day for 15 days or dienogest (0.0052 mg/day for 15 days. Mice of endometriosis model were made by implanting myometrial and endometrial tissues under the condition of immunodeficiency. The TGF-β, Bcl-2, Bax, NF-κB, COX-2, and PGE-2 were analyzed immunohistochemically. The increase of Bcl-2 expression in endometriosis was decreased significantly by genistein dosage of 0.78 and 1.3 mg/day (p < 0.05. The decrease of Bax expression in endometriosis was increased significantly by genistein dosage of 1.04 and 1.3 mg/day (p < 0.05. The implantation increased the expression of NF-κB, COX-2, and PGE significantly compared with the control group (p < 0.05. This increase was reduced significantly by the administration of genistein at dosage of 0.78 and 1.3 mg/day (p < 0.05. It can be concluded that genistein potentially inhibits endometriosis development through the normalization of apoptosis dysregulation, the inhibition of NF-κB and COX-2 pathways in the peritoneal tissues. Therefore, genistein can be used as a holistic treatment strategy for endometriosis.

  4. Optimization and planning of operating theatre activities: an original definition of pathways and process modeling.

    Science.gov (United States)

    Barbagallo, Simone; Corradi, Luca; de Ville de Goyet, Jean; Iannucci, Marina; Porro, Ivan; Rosso, Nicola; Tanfani, Elena; Testi, Angela

    2015-05-17

    The Operating Room (OR) is a key resource of all major hospitals, but it also accounts for up 40% of resource costs. Improving cost effectiveness, while maintaining a quality of care, is a universal objective. These goals imply an optimization of planning and a scheduling of the activities involved. This is highly challenging due to the inherent variable and unpredictable nature of surgery. A Business Process Modeling Notation (BPMN 2.0) was used for the representation of the "OR Process" (being defined as the sequence of all of the elementary steps between "patient ready for surgery" to "patient operated upon") as a general pathway ("path"). The path was then both further standardized as much as possible and, at the same time, keeping all of the key-elements that would allow one to address or define the other steps of planning, and the inherent and wide variability in terms of patient specificity. The path was used to schedule OR activity, room-by-room, and day-by-day, feeding the process from a "waiting list database" and using a mathematical optimization model with the objective of ending up in an optimized planning. The OR process was defined with special attention paid to flows, timing and resource involvement. Standardization involved a dynamics operation and defined an expected operating time for each operation. The optimization model has been implemented and tested on real clinical data. The comparison of the results reported with the real data, shows that by using the optimization model, allows for the scheduling of about 30% more patients than in actual practice, as well as to better exploit the OR efficiency, increasing the average operating room utilization rate up to 20%. The optimization of OR activity planning is essential in order to manage the hospital's waiting list. Optimal planning is facilitated by defining the operation as a standard pathway where all variables are taken into account. By allowing a precise scheduling, it feeds the process of

  5. Effect of Bundled Payments and Health Care Reform as Alternative Payment Models in Total Joint Arthroplasty: A Clinical Review.

    Science.gov (United States)

    Siddiqi, Ahmed; White, Peter B; Mistry, Jaydev B; Gwam, Chukwuweike U; Nace, James; Mont, Michael A; Delanois, Ronald E

    2017-08-01

    In an effort to control rising healthcare costs, healthcare reforms have developed initiatives to evaluate the efficacy of alternative payment models (APMs) for Medicare reimbursements. The Center for Medicare and Medicaid Services Innovation Center (CMMSIC) introduced the voluntary Bundled Payments for Care Improvement (BPCI) model experiment as a means to curtail Medicare cost by allotting a fixed payment for an episode of care. The purpose of this review is to (1) summarize the preliminary clinical results of the BPCI and (2) discuss how it has led to other healthcare reforms and alternative payment models. A literature search was performed using PubMed and the CMMSIC to explore different APMs and clinical results after implementation. All studies that were not in English or unrelated to the topic were excluded. Preliminary results of bundled payment models have shown reduced costs in total joint arthroplasty largely by reducing hospital length of stay, decreasing readmission rates, as well as reducing the number of patients sent to in-patient rehabilitation facilities. In order to refine episode of care bundles, CMMSIC has also developed other initiatives such as the Comprehensive Care for Joint Replacement (CJR) pathway and Surgical Hip and Femur Fracture (SHFFT). Despite the unknown future of the Affordable Care Act, BPCI, and CJR, preliminary results of alternative models have shown promise to reduce costs and improve quality of care. Moving into the future, surgeon control of the BPCI and CJR bundle should be investigated to further improve patient care and maximize financial compensation. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. A molecular systems approach to modelling human skin pigmentation: identifying underlying pathways and critical components.

    Science.gov (United States)

    Raghunath, Arathi; Sambarey, Awanti; Sharma, Neha; Mahadevan, Usha; Chandra, Nagasuma

    2015-04-29

    Ultraviolet radiations (UV) serve as an environmental stress for human skin, and result in melanogenesis, with the pigment melanin having protective effects against UV induced damage. This involves a dynamic and complex regulation of various biological processes that results in the expression of melanin in the outer most layers of the epidermis, where it can exert its protective effect. A comprehensive understanding of the underlying cross talk among different signalling molecules and cell types is only possible through a systems perspective. Increasing incidences of both melanoma and non-melanoma skin cancers necessitate the need to better comprehend UV mediated effects on skin pigmentation at a systems level, so as to ultimately evolve knowledge-based strategies for efficient protection and prevention of skin diseases. A network model for UV-mediated skin pigmentation in the epidermis was constructed and subjected to shortest path analysis. Virtual knock-outs were carried out to identify essential signalling components. We describe a network model for UV-mediated skin pigmentation in the epidermis. The model consists of 265 components (nodes) and 429 directed interactions among them, capturing the manner in which one component influences the other and channels information. Through shortest path analysis, we identify novel signalling pathways relevant to pigmentation. Virtual knock-outs or perturbations of specific nodes in the network have led to the identification of alternate modes of signalling as well as enabled determining essential nodes in the process. The model presented provides a comprehensive picture of UV mediated signalling manifesting in human skin pigmentation. A systems perspective helps provide a holistic purview of interconnections and complexity in the processes leading to pigmentation. The model described here is extensive yet amenable to expansion as new data is gathered. Through this study, we provide a list of important proteins essential

  7. Nitrogen uptake and regeneration pathways in the equatorial Pacific: a basin scale modeling study

    Directory of Open Access Journals (Sweden)

    R. Le Borgne

    2009-11-01

    Full Text Available It is well known that most primary production is fueled by regenerated nitrogen in the open ocean. Therefore, studying the nitrogen cycle by focusing on uptake and regeneration pathways would advance our understanding of nitrogen dynamics in the marine ecosystem. Here, we carry out a basin-scale modeling study, by assessing model simulations of nitrate and ammonium, and rates of nitrate uptake, ammonium uptake and regeneration in the equatorial Pacific. Model-data comparisons show that the model is able to reproduce many observed features of nitrate, ammonium, such as the deep ammonium maximum (DAM. The model also reproduces the observed de-coupling of ammonium uptake and regeneration, i.e., regeneration rate greater than uptake rate in the lower euphotic zone. The de-coupling largely explains the observed DAM in the equatorial Pacific Ocean. Our study indicates that zooplankton excretion and remineralization of organic nitrogen play a different role in nitrogen regeneration. Rates of zooplankton excretion vary from <0.01 mmol m−3 d−1 to 0.1 mmol m−3 d−1 in the upper euphotic zone while rates of remineralization fall within a narrow range (0.015–0.025 mmol m−3 d−1 . Zooplankton excretion contributes up to 70% of total ammonium regeneration in the euphotic zone, and is largely responsible for the spatial variability of nitrogen regeneration. However, remineralization provides a steady supply of ammonium in the upper ocean, and is a major source of inorganic nitrogen for the oligotrophic regions. Overall, ammonium generation and removal are approximately balanced over the top 150 m in the equatorial Pacific.

  8. Variability along the Atlantic water pathway in the forced Norwegian Earth System Model

    Science.gov (United States)

    Langehaug, H. R.; Sandø, A. B.; Årthun, M.; Ilıcak, M.

    2018-03-01

    The growing attention on mechanisms that can provide predictability on interannual-to-decadal time scales, makes it necessary to identify how well climate models represent such mechanisms. In this study we use a high (0.25° horizontal grid) and a medium (1°) resolution version of a forced global ocean-sea ice model, utilising the Norwegian Earth System Model, to assess the impact of increased ocean resolution. Our target is the simulation of temperature and salinity anomalies along the pathway of warm Atlantic water in the subpolar North Atlantic and the Nordic Seas. Although the high resolution version has larger biases in general at the ocean surface, the poleward propagation of thermohaline anomalies is better resolved in this version, i.e., the time for an anomaly to travel northward is more similar to observation based estimates. The extent of these anomalies can be rather large in both model versions, as also seen in observations, e.g., stretching from Scotland to northern Norway. The easternmost branch into the Nordic and Barents Seas, carrying warm Atlantic water, is also improved by higher resolution, both in terms of mean heat transport and variability in thermohaline properties. A more detailed assessment of the link between the North Atlantic Ocean circulation and the thermohaline anomalies at the entrance of the Nordic Seas reveals that the high resolution is more consistent with mechanisms that are previously published. This suggests better dynamics and variability in the subpolar region and the Nordic Seas in the high resolution compared to the medium resolution. This is most likely due a better representation of the mean circulation in the studied region when using higher resolution. As the poleward propagation of ocean heat anomalies is considered to be a key source of climate predictability, we recommend that similar methodology presented herein should be performed on coupled climate models that are used for climate prediction.

  9. Prevention of Bronchial Hyperplasia by EGFR Pathway Inhibitors in an Organotypic Culture Model

    Science.gov (United States)

    Lee, Jangsoon; Ryu, Seung-Hee; Kang, Shin Myung; Chung, Wen-Cheng; Gold, Kathryn Ann; Kim, Edward S.; Hittelman, Walter N.; Hong, Waun Ki; Koo, Ja Seok

    2011-01-01

    Lung cancer is the leading cause of cancer-related mortality worldwide. Early detection or prevention strategies are urgently needed to increase survival. Hyperplasia is the first morphologic change that occurs in the bronchial epithelium during lung cancer development, followed by squamous metaplasia, dysplasia, carcinoma in situ, and invasive tumor. The current study was designed to determine the molecular mechanisms that control bronchial epithelium hyperplasia. Using primary normal human tracheobronchial epithelial (NHTBE) cells cultured using the 3-dimensional organotypic method, we found that the epidermal growth factor receptor (EGFR) ligands EGF, transforming growth factor-alpha, and amphiregulin induced hyperplasia, as determined by cell proliferation and multilayered epithelium formation. We also found that EGF induced increased cyclin D1 expression, which plays a critical role in bronchial hyperplasia; this overexpression was mediated by activating the mitogen-activated protein kinase pathway but not the phosphoinositide 3-kinase/Akt signaling pathway. Erlotinib, an EGFR tyrosine kinase inhibitor, and U0126, a MEK inhibitor, completely inhibited EGF-induced hyperplasia. Furthermore, a promoter analysis revealed that the activator protein-1 transcription factor regulates EGF-induced cyclin D1 overexpression. Activator protein-1 depletion using siRNA targeting its c-Jun component completely abrogated EGF-induced cyclin D1 expression. In conclusion, we demonstrated that bronchial hyperplasia can be modeled in vitro using primary NHTBE cells maintained in a 3-dimensional (3-D) organotypic culture. EGFR and MEK inhibitors completely blocked EGF-induced bronchial hyperplasia, suggesting that they have a chemopreventive role. PMID:21505178

  10. Multi-pathway exposure modeling of chemicals in cosmetics with application to shampoo.

    Science.gov (United States)

    Ernstoff, Alexi S; Fantke, Peter; Csiszar, Susan A; Henderson, Andrew D; Chung, Susie; Jolliet, Olivier

    2016-01-01

    We present a novel multi-pathway, mass balance based, fate and exposure model compatible with life cycle and high-throughput screening assessments of chemicals in cosmetic products. The exposures through product use as well as post-use emissions and environmental media were quantified based on the chemical mass originally applied via a product, multiplied by the product intake fractions (PiF, the fraction of a chemical in a product that is taken in by exposed persons) to yield intake rates. The average PiFs for the evaluated chemicals in shampoo ranged from 3×10(-4) up to 0.3 for rapidly absorbed ingredients. Average intake rates ranged between nano- and micrograms per kilogram bodyweight per day; the order of chemical prioritization was strongly affected by the ingredient concentration in shampoo. Dermal intake and inhalation (for 20% of the evaluated chemicals) during use dominated exposure, while the skin permeation coefficient dominated the estimated uncertainties. The fraction of chemical taken in by a shampoo user often exceeded, by orders of magnitude, the aggregated fraction taken in by the population through post-use environmental emissions. Chemicals with relatively high octanol-water partitioning and/or volatility, and low molecular weight tended to have higher use stage exposure. Chemicals with low intakes during use (<1%) and subsequent high post-use emissions, however, may yield comparable intake for a member of the general population. The presented PiF based framework offers a novel and critical advancement for life cycle assessments and high-throughput exposure screening of chemicals in cosmetic products demonstrating the importance of consistent consideration of near- and far-field multi-pathway exposures. Copyright © 2016 Elsevier Ltd. All rights reserved.

  11. Pathways to a low-carbon economy for the UK with the macro-econometric E3MG model

    International Nuclear Information System (INIS)

    Dagoumas, A.S.; Barker, T.S.

    2010-01-01

    This paper examines different carbon pathways for achieving deep CO 2 reduction targets for the UK using a macro-econometric hybrid model E3MG, which stands for Energy-Economy-Environment Model at the Global level. The E3MG, with the UK as one of its regions, combines a top-down approach for modeling the global economy and for estimating the aggregate and disaggregate energy demand and a bottom-up approach (Energy Technology subModel, ETM) for simulating the power sector, which then provides feedback to the energy demand equations and the whole economy. The ETM submodel uses a probabilistic approach and historical data for estimating the penetration levels of the different technologies, considering their economic, technical and environmental characteristics. Three pathway scenarios (CFH, CLC and CAM) simulate the CO 2 reduction by 40%, 60% and 80% by 2050 compared to 1990 levels respectively and are compared with a reference scenario (REF), with no reduction target. The targets are modeled as the UK contribution to an international mitigation effort, such as achieving the G8 reduction targets, which is a more realistic political framework for the UK to move towards deep reductions rather than moving alone. This paper aims to provide modeling evidence that deep reduction targets can be met through different carbon pathways while also assessing the macroeconomic effects of the pathways on GDP and investment.

  12. Global modeling of secondary organic aerosol formation from aromatic hydrocarbons: high- vs. low-yield pathways

    Directory of Open Access Journals (Sweden)

    D. K. Henze

    2008-05-01

    Full Text Available Formation of SOA from the aromatic species toluene, xylene, and, for the first time, benzene, is added to a global chemical transport model. A simple mechanism is presented that accounts for competition between low and high-yield pathways of SOA formation, wherein secondary gas-phase products react further with either nitric oxide (NO or hydroperoxy radical (HO2 to yield semi- or non-volatile products, respectively. Aromatic species yield more SOA when they react with OH in regions where the [NO]/[HO2] ratios are lower. The SOA yield thus depends upon the distribution of aromatic emissions, with biomass burning emissions being in areas with lower [NO]/[HO2] ratios, and the reactivity of the aromatic with respect to OH, as a lower initial reactivity allows transport away from industrial source regions, where [NO]/[HO2] ratios are higher, to more remote regions, where this ratio is lower and, hence, the ultimate yield of SOA is higher. As a result, benzene is estimated to be the most important aromatic species with regards to global formation of SOA, with a total production nearly equal that of toluene and xylene combined. Global production of SOA from aromatic sources via the mechanisms identified here is estimated at 3.5 Tg/yr, resulting in a global burden of 0.08 Tg, twice as large as previous estimates. The contribution of these largely anthropogenic sources to global SOA is still small relative to biogenic sources, which are estimated to comprise 90% of the global SOA burden, about half of which comes from isoprene. Uncertainty in these estimates owing to factors ranging from the atmospheric relevance of chamber conditions to model deficiencies result in an estimated range of SOA production from aromatics of 2–12 Tg/yr. Though this uncertainty range affords a significant anthropogenic contribution to global SOA, it is evident from comparisons to recent observations that additional pathways for

  13. Identification of Alternative Vapor Intrusion Pathways Using Controlled Pressure Testing, Soil Gas Monitoring, and Screening Model Calculations.

    Science.gov (United States)

    Guo, Yuanming; Holton, Chase; Luo, Hong; Dahlen, Paul; Gorder, Kyle; Dettenmaier, Erik; Johnson, Paul C

    2015-11-17

    Vapor intrusion (VI) pathway assessment and data interpretation have been guided by an historical conceptual model in which vapors originating from contaminated soil or groundwater diffuse upward through soil and are swept into a building by soil gas flow induced by building underpressurization. Recent studies reveal that alternative VI pathways involving neighborhood sewers, land drains, and other major underground piping can also be significant VI contributors, even to buildings beyond the delineated footprint of soil and groundwater contamination. This work illustrates how controlled-pressure-method testing (CPM), soil gas sampling, and screening-level emissions calculations can be used to identify significant alternative VI pathways that might go undetected by conventional sampling under natural conditions at some sites. The combined utility of these tools is shown through data collected at a long-term study house, where a significant alternative VI pathway was discovered and altered so that it could be manipulated to be on or off. Data collected during periods of natural and CPM conditions show that the alternative pathway was significant, but its presence was not identifiable under natural conditions; it was identified under CPM conditions when measured emission rates were 2 orders of magnitude greater than screening-model estimates and subfoundation vertical soil gas profiles changed and were no longer consistent with the conventional VI conceptual model.

  14. Assessment of Food Chain Pathway Parameters in Biosphere Models: Annual Progress Report for Fiscal Year 2004

    Energy Technology Data Exchange (ETDEWEB)

    Napier, Bruce A.; Krupka, Kenneth M.; Fellows, Robert J.; Cataldo, Dominic A.; Valenta, Michelle M.; Gilmore, Tyler J.

    2004-12-02

    This Annual Progress Report describes the work performed and summarizes some of the key observations to date on the U.S. Nuclear Regulatory Commission’s project Assessment of Food Chain Pathway Parameters in Biosphere Models, which was established to assess and evaluate a number of key parameters used in the food-chain models used in performance assessments of radioactive waste disposal facilities. Section 2 of this report describes activities undertaken to collect samples of soils from three regions of the United States, the Southeast, Northwest, and Southwest, and perform analyses to characterize their physical and chemical properties. Section 3 summarizes information gathered regarding agricultural practices and common and unusual crops grown in each of these three areas. Section 4 describes progress in studying radionuclide uptake in several representative crops from the three soil types in controlled laboratory conditions. Section 5 describes a range of international coordination activities undertaken by Project staff in order to support the underlying data needs of the Project. Section 6 provides a very brief summary of the status of the GENII Version 2 computer program, which is a “client” of the types of data being generated by the Project, and for which the Project will be providing training to the US NRC staff in the coming Fiscal Year. Several appendices provide additional supporting information.

  15. [Mechanistic modelling allows to assess pathways of DNA lesion interactions underlying chromosome aberration formation].

    Science.gov (United States)

    Eĭdel'man, Iu A; Slanina, S V; Sal'nikov, I V; Andreev, S G

    2012-12-01

    The knowledge of radiation-induced chromosomal aberration (CA) mechanisms is required in many fields of radiation genetics, radiation biology, biodosimetry, etc. However, these mechanisms are yet to be quantitatively characterised. One of the reasons is that the relationships between primary lesions of DNA/chromatin/chromosomes and dose-response curves for CA are unknown because the pathways of lesion interactions in an interphase nucleus are currently inaccessible for direct experimental observation. This article aims for the comparative analysis of two principally different scenarios of formation of simple and complex interchromosomal exchange aberrations: by lesion interactions at chromosome territories' surface vs. in the whole space of the nucleus. The analysis was based on quantitative mechanistic modelling of different levels of structures and processes involved in CA formation: chromosome structure in an interphase nucleus, induction, repair and interactions of DNA lesions. It was shown that the restricted diffusion of chromosomal loci, predicted by computational modelling of chromosome organization, results in lesion interactions in the whole space of the nucleus being impossible. At the same time, predicted features of subchromosomal dynamics agrees well with in vivo observations and does not contradict the mechanism of CA formation at the surface of chromosome territories. On the other hand, the "surface mechanism" of CA formation, despite having certain qualities, proved to be insufficient to explain high frequency of complex exchange aberrations observed by mFISH technique. The alternative mechanism, CA formation on nuclear centres is expected to be sufficient to explain frequent complex exchanges.

  16. Possible pathways between depression, emotional and external eating. A structural equation model.

    Science.gov (United States)

    Ouwens, Machteld A; van Strien, Tatjana; van Leeuwe, Jan F J

    2009-10-01

    Emotional and external eating appear to co-occur and both have been shown to correlate to neuroticism, especially depression. However, there is evidence suggesting that emotional and external eating are independent constructs. In this study we revisited the relation between depression, emotional, and external eating. Using structural equation modelling, we examined whether depression, emotional and external eating are directly related and also indirectly related through the intervening concepts alexithymia and impulsivity. Participants were 549 females concerned about their weight. They filled out instruments on emotional and external eating, depression, alexithymia, and impulse regulation. The relational structure between the model variables was explored for one half of the participants and this solution was checked using the other half. Our data showed a moderate relationship between emotional and external eating. Depression was positively and directly associated with emotional eating, but not with external eating. In addition, depression was indirectly related to emotional eating through both alexithymia and impulsivity. A significant relation was found between impulsivity and external eating. Results suggest potential mediating pathways between depression and emotional eating, while no relation appeared to exist between depression and external eating. Emotional and external eating would appear to be different constructs.

  17. Pathways to Mexico’s climate change mitigation targets: A multi-model analysis

    International Nuclear Information System (INIS)

    Veysey, Jason; Octaviano, Claudia; Calvin, Katherine; Martinez, Sara Herreras; Kitous, Alban; McFarland, James; Zwaan, Bob van der

    2016-01-01

    Mexico’s climate policy sets ambitious national greenhouse gas (GHG) emission reduction targets—30% versus a business-as-usual baseline by 2020, 50% versus 2000 by 2050. However, these goals are at odds with recent energy and emission trends in the country. Both energy use and GHG emissions in Mexico have grown substantially over the last two decades. We investigate how Mexico might reverse current trends and reach its mitigation targets by exploring results from energy system and economic models involved in the CLIMACAP-LAMP project. To meet Mexico’s emission reduction targets, all modeling groups agree that decarbonization of electricity is needed, along with changes in the transport sector, either to more efficient vehicles or a combination of more efficient vehicles and lower carbon fuels. These measures reduce GHG emissions as well as emissions of other air pollutants. The models find different energy supply pathways, with some solutions based on renewable energy and others relying on biomass or fossil fuels with carbon capture and storage. The economy-wide costs of deep mitigation could range from 2% to 4% of GDP in 2030, and from 7% to 15% of GDP in 2050. Our results suggest that Mexico has some flexibility in designing deep mitigation strategies, and that technological options could allow Mexico to achieve its emission reduction targets, albeit at a cost to the country. - Highlights: • We explore paths to deep mitigation for Mexico (50% cut in GHG emissions by 2050). • We present results from six models and compare them with Mexican climate policy. • We find a range of potential paths and costs, implying options for policy makers. • An important commonality between the paths is a decarbonized electricity supply. • Estimated mitigation costs vary but are higher than official published estimates.

  18. Annual Perspectives in Mathematics Education 2016: Mathematical Modeling and Modeling Mathematics

    Science.gov (United States)

    Hirsch, Christian R., Ed.; McDuffie, Amy Roth, Ed.

    2016-01-01

    Mathematical modeling plays an increasingly important role both in real-life applications--in engineering, business, the social sciences, climate study, advanced design, and more--and within mathematics education itself. This 2016 volume of "Annual Perspectives in Mathematics Education" ("APME") focuses on this key topic from a…

  19. Caenorhabditis elegans as Model System in Pharmacology and Toxicology: Effects of Flavonoids on Redox-Sensitive Signalling Pathways and Ageing

    Science.gov (United States)

    Koch, Karoline; Havermann, Susannah; Büchter, Christian

    2014-01-01

    Flavonoids are secondary plant compounds that mediate diverse biological activities, for example, by scavenging free radicals and modulating intracellular signalling pathways. It has been shown in various studies that distinct flavonoid compounds enhance stress resistance and even prolong the life span of organisms. In the last years the model organism C. elegans has gained increasing importance in pharmacological and toxicological sciences due to the availability of various genetically modified nematode strains, the simplicity of modulating genes by RNAi, and the relatively short life span. Several studies have been performed demonstrating that secondary plant compounds influence ageing, stress resistance, and distinct signalling pathways in the nematode. Here we present an overview of the modulating effects of different flavonoids on oxidative stress, redox-sensitive signalling pathways, and life span in C. elegans introducing the usability of this model system for pharmacological and toxicological research. PMID:24895670

  20. Caenorhabditis elegans as Model System in Pharmacology and Toxicology: Effects of Flavonoids on Redox-Sensitive Signalling Pathways and Ageing

    Directory of Open Access Journals (Sweden)

    Karoline Koch

    2014-01-01

    Full Text Available Flavonoids are secondary plant compounds that mediate diverse biological activities, for example, by scavenging free radicals and modulating intracellular signalling pathways. It has been shown in various studies that distinct flavonoid compounds enhance stress resistance and even prolong the life span of organisms. In the last years the model organism C. elegans has gained increasing importance in pharmacological and toxicological sciences due to the availability of various genetically modified nematode strains, the simplicity of modulating genes by RNAi, and the relatively short life span. Several studies have been performed demonstrating that secondary plant compounds influence ageing, stress resistance, and distinct signalling pathways in the nematode. Here we present an overview of the modulating effects of different flavonoids on oxidative stress, redox-sensitive signalling pathways, and life span in C. elegans introducing the usability of this model system for pharmacological and toxicological research.

  1. A systematic model identification method for chemical transformation pathways – the case of heroin biomarkers in wastewater

    DEFF Research Database (Denmark)

    Ramin, Pedram; Valverde Pérez, Borja; Polesel, Fabio

    2017-01-01

    This study presents a novel statistical approach for identifying sequenced chemical transformation pathways in combination with reaction kinetics models. The proposed method relies on sound uncertainty propagation by considering parameter ranges and associated probability distribution obtained...... at any given transformation pathway levels as priors for parameter estimation at any subsequent transformation levels. The method was applied to calibrate a model predicting the transformation in untreated wastewater of six biomarkers, excreted following human metabolism of heroin and codeine. The method....... Results obtained suggest that the method developed has the potential to outperform conventional approaches in terms of prediction accuracy, transformation pathway identification and parameter identifiability. This method can be used in conjunction with optimal experimental designs to effectively identify...

  2. Fabrication and Testing of Prototype APM-Clad UO{sub 2} Fuel Elements; Fabrication et essai de prototypes de cartouches de combustible en bioxyde d'uranium gaine d'aluminium (APM); Izgotovlenie i ispytanie prototipa toplivnykh ehlementov na osnove UO{sub 2} s obolochkoj iz alyuminiya metodom poroshkovoj metallurgii; Elaboracion y ensayo de elementos combustibles prototipo de UO{sub 2} con revestimiento de aluminio sinterizado

    Energy Technology Data Exchange (ETDEWEB)

    Ballif, III, J. L.; Friske, W. H.; Gordon, R. B. [Atomics International, Canoga Park, California (United States)

    1963-11-15

    In support of the 50-MW(e) Prototype Organic Power Reactor Programme (POPR), extensive development work has been performed on aluminium powder metallurgy (ARM) products, toward their use as cladding for UO{sub 2} fuel. As part of this development work, eutectic bonding, flash butt welding, and cold-pressure welding were investigated as methods for making end closures in die fuel element cladding. Vibratory packing was studied as a means of filling APM tubes with UO{sub 2}. Out-of-pile tests were conducted to obtain information on APM-UO{sub 2} compatibility. This work revealed that, under present conditions, eutectic bonding was the most suitable method for making end closures; vibratory packing produced fuel densities in the range of 80 to 88% of theoretical density; and no APM-UO{sub 2} reaction took place in the range of POPR operating temperatures (850{sup o}F maximum fuel-cladding interface temperature). As a result o f this development work, five APM-clad UO{sub 2} prototype fuel elements have been fabricated for testing in the Organic Moderated Reactor Experiment (OMRE). Each element consisted of 24 or 25 APM-clad fuel rods, arranged in a 5 x 5 array in a nickel-plated steel or an APM fuel box. To increase surface area, the extruded APM cladding had eight fins which were spiralled to a pitch of 45 or 90e/ ft to further improve heat transfer. The fuel rod end closures were made by eutectic bonding of silver-plated aluminium end plugs to the APM tubing. The elements were instrumented to: (1) Measure cladding surface and coolant temperatures, (2) Detect fuel rod failure, (3) Change coolant velocity (means of achieving peak cladding surface temperature of 850{sup o}F), (4) Measure coolant velocity, and (5) Measure fission gas build-up. These elements have been installed in the OMRE with target fuel burn-ups of 25000 to 30000 MWd/t of uranium. As of 1 April 1963, they had achieved accumulated burn-ups ranging from 7700 to 12 000 MWd/t of uranium. Two of the

  3. Intra-amniotic pharmacological blockade of inflammatory signalling pathways in an ovine chorioamnionitis model.

    Science.gov (United States)

    Ireland, D J; Kemp, M W; Miura, Y; Saito, M; Newnham, J P; Keelan, J A

    2015-05-01

    Intrauterine inflammation (IUI) associated with infection is the major cause of preterm birth (PTB) at PTBs. Pharmacological strategies to prevent PTB and improve fetal outcomes will likely require both antimicrobial and anti-inflammatory therapies. Here we investigated the effects of two cytokine-suppressive anti-inflammatory drugs (CSAIDs), compounds that specifically target inflammatory signalling pathways, in an ovine model of lipopolysaccharide (LPS)-induced chorioamnionitis. Chronically catheterized ewes at 116 days gestation (n = 7/group) received an intra-amniotic (IA) bolus of LPS (10 mg) plus vehicle or CSAIDS: TPCA-1 (1.2 mg/kg fetal weight) or 5z-7-oxozeaenol (OxZnl; 0.4 mg/kg fetal weight); controls received vehicle (dimethylsulphoxide). Amniotic fluid (AF), fetal and maternal blood samples were taken 0, 2, 6, 12, 24 and 48 h later; tissues were taken at autopsy (48 h). Administration of TPCA-1 or OxZnl abrogated the stimulatory effects of LPS (P < 0.01 versus vehicle control) on production of PGE2 in AF, with lesser (non-significant) effects on IL-6 production. Fetal membrane polymorphonuclear cell infiltration score was significantly higher in LPS versus vehicle control animals (P < 0.01), and this difference was absent with TPCA-1 and OxZnl treatment. LPS-induced systemic fetal inflammation was highly variable, with no significant effects of CSAIDs observed. Lung inflammation was evident with LPS exposure, but unaffected by CSAID treatment. We have shown in a large animal model that IA administration of a single dose of CSAIDs can suppress LPS-induced IA inflammatory responses, while fetal effects were minimal. Further development and investigation of these compounds in infectious models is warranted. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  4. Modeling pathways of riverine nitrogen and phosphorus in the Baltic Sea

    Science.gov (United States)

    Radtke, H.; Neumann, T.; Voss, M.; Fennel, W.

    2012-09-01

    A better understanding of the fate of nutrients entering the Baltic Sea ecosystem is an important issue with implications for environmental management. There are two sources of nitrogen and phosphorus: riverine input and atmospheric deposition. In the case of nitrogen, the fixation of dinitrogen by diazotrophic bacteria represents a third source. From an analysis of stable nitrogen isotope ratios it was suggested that most of the riverine nitrogen is sequestered in the coastal rim, specifically along the southern Baltic Sea coast with its coarse sediments, whereas nitrogen from fixation dominates the central basins. However, pathways of nutrients and timescales between the input of the nutrients and their arrival in different basins are difficult to obtain from direct measurements. To elucidate this problem, we use a source attribution technique in a three-dimensional ecosystem model, ERGOM, to track nutrients originating from various rivers. An “age” variable is attributed to the marked elements to indicate their propagation speeds and residence times. In this paper, we specifically investigate the spreading of nitrogen and phosphorus from the riverine discharges of the Oder, Vistula, Neman and Daugava. We demonstrate which regions they are transported to and for how long they remain in the ecosystem. The model results show good agreement with source estimations from observed δ15N values in sediments. The model results suggest that 95% of nitrogen is lost by denitrification in sediments, after an average time of 1.4 years for riverine nitrogen. The residence time of riverine phosphorus is much longer and exceeds our simulated period of 35 years.

  5. Risk assessment through drinking water pathway via uncertainty modeling of contaminant transport using soft computing

    International Nuclear Information System (INIS)

    Datta, D.; Ranade, A.K.; Pandey, M.; Sathyabama, N.; Kumar, Brij

    2012-01-01

    The basic objective of an environmental impact assessment (EIA) is to build guidelines to reduce the associated risk or mitigate the consequences of the reactor accident at its source to prevent deterministic health effects, to reduce the risk of stochastic health effects (eg. cancer and severe hereditary effects) as much as reasonable achievable by implementing protective actions in accordance with IAEA guidance (IAEA Safety Series No. 115, 1996). The measure of exposure being the basic tool to take any appropriate decisions related to risk reduction, EIA is traditionally expressed in terms of radiation exposure to the member of the public. However, models used to estimate the exposure received by the member of the public are governed by parameters some of which are deterministic with relative uncertainty and some of which are stochastic as well as imprecise (insufficient knowledge). In an admixture environment of this type, it is essential to assess the uncertainty of a model to estimate the bounds of the exposure to the public to invoke a decision during an event of nuclear or radiological emergency. With a view to this soft computing technique such as evidence theory based assessment of model parameters is addressed to compute the risk or exposure to the member of the public. The possible pathway of exposure to the member of the public in the aquatic food stream is the drinking of water. Accordingly, this paper presents the uncertainty analysis of exposure via uncertainty analysis of the contaminated water. Evidence theory finally addresses the uncertainty in terms of lower bound as belief measure and upper bound of exposure as plausibility measure. In this work EIA is presented using evidence theory. Data fusion technique is used to aggregate the knowledge on the uncertain information. Uncertainty of concentration and exposure is expressed as an interval of belief, plausibility

  6. Pathway models for analysing and managing the introduction of alien plant pests—an overview and categorization

    Science.gov (United States)

    J.C. Douma; M. Pautasso; R.C. Venette; C. Robinet; L. Hemerik; M.C.M. Mourits; J. Schans; W. van der Werf

    2016-01-01

    Alien plant pests are introduced into new areas at unprecedented rates through global trade, transport, tourism and travel, threatening biodiversity and agriculture. Increasingly, the movement and introduction of pests is analysed with pathway models to provide risk managers with quantitative estimates of introduction risks and effectiveness of management options....

  7. Comprehensive School Mental Health: An Integrated "School-Based Pathway to Care" Model for Canadian Secondary Schools

    Science.gov (United States)

    Wei, Yifeng; Kutcher, Stan; Szumilas, Magdalena

    2011-01-01

    Adolescence is a critical period for the promotion of mental health and the treatment of mental disorders. Schools are well-positioned to address adolescent mental health. This paper describes a school mental health model, "School-Based Pathway to Care," for Canadian secondary schools that links schools with primary care providers and…

  8. Hedonic tone and activation level in the mood-creativity link : Toward a dual pathway to creativity model

    NARCIS (Netherlands)

    De Dreu, Carsten K. W.; Baas, Matthijs; Nijstad, Bernard A.

    To understand when and why mood states influence creativity, the authors developed and tested a dual pathway to creativity model; creative fluency (number of ideas or insights) and originality (novelty) are functions of cognitive flexibility, persistence, or some combination thereof. Invoking work

  9. An extension of the Néel-Brown model for systems with multiple switching pathways

    Energy Technology Data Exchange (ETDEWEB)

    Roy, Arnab; Kumar, P.S. Anil, E-mail: anil@physics.iisc.ernet.in

    2017-02-15

    TheNéel-Brown model is the most widely accepted model for the description of magnetization reversal by thermal excitation. This model predicts a decreasing average switching field and an increasing width ΔH of switching field distribution as the temperature is increased, and has been found to hold good on several occasions. However, for a few classes of systems, the temperature dependence of ΔH shows the opposite trend, and so far no satisfactory explanation exists. We present here an experimental study of switching field statistics of permalloy (Ni{sub 80}Fe{sub 20}) thin films on Si(100) grown by pulsed laser ablation. It was seen that the sample deviates from the Neel-Brown behavior in the manner described above. We performed calculations based on a natural extension of the Néel-Brown model, which incorporated multiple reversal pathways characterized by a Gaussian distribution of coercive fields. Calculations based on this model for different values of the width parameter σ{sub HSW} show two distinct kinds of behavior. At low values of σ{sub HSW}, the total width ΔH is limited by thermal broadening according to the traditional Neel-Brown expression. This regime is characterized by an increasing ΔH with temperature. For high σ{sub HSW}, the broadening is dominated by σ{sub HSW}, which masks thermal broadening. In this regime, ΔH decreases with increasing temperature. Whereas the experimentally observed temperature dependence of the average switching field was found to be in good agreement with this model, qualitative agreement with regard to the temperature dependence of ΔH could be observed only for relaxation times lower than ~10{sup −40} s, which is much smaller than Néel-Brown relaxation times (10{sup −9}–10{sup −19} s) usually encountered in the literature. - Highlights: • The Néel-Brown model for magnetization reversal over an energy barrier due to thermal excitation is a widely accepted mechanism for magnetization reversal, and has

  10. Naturally occurring melanomas in dogs as models for non-UV pathways of human melanomas.

    Science.gov (United States)

    Gillard, Marc; Cadieu, Edouard; De Brito, Clotilde; Abadie, Jérôme; Vergier, Béatrice; Devauchelle, Patrick; Degorce, Frédérique; Dréano, Stephane; Primot, Aline; Dorso, Laetitia; Lagadic, Marie; Galibert, Francis; Hédan, Benoit; Galibert, Marie-Dominique; André, Catherine

    2014-01-01

    Spontaneously occurring melanomas are frequent in dogs. They appear at the same localizations as in humans, i.e. skin, mucosal sites, nail matrix and eyes. They display variable behaviors: tumors at oral localizations are more frequent and aggressive than at other anatomical sites. Interestingly, dog melanomas are associated with strong breed predispositions and overrepresentation of black-coated dogs. Epidemiological analysis of 2350 affected dogs showed that poodles are at high risk of developing oral melanoma, while schnauzers or Beauce shepherds mostly developped cutaneous melanoma. Clinical and histopathological analyses were performed on a cohort of 153 cases with a 4-yr follow-up. Histopathological characterization showed that most canine tumors are intradermal and homologous to human rare morphological melanomas types - 'nevocytoid type' and 'animal type'-. Tumor cDNA sequencing data, obtained from 95 dogs for six genes, relevant to human melanoma classification, detected somatic mutations in oral melanoma, in NRAS and PTEN genes, at human hotspot sites, but not in BRAF. Altogether, these findings support the relevance of the dog model for comparative oncology of melanomas, especially for the elucidation of non-UV induced pathways. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  11. Pathway analysis and exposure assessment: MEPAS modeling for nonradiological chemical contaminants at the Hanford Site

    International Nuclear Information System (INIS)

    Blanton, M.L.; Dirkes, R.; Buck, J.; Cooper, A.; Castieton, K.; Glantz, C.

    1995-01-01

    A Chemical Pathway Analysis and Exposure Assessment was performed by the Surface Environmental Surveillance Project (SESP). The SESP monitors air, surface water, sediment, agricultural products, vegetation, soil, and wildlife in order to assess onsite of offsite environmental impacts and offsite human health risk at the Hanford Site. The objectives of this study are (1) determine if a nonradiological chemical monitoring program is warranted for the Hanford Site, (2) ensure that the selection of surveillance parameters such as media, sampling location, and analytes are chosen in a manner that is scientifically sound and cost-efficient, and (3) identify specific nonradiological chemicals of concern (COC) for the Hanford Site. The basis for identification of COC for the Hanford Site was an extensive literature review. The model was also used to predict COC concentrations required onsite to achieve an offsite cancer incidence of 1 E-6 and a hazard quotient of 1.0. This study indicated that nonradiological chemical contamination occurring onsite does not pose a significant offsite human health risk. The highest cancer incidence to the offsite maximally exposed individual from COC was from arsenic (1.76E-1 0); the highest hazard quotient was chromium VI (1.48E-04)

  12. On a Generalized Entropy Measure Leading to the Pathway Model with a Preliminary Application to Solar Neutrino Data

    Directory of Open Access Journals (Sweden)

    Hans J. Haubold

    2013-09-01

    Full Text Available An entropy for the scalar variable case, parallel to Havrda-Charvat entropy, was introduced by the first author, and the properties and its connection to Tsallis non-extensive statistical mechanics and the Mathai pathway model were examined by the authors in previous papers. In the current paper, we extend the entropy to cover the scalar case, multivariable case, and matrix variate case. Then, this measure is optimized under different types of restrictions, and a number of models in the multivariable case and matrix variable case are obtained. Connections of these models to problems in statistical and physical sciences are pointed out. An application of the simplest case of the pathway model to the interpretation of solar neutrino data by applying standard deviation analysis and diffusion entropy analysis is provided.

  13. Pathway modeling of microarray data: A case study of pathway activity changes in the testis following in utero exposure to dibutyl phthalate (DBP)

    International Nuclear Information System (INIS)

    Ovacik, Meric A.; Sen, Banalata; Euling, Susan Y.; Gaido, Kevin W.; Ierapetritou, Marianthi G.; Androulakis, Ioannis P.

    2013-01-01

    Pathway activity level analysis, the approach pursued in this study, focuses on all genes that are known to be members of metabolic and signaling pathways as defined by the KEGG database. The pathway activity level analysis entails singular value decomposition (SVD) of the expression data of the genes constituting a given pathway. We explore an extension of the pathway activity methodology for application to time-course microarray data. We show that pathway analysis enhances our ability to detect biologically relevant changes in pathway activity using synthetic data. As a case study, we apply the pathway activity level formulation coupled with significance analysis to microarray data from two different rat testes exposed in utero to Dibutyl Phthalate (DBP). In utero DBP exposure in the rat results in developmental toxicity of a number of male reproductive organs, including the testes. One well-characterized mode of action for DBP and the male reproductive developmental effects is the repression of expression of genes involved in cholesterol transport, steroid biosynthesis and testosterone synthesis that lead to a decreased fetal testicular testosterone. Previous analyses of DBP testes microarray data focused on either individual gene expression changes or changes in the expression of specific genes that are hypothesized, or known, to be important in testicular development and testosterone synthesis. However, a pathway analysis may inform whether there are additional affected pathways that could inform additional modes of action linked to DBP developmental toxicity. We show that Pathway activity analysis may be considered for a more comprehensive analysis of microarray data

  14. Pathway modeling of microarray data: A case study of pathway activity changes in the testis following in utero exposure to dibutyl phthalate (DBP)

    Energy Technology Data Exchange (ETDEWEB)

    Ovacik, Meric A. [Chemical and Biochemical Engineering Department, Rutgers University, Piscataway, NJ 08854 (United States); Sen, Banalata [National Center for Environmental Assessment, U.S. Environmental Protection Agency, Research Triangle Park, NC 27709 (United States); Euling, Susan Y. [National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC 20460 (United States); Gaido, Kevin W. [U.S. Food and Drug Administration, Center for Veterinary Medicine, Office of New Animal Drug Evaluation, Division of Human Food Safety, Rockville, MD 20855 (United States); Ierapetritou, Marianthi G. [Chemical and Biochemical Engineering Department, Rutgers University, Piscataway, NJ 08854 (United States); Androulakis, Ioannis P., E-mail: yannis@rci.rutgers.edu [Chemical and Biochemical Engineering Department, Rutgers University, Piscataway, NJ 08854 (United States); Biomedical Engineering Department, Rutgers University, NJ 08854 (United States)

    2013-09-15

    Pathway activity level analysis, the approach pursued in this study, focuses on all genes that are known to be members of metabolic and signaling pathways as defined by the KEGG database. The pathway activity level analysis entails singular value decomposition (SVD) of the expression data of the genes constituting a given pathway. We explore an extension of the pathway activity methodology for application to time-course microarray data. We show that pathway analysis enhances our ability to detect biologically relevant changes in pathway activity using synthetic data. As a case study, we apply the pathway activity level formulation coupled with significance analysis to microarray data from two different rat testes exposed in utero to Dibutyl Phthalate (DBP). In utero DBP exposure in the rat results in developmental toxicity of a number of male reproductive organs, including the testes. One well-characterized mode of action for DBP and the male reproductive developmental effects is the repression of expression of genes involved in cholesterol transport, steroid biosynthesis and testosterone synthesis that lead to a decreased fetal testicular testosterone. Previous analyses of DBP testes microarray data focused on either individual gene expression changes or changes in the expression of specific genes that are hypothesized, or known, to be important in testicular development and testosterone synthesis. However, a pathway analysis may inform whether there are additional affected pathways that could inform additional modes of action linked to DBP developmental toxicity. We show that Pathway activity analysis may be considered for a more comprehensive analysis of microarray data.

  15. Network dynamics in nociceptive pathways assessed by the neuronal avalanche model

    Directory of Open Access Journals (Sweden)

    Wu José

    2012-04-01

    Full Text Available Abstract Background Traditional electroencephalography provides a critical assessment of pain responses. The perception of pain, however, may involve a series of signal transmission pathways in higher cortical function. Recent studies have shown that a mathematical method, the neuronal avalanche model, may be applied to evaluate higher-order network dynamics. The neuronal avalanche is a cascade of neuronal activity, the size distribution of which can be approximated by a power law relationship manifested by the slope of a straight line (i.e., the α value. We investigated whether the neuronal avalanche could be a useful index for nociceptive assessment. Findings Neuronal activity was recorded with a 4 × 8 multichannel electrode array in the primary somatosensory cortex (S1 and anterior cingulate cortex (ACC. Under light anesthesia, peripheral pinch stimulation increased the slope of the α value in both the ACC and S1, whereas brush stimulation increased the α value only in the S1. The increase in α values was blocked in both regions under deep anesthesia. The increase in α values in the ACC induced by peripheral pinch stimulation was blocked by medial thalamic lesion, but the increase in α values in the S1 induced by brush and pinch stimulation was not affected. Conclusions The neuronal avalanche model shows a critical state in the cortical network for noxious-related signal processing. The α value may provide an index of brain network activity that distinguishes the responses to somatic stimuli from the control state. These network dynamics may be valuable for the evaluation of acute nociceptive processes and may be applied to chronic pathological pain conditions.

  16. FOODCHAIN: a Monte Carlo model to estimate individual exposure to airborne pollutants via the foodchain pathway

    International Nuclear Information System (INIS)

    Dixon, E.; Holton, G.A.

    1984-01-01

    Ingestion of contaminated food due to the airborne release of radionuclides or chemical pollutants is a particularly difficult human exposure pathway to quantify. There are a number of important physical and biological processes such as atmospheric deposition and plant uptake to consider. These processes are approximate by techniques encoded in the computer program TEREX. Once estimates of pollutant concentrations are made, the problem can be reduced to computing exposure from ingestion of the food. Some assessments do not account for where the contaminated food is eaten, while others limit consumption to meat and vegetables produced within the affected area. While those approaches lead to an upper bound of exposure, a more realistic assumption is that if locally produced food is not sufficient to meet the dietary needs of the local populace, then uncontaminated food will be imported. This is the approach taken by the computer model FOODCHAIN. Exposures via ingestion of six basic types of food are modeled: beef, milk, grains, leafy vegetables, exposed produce (edible parts are exposed to atmospheric deposition), and protected produce (edible parts are protected from atmospheric deposition). Intake requirements for these six foods are based on a standard diet. Using TEREX-produced site-specific crop production values and food contamination values, FOODCHAIN randomly samples pollutant concentrations in each of the six foodstuffs in an inerative manner. Consumption of a particular food is weighted by a factor proportional to the total production of that food within the area studied. The exposures due to consumption of each of the six foodstuffs are summed to produce the total exposure for each randomly calculated diet

  17. Targeting the LRP5 pathway improves bone properties in a mouse model of osteogenesis imperfecta.

    Science.gov (United States)

    Jacobsen, Christina M; Barber, Lauren A; Ayturk, Ugur M; Roberts, Heather J; Deal, Lauren E; Schwartz, Marissa A; Weis, MaryAnn; Eyre, David; Zurakowski, David; Robling, Alexander G; Warman, Matthew L

    2014-10-01

    The cell surface receptor low-density lipoprotein receptor-related protein 5 (LRP5) is a key regulator of bone mass and bone strength. Heterozygous missense mutations in LRP5 cause autosomal dominant high bone mass (HBM) in humans by reducing binding to LRP5 by endogenous inhibitors, such as sclerostin (SOST). Mice heterozygous for a knockin allele (Lrp5(p.A214V) ) that is orthologous to a human HBM-causing mutation have increased bone mass and strength. Osteogenesis imperfecta (OI) is a skeletal fragility disorder predominantly caused by mutations that affect type I collagen. We tested whether the LRP5 pathway can be used to improve bone properties in animal models of OI. First, we mated Lrp5(+/p.A214V) mice to Col1a2(+/p.G610C) mice, which model human type IV OI. We found that Col1a2(+/p.G610C) ;Lrp5(+/p.A214V) offspring had significantly increased bone mass and strength compared to Col1a2(+/p.G610C) ;Lrp5(+/+) littermates. The improved bone properties were not a result of altered mRNA expression of type I collagen or its chaperones, nor were they due to changes in mutant type I collagen secretion. Second, we treated Col1a2(+/p.G610C) mice with a monoclonal antibody that inhibits sclerostin activity (Scl-Ab). We found that antibody-treated mice had significantly increased bone mass and strength compared to vehicle-treated littermates. These findings indicate increasing bone formation, even without altering bone collagen composition, may benefit patients with OI. © 2014 American Society for Bone and Mineral Research.

  18. Tracing contaminant pathways in sandy heterogeneous glaciofluvial sediments using a sedimentary depositional model

    International Nuclear Information System (INIS)

    Webb, E.K.; Anderson, M.P.

    1990-01-01

    Heterogeneous sedimentary deposits present complications for tracking contaminant movement by causing a complex advective flow field. Connected areas of high conductivity produce so-called fast paths that control movement of solutes. Identifying potential fast paths and describing the variation in hydraulic properties was attempted through simulating the deposition of a glaciofluvial deposit (outwash). Glaciofluvial deposits usually consist of several depositional facies, each of which has different physical characteristics, depositional structures and hydraulic properties. Therefore, it is unlikely that the property of stationarity (a constant mean hydraulic conductivity and a mono-modal probability distribution) holds for an entire glaciofluvial sequence. However, the process of dividing an outwash sequence into geologic facies presumably identifies units of material with similar physical characteristics. It is proposed that patterns of geologic facies determined by field observation can be quantified by mathematical simulation of sediment deposition. Subsequently, the simulated sediment distributions can be used to define the distribution of hydrogeologic parameters and locate possible fast paths. To test this hypothesis, a hypothetical glacial outwash deposit based on geologic facies descriptions contained in the literature was simulated using a sedimentary depositional model, SEDSIM, to produce a three-dimensional description of sediment grain size distributions. Grain size distributions were then used to estimate the spatial distribution of hydraulic conductivity. Subsequently a finite-difference flow model and linked particle tracking algorithm were used to trace conservative transport pathways. This represents a first step in describing the spatial heterogeneity of hydrogeologic characteristics for glaciofluvial and other braided stream environments. (Author) (39 refs., 7 figs.)

  19. LitPathExplorer: a confidence-based visual text analytics tool for exploring literature-enriched pathway models.

    Science.gov (United States)

    Soto, Axel J; Zerva, Chrysoula; Batista-Navarro, Riza; Ananiadou, Sophia

    2018-04-15

    Pathway models are valuable resources that help us understand the various mechanisms underpinning complex biological processes. Their curation is typically carried out through manual inspection of published scientific literature to find information relevant to a model, which is a laborious and knowledge-intensive task. Furthermore, models curated manually cannot be easily updated and maintained with new evidence extracted from the literature without automated support. We have developed LitPathExplorer, a visual text analytics tool that integrates advanced text mining, semi-supervised learning and interactive visualization, to facilitate the exploration and analysis of pathway models using statements (i.e. events) extracted automatically from the literature and organized according to levels of confidence. LitPathExplorer supports pathway modellers and curators alike by: (i) extracting events from the literature that corroborate existing models with evidence; (ii) discovering new events which can update models; and (iii) providing a confidence value for each event that is automatically computed based on linguistic features and article metadata. Our evaluation of event extraction showed a precision of 89% and a recall of 71%. Evaluation of our confidence measure, when used for ranking sampled events, showed an average precision ranging between 61 and 73%, which can be improved to 95% when the user is involved in the semi-supervised learning process. Qualitative evaluation using pair analytics based on the feedback of three domain experts confirmed the utility of our tool within the context of pathway model exploration. LitPathExplorer is available at http://nactem.ac.uk/LitPathExplorer_BI/. sophia.ananiadou@manchester.ac.uk. Supplementary data are available at Bioinformatics online.

  20. Pathways from Trauma to Psychotic Experiences: A Theoretically Informed Model of Posttraumatic Stress in Psychosis

    Directory of Open Access Journals (Sweden)

    Amy Hardy

    2017-05-01

    Full Text Available In recent years, empirical data and theoretical accounts relating to the relationship between childhood victimization and psychotic experiences have accumulated. Much of this work has focused on co-occurring Posttraumatic Stress Disorder or putative causal mechanisms in isolation from each other. The complexity of posttraumatic stress reactions experienced in psychosis remains poorly understood. This paper therefore attempts to synthesize the current evidence base into a theoretically informed, multifactorial model of posttraumatic stress in psychosis. Three trauma-related vulnerability factors are proposed to give rise to intrusions and to affect how people appraise and cope with them. First, understandable attempts to survive trauma become habitual ways of regulating emotion, manifesting in cognitive-affective, behavioral and interpersonal responses. Second, event memories, consisting of perceptual and episodic representations, are impacted by emotion experienced during trauma. Third, personal semantic memory, specifically appraisals of the self and others, are shaped by event memories. It is proposed these vulnerability factors have the potential to lead to two types of intrusions. The first type is anomalous experiences arising from emotion regulation and/or the generation of novel images derived from trauma memory. The second type is trauma memory intrusions reflecting, to varying degrees, the retrieval of perceptual, episodic and personal semantic representations. It is speculated trauma memory intrusions may be experienced on a continuum from contextualized to fragmented, depending on memory encoding and retrieval. Personal semantic memory will then impact on how intrusions are appraised, with habitual emotion regulation strategies influencing people’s coping responses to these. Three vignettes are outlined to illustrate how the model accounts for different pathways between victimization and psychosis, and implications for therapy are

  1. Examination of a climate stabilization pathway via zero-emissions using Earth system models

    International Nuclear Information System (INIS)

    Nohara, Daisuke; Tsutsui, J; Watanabe, S; Tachiiri, K; Hajima, T; Okajima, H; Matsuno, T

    2015-01-01

    Long-term climate experiments up to the year 2300 have been conducted using two full-scale complex Earth system models (ESMs), CESM1(BGC) and MIROC-ESM, for a CO 2 emissions reduction pathway, termed Z650, where annual CO 2 emissions peak at 11 PgC in 2020, decline by 50% every 30 years, and reach zero in 2160. The results have been examined by focusing on the approximate linear relationship between the temperature increase and cumulative CO 2 emissions. Although the temperature increase is nearly proportional to the cumulative CO 2 emissions in both models, this relationship does not necessarily provide a robust basis for the restriction of CO 2 emissions because it is substantially modulated by non-CO 2 forcing. CO 2 -induced warming, estimated from the atmospheric CO 2 concentrations in the models, indicates an approximate compensation of nonlinear changes between fast-mode responses to concentration changes at less than 10 years and slow-mode response at more than 100 years due to the thermal inertia of the ocean. In this estimate, CESM1(BGC) closely approximates a linear trend of 1.7 °C per 1000 PgC, whereas MIROC-ESM shows a deviation toward higher temperatures after the emissions peak, from 1.8 °C to 2.4 °C per 1000 PgC over the range of 400–850 PgC cumulative emissions corresponding to years 2000–2050. The evolution of temperature under zero emissions, 2160–2300, shows a slight decrease of about 0.1 °C per century in CESM1(BGC), but remains almost constant in MIROC-ESM. The fast-mode response toward the equilibrium state decreases with a decrease in the airborne fraction owing to continued CO 2 uptake (carbon cycle inertia), whereas the slow-mode response results in more warming owing to continued heat uptake (thermal inertia). Several specific differences are noted between the two models regarding the degree of this compensation and in some key regional aspects associated with sustained warming and long-term climate risks. Overall, elevated

  2. Modeling the Intra- and Extracellular Cytokine Signaling Pathway under Heat Stroke in the Liver

    Science.gov (United States)

    2013-09-05

    to be construed as official or as reflecting the views of the Army or the Department of Defense. Citations of commercial organizations and trade names...commercial organizations and trade names in this report do not constitute an official Department of the Army endorsement or approval of the products or...pathway. Nature Medicine 6: 422–428. 93. Murray PJ (2007) The jak-stat signaling pathway: Input and output intergration . Journal of Immunology 178

  3. Cerebrospinal and Interstitial Fluid Transport via the Glymphatic Pathway Modeled by Optimal Mass Transport

    OpenAIRE

    Ratner, Vadim; Gao, Yi; Lee, Hedok; Elkin, Rena; Nedergaard, Maiken; Benveniste, Helene; Tannenbaum, Allen

    2017-01-01

    The glymphatic pathway is a system which facilitates continuous cerebrospinal fluid (CSF) and interstitial fluid (ISF) exchange and plays a key role in removing waste products from the rodent brain. Dysfunction of the glymphatic pathway may be implicated in the pathophysiology of Alzheimer's disease. Intriguingly, the glymphatic system is most active during deep wave sleep general anesthesia. By using paramagnetic tracers administered into CSF of rodents, we previously showed the utility of M...

  4. Modelling the Interplay between Childhood and Adult Adversity in Pathways to Psychosis

    Science.gov (United States)

    Morgan, Craig; Reininghaus, Ulrich; Fearon, Paul; Hutchinson, Gerard; Morgan, Kevin; Dazzan, Paola; Boydell, Jane; Kirkbride, James; Doody, Gillian A; Jones, Peter B; Murray, Robin M; Craig, Tom

    2014-01-01

    Background There is evidence that a range of socio-environmental exposures are associated with an increased risk of psychosis. However, despite the fact that such factors probably combine in complex ways to increase risk, the majority of studies have tended to consider each exposure separately. In light of this, we sought to extend previous analyses of data from the ÆSOP study on childhood and adult markers of disadvantage to examine how they combine to increase risk of psychosis, testing both mediation (path) models and synergistic effects. Method All patients with a first episode of psychosis who made contact with psychiatric services in defined catchment areas in London and Nottingham, UK (n = 390) and a series of community controls (n = 391) were included in the ÆSOP study. Data relating to clinical and social variables, including parental separation and loss, education and adult disadvantage, were collected from cases and controls. Results There was evidence that the effect of separation from, but not death of, a parent in childhood on risk of psychosis was partially mediated through subsequent poor educational attainment (no qualifications), adult social disadvantage and, to a lesser degree, low self-esteem. In addition, there was strong evidence that separation from, but not death of, a parent combined synergistically with subsequent disadvantage to increase risk. These effects held for all ethnic groups in the sample. Conclusions Exposure to childhood and adult disadvantage may combine in complex ways to push some individuals along a predominantly socio-developmental pathway to psychosis. PMID:23590972

  5. Spatially Explicit Modeling Reveals Cephalopod Distributions Match Contrasting Trophic Pathways in the Western Mediterranean Sea.

    Directory of Open Access Journals (Sweden)

    Patricia Puerta

    Full Text Available Populations of the same species can experience different responses to the environment throughout their distributional range as a result of spatial and temporal heterogeneity in habitat conditions. This highlights the importance of understanding the processes governing species distribution at local scales. However, research on species distribution often averages environmental covariates across large geographic areas, missing variability in population-environment interactions within geographically distinct regions. We used spatially explicit models to identify interactions between species and environmental, including chlorophyll a (Chla and sea surface temperature (SST, and trophic (prey density conditions, along with processes governing the distribution of two cephalopods with contrasting life-histories (octopus and squid across the western Mediterranean Sea. This approach is relevant for cephalopods, since their population dynamics are especially sensitive to variations in habitat conditions and rarely stable in abundance and location. The regional distributions of the two cephalopod species matched two different trophic pathways present in the western Mediterranean Sea, associated with the Gulf of Lion upwelling and the Ebro river discharges respectively. The effects of the studied environmental and trophic conditions were spatially variant in both species, with usually stronger effects along their distributional boundaries. We identify areas where prey availability limited the abundance of cephalopod populations as well as contrasting effects of temperature in the warmest regions. Despite distributional patterns matching productive areas, a general negative effect of Chla on cephalopod densities suggests that competition pressure is common in the study area. Additionally, results highlight the importance of trophic interactions, beyond other common environmental factors, in shaping the distribution of cephalopod populations. Our study presents

  6. A zebrafish model for uremic toxicity: role of the complement pathway.

    Science.gov (United States)

    Berman, Nathaniel; Lectura, Melisa; Thurman, Josh; Reinecke, James; Raff, Amanda C; Melamed, Michal L; Reinecke, James; Quan, Zhe; Evans, Todd; Meyer, Timothy W; Hostetter, Thomas H

    2013-01-01

    Many organic solutes accumulate in end-stage renal disease (ESRD) and some are poorly removed with urea-based prescriptions for hemodialysis. However, their toxicities have been difficult to assess. We have employed an animal model, the zebrafish embryo, to test the toxicity of uremic serum compared to control. Serum was obtained from stable ESRD patients predialysis or from normal subjects. Zebrafish embryos 24 h postfertilization were exposed to experimental media at a water:human serum ratio of 3:1. Those exposed to serum from uremic subjects had significantly reduced survival at 8 h (19 ± 18 vs. 94 ± 6%, p 50 kDa, respectively). Heating serum abrogated its toxicity. EDTA, a potent inhibitor of complement by virtue of calcium chelation, reduced the toxicity of uremic serum compared to untreated uremic serum (96 ± 5 vs. 28 ± 20% survival, p < 0.016, chelated vs. nonchelated serum, respectively). Anti-factor B, a specific inhibitor of the alternative complement pathway, reduced the toxicity of uremic serum, compared to untreated uremic serum (98 ± 6 vs. 3 ± 9% survival, p < 0.016, anti-factor B treated vs. nontreated, respectively). Uremic serum is thus more toxic to zebrafish embryos than normal serum. Furthermore, this toxicity is associated with a fraction of large size, is inactivated by heat, and is reduced by both specific and nonspecific inhibitors of complement activation. Together these data lend support to the hypothesis that at least some uremic toxicities may be mediated by complement. Copyright © 2013 S. Karger AG, Basel.

  7. An examination of two pathways to tropical cyclogenesis occurring in idealized simulations with a cloud-resolving numerical model

    Directory of Open Access Journals (Sweden)

    M. E. Nicholls

    2013-06-01

    Full Text Available Simulations are conducted with a cloud-resolving numerical model to examine the transformation of a weak incipient mid-level cyclonic vortex into a tropical cyclone. Results demonstrate that two distinct pathways are possible and that development along a particular pathway is sensitive to model physics and initial conditions. One pathway involves a steady increase of the surface winds to tropical cyclone strength as the radius of maximum winds gradually decreases. A notable feature of this evolution is the creation of small-scale lower tropospheric cyclonic vorticity anomalies by deep convective towers and subsequent merger and convergence by the low-level secondary circulation. The second pathway also begins with a strengthening low-level circulation, but eventually a significantly stronger mid-level circulation develops. Cyclogenesis occurs subsequently when a small-scale surface concentrated vortex forms abruptly near the center of the larger-scale circulation. The small-scale vortex is warm core throughout the troposphere and results in a fall in local surface pressure of a few millibars. It usually develops rapidly, undergoing a modest growth to form a small tropical cyclone. Many of the simulated systems approach or reach tropical cyclone strength prior to development of a prominent mid-level vortex so that the subsequent formation of a strong small-scale surface concentrated vortex in these cases could be considered intensification rather than genesis. Experiments are performed to investigate the dependence on the inclusion of the ice phase, radiation, the size and strength of the incipient mid-level vortex, the amount of moisture present in the initial vortex, and the sea surface temperature. Notably, as the sea surface temperature is raised, the likelihood of development along the second pathway is increased. This appears to be related to an increased production of ice. The sensitivity of the pathway taken to model physics and initial

  8. Modeling of the Dorsal Gradient across Species Reveals Interaction between Embryo Morphology and Toll Signaling Pathway during Evolution

    Science.gov (United States)

    Koslen, Hannah R.; Chiel, Hillel J.; Mizutani, Claudia Mieko

    2014-01-01

    Morphogenetic gradients are essential to allocate cell fates in embryos of varying sizes within and across closely related species. We previously showed that the maternal NF-κB/Dorsal (Dl) gradient has acquired different shapes in Drosophila species, which result in unequally scaled germ layers along the dorso-ventral axis and the repositioning of the neuroectodermal borders. Here we combined experimentation and mathematical modeling to investigate which factors might have contributed to the fast evolutionary changes of this gradient. To this end, we modified a previously developed model that employs differential equations of the main biochemical interactions of the Toll (Tl) signaling pathway, which regulates Dl nuclear transport. The original model simulations fit well the D. melanogaster wild type, but not mutant conditions. To broaden the applicability of this model and probe evolutionary changes in gradient distributions, we adjusted a set of 19 independent parameters to reproduce three quantified experimental conditions (i.e. Dl levels lowered, nuclear size and density increased or decreased). We next searched for the most relevant parameters that reproduce the species-specific Dl gradients. We show that adjusting parameters relative to morphological traits (i.e. embryo diameter, nuclear size and density) alone is not sufficient to reproduce the species Dl gradients. Since components of the Tl pathway simulated by the model are fast-evolving, we next asked which parameters related to Tl would most effectively reproduce these gradients and identified a particular subset. A sensitivity analysis reveals the existence of nonlinear interactions between the two fast-evolving traits tested above, namely the embryonic morphological changes and Tl pathway components. Our modeling further suggests that distinct Dl gradient shapes observed in closely related melanogaster sub-group lineages may be caused by similar sequence modifications in Tl pathway components, which

  9. Small RNA pathways and diversity in model legumes: lessons from genomics.

    Directory of Open Access Journals (Sweden)

    Pilar eBustos-Sanmamed

    2013-07-01

    Full Text Available Small non coding RNAs (smRNA participate in the regulation of development, cell differentiation, adaptation to environmental constraints and defense responses in plants. They negatively regulate gene expression by degrading specific mRNA targets, repressing their translation or modifying chromatin conformation through homologous interaction with target loci. MicroRNAs (miRNA and short-interfering RNAs (siRNA are generated from long double stranded RNA (dsRNA that are cleaved into 20- to 24-nucleotide dsRNAs by RNase III proteins called DICERs (DCL. One strand of the duplex is then loaded onto effective complexes containing different ARGONAUTE (AGO proteins. In this review, we explored smRNA diversity in model legumes and compiled available data from miRBAse, the miRNA database, and from 22 reports of smRNA deep sequencing or miRNA identification genome-wide in Medicago truncatula, Glycine max and Lotus japonicus. In addition to conserved miRNAs present in other plant species, 229, 179 and 35 novel miRNA families were identified respectively in these 3 legumes, among which several seems legume-specific. New potential functions of several miRNAs in the legume-specific nodulation process are discussed. Furthermore, a new category of siRNA, the phased siRNAs, which seems to mainly regulate disease-resistance genes, was recently discovered in legumes. Despite that the genome sequence of model legumes are not yet fully completed, further analysis was performed by database mining of gene families and protein characteristics of DCLs and AGOs in these genomes. Although most components of the smRNA pathways are conserved, identifiable homologs of key smRNA players from non-legumes could not yet be detected in M. truncatula available genomic and expressed sequence databases. In addition, an important gene diversification was observed in the three legumes. Functional significance of these variant isoforms may reflect peculiarities of smRNA biogenesis in

  10. On the discovery of fast molecular gas in the UFO/BAL quasar APM 08279+5255 at z = 3.912

    Science.gov (United States)

    Feruglio, C.; Ferrara, A.; Bischetti, M.; Downes, D.; Neri, R.; Ceccarelli, C.; Cicone, C.; Fiore, F.; Gallerani, S.; Maiolino, R.; Menci, N.; Piconcelli, E.; Vietri, G.; Vignali, C.; Zappacosta, L.

    2017-12-01

    We have performed a high sensitivity observation of the UFO/BAL quasar APM 08279+5255 at z = 3.912 with NOEMA at 3.2 mm, aimed at detecting fast moving molecular gas. We report the detection of blueshifted CO(4-3) with maximum velocity (v95%) of -1340 km s-1, with respect to the systemic peak emission, and a luminosity of L' = 9.9 × 109μ-1 K km s-1 pc-2, where μ is the lensing magnification factor. We discuss various scenarios for the nature of this emission and conclude that this is the first detection of fast molecular gas at redshift > 3. We derived a mass flow rate of molecular gas in the range Ṁ = 3-7.4 × 103M⊙/yr and momentum boost ṖOF/ṖAGN 2-6, which is therefore consistent with a momentum conserving flow. For the largest ṖOF the scaling is also consistent with an energy conserving flow with an efficiency of 10-20%. The present data can hardly discriminate between the two expansion modes. The mass loading factor of the molecular outflow η = ṀOF/SFR is ≫ 1. We also detected a molecular emission line at a frequency of 94.83 GHz corresponding to a rest-frame frequency of 465.8 GHz; we tentatively identified this frequency with the cation molecule N2H+(5-4), which would be the first detection of this species at high redshift. We discuss the alternative possibility that this emission is due to a CO emission line from the, so far undetected, lens galaxy. Further observations of additional transitions of the same species with NOEMA can discriminate between the two scenarios. This work is based on observations carried out under project numbers S15CW and E15AF with the IRAM NOEMA Interferometer. IRAM is supported by INSU/CNRS (France), MPG (Germany), and IGN (Spain). The reduced spectrum (FITS file) is only available at the CDS via anonymous ftp to http://cdsarc.u-strasbg.fr (http://130.79.128.5) or via http://cdsarc.u-strasbg.fr/viz-bin/qcat?J/A+A/608/A30

  11. Exploring metabolic pathway disruption in the subchronic phencyclidine model of schizophrenia with the Generalized Singular Value Decomposition

    Directory of Open Access Journals (Sweden)

    Morris Brian J

    2011-05-01

    Full Text Available Abstract Background The quantification of experimentally-induced alterations in biological pathways remains a major challenge in systems biology. One example of this is the quantitative characterization of alterations in defined, established metabolic pathways from complex metabolomic data. At present, the disruption of a given metabolic pathway is inferred from metabolomic data by observing an alteration in the level of one or more individual metabolites present within that pathway. Not only is this approach open to subjectivity, as metabolites participate in multiple pathways, but it also ignores useful information available through the pairwise correlations between metabolites. This extra information may be incorporated using a higher-level approach that looks for alterations between a pair of correlation networks. In this way experimentally-induced alterations in metabolic pathways can be quantitatively defined by characterizing group differences in metabolite clustering. Taking this approach increases the objectivity of interpreting alterations in metabolic pathways from metabolomic data. Results We present and justify a new technique for comparing pairs of networks--in our case these networks are based on the same set of nodes and there are two distinct types of weighted edges. The algorithm is based on the Generalized Singular Value Decomposition (GSVD, which may be regarded as an extension of Principle Components Analysis to the case of two data sets. We show how the GSVD can be interpreted as a technique for reordering the two networks in order to reveal clusters that are exclusive to only one. Here we apply this algorithm to a new set of metabolomic data from the prefrontal cortex (PFC of a translational model relevant to schizophrenia, rats treated subchronically with the N-methyl-D-Aspartic acid (NMDA receptor antagonist phencyclidine (PCP. This provides us with a means to quantify which predefined metabolic pathways (Kyoto

  12. Stanniocalcin-1 Protects a Mouse Model from Renal Ischemia-Reperfusion Injury by Affecting ROS-Mediated Multiple Signaling Pathways.

    Science.gov (United States)

    Liu, Dajun; Shang, Huiping; Liu, Ying

    2016-07-12

    Stanniocalcin-1 (STC-1) protects against renal ischemia-reperfusion injury (RIRI). However, the molecular mechanisms remain widely unknown. STC-1 inhibits reactive oxygen species (ROS), whereas most ROS-mediated pathways are associated with ischemic injury. Therefore, to explore the mechanism, the effects of STC-1 on ROS-medicated pathways were studied. Non-traumatic vascular clamps were used to establish RIRI mouse models. The serum levels of STC-1, interleukin-6 (IL-6), interferon (IFN) γ, P53, and capase-3 were measured by ELISA kits. Superoxide dismutase (SOD) and malondialdehyde (MDA) were measured by fluorescence spectrofluorometer. All these molecules changed significantly in a RIRI model mouse when compared with those in a sham control. Kidney cells were isolated from sham and model mice. STC-1 was overexpressed or knockout in these kidney cells. The molecules in ROS-medicated pathways were measured by real-time quantitative PCR and Western blot. The results showed that STC-1 is an effective ROS scavenger. The serum levels of STC-1, MDA and SOD activity were increased while the serum levels of IL-6, iIFN-γ, P53, and capase-3 were decreased in a model group when compared with a sham control (p ROS-mediated molecules. Therefore, STC-1 maybe improve anti-inflammation, anti-oxidant and anti-apoptosis activities by affecting ROS-mediated pathways, especially the phospho-modifications of the respective proteins, resulting in the increase of SOD and reduce of capase-3, p53, IL-6 and IFN-γ.

  13. An Efficient Computational Model to Predict Protonation at the Amide Nitrogen and Reactivity along the C–N Rotational Pathway

    Science.gov (United States)

    Szostak, Roman; Aubé, Jeffrey

    2015-01-01

    N-protonation of amides is critical in numerous biological processes, including amide bonds proteolysis and protein folding, as well as in organic synthesis as a method to activate amide bonds towards unconventional reactivity. A computational model enabling prediction of protonation at the amide bond nitrogen atom along the C–N rotational pathway is reported. Notably, this study provides a blueprint for the rational design and application of amides with a controlled degree of rotation in synthetic chemistry and biology. PMID:25766378

  14. Rapamycin targeting mTOR and hedgehog signaling pathways blocks human rhabdomyosarcoma growth in xenograft murine model

    Energy Technology Data Exchange (ETDEWEB)

    Kaylani, Samer Z. [Division of Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, 1600 7th Avenue South, ACC 414, Birmingham, AL 35233 (United States); Xu, Jianmin; Srivastava, Ritesh K. [Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, 1530 3rd Avenue South, VH 509, Birmingham, AL 35294-0019 (United States); Kopelovich, Levy [Division of Cancer Prevention, National Cancer Institute, Bethesda (United States); Pressey, Joseph G. [Division of Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, 1600 7th Avenue South, ACC 414, Birmingham, AL 35233 (United States); Athar, Mohammad, E-mail: mathar@uab.edu [Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, 1530 3rd Avenue South, VH 509, Birmingham, AL 35294-0019 (United States)

    2013-06-14

    Graphical abstract: Intervention of poorly differentiated RMS by rapamycin: In poorly differentiated RMS, rapamycin blocks mTOR and Hh signaling pathways concomitantly. This leads to dampening in cell cycle regulation and induction of apoptosis. This study provides a rationale for the therapeutic intervention of poorly differentiated RMS by treating patients with rapamycin alone or in combination with other chemotherapeutic agents. -- Highlights: •Rapamycin abrogates RMS tumor growth by modulating proliferation and apoptosis. •Co-targeting mTOR/Hh pathways underlie the molecular basis of effectiveness. •Reduction in mTOR/Hh pathways diminish EMT leading to reduced invasiveness. -- Abstract: Rhabdomyosarcomas (RMS) represent the most common childhood soft-tissue sarcoma. Over the past few decades outcomes for low and intermediate risk RMS patients have slowly improved while patients with metastatic or relapsed RMS still face a grim prognosis. New chemotherapeutic agents or combinations of chemotherapies have largely failed to improve the outcome. Based on the identification of novel molecular targets, potential therapeutic approaches in RMS may offer a decreased reliance on conventional chemotherapy. Thus, identification of effective therapeutic agents that specifically target relevant pathways may be particularly beneficial for patients with metastatic and refractory RMS. The PI3K/AKT/mTOR pathway has been found to be a potentially attractive target in RMS therapy. In this study, we provide evidence that rapamycin (sirolimus) abrogates growth of RMS development in a RMS xenograft mouse model. As compared to a vehicle-treated control group, more than 95% inhibition in tumor growth was observed in mice receiving parenteral administration of rapamycin. The residual tumors in rapamycin-treated group showed significant reduction in the expression of biomarkers indicative of proliferation and tumor invasiveness. These tumors also showed enhanced apoptosis

  15. Regulation of skeletal muscle growth by the IGF1-Akt/PKB pathway: insights from genetic models

    Directory of Open Access Journals (Sweden)

    Schiaffino Stefano

    2011-01-01

    Full Text Available Abstract A highly conserved signaling pathway involving insulin-like growth factor 1 (IGF1, and a cascade of intracellular components that mediate its effects, plays a major role in the regulation of skeletal muscle growth. A central component in this cascade is the kinase Akt, also called protein kinase B (PKB, which controls both protein synthesis, via the kinases mammalian target of rapamycin (mTOR and glycogen synthase kinase 3β (GSK3β, and protein degradation, via the transcription factors of the FoxO family. In this paper, we review the composition and function of this pathway in skeletal muscle fibers, focusing on evidence obtained in vivo by transgenic and knockout models and by muscle transient transfection experiments. Although this pathway is essential for muscle growth during development and regeneration, its role in adult muscle response to mechanical load is less clear. A full understanding of the operation of this pathway could help to design molecularly targeted therapeutics aimed at preventing muscle wasting, which occurs in a variety of pathologic contexts and in the course of aging.

  16. Modeling Ignition of a Heptane Isomer: Improved Thermodynamics, Reaction Pathways, Kinetic, and Rate Rule Optimizations for 2-Methylhexane

    KAUST Repository

    Mohamed, Samah; Cai, Liming; Khaled, Fathi; Banyon, Colin; Wang, Zhandong; Rachidi, Mariam El; Pitsch, Heinz; Curran, Henry J.; Farooq, Aamir; Sarathy, Mani

    2016-01-01

    Accurate chemical kinetic combustion models of lightly branched alkanes (e.g., 2-methylalkanes) are important to investigate the combustion behavior of real fuels. Improving the fidelity of existing kinetic models is a necessity, as new experiments and advanced theories show inaccuracies in certain portions of the models. This study focuses on updating thermodynamic data and the kinetic reaction mechanism for a gasoline surrogate component, 2-methylhexane, based on recently published thermodynamic group values and rate rules derived from quantum calculations and experiments. Alternative pathways for the isomerization of peroxy-alkylhydroperoxide (OOQOOH) radicals are also investigated. The effects of these updates are compared against new high-pressure shock tube and rapid compression machine ignition delay measurements. It is shown that rate constant modifications are required to improve agreement between kinetic modeling simulations and experimental data. We further demonstrate the ability to optimize the kinetic model using both manual and automated techniques for rate parameter tunings to improve agreement with the measured ignition delay time data. Finally, additional low temperature chain branching reaction pathways are shown to improve the model’s performance. The present approach to model development provides better performance across extended operating conditions while also strengthening the fundamental basis of the model.

  17. Modeling Ignition of a Heptane Isomer: Improved Thermodynamics, Reaction Pathways, Kinetic, and Rate Rule Optimizations for 2-Methylhexane

    KAUST Repository

    Mohamed, Samah

    2016-03-21

    Accurate chemical kinetic combustion models of lightly branched alkanes (e.g., 2-methylalkanes) are important to investigate the combustion behavior of real fuels. Improving the fidelity of existing kinetic models is a necessity, as new experiments and advanced theories show inaccuracies in certain portions of the models. This study focuses on updating thermodynamic data and the kinetic reaction mechanism for a gasoline surrogate component, 2-methylhexane, based on recently published thermodynamic group values and rate rules derived from quantum calculations and experiments. Alternative pathways for the isomerization of peroxy-alkylhydroperoxide (OOQOOH) radicals are also investigated. The effects of these updates are compared against new high-pressure shock tube and rapid compression machine ignition delay measurements. It is shown that rate constant modifications are required to improve agreement between kinetic modeling simulations and experimental data. We further demonstrate the ability to optimize the kinetic model using both manual and automated techniques for rate parameter tunings to improve agreement with the measured ignition delay time data. Finally, additional low temperature chain branching reaction pathways are shown to improve the model’s performance. The present approach to model development provides better performance across extended operating conditions while also strengthening the fundamental basis of the model.

  18. Conical Intersections, charge localization, and photoisomerization pathway selection in a minimal model of a degenerate monomethine dye

    International Nuclear Information System (INIS)

    Olsen, Seth; McKenzie, Ross H.

    2009-01-01

    We propose a minimal model Hamiltonian for the electronic structure of a monomethine dye, in order to describe the photoisomerization of such dyes. The model describes interactions between three diabatic electronic states, each of which can be associated with a valence bond structure. Monomethine dyes are characterized by a charge-transfer resonance; the indeterminacy of the single-double bonding structure dictated by the resonance is reflected in a duality of photoisomerization pathways corresponding to the different methine bonds. The possible multiplicity of decay channels complicates mechanistic models of the effect of the environment on fluorescent quantum yields, as well as coherent control strategies. We examine the extent and topology of intersection seams between the electronic states of the dye and how they relate to charge localization and selection between different decay pathways. We find that intersections between the S 1 and S 0 surfaces only occur for large twist angles. In contrast, S 2 /S 1 intersections can occur near the Franck-Condon region. When the molecule has left-right symmetry, all intersections are associated with con- or disrotations and never with single bond twists. For asymmetric molecules (i.e., where the bridge couples more strongly to one end) the S 2 and S 1 surfaces bias torsion about different bonds. Charge localization and torsion pathway biasing are correlated. We relate our observations with several recent experimental and theoretical results, which have been obtained for dyes with similar structure.

  19. Development of a Novel Quantitative Adverse Outcome Pathway Predictive Model for Lung Cancer

    Science.gov (United States)

    Traditional methods for carcinogenicity testing are resource-intensive, retrospective, and time consuming. An increasing testing burden has generated interest in the adverse outcome pathway (AOP) concept as a tool to evaluate chemical safety in a more efficient, rapid and effecti...

  20. Shape of scoria cones on Mars: Insights from numerical modeling of ballistic pathways

    Czech Academy of Sciences Publication Activity Database

    Brož, Petr; Čadek, O.; Hauber, E.; Rossi, A. P.

    2014-01-01

    Roč. 406, November (2014), s. 14-23 ISSN 0012-821X Institutional support: RVO:67985530 Keywords : Mars * explosive volcanism * scoria cone * ballistic pathway Subject RIV: DC - Siesmology, Volcanology, Earth Structure Impact factor: 4.734, year: 2014

  1. Three Models of Anthrax Toxin Effects on the MAP-Kinase Pathway and Macrophage Survival

    Science.gov (United States)

    2008-03-01

    2005). Apic, Gordana, Tijana Ignjatovic, Scott Boyer , and Robert B. Russell. “Illuminating drug discovery with biological pathways,” FEBS Letters...Molecular Biology Reviews, 68(2): 320–344 (June 2004). Sauro, Herbert M. and Boris N. Kholodenko. “Quantitative analysis of signaling networks

  2. Focal Solute Trapping and Global Glymphatic Pathway Impairment in a Murine Model of Multiple Microinfarcts

    DEFF Research Database (Denmark)

    Wang, Minghuan; Ding, Fengfei; Deng, SaiYue

    2017-01-01

    for Alzheimer's disease is unclear. The glymphatic system, which is a brain-wide perivascular network that supports the recirculation of CSF through the brain parenchyma, facilitates the clearance of interstitial solutes including amyloid β and tau. We investigated whether glymphatic pathway function.......SIGNIFICANCE STATEMENT Microinfarcts, small (glymphatic system is a brain-wide network of channels surrounding brain...

  3. Catalytic Hydrotreatment of Fast Pyrolysis Oil : Model Studies on Reaction Pathways for the Carbohydrate Fraction

    NARCIS (Netherlands)

    Wildschut, J.; Arentz, J.; Rasrendra, C. B.; Venderbosch, R. H.; Heeres, H. J.

    2009-01-01

    Fast pyrolysis oil can be upgraded by a catalytic hydrotreatment (250-400 degrees C, 100-200 bar) using heterogeneous catalysts such as Ru/C to hydrocarbon-like products that can serve as liquid transportation fuels. Insight into the complex reaction pathways of the various component fractions

  4. STEP-TRAMM - A modeling interface for simulating localized rainfall induced shallow landslides and debris flow runout pathways

    Science.gov (United States)

    Or, D.; von Ruette, J.; Lehmann, P.

    2017-12-01

    Landslides and subsequent debris-flows initiated by rainfall represent a common natural hazard in mountainous regions. We integrated a landslide hydro-mechanical triggering model with a simple model for debris flow runout pathways and developed a graphical user interface (GUI) to represent these natural hazards at catchment scale at any location. The STEP-TRAMM GUI provides process-based estimates of the initiation locations and sizes of landslides patterns based on digital elevation models (SRTM) linked with high resolution global soil maps (SoilGrids 250 m resolution) and satellite based information on rainfall statistics for the selected region. In the preprocessing phase the STEP-TRAMM model estimates soil depth distribution to supplement other soil information for delineating key hydrological and mechanical properties relevant to representing local soil failure. We will illustrate this publicly available GUI and modeling platform to simulate effects of deforestation on landslide hazards in several regions and compare model outcome with satellite based information.

  5. Identifying the Gene Signatures from Gene-Pathway Bipartite Network Guarantees the Robust Model Performance on Predicting the Cancer Prognosis

    Directory of Open Access Journals (Sweden)

    Li He

    2014-01-01

    Full Text Available For the purpose of improving the prediction of cancer prognosis in the clinical researches, various algorithms have been developed to construct the predictive models with the gene signatures detected by DNA microarrays. Due to the heterogeneity of the clinical samples, the list of differentially expressed genes (DEGs generated by the statistical methods or the machine learning algorithms often involves a number of false positive genes, which are not associated with the phenotypic differences between the compared clinical conditions, and subsequently impacts the reliability of the predictive models. In this study, we proposed a strategy, which combined the statistical algorithm with the gene-pathway bipartite networks, to generate the reliable lists of cancer-related DEGs and constructed the models by using support vector machine for predicting the prognosis of three types of cancers, namely, breast cancer, acute myeloma leukemia, and glioblastoma. Our results demonstrated that, combined with the gene-pathway bipartite networks, our proposed strategy can efficiently generate the reliable cancer-related DEG lists for constructing the predictive models. In addition, the model performance in the swap analysis was similar to that in the original analysis, indicating the robustness of the models in predicting the cancer outcomes.

  6. Histological evidence of reproductive activity in lizards from the APM Manso, Chapada dos Guimarães, Mato Grosso State, Brazil - doi: 10.4025/actascibiolsci.v34i3.9228

    Directory of Open Access Journals (Sweden)

    Adelina Ferreira

    2012-06-01

    Full Text Available The construction of dams causes major impacts on fauna by changing or eliminating irreversibly their habitats. The resulting changes lead to deep potential modifications on reproductive biology and population structure of lizards, snakes and amphisbaenas. The reservoir in the Multiple Use Area of Manso (APM-Manso is located near to Chapada dos Guimarães National Park, in Mato Grosso State. We analyzed comparatively the male gonads of Anolis meridionalis, Colobosaura modesta, Cercosaura ocellata, Cnemidophorus ocellifer, Hoplocercus spinosus, Bachia bresslaui, Mabuya frenata, Micrablepharus atticolus and Tropidurus oreadicus, from APM-Manso, aiming to verify possible changes in the reproductive success according to environmental changes. Before the impoundment  A. meridionalis, Colobosaura modesta, Cercosaura ocellata, M. atticolus and T. oreadicus showed up reproductive. However, during the impoundment period they presented changes in seminiferous tubules, evidenced by the absence of spermatids and spermatozoids. B. bresslaui and M. frenata had no differences in the seminiferous tubules before and after the impoundment, being reproductive in both moments. The damming and the formation of the lake of Manso reservoir may have interfered on the reproduction of some lizards species, especially if the reproductive cycle is regulated by the rainfall of the habitat. 

  7. The Wnt signalling pathway is upregulated in an in vitro model of acquired tamoxifen resistant breast cancer

    International Nuclear Information System (INIS)

    Loh, Yan Ni; Hedditch, Ellen L; Baker, Laura A; Jary, Eve; Ward, Robyn L; Ford, Caroline E

    2013-01-01

    Acquired resistance to Tamoxifen remains a critical problem in breast cancer patient treatment, yet the underlying causes of resistance have not been fully elucidated. Abberations in the Wnt signalling pathway have been linked to many human cancers, including breast cancer, and appear to be associated with more metastatic and aggressive types of cancer. Here, our aim was to investigate if this key pathway was involved in acquired Tamoxifen resistance, and could be targeted therapeutically. An in vitro model of acquired Tamoxifen resistance (named TamR) was generated by growing the estrogen receptor alpha (ER) positive MCF7 breast cancer cell line in increasing concentrations of Tamoxifen (up to 5 uM). Alterations in the Wnt signalling pathway and epithelial to mesenchymal transition (EMT) in response to Tamoxifen and treatment with the Wnt inhibitor, IWP-2 were measured via quantitative RT-PCR (qPCR) and TOP/FOP Wnt reporter assays. Resistance to Tamoxifen, and effects of IWP-2 treatment were determined by MTT proliferation assays. TamR cells exhibited increased Wnt signalling as measured via the TOP/FOP Wnt luciferase reporter assays. Genes associated with both the β-catenin dependent (AXIN2, MYC, CSNK1A1) and independent arms (ROR2, JUN), as well as general Wnt secretion (PORCN) of the Wnt signalling pathway were upregulated in the TamR cells compared to the parental MCF7 cell line. Treatment of the TamR cell line with human recombinant Wnt3a (rWnt3a) further increased the resistance of both MCF7 and TamR cells to the anti-proliferative effects of Tamoxifen treatment. TamR cells demonstrated increased expression of EMT markers (VIM, TWIST1, SNAI2) and decreased CDH1, which may contribute to their resistance to Tamoxifen. Treatment with the Wnt inhibitor, IWP-2 inhibited cell proliferation and markers of EMT. These data support the role of the Wnt signalling pathway in acquired resistance to Tamoxifen. Further research into the mechanism by which activated Wnt

  8. Use of a simplified pathways model to improve the environmental surveillance program at the radioactive waste management complex of the Idaho National Engineering Laboratory (INEL)

    International Nuclear Information System (INIS)

    Case, M.J.; Rope, S.K.

    1985-01-01

    Systems analysis, including a simple pathways model based on first-order kinetics, is a useful way to design or improve environmental monitoring networks. This method allows investigators and administrators to consider interactions that may be occurring in the system and provides guidance in determining the need to collect data on various system components and processes. A simplified pathways model of radionuclide movement from low-level waste and transuranic waste buried at the Radioactive Waste Management Complex was developed (1) to identify critical pathways that should be monitored and (2) to identify key input parameters that need investigation by special studies. The model was modified from the Savannah River Laboratory DOSTOMAN code. Site-specific data were used in the model, if available. Physical and biological pathways include airborne and waterborne transport of surface soil, subsurface migration to the aquifer, waste container degradation, plant uptake, small mammal burrowing, and a few simplified food chain pathways. The model was run using a set of radionuclides determined to be significant in terms of relative hazard. Critical transport pathways which should be monitored were selected based on relative influence on model results. Key input parameters were identified for possible special studies by evaluating the sensitivity of model response to the parameters used to define transport pathways. A description of the approaches used and the guidance recommended to improve the environmental surveillance program are presented in this paper. 5 references, 1 figure, 2 tables

  9. PATHWAY: a dynamic foodchain model to predict radionuclide ingestion after fallout deposition. Final report, September 17, 1979-December 31, 1985

    International Nuclear Information System (INIS)

    Whicker, F.W.; Kirchner, T.B.

    1986-01-01

    This paper describes the structure and basis for parameter values of a computerized foodchain transport model for radionuclides. The model, called ''PATHWAY,'' estimates the time-integrated intake by humans of twenty radionuclides after a single deposition of radioactive material from the atmosphere to the landscape. The model solves a set of differential equations to estimate the inventories and concentrations of radionuclides in three soil layers and numerous types of vegetation, animal tissues and animal products as a function of time following a deposition event. Dynamic processes considered in the model include foliar interception, weathering and absorption; plant growth, uptake, harvest and senescence; soil resuspension, percolation, leaching and tillage; radioactive decay; livestock ingestion, absorption, excretion; and etc. An age- and sex-specific human diet is embodied in the model to permit calculation of time-dependent radionuclide ingestion rates, which are then numerically integrated. 3 figs., 10 tabs

  10. Youth at ultra high risk for psychosis: using the Revised Network Episode Model to examine pathways to mental health care.

    Science.gov (United States)

    Boydell, Katherine M; Volpe, Tiziana; Gladstone, Brenda M; Stasiulis, Elaine; Addington, Jean

    2013-05-01

    This paper aims to identify the ways in which youth at ultra high risk for psychosis access mental health services and the factors that advance or delay help seeking, using the Revised Network Episode Model (REV NEM) of mental health care. A case study approach documents help-seeking pathways, encompassing two qualitative interviews with 10 young people and 29 significant others. Theoretical propositions derived from the REV NEM are explored, consisting of the content, structure and function of the: (i) family; (ii) community and school; and (iii) treatment system. Although the aspects of the REV NEM are supported and shape pathways to care, we consider rethinking the model for help seeking with youth at ultra high risk for psychosis. The pathway concept is important to our understanding of how services and supports are received and experienced over time. Understanding this process and the strategies that support positive early intervention on the part of youth and significant others is critical. © 2012 Wiley Publishing Asia Pty Ltd.

  11. Effect of QSKL on MAPK and RhoA Pathways in a Rat Model of Heart Failure

    Directory of Open Access Journals (Sweden)

    Kai Xia

    2017-01-01

    Full Text Available Qishenkeli (QSKL is one of the Chinese medicine formulae for treating heart failure and has been shown to have an antifibrotic effect. However, the mechanism of its therapeutic effects remains unclear. In this study, we aimed to explore whether QSKL could exert an antifibrotic effect by attenuating ras homolog family member A (RhoA and mitogen activated protein kinase (MAPK pathways. Rats were randomly divided into sham group, model group, QSKL group, and positive control group. Heart failure was induced by ligation of the left ventricle anterior descending artery. Cardiac functions were measured by echocardiography and collagen deposition was assessed by Masson staining. Expressions of the key molecules involved in the RhoA and MAPK pathways were also measured. Twenty-one days after surgery, cardiac functions were severely impaired and collagen deposition was remarkable, while QSKL treatment could improve heart functions and alleviate collagen deposition. Further results demonstrated that the effects may be mediated by suppressing expressions of extracellular signal-regulated kinase (ERK and c-Jun N-terminal kinase (JNK. Moreover, expressions of RhoA, Rho-associated protein kinase 1/2 (ROCK1/2, and phosphorylated myosin light chain (p-MLC were also downregulated by QSKL compared with the model group. The cardioprotective mechanism of QSKL on heart failure is probably mediated by regulating both the MAPK and RhoA signaling pathways.

  12. Cerebrospinal Fluid and Interstitial Fluid Motion via the Glymphatic Pathway Modelled by Optimal Mass Transport

    OpenAIRE

    Benveniste, Helene; Nedergaard, Maikan; Lee, Hedok; Gao, Yi; Tannenbaum, Allen; Ratner, Vadim

    2016-01-01

    It was recently shown that the brain-wide cerebrospinal fluid (CSF) and interstitial fluid exchange system designated the `glymphatic pathway' plays a key role in removing waste products from the brain, similarly to the lymphatic system in other body organs [1,2]. It is therefore important to study the flow patterns of glymphatic transport through the live brain in order to better understand its functionality in normal and pathological states. Unlike blood, the CSF does not flow rapidly throu...

  13. A thermodynamic solution model for calcium carbonate: Towards an understanding of multi-equilibria precipitation pathways

    OpenAIRE

    Donnet, Marcel; Bowen, Paul; Lemaître, Jacques

    2009-01-01

    Thermodynamic solubility calculations are normally only related to thermodynamic equilibria in solution. In this paper, we extend the use of such solubility calculations to help elucidate possible precipitation reaction pathways during the entire reaction. We also estimate the interfacial energy of particles using only solubility data by a modification of Mersmann’s approach. We have carried this out by considering precipitation reactions as a succession of small quasi-equilibrium states. Thu...

  14. Modeling most likely pathways for smuggling radioactive and special nuclear materials on a worldwide multimodal transportation network

    Energy Technology Data Exchange (ETDEWEB)

    Saeger, Kevin J [Los Alamos National Laboratory; Cuellar, Leticia [Los Alamos National Laboratory

    2010-01-01

    Nuclear weapons proliferation is an existing and growing worldwide problem. To help with devising strategies and supporting decisions to interdict the transport of nuclear material, we developed the Pathway Analysis, Threat Response and Interdiction Options Tool (PATRIOT) that provides an analytical approach for evaluating the probability that an adversary smuggling radioactive or special nuclear material will be detected during transit. We incorporate a global, multi-modal transportation network, explicit representation of designed and serendipitous detection opportunities, and multiple threat devices, material types, and shielding levels. This paper presents the general structure of PATRIOT, and focuses on the theoretical framework used to model the reliabilities of all network components that are used to predict the most likely pathways to the target.

  15. Modeling most likely pathways for smuggling radioactive and special nuclear materials on a worldwide multi-modal transportation network

    Energy Technology Data Exchange (ETDEWEB)

    Saeger, Kevin J [Los Alamos National Laboratory; Cuellar, Leticia [Los Alamos National Laboratory

    2010-10-28

    Nuclear weapons proliferation is an existing and growing worldwide problem. To help with devising strategies and supporting decisions to interdict the transport of nuclear material, we developed the Pathway Analysis, Threat Response and Interdiction Options Tool (PATRIOT) that provides an analytical approach for evaluating the probability that an adversary smuggling radioactive or special nuclear material will be detected during transit. We incorporate a global, multi-modal transportation network, explicit representation of designed and serendipitous detection opportunities, and multiple threat devices, material types, and shielding levels. This paper presents the general structure of PATRIOT, all focuses on the theoretical framework used to model the reliabilities of all network components that are used to predict the most likely pathways to the target.

  16. Global developmental gene expression and pathway analysis of normal brain development and mouse models of human neuronal migration defects.

    Directory of Open Access Journals (Sweden)

    Tiziano Pramparo

    2011-03-01

    Full Text Available Heterozygous LIS1 mutations are the most common cause of human lissencephaly, a human neuronal migration defect, and DCX mutations are the most common cause of X-linked lissencephaly. LIS1 is part of a protein complex including NDEL1 and 14-3-3ε that regulates dynein motor function and microtubule dynamics, while DCX stabilizes microtubules and cooperates with LIS1 during neuronal migration and neurogenesis. Targeted gene mutations of Lis1, Dcx, Ywhae (coding for 14-3-3ε, and Ndel1 lead to neuronal migration defects in mouse and provide models of human lissencephaly, as well as aid the study of related neuro-developmental diseases. Here we investigated the developing brain of these four mutants and wild-type mice using expression microarrays, bioinformatic analyses, and in vivo/in vitro experiments to address whether mutations in different members of the LIS1 neuronal migration complex lead to similar and/or distinct global gene expression alterations. Consistent with the overall successful development of the mutant brains, unsupervised clustering and co-expression analysis suggested that cell cycle and synaptogenesis genes are similarly expressed and co-regulated in WT and mutant brains in a time-dependent fashion. By contrast, focused co-expression analysis in the Lis1 and Ndel1 mutants uncovered substantial differences in the correlation among pathways. Differential expression analysis revealed that cell cycle, cell adhesion, and cytoskeleton organization pathways are commonly altered in all mutants, while synaptogenesis, cell morphology, and inflammation/immune response are specifically altered in one or more mutants. We found several commonly dysregulated genes located within pathogenic deletion/duplication regions, which represent novel candidates of human mental retardation and neurocognitive disabilities. Our analysis suggests that gene expression and pathway analysis in mouse models of a similar disorder or within a common pathway can

  17. Caesium-137 and strontium-90 in the food chains: model development using fallout data. [Pasture-cow-milk pathway

    Energy Technology Data Exchange (ETDEWEB)

    Haywood, S M [National Radiological Protection Board, Harwell (UK)

    1980-11-01

    The development of the models for the movement of /sup 137/Cs and /sup 90/Sr in the pasture-cow-milk pathway is briefly discussed. Using recorded deposition rates of these radionuclides as input to the basic model, it was found that the models for /sup 137/Cs and /sup 90/Sr in their initial form were found to predict higher levels of activity in milk than those recorded. The predicted contributions of the processes of root uptake into pasture grass and the resuspension of deposited activity on to pasture surfaces were shown to be responsible for much of the overestimation. Following a re-evaluation of all transfer parameters, major improvements in the quality of fit between the model predictions and measured levels of /sup 137/Cs and /sup 90/Sr in milk were obtained.

  18. Group spike-and-slab lasso generalized linear models for disease prediction and associated genes detection by incorporating pathway information.

    Science.gov (United States)

    Tang, Zaixiang; Shen, Yueping; Li, Yan; Zhang, Xinyan; Wen, Jia; Qian, Chen'ao; Zhuang, Wenzhuo; Shi, Xinghua; Yi, Nengjun

    2018-03-15

    Large-scale molecular data have been increasingly used as an important resource for prognostic prediction of diseases and detection of associated genes. However, standard approaches for omics data analysis ignore the group structure among genes encoded in functional relationships or pathway information. We propose new Bayesian hierarchical generalized linear models, called group spike-and-slab lasso GLMs, for predicting disease outcomes and detecting associated genes by incorporating large-scale molecular data and group structures. The proposed model employs a mixture double-exponential prior for coefficients that induces self-adaptive shrinkage amount on different coefficients. The group information is incorporated into the model by setting group-specific parameters. We have developed a fast and stable deterministic algorithm to fit the proposed hierarchal GLMs, which can perform variable selection within groups. We assess the performance of the proposed method on several simulated scenarios, by varying the overlap among groups, group size, number of non-null groups, and the correlation within group. Compared with existing methods, the proposed method provides not only more accurate estimates of the parameters but also better prediction. We further demonstrate the application of the proposed procedure on three cancer datasets by utilizing pathway structures of genes. Our results show that the proposed method generates powerful models for predicting disease outcomes and detecting associated genes. The methods have been implemented in a freely available R package BhGLM (http://www.ssg.uab.edu/bhglm/). nyi@uab.edu. Supplementary data are available at Bioinformatics online.

  19. Waste-to-wheel analysis of anaerobic-digestion-based renewable natural gas pathways with the GREET model.

    Energy Technology Data Exchange (ETDEWEB)

    Han, J.; Mintz, M.; Wang, M. (Energy Systems)

    2011-12-14

    In 2009, manure management accounted for 2,356 Gg or 107 billion standard cubic ft of methane (CH{sub 4}) emissions in the United States, equivalent to 0.5% of U.S. natural gas (NG) consumption. Owing to the high global warming potential of methane, capturing and utilizing this methane source could reduce greenhouse gas (GHG) emissions. The extent of that reduction depends on several factors - most notably, how much of this manure-based methane can be captured, how much GHG is produced in the course of converting it to vehicular fuel, and how much GHG was produced by the fossil fuel it might displace. A life-cycle analysis was conducted to quantify these factors and, in so doing, assess the impact of converting methane from animal manure into renewable NG (RNG) and utilizing the gas in vehicles. Several manure-based RNG pathways were characterized in the GREET (Greenhouse gases, Regulated Emissions, and Energy use in Transportation) model, and their fuel-cycle energy use and GHG emissions were compared to petroleum-based pathways as well as to conventional fossil NG pathways. Results show that despite increased total energy use, both fossil fuel use and GHG emissions decline for most RNG pathways as compared with fossil NG and petroleum. However, GHG emissions for RNG pathways are highly dependent on the specifics of the reference case, as well as on the process energy emissions and methane conversion factors assumed for the RNG pathways. The most critical factors are the share of flared controllable CH{sub 4} and the quantity of CH{sub 4} lost during NG extraction in the reference case, the magnitude of N{sub 2}O lost in the anaerobic digestion (AD) process and in AD residue, and the amount of carbon sequestered in AD residue. In many cases, data for these parameters are limited and uncertain. Therefore, more research is needed to gain a better understanding of the range and magnitude of environmental benefits from converting animal manure to RNG via AD.

  20. Waste-to-wheel analysis of anaerobic-digestion-based renewable natural gas pathways with the GREET model

    International Nuclear Information System (INIS)

    Han, J.; Mintz, M.; Wang, M.

    2011-01-01

    In 2009, manure management accounted for 2,356 Gg or 107 billion standard cubic ft of methane (CH 4 ) emissions in the United States, equivalent to 0.5% of U.S. natural gas (NG) consumption. Owing to the high global warming potential of methane, capturing and utilizing this methane source could reduce greenhouse gas (GHG) emissions. The extent of that reduction depends on several factors - most notably, how much of this manure-based methane can be captured, how much GHG is produced in the course of converting it to vehicular fuel, and how much GHG was produced by the fossil fuel it might displace. A life-cycle analysis was conducted to quantify these factors and, in so doing, assess the impact of converting methane from animal manure into renewable NG (RNG) and utilizing the gas in vehicles. Several manure-based RNG pathways were characterized in the GREET (Greenhouse gases, Regulated Emissions, and Energy use in Transportation) model, and their fuel-cycle energy use and GHG emissions were compared to petroleum-based pathways as well as to conventional fossil NG pathways. Results show that despite increased total energy use, both fossil fuel use and GHG emissions decline for most RNG pathways as compared with fossil NG and petroleum. However, GHG emissions for RNG pathways are highly dependent on the specifics of the reference case, as well as on the process energy emissions and methane conversion factors assumed for the RNG pathways. The most critical factors are the share of flared controllable CH 4 and the quantity of CH 4 lost during NG extraction in the reference case, the magnitude of N 2 O lost in the anaerobic digestion (AD) process and in AD residue, and the amount of carbon sequestered in AD residue. In many cases, data for these parameters are limited and uncertain. Therefore, more research is needed to gain a better understanding of the range and magnitude of environmental benefits from converting animal manure to RNG via AD.

  1. Rivaroxaban attenuates thrombosis by targeting the NF-κB signaling pathway in a rat model of deep venous thrombus.

    Science.gov (United States)

    Ma, Junhao; Li, Xinxi; Wang, Yang; Yang, Zhenwei; Luo, Jun

    2017-12-01

    Anticoagulant therapy is commonly used for the prevention and treatment of patients with deep venous thrombus. Evidence has shown that rivaroxaban is a potential oral anticoagulant drug for the acute treatment of venous thromboembolism. However, the rivaroxaban-mediated molecular mechanism involved in the progression of deep venous thrombosis has not been investigated. In the present study, we investigated the efficacy of rivaroxaban and the underlying signaling pathways in the prevention and treatment of rats with deep venous thrombosis. A rat model with deep vein thrombus formation was established and received treatment with rivaroxaban or PBS as control. The thrombin-activatable fibrinolysis inhibitor (TAFI) and plasminogen activator inhibitor-1 (PAI-1) were analyzed both in vitro and in vivo. The progression of thrombosis and stroke was evaluated after treatment with rivaroxaban or PBS. Nuclear factor-κB (NF-κB) signaling pathway in venous endothelial cells and in the rat model of deep venous thrombus was assessed. The therapeutic effects of rivaroxaban were evaluated as determined by changes in deep venous thrombosis in the rat model. Our results showed that rivaroxaban markedly inhibited TAFI and PAI-1 expression levels, neutrophils, tissue factor, neutrophil extracellular traps (NETs), myeloperoxidase and macrophages in venous endothelial cells and in the rat model of deep venous thrombus. Expression levels of ADP, PAIs, von Willebrand factor (vWF) and thromboxane were downregulated in vein endothelial cells and in serum from the experimental rats. Importantly, the incidences of inferior vena cava filter thrombus were protected by rivaroxaban during heparin-induced thrombolysis deep venous thrombosis in the rat model. We observed that activity of the NF-κB signaling pathway was inhibited by rivaroxaban in vein endothelial cells both in vitro and in vivo. Notably, immunohistology indicated that rivaroxaban attenuated deep venous thrombosis and the

  2. Characterization of subtle brain abnormalities in a mouse model of Hedgehog pathway antagonist-induced cleft lip and palate.

    Science.gov (United States)

    Lipinski, Robert J; Holloway, Hunter T; O'Leary-Moore, Shonagh K; Ament, Jacob J; Pecevich, Stephen J; Cofer, Gary P; Budin, Francois; Everson, Joshua L; Johnson, G Allan; Sulik, Kathleen K

    2014-01-01

    Subtle behavioral and cognitive deficits have been documented in patient cohorts with orofacial clefts (OFCs). Recent neuroimaging studies argue that these traits are associated with structural brain abnormalities but have been limited to adolescent and adult populations where brain plasticity during infancy and childhood may be a confounding factor. Here, we employed high resolution magnetic resonance microscopy to examine primary brain morphology in a mouse model of OFCs. Transient in utero exposure to the Hedgehog (Hh) signaling pathway antagonist cyclopamine resulted in a spectrum of facial dysmorphology, including unilateral and bilateral cleft lip and palate, cleft of the secondary palate only, and a non-cleft phenotype marked by midfacial hypoplasia. Relative to controls, cyclopamine-exposed fetuses exhibited volumetric differences in several brain regions, including hypoplasia of the pituitary gland and olfactory bulbs, hyperplasia of the forebrain septal region, and expansion of the third ventricle. However, in affected fetuses the corpus callosum was intact and normal division of the forebrain was observed. This argues that temporally-specific Hh signaling perturbation can result in typical appearing OFCs in the absence of holoprosencephaly--a condition classically associated with Hh pathway inhibition and frequently co-occurring with OFCs. Supporting the premise that some forms of OFCs co-occur with subtle brain malformations, these results provide a possible ontological basis for traits identified in clinical populations. They also argue in favor of future investigations into genetic and/or environmental modulation of the Hh pathway in the etiopathogenesis of orofacial clefting.

  3. AIR AND RADON PATHWAY MODELING FOR THE F-AREA TANK FARM

    International Nuclear Information System (INIS)

    Dixon, K; Mark Phifer, M

    2007-01-01

    The F-Area Tank Farm (FTF) is located within F-Area in the General Separations Area (GSA) of the Savannah River Site (SRS) as seen in Figure 1. The GSA contains the F and H Area Separations Facilities, the S-Area Defense Waste Processing Facility, the Z-Area Saltstone Facility, and the E-Area Low-Level Waste Disposal Facilities. The FTF is a nearly rectangular shaped area and comprises approximately 20 acres, which is bounded by SRS coordinates N 76,604.5 to N 77,560.0 and E 52,435.0 to E 53,369.0. SRS is in the process of preparing a Performance Assessment (PA) to support FTF closure. As part of the PA process, an analysis was conducted to evaluate the potential magnitude of gaseous release of radionuclides from the FTF over the 100-year institutional control period and 10,000-year post-closure compliance period. Specifically, an air and radon pathways analysis has been conducted to estimate the flux of volatile radionuclides and radon at the ground surface due to residual waste remaining in the tanks following closure. This analysis was used as the basis to estimate the dose to the maximally exposed individual (MEI) for the air pathway per Curie (Ci) of each radionuclide remaining in the combined FTF waste tanks. For the air pathway analysis, several gaseous radionuclides were considered. These included carbon-14 (C-14), chlorine-36 (Cl-36), iodine-129 (I-129), selenium-79 (Se-79), antimony-125 (Sb-125), tin-126 (Sn-126), tritium (H-3), and technetium-99 (Tc-99). The dose to the MEI was estimated at the SRS Boundary during the 100 year institutional control period. For the 10,000 year post closure compliance period, the dose to the MEI was estimated at the 100 m compliance point. For the radon pathway analysis, five parent radionuclides and their progeny were analyzed. These parent radionuclides included uranium-238 (U-238), plutonium-238 (Pu-238), uranium-234 (U-234), thorium-230 (Th-230), and radium-226 (Ra-226). The peak flux of radon-222 due to each parent

  4. Transcriptomic analysis in a Drosophila model identifies previously implicated and novel pathways in the therapeutic mechanism in neuropsychiatric disorders

    Directory of Open Access Journals (Sweden)

    Priyanka eSingh

    2011-03-01

    Full Text Available We have taken advantage of a newly described Drosophila model to gain insights into the potential mechanism of antiepileptic drugs (AEDs, a group of drugs that are widely used in the treatment of several neurological and psychiatric conditions besides epilepsy. In the recently described Drosophila model that is inspired by pentylenetetrazole (PTZ induced kindling epileptogenesis in rodents, chronic PTZ treatment for seven days causes a decreased climbing speed and an altered CNS transcriptome, with the latter mimicking gene expression alterations reported in epileptogenesis. In the model, an increased climbing speed is further observed seven days after withdrawal from chronic PTZ. We used this post-PTZ withdrawal regime to identify potential AED mechanism. In this regime, treatment with each of the five AEDs tested, namely, ethosuximide (ETH, gabapentin (GBP, vigabatrin (VGB, sodium valproate (NaVP and levetiracetam (LEV, resulted in rescuing of the altered climbing behavior. The AEDs also normalized PTZ withdrawal induced transcriptomic perturbation in fly heads; whereas AED untreated flies showed a large number of up- and down-regulated genes which were enriched in several processes including gene expression and cell communication, the AED treated flies showed differential expression of only a small number of genes that did not enrich gene expression and cell communication processes. Gene expression and cell communication related upregulated genes in AED untreated flies overrepresented several pathways - spliceosome, RNA degradation, and ribosome in the former category, and inositol phosphate metabolism, phosphatidylinositol signaling, endocytosis and hedgehog signaling in the latter. Transcriptome remodeling effect of AEDs was overall confirmed by microarray clustering that clearly separated the profiles of AED treated and untreated flies. Besides being consistent with previously implicated pathways, our results provide evidence for a role of

  5. A quantitative model of the major pathways for radiation-induced DNA double-strand break repair

    International Nuclear Information System (INIS)

    Belov, O.V.; Krasavin, E.A.; Lyashko, M.S.; Batmunkh, M.; Sweilam, N.H.

    2014-01-01

    We have developed a model approach to simulate the major pathways of DNA double-strand break (DSB) repair in mammalian and human cells. The proposed model shows a possible mechanistic explanation of the basic regularities of DSB processing through the nonhomologous end-joining (NHEJ), homologous recombination (HR), and single-strand annealing (SSA). It reconstructs the time-courses of radiation-induced foci specific to particular repair processes including the major intermediate stages. The model is validated for ionizing radiations of a wide range of linear energy transfer (0.2-236 keV/μm) including a relatively broad spectrum of heavy ions. The appropriate set of reaction rate constants was suggested to satisfy the kinetics of DSB rejoining for the considered types of exposure. The simultaneous assessment of three repair pathways allows one to describe their possible biological relations in response to radiation. With the help of the proposed approach, we reproduce several experimental data sets on γ-H2AX foci remaining in different types of cells including those defective in NHEJ, HR, or SSA functions.

  6. The role of the ubiquitination–proteasome pathway in breast cancer: Use of mouse models for analyzing ubiquitination processes

    International Nuclear Information System (INIS)

    Rossi, Sabrina; Loda, Massimo

    2003-01-01

    Turnover of several regulatory proteins results from targeted destruction via ubiquitination and subsequent degradation through the proteosome. The timely and irreversible degradation of critical regulators is essential for normal cellular function. The precise biochemical mechanisms that are involved in protein turnover by ubiquitin-mediated degradation have been elucidated using in vitro assays and cell culture systems. However, pathways that lead to ubiquitination of critical regulatory proteins in vivo are more complex, and have both temporal and tissue-specific differences. In vivo models will allow identification of substrates and enzymes of the ubiquitin–proteosome pathway that play important roles in selected tissues and diseases. In addition, assessment of the therapeutic efficacy of drugs designed to inhibit or enhance protein turnover by ubiquitination requires in vivo models. In the present review we describe selected examples of transgenic and knockout models of proteins that are known either to be regulated by ubiquitin-mediated degradation or to have a catalytic function in this process, and to play an important role in breast cancer. We outline the functions of these proteins in vivo and focus on knowledge gained in the comparison of in vivo behavior predicted from cell-free in vitro data or from experiments conducted in cell culture systems

  7. Creating Agent-Based Energy Transition Management Models That Can Uncover Profitable Pathways to Climate Change Mitigation

    Directory of Open Access Journals (Sweden)

    Auke Hoekstra

    2017-01-01

    Full Text Available The energy domain is still dominated by equilibrium models that underestimate both the dangers and opportunities related to climate change. In reality, climate and energy systems contain tipping points, feedback loops, and exponential developments. This paper describes how to create realistic energy transition management models: quantitative models that can discover profitable pathways from fossil fuels to renewable energy. We review the literature regarding agent-based economics, disruptive innovation, and transition management and determine the following requirements. Actors must be detailed, heterogeneous, interacting, learning, and strategizing. Technology should be represented as a detailed and heterogeneous portfolio that can develop in a bottom-up manner, using endogenous feedback loops. Assumptions about discount rates and the social cost of carbon should be configurable. The model should contain interactions between the global, national, local, and individual level. A review of modelling techniques shows that equilibrium models are unsuitable and that system dynamics and discrete event simulation are too limited. The agent-based approach is found to be uniquely suited for the complex adaptive sociotechnical systems that must be modelled. But the choice for agent-based models does not mean a rejection of other approaches because they can be accommodated within the agent-based framework. We conclude with practical guidelines.

  8. Selection of personalized patient therapy through the use of knowledge-based computational models that identify tumor-driving signal transduction pathways.

    Science.gov (United States)

    Verhaegh, Wim; van Ooijen, Henk; Inda, Márcia A; Hatzis, Pantelis; Versteeg, Rogier; Smid, Marcel; Martens, John; Foekens, John; van de Wiel, Paul; Clevers, Hans; van de Stolpe, Anja

    2014-06-01

    Increasing knowledge about signal transduction pathways as drivers of cancer growth has elicited the development of "targeted drugs," which inhibit aberrant signaling pathways. They require a companion diagnostic test that identifies the tumor-driving pathway; however, currently available tests like estrogen receptor (ER) protein expression for hormonal treatment of breast cancer do not reliably predict therapy response, at least in part because they do not adequately assess functional pathway activity. We describe a novel approach to predict signaling pathway activity based on knowledge-based Bayesian computational models, which interpret quantitative transcriptome data as the functional output of an active signaling pathway, by using expression levels of transcriptional target genes. Following calibration on only a small number of cell lines or cohorts of patient data, they provide a reliable assessment of signaling pathway activity in tumors of different tissue origin. As proof of principle, models for the canonical Wnt and ER pathways are presented, including initial clinical validation on independent datasets from various cancer types. ©2014 American Association for Cancer Research.

  9. Estimating environmental co-benefits of U.S. low-carbon pathways using an integrated assessment model with state-level resolution.

    Science.gov (United States)

    Ou, Yang; Shi, Wenjing; Smith, Steven J; Ledna, Catherine M; West, J Jason; Nolte, Christopher G; Loughlin, Daniel H

    2018-04-15

    There are many technological pathways that can lead to reduced carbon dioxide emissions. However, these pathways can have substantially different impacts on other environmental endpoints, such as air quality and energy-related water demand. This study uses an integrated assessment model with state-level resolution of the energy system to compare environmental impacts of alternative low-carbon pathways for the United States. One set of pathways emphasizes nuclear energy and carbon capture and storage, while another set emphasizes renewable energy, including wind, solar, geothermal power, and bioenergy. These are compared with pathways in which all technologies are available. Air pollutant emissions, mortality costs attributable to particulate matter smaller than 2.5 μm in diameter, and energy-related water demands are evaluated for 50% and 80% carbon dioxide reduction targets in 2050. The renewable low-carbon pathways require less water withdrawal and consumption than the nuclear and carbon capture pathways. However, the renewable low-carbon pathways modeled in this study produce higher particulate matter-related mortality costs due to greater use of biomass in residential heating. Environmental co-benefits differ among states because of factors such as existing technology stock, resource availability, and environmental and energy policies.

  10. mTOR pathway inhibition prevents neuroinflammation and neuronal death in a mouse model of cerebral palsy.

    Science.gov (United States)

    Srivastava, Isha N; Shperdheja, Jona; Baybis, Marianna; Ferguson, Tanya; Crino, Peter B

    2016-01-01

    Mammalian target of rapamycin (mTOR) pathway signaling governs cellular responses to hypoxia and inflammation including induction of autophagy and cell survival. Cerebral palsy (CP) is a neurodevelopmental disorder linked to hypoxic and inflammatory brain injury however, a role for mTOR modulation in CP has not been investigated. We hypothesized that mTOR pathway inhibition would diminish inflammation and prevent neuronal death in a mouse model of CP. Mouse pups (P6) were subjected to hypoxia-ischemia and lipopolysaccharide-induced inflammation (HIL), a model of CP causing neuronal injury within the hippocampus, periventricular white matter, and neocortex. mTOR pathway inhibition was achieved with rapamycin (an mTOR inhibitor; 5mg/kg) or PF-4708671 (an inhibitor of the downstream p70S6kinase, S6K, 75 mg/kg) immediately following HIL, and then for 3 subsequent days. Phospho-activation of the mTOR effectors p70S6kinase and ribosomal S6 protein and expression of hypoxia inducible factor 1 (HIF-1α) were assayed. Neuronal cell death was defined with Fluoro-Jade C (FJC) and autophagy was measured using Beclin-1 and LC3II expression. Iba-1 labeled, activated microglia were quantified. Neuronal death, enhanced HIF-1α expression, and numerous Iba-1 labeled, activated microglia were evident at 24 and 48 h following HIL. Basal mTOR signaling, as evidenced by phosphorylated-S6 and -S6K levels, was unchanged by HIL. Rapamycin or PF-4,708,671 treatment significantly reduced mTOR signaling, neuronal death, HIF-1α expression, and microglial activation, coincident with enhanced expression of Beclin-1 and LC3II, markers of autophagy induction. mTOR pathway inhibition prevented neuronal death and diminished neuroinflammation in this model of CP. Persistent mTOR signaling following HIL suggests a failure of autophagy induction, which may contribute to neuronal death in CP. These results suggest that mTOR signaling may be a novel therapeutic target to reduce neuronal cell death in

  11. Parameter-free methods distinguish Wnt pathway models and guide design of experiments

    KAUST Repository

    MacLean, Adam L.; Rosen, Zvi; Byrne, Helen M.; Harrington, Heather A.

    2015-01-01

    models can fit this time course. We appeal to algebraic methods (concepts from chemical reaction network theory and matroid theory) to analyze the models without recourse to specific parameter values. These approaches provide insight into aspects of Wnt

  12. Three Models of Anthrax Toxin Effects on the MAP-Kinase Pathway and Macrophage Survival

    National Research Council Canada - National Science Library

    Schneider, Daniel J

    2008-01-01

    .... This research modifies three published MAPK models to reflect this signal inhibition and to estimate a first-order reaction rate by fitting the models to published viability data for two macrophage...

  13. Biosphere modelling for a deep radioactive waste repository: site-specific consideration of the groundwater-soil pathway

    International Nuclear Information System (INIS)

    Grogan, H.A.; Baeyens, B.; Mueller, H.; Dorp, F. van

    1991-07-01

    Scenario evaluations indicate that groundwater is the most probable pathway for released radionuclides to reach the biosphere from a deep underground nuclear waste repository. This report considers a small valley in northern Switzerland where the transport of groundwater to surface soil might be possible. The hydrological situation has been examined to allow a system of compartments and fluxes for modelling this pathway with respect to the release of radionuclides from an underground repository to be produced. Assuming present day conditions the best estimate surface soil concentrations are calculated by dividing the soil into two layers (deep soil, surface soil) and assuming an annual upward flux of 10 mm from the groundwater through the two soil layers. A constant unit activity concentration is assumed for the radionuclides in the groundwater. It is concluded that the resultant best estimate values must still be considered to be biased on the conservative side, in view of the fact that the more typical situation is likely to be that no groundwater reaches the surface soil. Upper and lower estimates for the surface soil radionuclide concentrations are based on the parameter perturbation results which were carried out for three key parameters, i.e. precipitation surplus, upward flux and solid-liquid distribution coefficients (K d ). It is noted that attention must be given to the functional relationships which exist between various model parameters. Upper estimates for the surface soil concentration are determined assuming a higher annual upward flux (100 mm) as well as a more conservative K d value compared with the base case. This gives rise to surface soil concentrations more than two orders of magnitude higher than the best estimate values. The lower estimated are more easily assigned assuming that no activity reaches the surface soil via this pathway. (author) 18 figs., 4 tabs., refs

  14. Well-to-Wheels analysis of landfill gas-based pathways and their addition to the GREET model.

    Energy Technology Data Exchange (ETDEWEB)

    Mintz, M.; Han, J.; Wang, M.; Saricks, C.; Energy Systems

    2010-06-30

    Today, approximately 300 million standard cubic ft/day (mmscfd) of natural gas and 1600 MW of electricity are produced from the decomposition of organic waste at 519 U.S. landfills (EPA 2010a). Since landfill gas (LFG) is a renewable resource, this energy is considered renewable. When used as a vehicle fuel, compressed natural gas (CNG) produced from LFG consumes up to 185,000 Btu of fossil fuel and generates from 1.5 to 18.4 kg of carbon dioxide-equivalent (CO{sub 2}e) emissions per million Btu of fuel on a 'well-to-wheel' (WTW) basis. This compares with approximately 1.1 million Btu and 78.2 kg of CO{sub 2}e per million Btu for CNG from fossil natural gas and 1.2 million Btu and 97.5 kg of CO{sub 2}e per million Btu for petroleum gasoline. Because of the additional energy required for liquefaction, LFG-based liquefied natural gas (LNG) requires more fossil fuel (222,000-227,000 Btu/million Btu WTW) and generates more GHG emissions (approximately 22 kg CO{sub 2}e /MM Btu WTW) if grid electricity is used for the liquefaction process. However, if some of the LFG is used to generate electricity for gas cleanup and liquefaction (or compression, in the case of CNG), vehicle fuel produced from LFG can have no fossil fuel input and only minimal GHG emissions (1.5-7.7 kg CO{sub 2}e /MM Btu) on a WTW basis. Thus, LFG-based natural gas can be one of the lowest GHG-emitting fuels for light- or heavy-duty vehicles. This report discusses the size and scope of biomethane resources from landfills and the pathways by which those resources can be turned into and utilized as vehicle fuel. It includes characterizations of the LFG stream and the processes used to convert low-Btu LFG into high-Btu renewable natural gas (RNG); documents the conversion efficiencies and losses of those processes, the choice of processes modeled in GREET, and other assumptions used to construct GREET pathways; and presents GREET results by pathway stage. GREET estimates of well-to-pump (WTP

  15. Regional-scale brine migration along vertical pathways due to CO2 injection - Part 1: The participatory modeling approach

    Science.gov (United States)

    Scheer, Dirk; Konrad, Wilfried; Class, Holger; Kissinger, Alexander; Knopf, Stefan; Noack, Vera

    2017-06-01

    Saltwater intrusion into potential drinking water aquifers due to the injection of CO2 into deep saline aquifers is one of the potential hazards associated with the geological storage of CO2. Thus, in a site selection process, models for predicting the fate of the displaced brine are required, for example, for a risk assessment or the optimization of pressure management concepts. From the very beginning, this research on brine migration aimed at involving expert and stakeholder knowledge and assessment in simulating the impacts of injecting CO2 into deep saline aquifers by means of a participatory modeling process. The involvement exercise made use of two approaches. First, guideline-based interviews were carried out, aiming at eliciting expert and stakeholder knowledge and assessments of geological structures and mechanisms affecting CO2-induced brine migration. Second, a stakeholder workshop including the World Café format yielded evaluations and judgments of the numerical modeling approach, scenario selection, and preliminary simulation results. The participatory modeling approach gained several results covering brine migration in general, the geological model sketch, scenario development, and the review of the preliminary simulation results. These results were included in revised versions of both the geological model and the numerical model, helping to improve the analysis of regional-scale brine migration along vertical pathways due to CO2 injection.

  16. Cybernetic modeling based on pathway analysis for Penicillium chrysogenum fed-batch fermentation.

    Science.gov (United States)

    Geng, Jun; Yuan, Jingqi

    2010-08-01

    A macrokinetic model employing cybernetic methodology is proposed to describe mycelium growth and penicillin production. Based on the primordial and complete metabolic network of Penicillium chrysogenum found in the literature, the modeling procedure is guided by metabolic flux analysis and cybernetic modeling framework. The abstracted cybernetic model describes the transients of the consumption rates of the substrates, the assimilation rates of intermediates, the biomass growth rate, as well as the penicillin formation rate. Combined with the bioreactor model, these reaction rates are linked with the most important state variables, i.e., mycelium, substrate and product concentrations. Simplex method is used to estimate the sensitive parameters of the model. Finally, validation of the model is carried out with 20 batches of industrial-scale penicillin cultivation.

  17. Edaravone attenuates neuronal apoptosis in hypoxic-ischemic brain damage rat model via suppression of TRAIL signaling pathway.

    Science.gov (United States)

    Li, Chunyi; Mo, Zhihuai; Lei, Junjie; Li, Huiqing; Fu, Ruying; Huang, Yanxia; Luo, Shijian; Zhang, Lei

    2018-06-01

    Edaravone is a new type of oxygen free radical scavenger and able to attenuate various brain damage including hypoxic-ischemic brain damage (HIBD). This study was aimed at investigating the neuroprotective mechanism of edaravone in rat hypoxic-ischemic brain damage model and its correlation with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) signaling pathway. 75 seven-day-old Sprague-Dawley neonatal rats were equally divided into three groups: sham-operated group (sham), HIBD group and HIBD rats injected with edaravone (HIBD + EDA) group. Neurological severity and space cognitive ability of rats in each group were evaluated using Longa neurological severity score and Morris water maze testing. TUNEL assay and flow cytometry were used to determine brain cell apoptosis. Western blot was used to estimate the expression level of death receptor-5 (DR5), Fas-associated protein with death domain (FADD), caspase 8, B-cell lymphoma-2 (Bcl-2) and Bcl-2 associated X protein (Bax). In addition, immunofluorescence was performed to detect caspase 3. Edaravone reduced neurofunctional damage caused by HIBD and improved the cognitive capability of rats. The above experiment results suggested that edaravone could down-regulate the expression of active caspase 3 protein, thereby relieving neuronal apoptosis. Taken together, edaravone could attenuate neuronal apoptosis in rat hypoxic-ischemic brain damage model via suppression of TRAIL signaling pathway, which also suggested that edaravone might be an effective therapeutic strategy for HIBD clinical treatment. Copyright © 2018 Elsevier Ltd. All rights reserved.

  18. Monitoring UV-induced signalling pathways in an ex vivo skin organ culture model using phospho-antibody array.

    Science.gov (United States)

    Lenain, Christelle; Gamboa, Bastien; Perrin, Agnes; Séraïdaris, Alexia; Bertino, Béatrice; Rival, Yves; Bernardi, Mathieu; Piwnica, David; Méhul, Bruno

    2018-05-01

    We investigated UV-induced signalling in an ex vivo skin organ culture model using phospho-antibody array. Phosphorylation modulations were analysed in time-course experiments following exposure to solar-simulated UV and validated by Western blot analyses. We found that UV induced P-p38 and its substrates, P-ERK1/2 and P-AKT, which were previously shown to be upregulated by UV in cultured keratinocytes and in vivo human skin. This indicates that phospho-antibody array applied to ex vivo skin organ culture is a relevant experimental system to investigate signalling events following perturbations. As the identified proteins are components of pathways implicated in skin tumorigenesis, UV-exposed skin organ culture model could be used to investigate the effect on these pathways of NMSC cancer drug candidates. In addition, we found that phospho-HCK is induced upon UV exposure, producing a new candidate for future studies investigating its role in the skin response to UV and UV-induced carcinogenesis. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  19. Exercise Activates p53 and Negatively Regulates IGF-1 Pathway in Epidermis within a Skin Cancer Model.

    Science.gov (United States)

    Yu, Miao; King, Brenee; Ewert, Emily; Su, Xiaoyu; Mardiyati, Nur; Zhao, Zhihui; Wang, Weiqun

    2016-01-01

    Exercise has been previously reported to lower cancer risk through reducing circulating IGF-1 and IGF-1-dependent signaling in a mouse skin cancer model. This study aims to investigate the underlying mechanisms by which exercise may down-regulate the IGF-1 pathway via p53 and p53-related regulators in the skin epidermis. Female SENCAR mice were pair-fed an AIN-93 diet with or without 10-week treadmill exercise at 20 m/min, 60 min/day and 5 days/week. Animals were topically treated with TPA 2 hours before sacrifice and the target proteins in the epidermis were analyzed by both immunohistochemistry and Western blot. Under TPA or vehicle treatment, MDM2 expression was significantly reduced in exercised mice when compared with sedentary control. Meanwhile, p53 was significantly elevated. In addition, p53-transcriptioned proteins, i.e., p21, IGFBP-3, and PTEN, increased in response to exercise. There was a synergy effect between exercise and TPA on the decreased MDM2 and increased p53, but not p53-transcripted proteins. Taken together, exercise appeared to activate p53, resulting in enhanced expression of p21, IGFBP-3, and PTEN that might induce a negative regulation of IGF-1 pathway and thus contribute to the observed cancer prevention by exercise in this skin cancer model.

  20. Comparison of different two-pathway models for describing the combined effect of DO and nitrite on the nitrous oxide production by ammonia-oxidizing bacteria.

    Science.gov (United States)

    Lang, Longqi; Pocquet, Mathieu; Ni, Bing-Jie; Yuan, Zhiguo; Spérandio, Mathieu

    2017-02-01

    The aim of this work is to compare the capability of two recently proposed two-pathway models for predicting nitrous oxide (N 2 O) production by ammonia-oxidizing bacteria (AOB) for varying ranges of dissolved oxygen (DO) and nitrite. The first model includes the electron carriers whereas the second model is based on direct coupling of electron donors and acceptors. Simulations are confronted to extensive sets of experiments (43 batches) from different studies with three different microbial systems. Despite their different mathematical structures, both models could well and similarly describe the combined effect of DO and nitrite on N 2 O production rate and emission factor. The model-predicted contributions for nitrifier denitrification pathway and hydroxylamine pathway also matched well with the available isotopic measurements. Based on sensitivity analysis, calibration procedures are described and discussed for facilitating the future use of those models.

  1. Use of the food-chain model FOOD III and the soil model SCEMR to assess irrigation as a biosphere pathway

    International Nuclear Information System (INIS)

    Sheppard, S.C.

    1985-02-01

    Irrigation of contaminated water onto crop land is a relatively direct pathway for radionuclides to deliver a radiation dose to man. Irrigation was not originally included in the SYVAC assessment model for the Precambrian Shield because no irrigation is currently practised in the region. This report re-evaluates this decision. An analysis of meteorological data shows that crop yield in northern Ontario would benefit from irrigation. Thus, incentives are present for subsistence-scale, and perhaps commercial-scale, irrigation of surface or well water. A food-chain analysis indicated that irrigation with contaminated water could deliver a dose comparable to direct consumption (drinking) of the same water, for some radionuclides. Long-term contamination of soil through irrigation was predicted to be a substantial hazard, even when soil leaching was incorporated into the food-chain model. This report presents parameter estimates that could be used to incorporate irrigation as a pathway in the SYVAC code and will constitute the basis for further decisions concerning this pathway

  2. Moringin activates Wnt canonical pathway by inhibiting GSK3β in a mouse model of experimental autoimmune encephalomyelitis

    Directory of Open Access Journals (Sweden)

    Giacoppo S

    2016-10-01

    Full Text Available Sabrina Giacoppo,1 Thangavelu Soundara Rajan,1 Gina Rosalinda De Nicola,2 Renato Iori,2 Placido Bramanti,1 Emanuela Mazzon1 1IRCCS Centre Neurolesi “Bonino-Pulejo”, Messina, Italy; 2Council for Agricultural Research and Economics, Research Centre for Industrial Crops (CREA-CIN, Bologna, Italy Abstract: Aberrant canonical Wnt–β-catenin signaling has been reported in multiple sclerosis (MS, although the results are controversial. The present study aimed to examine the role of the Wnt–β-catenin pathway in experimental MS and also to test moringin (4-[α-L-rhamnopyranosyloxy]-benzyl isothiocyanate, resulting from exogenous myrosinase hydrolysis of the natural phytochemical glucomoringin 4(α-L-rhamnosyloxy-benzyl glucosinolate as a modulator of neuroinflammation via the β-catenin–PPARγ axis. Experimental autoimmune encephalomyelitis (EAE, the most common model of MS, was induced in C57BL/6 mice by immunization with MOG35–55. Released moringin (10 mg/kg glucomoringin +5 µL myrosinase/mouse was administered daily for 1 week before EAE induction and continued until mice were killed on day 28 after EAE induction. Our results clearly showed that the Wnt–β-catenin pathway was downregulated in the EAE model, whereas moringin pretreatment was able to avert this. Moringin pretreatment normalizes the aberrant Wnt–β-catenin pathway, resulting in GSK3β inhibition and β-catenin upregulation, which regulates T-cell activation (CD4 and FoxP3, suppresses the main inflammatory mediators (IL-1β, IL-6, and COX2, through activation of PPARγ. In addition, moringin attenuates apoptosis by reducing the expression of the Fas ligand and cleaved caspase 9, and in parallel increases antioxidant Nrf2 expression in EAE mice. Taken together, our results provide an interesting discovery in identifying moringin as a modulator of the Wnt–β-catenin signaling cascade and as a new potential therapeutic target for MS treatment. Keywords: Wnt

  3. How Adverse Outcome Pathways Can Aid the Development and Use of Computational Prediction Models for Regulatory Toxicology

    Energy Technology Data Exchange (ETDEWEB)

    Wittwehr, Clemens; Aladjov, Hristo; Ankley, Gerald; Byrne, Hugh J.; de Knecht, Joop; Heinzle, Elmar; Klambauer, Günter; Landesmann, Brigitte; Luijten, Mirjam; MacKay, Cameron; Maxwell, Gavin; Meek, M. E. (Bette); Paini, Alicia; Perkins, Edward; Sobanski, Tomasz; Villeneuve, Dan; Waters, Katrina M.; Whelan, Maurice

    2016-12-19

    Efforts are underway to transform regulatory toxicology and chemical safety assessment from a largely empirical science based on direct observation of apical toxicity outcomes in whole organism toxicity tests to a predictive one in which outcomes and risk are inferred from accumulated mechanistic understanding. The adverse outcome pathway (AOP) framework has emerged as a systematic approach for organizing knowledge that supports such inference. We argue that this systematic organization of knowledge can inform and help direct the design and development of computational prediction models that can further enhance the utility of mechanistic and in silico data for chemical safety assessment. Examples of AOP-informed model development and its application to the assessment of chemicals for skin sensitization and multiple modes of endocrine disruption are provided. The role of problem formulation, not only as a critical phase of risk assessment, but also as guide for both AOP and complementary model development described. Finally, a proposal for actively engaging the modeling community in AOP-informed computational model development is made. The contents serve as a vision for how AOPs can be leveraged to facilitate development of computational prediction models needed to support the next generation of chemical safety assessment.

  4. Extending and Applying Spartan to Perform Temporal Sensitivity Analyses for Predicting Changes in Influential Biological Pathways in Computational Models.

    Science.gov (United States)

    Alden, Kieran; Timmis, Jon; Andrews, Paul S; Veiga-Fernandes, Henrique; Coles, Mark

    2017-01-01

    Through integrating real time imaging, computational modelling, and statistical analysis approaches, previous work has suggested that the induction of and response to cell adhesion factors is the key initiating pathway in early lymphoid tissue development, in contrast to the previously accepted view that the process is triggered by chemokine mediated cell recruitment. These model derived hypotheses were developed using spartan, an open-source sensitivity analysis toolkit designed to establish and understand the relationship between a computational model and the biological system that model captures. Here, we extend the functionality available in spartan to permit the production of statistical analyses that contrast the behavior exhibited by a computational model at various simulated time-points, enabling a temporal analysis that could suggest whether the influence of biological mechanisms changes over time. We exemplify this extended functionality by using the computational model of lymphoid tissue development as a time-lapse tool. By generating results at twelve- hour intervals, we show how the extensions to spartan have been used to suggest that lymphoid tissue development could be biphasic, and predict the time-point when a switch in the influence of biological mechanisms might occur.

  5. Human Models for Analysis of Pathways (H–MAPs) Center

    Data.gov (United States)

    Federal Laboratory Consortium — The need for human, organotypic culture models coupled with the requirements of contemporary toxin screening (i.e. reproducibility, high throughput, transferability...

  6. Production, pathways and budgets of melts in mid-ocean ridges: An enthalpy based thermo-mechanical model

    Science.gov (United States)

    Mandal, Nibir; Sarkar, Shamik; Baruah, Amiya; Dutta, Urmi

    2018-04-01

    Using an enthalpy based thermo-mechanical model we provide a theoretical evaluation of melt production beneath mid-ocean ridges (MORs), and demonstrate how the melts subsequently develop their pathways to sustain the major ridge processes. Our model employs a Darcy idealization of the two-phase (solid-melt) system, accounting enthalpy (ΔH) as a function of temperature dependent liquid fraction (ϕ). Random thermal perturbations imposed in this model set in local convection that drive melts to flow through porosity controlled pathways with a typical mushroom-like 3D structure. We present across- and along-MOR axis model profiles to show the mode of occurrence of melt-rich zones within mushy regions, connected to deeper sources by single or multiple feeders. The upwelling of melts experiences two synchronous processes: 1) solidification-accretion, and 2) eruption, retaining a large melt fraction in the framework of mantle dynamics. Using a bifurcation analysis we determine the threshold condition for melt eruption, and estimate the potential volumes of eruptible melts (∼3.7 × 106 m3/yr) and sub-crustal solidified masses (∼1-8.8 × 106 m3/yr) on an axis length of 500 km. The solidification process far dominates over the eruption process in the initial phase, but declines rapidly on a time scale (t) of 1 Myr. Consequently, the eruption rate takes over the solidification rate, but attains nearly a steady value as t > 1.5 Myr. We finally present a melt budget, where a maximum of ∼5% of the total upwelling melt volume is available for eruption, whereas ∼19% for deeper level solidification; the rest continue to participate in the sub-crustal processes.

  7. Plasmin-dependent proteolysis of tissue factor pathway inhibitor in a mouse model of endotoxemia.

    Science.gov (United States)

    Lupu, C; Herlea, O; Tang, H; Lijnen, R H; Lupu, F

    2013-01-01

    The development of a procoagulant state in sepsis, owing to aberrant expression of tissue factor (TF) and a sharp decrease in the level of its major inhibitor, TF pathway inhibitor (TFPI), could lead to microthrombotic organ failure. The mechanism for the decline in TFPI activity in the lung could involve plasmin-mediated cleavage of the inhibitor. To investigate the effect of plasmin generation on lung-associated TFPI activity, in normal conditions and during infusion of endotoxin (lipopolysaccharide [LPS]) in mice. Plasmin generation and TFPI activity were assayed in the lungs of mice deficient in tissue-type plasminogen (Plg) activator (t-PA) or Plg, at 2 h after LPS or saline injection. The sharp loss of lung-associated TFPI activity at 2 h after LPS challenge paralleled the abrupt increase in plasmin generation. TFPI activity was significantly retained in both t-PA(-/-) and Plg(-/-) mice, which are unable to generate plasmin. The increased plasmin generation during the early stages of sepsis could cleave/inactivate TFPI and thus lead to thrombotic complications. © 2012 International Society on Thrombosis and Haemostasis.

  8. Machine Learning Methods for Analysis of Metabolic Data and Metabolic Pathway Modeling.

    Science.gov (United States)

    Cuperlovic-Culf, Miroslava

    2018-01-11

    Machine learning uses experimental data to optimize clustering or classification of samples or features, or to develop, augment or verify models that can be used to predict behavior or properties of systems. It is expected that machine learning will help provide actionable knowledge from a variety of big data including metabolomics data, as well as results of metabolism models. A variety of machine learning methods has been applied in bioinformatics and metabolism analyses including self-organizing maps, support vector machines, the kernel machine, Bayesian networks or fuzzy logic. To a lesser extent, machine learning has also been utilized to take advantage of the increasing availability of genomics and metabolomics data for the optimization of metabolic network models and their analysis. In this context, machine learning has aided the development of metabolic networks, the calculation of parameters for stoichiometric and kinetic models, as well as the analysis of major features in the model for the optimal application of bioreactors. Examples of this very interesting, albeit highly complex, application of machine learning for metabolism modeling will be the primary focus of this review presenting several different types of applications for model optimization, parameter determination or system analysis using models, as well as the utilization of several different types of machine learning technologies.

  9. Lego Bricks and the Octet Rule: Molecular Models for Biochemical Pathways with Plastic, Interlocking Toy Bricks

    Science.gov (United States)

    Lin, Henry J.; Lehoang, Jennifer; Kwan, Isabel; Baghaee, Anita; Prasad, Priya; Ha-Chen, Stephanie J.; Moss, Tanesha; Woods, Jeremy D.

    2018-01-01

    The 8 studs on a 2 × 4 Lego brick conveniently represent the outer shell of electrons for carbon, nitrogen, and oxygen atoms. We used Lego bricks to model these atoms, which are then joined together to form molecules by following the Lewis octet rule. A variety of small biological molecules can be modeled in this way, such as most amino acids,…

  10. A kinetic model for the glucose/glycine Maillard reaction pathways

    NARCIS (Netherlands)

    Martins, S.I.F.S.; Boekel, van M.A.J.S.

    2005-01-01

    A comprehensive kinetic model for the glucose/glycine Maillard reaction is proposed based on an approach called multiresponse kinetic modelling. Special attention was paid to reactants, intermediates and end products: -fructose, N-(1-deoxy--fructos-1-yl)-glycine (DFG), 1-deoxy-2,3-hexodiulose and

  11. Machine Learning Methods for Analysis of Metabolic Data and Metabolic Pathway Modeling

    Science.gov (United States)

    Cuperlovic-Culf, Miroslava

    2018-01-01

    Machine learning uses experimental data to optimize clustering or classification of samples or features, or to develop, augment or verify models that can be used to predict behavior or properties of systems. It is expected that machine learning will help provide actionable knowledge from a variety of big data including metabolomics data, as well as results of metabolism models. A variety of machine learning methods has been applied in bioinformatics and metabolism analyses including self-organizing maps, support vector machines, the kernel machine, Bayesian networks or fuzzy logic. To a lesser extent, machine learning has also been utilized to take advantage of the increasing availability of genomics and metabolomics data for the optimization of metabolic network models and their analysis. In this context, machine learning has aided the development of metabolic networks, the calculation of parameters for stoichiometric and kinetic models, as well as the analysis of major features in the model for the optimal application of bioreactors. Examples of this very interesting, albeit highly complex, application of machine learning for metabolism modeling will be the primary focus of this review presenting several different types of applications for model optimization, parameter determination or system analysis using models, as well as the utilization of several different types of machine learning technologies. PMID:29324649

  12. Targeting Th17-IL-17 Pathway in Prevention of Micro-Invasive Prostate Cancer in a Mouse Model.

    Science.gov (United States)

    Zhang, Qiuyang; Liu, Sen; Ge, Dongxia; Cunningham, David M; Huang, Feng; Ma, Lin; Burris, Thomas P; You, Zongbing

    2017-06-01

    Chronic inflammation has been associated with the development and progression of human cancers including prostate cancer. The exact role of the inflammatory Th17-IL-17 pathway in prostate cancer remains unknown. In this study, we aimed to determine the importance of Th17 cells and IL-17 in a Pten-null prostate cancer mouse model. The Pten-null mice were treated by Th17 inhibitor SR1001 or anti-mouse IL-17 monoclonal antibody from 6 weeks of age up to 12 weeks of age. For SR1001 treatment, the mice were injected intraperitoneally (i.p.) twice a day with vehicle or SR1001, which was dissolved in a dimethylsulfoxide (DMSO) solution. All mice were euthanized for necropsy at 12 weeks of age. For IL-17 antibody treatment, the mice were injected intravenously (i.v.) once every two weeks with control IgG or rat anti-mouse IL-17 monoclonal antibody, which was dissolved in PBS. The injection time points were at 6, 8, and 10 weeks old. All mice were analyzed for the prostate phenotypes at 12 weeks of age. We found that either SR1001 or anti-IL-17 antibody treatment decreased the formation of micro-invasive prostate cancer in Pten-null mice. The SR1001 or anti-IL-17 antibody treated mouse prostates had reduced proliferation, increased apoptosis, and reduced angiogenesis, as well as reduced inflammatory cell infiltration. By assessing the epithelial-to-mesenchymal transition (EMT) markers, we found that SR1001 or anti-IL-17 antibody treated prostate tissues had weaker EMT phenotype compared to the control treated prostates. These results demonstrated that Th17-IL-17 pathway plays a key role in prostate cancer progression in Pten-null mice. Targeting Th17-IL-17 pathway could prevent micro-invasive prostate cancer formation in mice. Prostate 77:888-899, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  13. A high protein diet during pregnancy affects hepatic gene expression of energy sensing pathways along ontogenesis in a porcine model.

    Directory of Open Access Journals (Sweden)

    Michael Oster

    Full Text Available In rodent models and in humans the impact of gestational diets on the offspring's phenotype was shown experimentally and epidemiologically. The underlying programming of fetal development was shown to be associated with an increased risk of degenerative diseases in adulthood, including the metabolic syndrome. There are clues that diet-dependent modifications of the metabolism during fetal life can persist until adulthood. This leads to the hypothesis that the offspring's transcriptomes show short-term and long-term changes depending on the maternal diet. To this end pregnant German landrace gilts were fed either a high protein diet (HP, 30% CP or an adequate protein diet (AP, 12% CP throughout pregnancy. Hepatic transcriptome profiles of the offspring were analyzed at prenatal (94 dpc and postnatal stages (1, 28, 188 dpn. Depending on the gestational dietary exposure, mRNA expression levels of genes related to energy metabolism, N-metabolism, growth factor signaling pathways, lipid metabolism, nucleic acid metabolism and stress/immune response were affected either in a short-term or in a long-term manner. Gene expression profiles at fetal stage 94 dpc were almost unchanged between the diets. The gestational HP diet affected the hepatic expression profiles at prenatal and postnatal stages. The effects encompassed a modulation of the genome in terms of an altered responsiveness of energy and nutrient sensing pathways. Differential expression of genes related to energy production and nutrient utilization contribute to the maintenance of development and growth performance within physiological norms, however the modulation of these pathways may be accompanied by a predisposition for metabolic disturbances up to adult stages.

  14. Development of models for fast fluid pathways through unsaturated heterogeneous porous media

    International Nuclear Information System (INIS)

    Robey, T.H.

    1994-11-01

    The pre-waste-emplacement ground water travel time requirement is a regulatory criterion that specifies ground water travel time to the accessible environment shall be greater than 1,000 years. Satisfying the ground water travel time criterion for the potential repository at Yucca Mountain requires the study of fast travel path formation in the unsaturated zone and development of models that simulate the formation of fast paths. Conceptual models for unsaturated flow that have been used for total-systems performance assessment generally fall into the categories of composite-porosity or fracture models. The actual hydrologic conditions at Yucca Mountain are thought to lie somewhere between the extremes of these two types of models. The current study considers the effects of heterogeneities on composite-porosity models and seeks to develop numerical methods (and models) that can produce locally saturated zones where fracture flow can occur. The credibility of the model and numerical methods is investigated by using test data from the INTRAVAL project (Swedish Nuclear Inspectorate, 1992) to attempt to predict in-situ volumetric water content at specific locations in Yucca Mountain. Work based on the numerical methods presented in this study is eventually intended to allow the calculation of ground water travel times in heterogeneous media. 60 refs

  15. Children, computer exposure and musculoskeletal outcomes: the development of pathway models for school and home computer-related musculoskeletal outcomes.

    Science.gov (United States)

    Harris, Courtenay; Straker, Leon; Pollock, Clare; Smith, Anne

    2015-01-01

    Children's computer use is rapidly growing, together with reports of related musculoskeletal outcomes. Models and theories of adult-related risk factors demonstrate multivariate risk factors associated with computer use. Children's use of computers is different from adult's computer use at work. This study developed and tested a child-specific model demonstrating multivariate relationships between musculoskeletal outcomes, computer exposure and child factors. Using pathway modelling, factors such as gender, age, television exposure, computer anxiety, sustained attention (flow), socio-economic status and somatic complaints (headache and stomach pain) were found to have effects on children's reports of musculoskeletal symptoms. The potential for children's computer exposure to follow a dose-response relationship was also evident. Developing a child-related model can assist in understanding risk factors for children's computer use and support the development of recommendations to encourage children to use this valuable resource in educational, recreational and communication environments in a safe and productive manner. Computer use is an important part of children's school and home life. Application of this developed model, that encapsulates related risk factors, enables practitioners, researchers, teachers and parents to develop strategies that assist young people to use information technology for school, home and leisure in a safe and productive manner.

  16. Assessing the roles of impulsivity, food-related cognitions, BMI, and demographics in the dual pathway model of binge eating among men and women.

    Science.gov (United States)

    Mason, Tyler B; Lewis, Robin J

    2015-08-01

    The dual pathway model is a widely accepted model of binge eating that focuses on the role of sociocultural factors, negative affect, and dietary restraint. However, less is known about demographic (e.g., gender and ethnicity) differences in the model and the role of other variables in the model. To further our understanding of the dual pathway model of binge eating, the current study examined the role of demographics (i.e., gender, race, BMI, parental education and obesity), impulsivity, and food-related cognitions in the dual pathway model. A sample of college students completed a battery of measures. Multi-group structural equation modeling was used to evaluate the dual pathway model separately for men and women. Results supported the dual pathway model of binge eating among men and women, and also supported food-related cognitions as an important variable prior to binge eating. In other words, body shame was associated with more dietary restraint and negative affect, and in turn, dietary restraint and negative affect were associated with increased negative food-related cognitions. Then, food-related cognitions predicted binge eating. Additionally impulsivity was related to body shame, negative affect, and food-related cognitions, but was unrelated to binge eating after controlling for the other variables. Racial differences existed among women in BMI and body shame, but there were no racial differences among men. Our results suggest that the dual pathway model adequately explains binge eating among men and women, but that food-related cognitions may be an imporant anteceden to binge eating. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. Is the authoritative parenting model effective in changing oral hygiene behavior in adolescents?

    Science.gov (United States)

    Brukienė, Vilma; Aleksejūnienė, Jolanta

    2012-12-01

    This study examined whether the authoritative parenting model (APM) is more effective than conventional approaches for changing adolescent oral hygiene behavior. A total of 247 adolescents were recruited using a cluster random-sampling method. Subject groups were randomly allocated into an intervention group (APM-based interventions), a Control Group 1 (conventional dental education and behavior modification) or a Control Group 2 (conventional behavior modification). The results were assessed after 3 and 12 months. Oral hygiene level was assessed as percent dental plaque and the ratio of plaque percent change (RPC). At the 3-month follow-up, there were significant differences among the groups; the APM group had the largest decrease in plaque levels (24.5%), Control Group 1 showed a decrease in plaque levels of 15.4% and Control Group 2 showed an increase in plaque levels of 2.8%. At the 12-month follow-up, an improvement was observed in all groups, but there were no statistically significant differences among the groups. In the short term, the intervention based on the APM was more effective in changing adolescent oral hygiene behavior compared with the conventional approaches. The reasons for long-term positive change after discontinued interventions in control groups need to be explored in future studies.

  18. Recent advances in modeling languages for pathway maps and computable biological networks.

    Science.gov (United States)

    Slater, Ted

    2014-02-01

    As our theories of systems biology grow more sophisticated, the models we use to represent them become larger and more complex. Languages necessarily have the expressivity and flexibility required to represent these models in ways that support high-resolution annotation, and provide for simulation and analysis that are sophisticated enough to allow researchers to master their data in the proper context. These languages also need to facilitate model sharing and collaboration, which is currently best done by using uniform data structures (such as graphs) and language standards. In this brief review, we discuss three of the most recent systems biology modeling languages to appear: BEL, PySB and BCML, and examine how they meet these needs. Copyright © 2014 Elsevier Ltd. All rights reserved.

  19. Short time effects of radiotherapy on lymphatic vessels and restorative lymphatic pathways: experimental approaches ina mouse model.

    Science.gov (United States)

    Pastouret, F; Lievens, P; Leduc, O; Bourgeois, P; Tournel, K; Lamote, J; Zirak, C; Leduc, A

    2014-06-01

    Radiotherapy (RT) is an important component in the therapeutic approach to oncologic conditions. This study presents the investigative results on the impact of RT on lymphatic vessels and on the regenerative response of the lymphatic system in a mouse model. We first irradiated 3 groups of ten mice using brachytherapy in a single treatment of 20 Gy. We then performed morphological examination of the irradiated lymphatic vessels using an in vivo microscopic transillumination technique at 2, 4, and 6 weeks. Next we evaluated lymphatic flow using lymphoscintigraphy and in vivo microscopy at 6 to 11 weeks in: 10 additional mice following irradiation as above (IR), in 10 mice following incision of a lymphatic vessel (I), and in a non-treated control group of 10 mice (N). Intact lymphatic vessels were observed in all mice at 2, 4, and 8 weeks following the single dose of radiotherapy in the first group of mice and normal lymphatic flow was fully restored in the irradiated (IR) and incised (I) mice indicating that the reparative substitution lymphatic pathways are functioning normally. We found that following irradiation with one dose of 20 Gy, lymphatic vessels were not visibly damaged and also that lymphatic flow was consistently restored and substitutive lymphatic pathways formed.

  20. Roles of different initial Maillard intermediates and pathways in meat flavor formation for cysteine-xylose-glycine model reaction systems.

    Science.gov (United States)

    Hou, Li; Xie, Jianchun; Zhao, Jian; Zhao, Mengyao; Fan, Mengdie; Xiao, Qunfei; Liang, Jingjing; Chen, Feng

    2017-10-01

    To explore initial Maillard reaction pathways and mechanisms for maximal formation of meaty flavors in heated cysteine-xylose-glycine systems, model reactions with synthesized initial Maillard intermediates, Gly-Amadori, TTCA (2-threityl-thiazolidine-4-carboxylic acids) and Cys-Amadori, were investigated. Relative relativities were characterized by spectrophotometrically monitoring the development of colorless degradation intermediates and browning reaction products. Aroma compounds formed were determined by solid-phase microextraction combined with GC-MS and GC-olfactometry. Gly-Amadori showed the fastest reaction followed by Cys-Amadori then TTCA. Free glycine accelerated reaction of TTCA, whereas cysteine inhibited that of Gly-Amadori due to association forming relatively stable thiazolidines. Cys-Amadori/Gly had the highest reactivity in development of both meaty flavors and brown products. TTCA/Gly favored yielding meaty flavors, whereas Gly-Amadori/Cys favored generation of brown products. Conclusively, initial formation of TTCA and pathway involving TTCA with glycine were more applicable to efficiently produce processed-meat flavorings in a cysteine-xylose-glycine system. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. Inhibition of multiple pathogenic pathways by histone deacetylase inhibitor SAHA in a corneal alkali-burn injury model

    Science.gov (United States)

    Li, Xinyu; Zhou, Qinbo; Hanus, Jakub; Anderson, Chastain; Zhang, Hongmei; Dellinger, Michael; Brekken, Rolf; Wang, Shusheng

    2013-01-01

    Neovascularization (NV) in the cornea is a major cause of vision impairment and corneal blindness. Hemangiogenesis and lymphangiogenesis induced by inflammation underlie the pathogenesis of corneal NV. The current mainstay treatment, corticosteroid, treats the inflammation associated with corneal NV, but is not satisfactory due to such side effects as cataract and the increase in intraocular pressure. It is imperative to develop a novel therapy that specifically targets the hemangiogenesis, lymphangiogenesis and inflammation pathways underlying corneal NV. Histone deacetylase inhibitors (HDACi) have been in clinical trials for cancer and other diseases. In particular, HDACi suberoylanilide hydroxamic acid (SAHA, vorinostat, Zolinza) has been approved by the FDA for the treatment of cutaneous T-cell lymphoma. The functional mechanism of SAHA in cancer and especially in corneal NV remains unclear. Here, we show that topical application of SAHA inhibits neovascularization in an alkali-burn corneal injury model. Mechanistically, SAHA inhibits corneal NV by repressing hemangiogenesis, inflammation pathways and previously overlooked lymphangiogenesis. Topical SAHA is well tolerated on the ocular surface. In addition, the potency of SAHA in corneal NV appears to be comparable to the current steroid therapy. SAHA may possess promising therapeutic potential in alkali-burn corneal injury and other inflammatory neovascularization disorders. PMID:23186311

  2. How Adverse Outcome Pathways Can Aid the Development and Use of Computational Prediction Models for Regulatory Toxicology.

    Science.gov (United States)

    Wittwehr, Clemens; Aladjov, Hristo; Ankley, Gerald; Byrne, Hugh J; de Knecht, Joop; Heinzle, Elmar; Klambauer, Günter; Landesmann, Brigitte; Luijten, Mirjam; MacKay, Cameron; Maxwell, Gavin; Meek, M E Bette; Paini, Alicia; Perkins, Edward; Sobanski, Tomasz; Villeneuve, Dan; Waters, Katrina M; Whelan, Maurice

    2017-02-01

    Efforts are underway to transform regulatory toxicology and chemical safety assessment from a largely empirical science based on direct observation of apical toxicity outcomes in whole organism toxicity tests to a predictive one in which outcomes and risk are inferred from accumulated mechanistic understanding. The adverse outcome pathway (AOP) framework provides a systematic approach for organizing knowledge that may support such inference. Likewise, computational models of biological systems at various scales provide another means and platform to integrate current biological understanding to facilitate inference and extrapolation. We argue that the systematic organization of knowledge into AOP frameworks can inform and help direct the design and development of computational prediction models that can further enhance the utility of mechanistic and in silico data for chemical safety assessment. This concept was explored as part of a workshop on AOP-Informed Predictive Modeling Approaches for Regulatory Toxicology held September 24-25, 2015. Examples of AOP-informed model development and its application to the assessment of chemicals for skin sensitization and multiple modes of endocrine disruption are provided. The role of problem formulation, not only as a critical phase of risk assessment, but also as guide for both AOP and complementary model development is described. Finally, a proposal for actively engaging the modeling community in AOP-informed computational model development is made. The contents serve as a vision for how AOPs can be leveraged to facilitate development of computational prediction models needed to support the next generation of chemical safety assessment. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology.

  3. Pathways to Tumorigenesis—Modeling Mutation Acquisition in Stem Cells and Their Progeny

    Directory of Open Access Journals (Sweden)

    Rina Ashkenazi

    2008-11-01

    Full Text Available Most adult tissues consist of stem cells, progenitors, and mature cells, and this hierarchical architecture may play an important role in the multistep process of carcinogenesis. Here, we develop and discuss the important predictions of a simple mathematical model of cancer initiation and early progression within a hierarchically structured tissue. This work presents a model that incorporates both the sequential acquisition of phenotype altering mutations and tissue hierarchy. The model simulates the progressive effect of accumulating mutations that lead to an increase in fitness or the induction of genetic instability. A novel aspect of the model is that symmetric self-renewal, asymmetric division, and differentiation are all incorporated, and this enables the quantitative study of the effect of mutations that deregulate the normal, homeostatic stem cell division pattern. The model is also capable of predicting changes in both tissue composition and in the progression of cells along their lineage at any given time and for various sequences of mutations. Simulations predict that the specific order in which mutations are acquired is crucial for determining the pace of cancer development. Interestingly, we find that the importance of genetic stability differs significantly depending on the physiological expression of mutations related to symmetric self-renewal and differentiation of stem and progenitor cells. In particular, mutations that lead to the alteration of the stem cell division pattern or the acquisition of some degree of immortality in committed progenitors lead to an early onset of cancer and diminish the impact of genetic instability.

  4. Data-driven reverse engineering of signaling pathways using ensembles of dynamic models.

    Directory of Open Access Journals (Sweden)

    David Henriques

    2017-02-01

    Full Text Available Despite significant efforts and remarkable progress, the inference of signaling networks from experimental data remains very challenging. The problem is particularly difficult when the objective is to obtain a dynamic model capable of predicting the effect of novel perturbations not considered during model training. The problem is ill-posed due to the nonlinear nature of these systems, the fact that only a fraction of the involved proteins and their post-translational modifications can be measured, and limitations on the technologies used for growing cells in vitro, perturbing them, and measuring their variations. As a consequence, there is a pervasive lack of identifiability. To overcome these issues, we present a methodology called SELDOM (enSEmbLe of Dynamic lOgic-based Models, which builds an ensemble of logic-based dynamic models, trains them to experimental data, and combines their individual simulations into an ensemble prediction. It also includes a model reduction step to prune spurious interactions and mitigate overfitting. SELDOM is a data-driven method, in the sense that it does not require any prior knowledge of the system: the interaction networks that act as scaffolds for the dynamic models are inferred from data using mutual information. We have tested SELDOM on a number of experimental and in silico signal transduction case-studies, including the recent HPN-DREAM breast cancer challenge. We found that its performance is highly competitive compared to state-of-the-art methods for the purpose of recovering network topology. More importantly, the utility of SELDOM goes beyond basic network inference (i.e. uncovering static interaction networks: it builds dynamic (based on ordinary differential equation models, which can be used for mechanistic interpretations and reliable dynamic predictions in new experimental conditions (i.e. not used in the training. For this task, SELDOM's ensemble prediction is not only consistently better

  5. p-Nitrophenol degradation by electro-Fenton process: Pathway, kinetic model and optimization using central composite design.

    Science.gov (United States)

    Meijide, J; Rosales, E; Pazos, M; Sanromán, M A

    2017-10-01

    The chemical process scale-up, from lab studies to industrial production, is challenging and requires deep knowledge of the kinetic model and the reactions that take place in the system. This knowledge is also useful in order to be employed for the reactor design and the determination of the optimal operational conditions. In this study, a model substituted phenol such as p-nitrophenol was degraded by electro-Fenton process and the reaction products yielded along the treatment were recorded. The kinetic model was developed using Matlab software and was based on main reactions that occurred until total mineralization which allowed predicting the degradation pathway under this advanced oxidation process. The predicted concentration profiles of p-nitrophenol, their intermediates and by-products in electro-Fenton process were validated with experimental assays and the results were consistent. Finally, based on the developed kinetic model the degradation process was optimized using central composite design taking as key parameters the ferrous ion concentration and current density. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. Pathways and impacts of nitrogen in water bodies: establishing a framework for integrated assessment modelling of management benefits

    DEFF Research Database (Denmark)

    Andersen, Mikael Skou; Kronvang, Brian; Carstensen, Jacob

    Monetization of environmental benefits has become relevant as an element of proportionality tests required for justifications under the EU’s Water Framework Directive article 4 (relating to benefits andcosts of measures). This study extends an impact pathway approach to analysis of aquatic...... the study demonstrates how state-of-the-art environmental modelling can be linked with valuation to provide an adequate cross-media assessment framework relevant to integrated water quality management. The results must be regarded as illustrative and more research is required in several areas to consolidate...... relationships relating to exposures. The findings nevertheless suggest the significance of health effects for overall monetary benefits related to ecological quality objectives for water....

  7. Pathway computation in models derived from bio-science text sources

    DEFF Research Database (Denmark)

    Andreasen, Troels; Bulskov, Henrik; Jensen, Per Anker

    2017-01-01

    This paper outlines a system, OntoScape, serving to accomplish complex inference tasks on knowledge bases and bio-models derived from life-science text corpora. The system applies so-called natural logic, a form of logic which is readable for humans. This logic affords ontological representations...

  8. Nucleation barrier reconstruction via the seeding method in a lattice model with competing nucleation pathways.

    Science.gov (United States)

    Lifanov, Yuri; Vorselaars, Bart; Quigley, David

    2016-12-07

    We study a three-species analogue of the Potts lattice gas model of nucleation from solution in a regime where partially disordered solute is a viable thermodynamic phase. Using a multicanonical sampling protocol, we compute phase diagrams for the system, from which we determine a parameter regime where the partially disordered phase is metastable almost everywhere in the temperature-fugacity plane. The resulting model shows non-trivial nucleation and growth behaviour, which we examine via multidimensional free energy calculations. We consider the applicability of the model in capturing the multi-stage nucleation mechanisms of polymorphic biominerals (e.g., CaCO 3 ). We then quantitatively explore the kinetics of nucleation in our model using the increasingly popular "seeding" method. We compare the resulting free energy barrier heights to those obtained via explicit free energy calculations over a wide range of temperatures and fugacities, carefully considering the propagation of statistical error. We find that the ability of the "seeding" method to reproduce accurate free energy barriers is dependent on the degree of supersaturation, and severely limited by the use of a nucleation driving force Δμ computed for bulk phases. We discuss possible reasons for this in terms of underlying kinetic assumptions, and those of classical nucleation theory.

  9. Unified modeling and feasibility study of novel green pathway of biomass to methanol/dimethylether

    International Nuclear Information System (INIS)

    Ravaghi-Ardebili, Zohreh; Manenti, Flavio

    2015-01-01

    Graphical abstract: Biomass-to-methanol/DME synthesis process layout. - Highlights: • Design, simulation, and control of the direct-storage concentrating solar plant. • Feasibility study of the low-temperature biomass gasification. • First-principles model of biomass gasifier. • First-principles model of one-step methanol/dimethylether synthesis reactor. • Integrated numerical platform for total plant simulation. - Abstract: A novel, integrated and unified process is proposed, modeled and studied for converting biomass to methanol (MeOH)/dimethylether (DME) to demonstrate its feasibility and applicability for the global industrial sector. The unified process consists of a concentrating solar power (CSP) plant, which supplies the produced steam to the biomass gasification process as well as to the downstream conversions to chemical commodities and energy carriers. To preserve the effectiveness of the biomass gasification with low-temperature solar-powered generated steam (approximately 400–410 °C), the gasification process is studied by means of a multi-complex (multi-scale, multi-phase, and multi-component) model and adapted to the novel proposed conditions. The syngas generated in the biomass gasification unit is then converted into MeOH/DME by means of one-step synthesis technology to improve the overall yield of the biomass-to-methanol process

  10. Representation of aerosol particles and associated transport pathways in regional climate modelling in Africa

    CSIR Research Space (South Africa)

    Garland, Rebecca M

    2016-11-01

    Full Text Available Aerosol particles can have large impacts on air quality and on the climate system. Regional climate models for Africa have not been well-tested and validated for their representation and simulation of aerosol particles. This study aimed to validate...

  11. Neural pathways in processing of sexual arousal: a dynamic causal modeling study.

    Science.gov (United States)

    Seok, J-W; Park, M-S; Sohn, J-H

    2016-09-01

    Three decades of research have investigated brain processing of visual sexual stimuli with neuroimaging methods. These researchers have found that sexual arousal stimuli elicit activity in a broad neural network of cortical and subcortical brain areas that are known to be associated with cognitive, emotional, motivational and physiological components. However, it is not completely understood how these neural systems integrate and modulated incoming information. Therefore, we identify cerebral areas whose activations were correlated with sexual arousal using event-related functional magnetic resonance imaging and used the dynamic causal modeling method for searching the effective connectivity about the sexual arousal processing network. Thirteen heterosexual males were scanned while they passively viewed alternating short trials of erotic and neutral pictures on a monitor. We created a subset of seven models based on our results and previous studies and selected a dominant connectivity model. Consequently, we suggest a dynamic causal model of the brain processes mediating the cognitive, emotional, motivational and physiological factors of human male sexual arousal. These findings are significant implications for the neuropsychology of male sexuality.

  12. Pathways to Life Success: A Conceptual Model of Financial Well-Being for Young Adults

    Science.gov (United States)

    Shim, Soyeon; Xiao, Jing J.; Barber, Bonnie L.; Lyons, Angela C.

    2009-01-01

    The purpose of this study is to describe and test a conceptual model of the potential antecedents and consequences of financial well-being in young adulthood. Data (N = 781) were collected via an online survey conducted at a large state university in the southwestern United States. Our results suggest that self-actualizing personal values,…

  13. On the computations analyzing natural optic flow : Quantitative model analysis of the blowfly motion vision pathway

    NARCIS (Netherlands)

    Lindemann, J.P.; Kern, R.; Hateren, J.H. van; Ritter, H.; Egelhaaf, M.

    2005-01-01

    For many animals, including humans, the optic flow generated on the eyes during locomotion is an important source of information about self-motion and the structure of the environment. The blowfly has been used frequently as a model system for experimental analysis of optic flow processing at the

  14. A structural equation modelling approach examining the pathways between safety climate, behaviour performance and workplace slipping

    Science.gov (United States)

    Swedler, David I; Verma, Santosh K; Huang, Yueng-Hsiang; Lombardi, David A; Chang, Wen-Ruey; Brennan, Melayne; Courtney, Theodore K

    2015-01-01

    Objective Safety climate has previously been associated with increasing safe workplace behaviours and decreasing occupational injuries. This study seeks to understand the structural relationship between employees’ perceptions of safety climate, performing a safety behaviour (ie, wearing slip-resistant shoes) and risk of slipping in the setting of limited-service restaurants. Methods At baseline, we surveyed 349 employees at 30 restaurants for their perceptions of their safety training and management commitment to safety as well as demographic data. Safety performance was identified as wearing slip-resistant shoes, as measured by direct observation by the study team. We then prospectively collected participants’ hours worked and number of slips weekly for the next 12 weeks. Using a confirmatory factor analysis, we modelled safety climate as a higher order factor composed of previously identified training and management commitment factors. Results The 349 study participants experienced 1075 slips during the 12-week follow-up. Confirmatory factor analysis supported modelling safety climate as a higher order factor composed of safety training and management commitment. In a structural equation model, safety climate indirectly affected prospective risk of slipping through safety performance, but no direct relationship between safety climate and slips was evident. Conclusions Results suggest that safety climate can reduce workplace slips through performance of a safety behaviour as well as suggesting a potential causal mechanism through which safety climate can reduce workplace injuries. Safety climate can be modelled as a higher order factor composed of safety training and management commitment. PMID:25710968

  15. Elucidation of xenobiotic metabolism pathways in human skin and human skin models by proteomic profiling.

    Directory of Open Access Journals (Sweden)

    Sven van Eijl

    Full Text Available BACKGROUND: Human skin has the capacity to metabolise foreign chemicals (xenobiotics, but knowledge of the various enzymes involved is incomplete. A broad-based unbiased proteomics approach was used to describe the profile of xenobiotic metabolising enzymes present in human skin and hence indicate principal routes of metabolism of xenobiotic compounds. Several in vitro models of human skin have been developed for the purpose of safety assessment of chemicals. The suitability of these epidermal models for studies involving biotransformation was assessed by comparing their profiles of xenobiotic metabolising enzymes with those of human skin. METHODOLOGY/PRINCIPAL FINDINGS: Label-free proteomic analysis of whole human skin (10 donors was applied and analysed using custom-built PROTSIFT software. The results showed the presence of enzymes with a capacity for the metabolism of alcohols through dehydrogenation, aldehydes through dehydrogenation and oxidation, amines through oxidation, carbonyls through reduction, epoxides and carboxylesters through hydrolysis and, of many compounds, by conjugation to glutathione. Whereas protein levels of these enzymes in skin were mostly just 4-10 fold lower than those in liver and sufficient to support metabolism, the levels of cytochrome P450 enzymes were at least 300-fold lower indicating they play no significant role. Four epidermal models of human skin had profiles very similar to one another and these overlapped substantially with that of whole skin. CONCLUSIONS/SIGNIFICANCE: The proteomics profiling approach was successful in producing a comprehensive analysis of the biotransformation characteristics of whole human skin and various in vitro skin models. The results show that skin contains a range of defined enzymes capable of metabolising different classes of chemicals. The degree of similarity of the profiles of the in vitro models indicates their suitability for epidermal toxicity testing. Overall, these

  16. Selenite exacerbates hepatic insulin resistance in mouse model of type 2 diabetes through oxidative stress-mediated JNK pathway

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, Jun, E-mail: hustzhj@hust.edu.cn; Xu, Gang; Bai, Zhaoshuai; Li, Kaicheng; Yan, Junyan; Li, Fen; Ma, Shuai; Xu, Huibi; Huang, Kaixun, E-mail: hxxzrf@hust.edu.cn

    2015-12-15

    Recent evidence suggests a potential pro-diabetic effect of selenite treatment in type 2 diabetics; however, the underlying mechanisms remain elusive. Here we investigated the effects and the underlying mechanisms of selenite treatment in a nongenetic mouse model of type 2 diabetes. High-fat diet (HFD)/streptozotocin (STZ)-induced diabetic mice were orally gavaged with selenite at 0.5 or 2.0 mg/kg body weight/day or vehicle for 4 weeks. High-dose selenite treatment significantly elevated fasting plasma insulin levels and insulin resistance index, in parallel with impaired glucose tolerance, insulin tolerance and pyruvate tolerance. High-dose selenite treatment also attenuated hepatic IRS1/Akt/FoxO1 signaling and pyruvate kinase gene expressions, but elevated the gene expressions of phosphoenolpyruvate carboxyl kinase (PEPCK), glucose 6-phosphatase (G6Pase), peroxisomal proliferator-activated receptor-γ coactivator 1α (PGC-1α) and selenoprotein P (SelP) in the liver. Furthermore, high-dose selenite treatment caused significant increases in MDA contents, protein carbonyl contents, and a decrease in GSH/GSSG ratio in the liver, concurrent with enhanced ASK1/MKK4/JNK signaling. Taken together, these findings suggest that high-dose selenite treatment exacerbates hepatic insulin resistance in mouse model of type 2 diabetes, at least in part through oxidative stress-mediated JNK pathway, providing new mechanistic insights into the pro-diabetic effect of selenite in type 2 diabetes. - Highlights: • Selenite exacerbates hepatic insulin resistance in HFD/STZ-induced diabetic mice. • Selenite elevates hepatic gluconeogenesis and reduces glycolysis in diabetic mice. • Selenite exacerbates hepatic oxidative stress and triggers JNK signaling pathway. • Selenite elevates hepatic selenoprotein P expression in diabetic mice.

  17. Fungi, bacteria and soil pH: the oxalate-carbonate pathway as a model for metabolic interaction.

    Science.gov (United States)

    Martin, Gaëtan; Guggiari, Matteo; Bravo, Daniel; Zopfi, Jakob; Cailleau, Guillaume; Aragno, Michel; Job, Daniel; Verrecchia, Eric; Junier, Pilar

    2012-11-01

    The oxalate-carbonate pathway involves the oxidation of calcium oxalate to low-magnesium calcite and represents a potential long-term terrestrial sink for atmospheric CO(2). In this pathway, bacterial oxalate degradation is associated with a strong local alkalinization and subsequent carbonate precipitation. In order to test whether this process occurs in soil, the role of bacteria, fungi and calcium oxalate amendments was studied using microcosms. In a model system with sterile soil amended with laboratory cultures of oxalotrophic bacteria and fungi, the addition of calcium oxalate induced a distinct pH shift and led to the final precipitation of calcite. However, the simultaneous presence of bacteria and fungi was essential to drive this pH shift. Growth of both oxalotrophic bacteria and fungi was confirmed by qPCR on the frc (oxalotrophic bacteria) and 16S rRNA genes, and the quantification of ergosterol (active fungal biomass) respectively. The experiment was replicated in microcosms with non-sterilized soil. In this case, the bacterial and fungal contribution to oxalate degradation was evaluated by treatments with specific biocides (cycloheximide and bronopol). Results showed that the autochthonous microflora oxidized calcium oxalate and induced a significant soil alkalinization. Moreover, data confirmed the results from the model soil showing that bacteria are essentially responsible for the pH shift, but require the presence of fungi for their oxalotrophic activity. The combined results highlight that the interaction between bacteria and fungi is essential to drive metabolic processes in complex environments such as soil. © 2012 Society for Applied Microbiology and Blackwell Publishing Ltd.

  18. Selenite exacerbates hepatic insulin resistance in mouse model of type 2 diabetes through oxidative stress-mediated JNK pathway

    International Nuclear Information System (INIS)

    Zhou, Jun; Xu, Gang; Bai, Zhaoshuai; Li, Kaicheng; Yan, Junyan; Li, Fen; Ma, Shuai; Xu, Huibi; Huang, Kaixun

    2015-01-01

    Recent evidence suggests a potential pro-diabetic effect of selenite treatment in type 2 diabetics; however, the underlying mechanisms remain elusive. Here we investigated the effects and the underlying mechanisms of selenite treatment in a nongenetic mouse model of type 2 diabetes. High-fat diet (HFD)/streptozotocin (STZ)-induced diabetic mice were orally gavaged with selenite at 0.5 or 2.0 mg/kg body weight/day or vehicle for 4 weeks. High-dose selenite treatment significantly elevated fasting plasma insulin levels and insulin resistance index, in parallel with impaired glucose tolerance, insulin tolerance and pyruvate tolerance. High-dose selenite treatment also attenuated hepatic IRS1/Akt/FoxO1 signaling and pyruvate kinase gene expressions, but elevated the gene expressions of phosphoenolpyruvate carboxyl kinase (PEPCK), glucose 6-phosphatase (G6Pase), peroxisomal proliferator-activated receptor-γ coactivator 1α (PGC-1α) and selenoprotein P (SelP) in the liver. Furthermore, high-dose selenite treatment caused significant increases in MDA contents, protein carbonyl contents, and a decrease in GSH/GSSG ratio in the liver, concurrent with enhanced ASK1/MKK4/JNK signaling. Taken together, these findings suggest that high-dose selenite treatment exacerbates hepatic insulin resistance in mouse model of type 2 diabetes, at least in part through oxidative stress-mediated JNK pathway, providing new mechanistic insights into the pro-diabetic effect of selenite in type 2 diabetes. - Highlights: • Selenite exacerbates hepatic insulin resistance in HFD/STZ-induced diabetic mice. • Selenite elevates hepatic gluconeogenesis and reduces glycolysis in diabetic mice. • Selenite exacerbates hepatic oxidative stress and triggers JNK signaling pathway. • Selenite elevates hepatic selenoprotein P expression in diabetic mice.

  19. A novel mouse model of tuberous sclerosis complex (TSC): eye-specific Tsc1-ablation disrupts visual-pathway development.

    Science.gov (United States)

    Jones, Iwan; Hägglund, Anna-Carin; Törnqvist, Gunilla; Nord, Christoffer; Ahlgren, Ulf; Carlsson, Leif

    2015-12-01

    Tuberous sclerosis complex (TSC) is an autosomal dominant syndrome that is best characterised by neurodevelopmental deficits and the presence of benign tumours (called hamartomas) in affected organs. This multi-organ disorder results from inactivating point mutations in either the TSC1 or the TSC2 genes and consequent activation of the canonical mammalian target of rapamycin complex 1 signalling (mTORC1) pathway. Because lesions to the eye are central to TSC diagnosis, we report here the generation and characterisation of the first eye-specific TSC mouse model. We demonstrate that conditional ablation of Tsc1 in eye-committed progenitor cells leads to the accelerated differentiation and subsequent ectopic radial migration of retinal ganglion cells. This results in an increase in retinal ganglion cell apoptosis and consequent regionalised axonal loss within the optic nerve and topographical changes to the contra- and ipsilateral input within the dorsal lateral geniculate nucleus. Eyes from adult mice exhibit aberrant retinal architecture and display all the classic neuropathological hallmarks of TSC, including an increase in organ and cell size, ring heterotopias, hamartomas with retinal detachment, and lamination defects. Our results provide the first major insight into the molecular etiology of TSC within the developing eye and demonstrate a pivotal role for Tsc1 in regulating various aspects of visual-pathway development. Our novel mouse model therefore provides a valuable resource for future studies concerning the molecular mechanisms underlying TSC and also as a platform to evaluate new therapeutic approaches for the treatment of this multi-organ disorder. © 2015. Published by The Company of Biologists Ltd.

  20. A simplified method for power-law modelling of metabolic pathways from time-course data and steady-state flux profiles.

    Science.gov (United States)

    Kitayama, Tomoya; Kinoshita, Ayako; Sugimoto, Masahiro; Nakayama, Yoichi; Tomita, Masaru

    2006-07-17

    In order to improve understanding of metabolic systems there have been attempts to construct S-system models from time courses. Conventionally, non-linear curve-fitting algorithms have been used for modelling, because of the non-linear properties of parameter estimation from time series. However, the huge iterative calculations required have hindered the development of large-scale metabolic pathway models. To solve this problem we propose a novel method involving power-law modelling of metabolic pathways from the Jacobian of the targeted system and the steady-state flux profiles by linearization of S-systems. The results of two case studies modelling a straight and a branched pathway, respectively, showed that our method reduced the number of unknown parameters needing to be estimated. The time-courses simulated by conventional kinetic models and those described by our method behaved similarly under a wide range of perturbations of metabolite concentrations. The proposed method reduces calculation complexity and facilitates the construction of large-scale S-system models of metabolic pathways, realizing a practical application of reverse engineering of dynamic simulation models from the Jacobian of the targeted system and steady-state flux profiles.

  1. A simplified method for power-law modelling of metabolic pathways from time-course data and steady-state flux profiles

    Directory of Open Access Journals (Sweden)

    Sugimoto Masahiro

    2006-07-01

    Full Text Available Abstract Background In order to improve understanding of metabolic systems there have been attempts to construct S-system models from time courses. Conventionally, non-linear curve-fitting algorithms have been used for modelling, because of the non-linear properties of parameter estimation from time series. However, the huge iterative calculations required have hindered the development of large-scale metabolic pathway models. To solve this problem we propose a novel method involving power-law modelling of metabolic pathways from the Jacobian of the targeted system and the steady-state flux profiles by linearization of S-systems. Results The results of two case studies modelling a straight and a branched pathway, respectively, showed that our method reduced the number of unknown parameters needing to be estimated. The time-courses simulated by conventional kinetic models and those described by our method behaved similarly under a wide range of perturbations of metabolite concentrations. Conclusion The proposed method reduces calculation complexity and facilitates the construction of large-scale S-system models of metabolic pathways, realizing a practical application of reverse engineering of dynamic simulation models from the Jacobian of the targeted system and steady-state flux profiles.

  2. Improvement of a predictive model of castration-resistant prostate cancer: functional genetic variants in TGFβ1 signaling pathway modulation.

    Directory of Open Access Journals (Sweden)

    Ana L Teixeira

    Full Text Available Prostate cancer (PC is the most frequently diagnosed cancer in men. The acquisition of castration-resistant (CR phenotype is associated with the activation of signaling pathways mediated by growth factors. The TGFβ1 and its receptors have an important role in tumor progression, being the pro-apoptotic function modulated by the expression of TGFBR2. A single nucleotide polymorphism -875 G > A in TGFBR2 gene has been described, which may influence the expression levels of the receptor. Our purpose was to investigate the potential role of TGFBR2-875G>A in PC risk and in the response to androgen deprivation therapy (ADT. TGFBR2-875G>A polymorphism was studied by allelic discrimination using real-time polymerase chain reaction (PCR in 891 patients with PC and 874 controls. A follow-up study was undertaken to evaluate response to ADT. The TGFBR2 and SMAD7 mRNA expression were analyzed by a quantitative real-time PCR. We found that TGFBR2-875GG homozygous patients present lower expression levels of TGFBR2 mRNA (AA/AG: 2(-ΔΔCT =1.5, P=0.016. GG genotype was also associated with higher Gleason grade (OR=1.51, P=0.019 and increased risk of an early relapse after ADT (HR=1.47, P=0.024. The concordance (c index analysis showed that the definition of profiles that contains information regarding tumor characteristics associated with genetic information present an increased capacity to predict the risk for CR development (c-index model 1: 0.683 vs model 2: 0.736 vs model 3: 0.746 vs model 4: 0.759. The TGFBR2-875G>A contribution to an early relapse in ADT patients, due to changes in mRNA expression, supports the involvement of TGFβ1 pathway in CRPC. Furthermore, according to our results, we hypothesize the potential benefits of the association of genetic information in predictive models of CR development.

  3. Mathematical Model of HIF-1 alpha Pathway, Oxygen Transport and Hypoxia

    Science.gov (United States)

    2017-09-01

    succinate inhibition and PHD negative feedback. Yucel & Kumaz 2007 Sensitivity of the angiogenic behaviour of a cancer cell to PHD and FIH. Dayan et al...With CF computed, CB can be calculated, and finally the CA leaving the gas exchange region. 3.2 HIF-1α Mathematical Model for Brain A...is dictated by the partial pressure of that gas in blood versus luminal contents. For methane and hydrogen, diffusion is always out of the lumen

  4. Impact of organic-mineral matter interactions on thermal reaction pathways for coal model compounds

    Energy Technology Data Exchange (ETDEWEB)

    Buchanan, A.C. III; Britt, P.F.; Struss, J.A. [Oak Ridge National Lab., TN (United States). Chemical and Analytical Sciences Div.

    1995-07-01

    Coal is a complex, heterogeneous solid that includes interdispersed mineral matter. However, knowledge of organic-mineral matter interactions is embryonic, and the impact of these interactions on coal pyrolysis and liquefaction is incomplete. Clay minerals, for example, are known to be effective catalysts for organic reactions. Furthermore, clays such as montmorillonite have been proposed to be key catalysts in the thermal alteration of lignin into vitrinite during the coalification process. Recent studies by Hatcher and coworkers on the evolution of coalified woods using microscopy and NMR have led them to propose selective, acid-catalyzed, solid state reaction chemistry to account for retained structural integrity in the wood. However, the chemical feasibility of such reactions in relevant solids is difficult to demonstrate. The authors have begun a model compound study to gain a better molecular level understanding of the effects in the solid state of organic-mineral matter interactions relevant to both coal formation and processing. To satisfy the need for model compounds that remain nonvolatile solids at temperatures ranging to 450 C, model compounds are employed that are chemically bound to the surface of a fumed silica (Si-O-C{sub aryl}linkage). The organic structures currently under investigation are phenethyl phenyl ether (C{sub 6}H{sub 5}CH{sub 2}CH{sub 2}OC{sub 6}H{sub 5}) derivatives, which serve as models for {beta}-alkyl aryl ether units that are present in lignin and lignitic coals. The solid-state chemistry of these materials at 200--450 C in the presence of interdispersed acid catalysts such as small particle size silica-aluminas and montmorillonite clay will be reported. Initial focus will be on defining the potential impact of these interactions on coal pyrolysis and liquefaction.

  5. Role of community pharmacists in asthma - Australian research highlighting pathways for future primary care models.

    Science.gov (United States)

    Saini, B; Krass, I; Smith, L; Bosnic-Anticevich, S; Armour, C

    2011-01-01

    Asthma is one of the most common chronic conditions affecting the Australian population. Amongst primary healthcare professionals, pharmacists are the most accessible and this places pharmacists in an excellent position to play a role in the management of asthma. Globally, trials of many community pharmacy-based asthma care models have provided evidence that pharmacist delivered interventions can improve clinical, humanistic and economic outcomes for asthma patients. In Australia, a decade of coordinated research efforts, in various aspects of asthma care, has culminated in the implementation trial of the Pharmacy Asthma Management Service (PAMS), a comprehensive disease management model.There has been research investigating asthma medication adherence through data mining, ways in which usual asthma care can be improved. Our research has focused on self-management education, inhaler technique interventions, spirometry trials, interprofessional models of care, and regional trials addressing the particular needs of rural communities. We have determined that inhaler technique education is a necessity and should be repeated if correct technique is to be maintained. We have identified this effectiveness of health promotion and health education, conducted within and outside the confines of the pharmacy, in public for a and settings such as schools, and established that this outreach role is particularly well received and increases the opportunity for people with asthma to engage in their asthma management.Our research has identified that asthma patients have needs which pharmacists delivering specialized models of care, can address. There is a lot of evidence for the effectiveness of asthma care by pharmacists, the future must involve integration of this role into primary care.

  6. Role of community pharmacists in asthma – Australian research highlighting pathways for future primary care models

    Directory of Open Access Journals (Sweden)

    Saini B

    2011-04-01

    Full Text Available Asthma is one of the most common chronic conditions affecting the Australian population. Amongst primary healthcare professionals, pharmacists are the most accessible and this places pharmacists in an excellent position to play a role in the management of asthma. Globally, trials of many community pharmacy-based asthma care models have provided evidence that pharmacist delivered interventions can improve clinical, humanistic and economic outcomes for asthma patients. In Australia, a decade of coordinated research efforts, in various aspects of asthma care, has culminated in the implementation trial of the Pharmacy Asthma Management Service (PAMS, a comprehensive disease management model. There has been research investigating asthma medication adherence through data mining, ways in which usual asthma care can be improved. Our research has focused on self-management education, inhaler technique interventions, spirometry trials, interprofessional models of care, and regional trials addressing the particular needs of rural communities. We have determined that inhaler technique education is a necessity and should be repeated if correct technique is to be maintained. We have identified this effectiveness of health promotion and health education, conducted within and outside the confines of the pharmacy, in public for a and settings such as schools, and established that this outreach role is particularly well received and increases the opportunity for people with asthma to engage in their asthma management. Our research has identified that asthma patients have needs which pharmacists delivering specialized models of care, can address. There is a lot of evidence for the effectiveness of asthma care by pharmacists, the future must involve integration of this role into primary care.

  7. A structural equation modelling approach examining the pathways between safety climate, behaviour performance and workplace slipping.

    Science.gov (United States)

    Swedler, David I; Verma, Santosh K; Huang, Yueng-Hsiang; Lombardi, David A; Chang, Wen-Ruey; Brennan, Melayne; Courtney, Theodore K

    2015-07-01

    Safety climate has previously been associated with increasing safe workplace behaviours and decreasing occupational injuries. This study seeks to understand the structural relationship between employees' perceptions of safety climate, performing a safety behaviour (ie, wearing slip-resistant shoes) and risk of slipping in the setting of limited-service restaurants. At baseline, we surveyed 349 employees at 30 restaurants for their perceptions of their safety training and management commitment to safety as well as demographic data. Safety performance was identified as wearing slip-resistant shoes, as measured by direct observation by the study team. We then prospectively collected participants' hours worked and number of slips weekly for the next 12 weeks. Using a confirmatory factor analysis, we modelled safety climate as a higher order factor composed of previously identified training and management commitment factors. The 349 study participants experienced 1075 slips during the 12-week follow-up. Confirmatory factor analysis supported modelling safety climate as a higher order factor composed of safety training and management commitment. In a structural equation model, safety climate indirectly affected prospective risk of slipping through safety performance, but no direct relationship between safety climate and slips was evident. Results suggest that safety climate can reduce workplace slips through performance of a safety behaviour as well as suggesting a potential causal mechanism through which safety climate can reduce workplace injuries. Safety climate can be modelled as a higher order factor composed of safety training and management commitment. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  8. Anger Can Help: A Transactional Model and Three Pathways of the Experience and Expression of Anger.

    Science.gov (United States)

    Butler, Mark H; Meloy-Miller, Kierea C; Seedall, Ryan B; Dicus, J Logan

    2017-07-23

    Anger is a significant human emotion with far-reaching implications for individuals and relationships. We propose a transactional model of anger that highlights its relational relevance and potentially positive function, in addition to problematic malformations. By evolutionary design, physical, self-concept, or attachment threats all similarly trigger diffuse physiological arousal, psychologically experienced as anger-emotion. Anger is first a signaling and motivational system. Anger is then formed to affirming, productive use or malformed to destructive ends. A functional, prosocial approach to anger organizes it for protective and corrective personal and relational adaptation. In our model, threat perception interacts with a person's view of self in relation to other to produce helpful or harmful anger. Inflated or collapsed views of self in relation to other produce distinct manifestations of destructive anger that are harmful to self, other, and relationship. Conversely, a balanced view of self in relation to other promotes constructive anger and catalyzes self, other, and relationship healing. Clinical use of the model to shape healing personal and relational contact with anger is explored. © 2017 Family Process Institute.

  9. Modeling the Role of the Glymphatic Pathway and Cerebral Blood Vessel Properties in Alzheimer's Disease Pathogenesis.

    Directory of Open Access Journals (Sweden)

    Christina Rose Kyrtsos

    Full Text Available Alzheimer's disease (AD is the most common cause of dementia in the elderly, affecting over 10% population over the age of 65 years. Clinically, AD is described by the symptom set of short term memory loss and cognitive decline, changes in mentation and behavior, and eventually long-term memory deficit as the disease progresses. On imaging studies, significant atrophy with subsequent increase in ventricular volume have been observed. Pathology on post-mortem brain specimens demonstrates the classic findings of increased beta amyloid (Aβ deposition and the presence of neurofibrillary tangles (NFTs within affected neurons. Neuroinflammation, dysregulation of blood-brain barrier transport and clearance, deposition of Aβ in cerebral blood vessels, vascular risk factors such as atherosclerosis and diabetes, and the presence of the apolipoprotein E4 allele have all been identified as playing possible roles in AD pathogenesis. Recent research has demonstrated the importance of the glymphatic system in the clearance of Aβ from the brain via the perivascular space surrounding cerebral blood vessels. Given the variety of hypotheses that have been proposed for AD pathogenesis, an interconnected, multilayer model offers a unique opportunity to combine these ideas into a single unifying model. Results of this model demonstrate the importance of vessel stiffness and heart rate in maintaining adequate clearance of Aβ from the brain.

  10. Site-specific parameter values for the Nuclear Regulatory Commission's food pathway dose model

    International Nuclear Information System (INIS)

    Hamby, D.M.

    1992-01-01

    Routine operations at the Savannah River Site (SRS) in Western South Carolina result in radionuclide releases to the atmosphere and to the Savannah River. The resulting radiation doses to the off-site maximum individual and the off-site population within 80 km of the SRS are estimated on a yearly basis. These estimates are currently generated using dose models prescribed for the commercial nuclear power industry by the Nuclear Regulatory Commission (NRC). The NRC provides default values for dose-model parameters for facilities without resources to develop site-specific values. A survey of land- and water-use characteristics for the Savannah River area has been conducted to determine site-specific values for water recreation, consumption, and agricultural parameters used in the NRC Regulatory Guide 1.109 (1977) dosimetric models. These site parameters include local characteristics of meat, milk, and vegetable production; recreational and commercial activities on the Savannah River; and meat, milk, vegetable, and seafood consumption rates. This paper describes how parameter data were obtained at the Savannah River Site and the impacts of such data on off-site dose. Dose estimates using site-specific parameter values are compared to estimates using the NRC default values

  11. Modeling the Role of the Glymphatic Pathway and Cerebral Blood Vessel Properties in Alzheimer's Disease Pathogenesis.

    Science.gov (United States)

    Kyrtsos, Christina Rose; Baras, John S

    2015-01-01

    Alzheimer's disease (AD) is the most common cause of dementia in the elderly, affecting over 10% population over the age of 65 years. Clinically, AD is described by the symptom set of short term memory loss and cognitive decline, changes in mentation and behavior, and eventually long-term memory deficit as the disease progresses. On imaging studies, significant atrophy with subsequent increase in ventricular volume have been observed. Pathology on post-mortem brain specimens demonstrates the classic findings of increased beta amyloid (Aβ) deposition and the presence of neurofibrillary tangles (NFTs) within affected neurons. Neuroinflammation, dysregulation of blood-brain barrier transport and clearance, deposition of Aβ in cerebral blood vessels, vascular risk factors such as atherosclerosis and diabetes, and the presence of the apolipoprotein E4 allele have all been identified as playing possible roles in AD pathogenesis. Recent research has demonstrated the importance of the glymphatic system in the clearance of Aβ from the brain via the perivascular space surrounding cerebral blood vessels. Given the variety of hypotheses that have been proposed for AD pathogenesis, an interconnected, multilayer model offers a unique opportunity to combine these ideas into a single unifying model. Results of this model demonstrate the importance of vessel stiffness and heart rate in maintaining adequate clearance of Aβ from the brain.

  12. Proper interpretation of dissolved nitrous oxide isotopes, production pathways, and emissions requires a modelling approach.

    Science.gov (United States)

    Thuss, Simon J; Venkiteswaran, Jason J; Schiff, Sherry L

    2014-01-01

    Stable isotopes ([Formula: see text]15N and [Formula: see text]18O) of the greenhouse gas N2O provide information about the sources and processes leading to N2O production and emission from aquatic ecosystems to the atmosphere. In turn, this describes the fate of nitrogen in the aquatic environment since N2O is an obligate intermediate of denitrification and can be a by-product of nitrification. However, due to exchange with the atmosphere, the [Formula: see text] values at typical concentrations in aquatic ecosystems differ significantly from both the source of N2O and the N2O emitted to the atmosphere. A dynamic model, SIDNO, was developed to explore the relationship between the isotopic ratios of N2O, N2O source, and the emitted N2O. If the N2O production rate or isotopic ratios vary, then the N2O concentration and isotopic ratios may vary or be constant, not necessarily concomitantly, depending on the synchronicity of production rate and source isotopic ratios. Thus prima facie interpretation of patterns in dissolved N2O concentrations and isotopic ratios is difficult. The dynamic model may be used to correctly interpret diel field data and allows for the estimation of the gas exchange coefficient, N2O production rate, and the production-weighted [Formula: see text] values of the N2O source in aquatic ecosystems. Combining field data with these modelling efforts allows this critical piece of nitrogen cycling and N2O flux to the atmosphere to be assessed.

  13. Effects of reaction-kinetic parameters on modeling reaction pathways in GaN MOVPE growth

    Science.gov (United States)

    Zhang, Hong; Zuo, Ran; Zhang, Guoyi

    2017-11-01

    In the modeling of the reaction-transport process in GaN MOVPE growth, the selections of kinetic parameters (activation energy Ea and pre-exponential factor A) for gas reactions are quite uncertain, which cause uncertainties in both gas reaction path and growth rate. In this study, numerical modeling of the reaction-transport process for GaN MOVPE growth in a vertical rotating disk reactor is conducted with varying kinetic parameters for main reaction paths. By comparisons of the molar concentrations of major Ga-containing species and the growth rates, the effects of kinetic parameters on gas reaction paths are determined. The results show that, depending on the values of the kinetic parameters, the gas reaction path may be dominated either by adduct/amide formation path, or by TMG pyrolysis path, or by both. Although the reaction path varies with different kinetic parameters, the predicted growth rates change only slightly because the total transport rate of Ga-containing species to the substrate changes slightly with reaction paths. This explains why previous authors using different chemical models predicted growth rates close to the experiment values. By varying the pre-exponential factor for the amide trimerization, it is found that the more trimers are formed, the lower the growth rates are than the experimental value, which indicates that trimers are poor growth precursors, because of thermal diffusion effect caused by high temperature gradient. The effective order for the contribution of major species to growth rate is found as: pyrolysis species > amides > trimers. The study also shows that radical reactions have little effect on gas reaction path because of the generation and depletion of H radicals in the chain reactions when NH2 is considered as the end species.

  14. Estimating environmental co-benefits of U.S. low-carbon pathways using an integrated assessment model with state-level resolution

    Energy Technology Data Exchange (ETDEWEB)

    Ou, Yang; Shi, Wenjing; Smith, Steven J.; Ledna, Catherine M.; West, J. Jason; Nolte, Christopher G.; Loughlin, Daniel H.

    2018-04-01

    There are many technological pathways that can lead to reduced carbon dioxide (CO2) emissions. However, these pathways can have substantially different impacts on other environmental endpoints, such as air quality and energy-related water demand. This study uses an integrated assessment model with state-level resolution of the U.S. energy system to compare environmental impacts of alternative low-carbon pathways. One set of pathways emphasizes nuclear energy and carbon capture and storage (NUC/CCS), while another set emphasizes renewable energy (RE). These are compared with pathways in which all technologies are available. Air pollutant emissions, mortality costs attributable to particulate matter less than 2.5 microns in diameter (PM2.5), and energy-related water demands are evaluated for 50% and 80% CO2 reduction targets in the U.S. in 2050. The RE low-carbon pathways require less water withdrawal and consumption than the NUC/CCS pathways because of the large cooling demands of nuclear power and CCS. However, the NUC/CCS low-carbon pathways produce greater health benefits, mainly because the NUC/CCS assumptions result in less primary PM2.5 emissions from residential wood combustion. Environmental co-benefits differ among states because of factors such as existing technology stock, resource availability, and environmental and energy policies. An important finding is that biomass in the building sector can offset some of the health co-benefits of the low-carbon pathways even though it plays only a minor role in reducing CO2 emissions.

  15. Host - HIF- 1alpha Pathway And Hypoxia: In Vitro Studies And Mathematical Model

    Science.gov (United States)

    2016-08-30

    E., Del Sal, G., Gustincich, S . (2010). Parkinson disease-associated DJ-1 required for the expression of the glial cell line-derived neurotrophic...other provision of law , no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a...Model 5a. CONTRACT NUMBER In-House 5b. GRANT NUMBER NA 5c. PROGRAM ELEMENT NUMBER 62202F 6. AUTHOR( S ) Robinson, Peter J.1, Molly E. Chapleau1

  16. Variations in environmental tritium doses due to meteorological data averaging and uncertainties in pathway model parameters

    Energy Technology Data Exchange (ETDEWEB)

    Kock, A.

    1996-05-01

    The objectives of this research are: (1) to calculate and compare off site doses from atmospheric tritium releases at the Savannah River Site using monthly versus 5 year meteorological data and annual source terms, including additional seasonal and site specific parameters not included in present annual assessments; and (2) to calculate the range of the above dose estimates based on distributions in model parameters given by uncertainty estimates found in the literature. Consideration will be given to the sensitivity of parameters given in former studies.

  17. Variations in environmental tritium doses due to meteorological data averaging and uncertainties in pathway model parameters

    International Nuclear Information System (INIS)

    Kock, A.

    1996-05-01

    The objectives of this research are: (1) to calculate and compare off site doses from atmospheric tritium releases at the Savannah River Site using monthly versus 5 year meteorological data and annual source terms, including additional seasonal and site specific parameters not included in present annual assessments; and (2) to calculate the range of the above dose estimates based on distributions in model parameters given by uncertainty estimates found in the literature. Consideration will be given to the sensitivity of parameters given in former studies

  18. Cross-interference of two model peroxisome proliferators in peroxisomal and estrogenic pathways in brown trout hepatocytes

    International Nuclear Information System (INIS)

    Madureira, Tânia Vieira; Pinheiro, Ivone; Malhão, Fernanda; Lopes, Célia; Urbatzka, Ralph; Castro, L. Filipe C.

    2017-01-01

    Highlights: • Brown trout hepatocytes seem to be a low responder to model peroxisome proliferators. • Most peroxisomal targets were not affected by Wy-14,643 and clofibrate exposures. • Some estrogenic-related genes were up-regulated after 150 μM of Wy-14,643. • Wy-14,643 increase VtgA and ERα mRNA levels, while ICI 182,780 revert the effect. • Cross-interference in peroxisomal and estrogenic pathways should be more explored. - Abstract: Peroxisome proliferators cause species-specific effects, which seem to be primarily transduced by peroxisome proliferator-activated receptor alpha (PPARα). Interestingly, PPARα has a close interrelationship with estrogenic signaling, and this latter has already been promptly activated in brown trout primary hepatocytes. Thus, and further exploring this model, we assess here the reactivity of two PPARα agonists in direct peroxisomal routes and, in parallel the cross-interferences in estrogen receptor (ER) mediated paths. To achieve these goals, three independent in vitro studies were performed using single exposures to clofibrate – CLF (50, 500 and 1000 μM), Wy-14,643 – Wy (50 and 150 μM), GW6471 – GW (1 and 10 μM), and mixtures, including PPARα agonist or antagonist plus an ER agonist or antagonist. Endpoints included gene expression analysis of peroxisome/lipidic related genes (encoding apolipoprotein AI – ApoAI, fatty acid binding protein 1 – Fabp1, catalase – Cat, 17 beta-hydroxysteroid dehydrogenase 4 – 17β-HSD4, peroxin 11 alpha – Pex11α, PPARαBb, PPARαBa and urate oxidase – Uox) and those encoding estrogenic targets (ERα, ERβ-1 and vitellogenin A – VtgA). A quantitative morphological approach by using a pre-validated catalase immunofluorescence technique allowed checking possible changes in peroxisomes. Our results show a low responsiveness of trout hepatocytes to model PPARα agonists in direct target receptor pathways. Additionally, we unveiled interferences in estrogenic

  19. Cross-interference of two model peroxisome proliferators in peroxisomal and estrogenic pathways in brown trout hepatocytes

    Energy Technology Data Exchange (ETDEWEB)

    Madureira, Tânia Vieira, E-mail: tvmadureira@icbas.up.pt [Interdisciplinary Centre of Marine and Environmental Research (CIIMAR/CIMAR), University of Porto (U. Porto), Terminal de Cruzeiros do Porto de Leixões, Av. General Norton de Matos s/n, 4450-208 Matosinhos (Portugal); Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto (U. Porto), Laboratory of Histology and Embryology, Department of Microscopy, Rua Jorge Viterbo Ferreira 228, P 4050-313 Porto (Portugal); Pinheiro, Ivone; Malhão, Fernanda; Lopes, Célia [Interdisciplinary Centre of Marine and Environmental Research (CIIMAR/CIMAR), University of Porto (U. Porto), Terminal de Cruzeiros do Porto de Leixões, Av. General Norton de Matos s/n, 4450-208 Matosinhos (Portugal); Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto (U. Porto), Laboratory of Histology and Embryology, Department of Microscopy, Rua Jorge Viterbo Ferreira 228, P 4050-313 Porto (Portugal); Urbatzka, Ralph [Interdisciplinary Centre of Marine and Environmental Research (CIIMAR/CIMAR), University of Porto (U. Porto), Terminal de Cruzeiros do Porto de Leixões, Av. General Norton de Matos s/n, 4450-208 Matosinhos (Portugal); Castro, L. Filipe C. [Interdisciplinary Centre of Marine and Environmental Research (CIIMAR/CIMAR), University of Porto (U. Porto), Terminal de Cruzeiros do Porto de Leixões, Av. General Norton de Matos s/n, 4450-208 Matosinhos (Portugal); Faculty of Sciences (FCUP), University of Porto (U. Porto), Department of Biology, Rua do Campo Alegre, P 4169-007 Porto (Portugal); and others

    2017-06-15

    Highlights: • Brown trout hepatocytes seem to be a low responder to model peroxisome proliferators. • Most peroxisomal targets were not affected by Wy-14,643 and clofibrate exposures. • Some estrogenic-related genes were up-regulated after 150 μM of Wy-14,643. • Wy-14,643 increase VtgA and ERα mRNA levels, while ICI 182,780 revert the effect. • Cross-interference in peroxisomal and estrogenic pathways should be more explored. - Abstract: Peroxisome proliferators cause species-specific effects, which seem to be primarily transduced by peroxisome proliferator-activated receptor alpha (PPARα). Interestingly, PPARα has a close interrelationship with estrogenic signaling, and this latter has already been promptly activated in brown trout primary hepatocytes. Thus, and further exploring this model, we assess here the reactivity of two PPARα agonists in direct peroxisomal routes and, in parallel the cross-interferences in estrogen receptor (ER) mediated paths. To achieve these goals, three independent in vitro studies were performed using single exposures to clofibrate – CLF (50, 500 and 1000 μM), Wy-14,643 – Wy (50 and 150 μM), GW6471 – GW (1 and 10 μM), and mixtures, including PPARα agonist or antagonist plus an ER agonist or antagonist. Endpoints included gene expression analysis of peroxisome/lipidic related genes (encoding apolipoprotein AI – ApoAI, fatty acid binding protein 1 – Fabp1, catalase – Cat, 17 beta-hydroxysteroid dehydrogenase 4 – 17β-HSD4, peroxin 11 alpha – Pex11α, PPARαBb, PPARαBa and urate oxidase – Uox) and those encoding estrogenic targets (ERα, ERβ-1 and vitellogenin A – VtgA). A quantitative morphological approach by using a pre-validated catalase immunofluorescence technique allowed checking possible changes in peroxisomes. Our results show a low responsiveness of trout hepatocytes to model PPARα agonists in direct target receptor pathways. Additionally, we unveiled interferences in estrogenic

  20. Unstable patterns and robust synchronization in a model of motor pathway in birdsong

    International Nuclear Information System (INIS)

    Moukam Kakmeni, F.M.; Bowong, S.; Nana, L.; Kofane, T.C.

    2006-10-01

    This paper investigates the fundamental dynamical mechanism responsible for transition to chaos in periodically modulated Duffing-Van der Pol oscillator. It is shown that a modulationally unstable pattern appears into an initially stable motionless state. A further spatiotemporal transition occurs with a sharp interface from the selected stable pattern to a stabilized pattern or chaotic state. Also, the synchronization of the chaotic state of the model is investigated. The results are discussed in the context of generalized synchronization. The main idea is to construct an augmented dynamical system from the synchronization error system, which is itself uncertain. The advantage of this method over existing results is that the synchronization time is explicitly computed. Numerical simulations are provided to verify the operation of the proposed algorithm. (author)

  1. Hybrid Methods and Atomistic Models to Explore Free Energies, Rates and Pathways of Protein Shape Changes

    DEFF Research Database (Denmark)

    Wang, Yong

    When I just joined the Lindor-Larsen group as a fresh PhD student, the Nobel Prize in Chemistry that year was awarded for the development of multiscale models for complex chemical systems" to prize the pioneering works of Martin Karplus, Michael Levitt and Arieh Warshel. As a computational......L), whose conformational dynamics however is still not fully understood. We found modern simulation methods and force elds are able to capture key aspects of how this protein changes its shape, paving the way for future studies for systems that are dicult to study experimentally. In Chapter 3, we...... revisited the problem of accurately quantifying the thermodynamics and kinetics, by following a novel route. In this route both of the forward and backward rates are calculated directly from MD simulations using a recently developed enhanced sampling method, called \\infrequent metadynamics...

  2. Canadian and United States regulatory models compared: doses from atmospheric pathways

    International Nuclear Information System (INIS)

    Peterson, S-R.

    1997-01-01

    CANDU reactors sold offshore are licensed primarily to satisfy Canadian Regulations. For radioactive emissions during normal operation, the Canadian Standards Association's CAN/CSA-N288.1-M87 is used. This standard provides guidelines and methodologies for calculating a rate of radionuclide release that exposes a member of the public to the annual dose limit. To calculate doses from air concentrations, either CSA-N288.1 or the Regulatory Guide 1.109 of the United States Nuclear Regulatory Commission, which has already been used to license light-water reactors in these countries, may be used. When dose predictions from CSA-N288.1 are compared with those from the U.S. Regulatory Guides, the differences in projected doses raise questions about the predictions. This report explains differences between the two models for ingestion, inhalation, external and immersion doses

  3. Identification of key uric acid synthesis pathway in a unique mutant silkworm Bombyx mori model of Parkinson's disease.

    Directory of Open Access Journals (Sweden)

    Hiroko Tabunoki

    Full Text Available Plasma uric acid (UA levels decrease following clinical progression and stage development of Parkinson's disease (PD. However, the molecular mechanisms underlying decreases in plasma UA levels remain unclear, and the potential to apply mutagenesis to a PD model has not previously been discovered. We identified a unique mutant of the silkworm Bombyx mori (B.mori op. Initially, we investigated the causality of the phenotypic "op" by microarray analysis using our constructed KAIKO functional annotation pipeline. Consequently, we found a novel UA synthesis-modulating pathway, from DJ-1 to xanthine oxidase, and established methods for large-scale analysis of gene expression in B. mori. We found that the mRNA levels of genes in this pathway were significantly lower in B. mori op mutants, indicating that downstream events in the signal transduction cascade might be prevented. Additionally, levels of B.mori tyrosine hydroxylase (TH and DJ-1 mRNA were significantly lower in the brain of B. mori op mutants. UA content was significantly lower in the B. mori op mutant tissues and hemolymph. The possibility that the B. mori op mutant might be due to loss of DJ-1 function was supported by the observed vulnerability to oxidative stress. These results suggest that UA synthesis, transport, elimination and accumulation are decreased by environmental oxidative stress in the B. mori op mutant. In the case of B. mori op mutants, the relatively low availability of UA appears to be due both to the oxidation of DJ-1 and to its expenditure to mitigate the effects of environmental oxidative stress. Our findings are expected to provide information needed to elucidate the molecular mechanism of decreased plasma UA levels in the clinical stage progression of PD.

  4. Atmospheric releases from severe nuclear accidents: Environmental transport and pathways to man: Modelling of radiation doses to man from Chernobyl releases

    International Nuclear Information System (INIS)

    Anspaugh, L.R.; Goldman, M.; Catlin, R.J.

    1987-01-01

    The Chernobyl accident released a large amount of highly fractionated radioactive debris, including approximately 89 PBq of 137 Cs. We calculated the resulting collective dose commitment to the Northern Hemisphere via the pathways of external exposure and ingestion of radionuclides withd food. We developed a rural/urban model of external dose and we used the PATHWAY model for ingestion. The results are a collective dose commitment of 630,000 person-Gy over the first year and 1,200,000 person-Gy over 50 years. 13 refs., 1 tab

  5. Metabolic Engineering and Modeling of Metabolic Pathways to Improve Hydrogen Production by Photosynthetic Bacteria

    Energy Technology Data Exchange (ETDEWEB)

    Jiao, Y. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Navid, A. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

    2014-12-19

    traits act as the biocatalysts of the process designed to both enhance the system efficiency of CO2 fixation and the net hydrogen production rate. Additionally we applied metabolic engineering approaches guided by computational modeling for the chosen model microorganisms to enable efficient hydrogen production.

  6. Breaking Down the Door: A Nonprofit Model Creating Pathways for Non-Traditional STEM Student Engagement

    Science.gov (United States)

    Pelaez, C.; Pelaez, J.

    2015-12-01

    Blueprint Earth was created as a nonprofit scientific research organization dedicated to conducting micro-scale interdisciplinary environmental investigations to generate macroscopic, system-level environmental understanding. The field data collection and analysis process was conceived to be dependent on student participation and collaboration with more senior scientists, effecting knowledge transfer and emphasizing the critical nature of interdisciplinary research in investigating complex, macroscopic questions. Recruiting for student volunteer researchers is conducted in academic institutions, and to date has focused primarily on the Los Angeles area. Self-selecting student participation has run contrary to traditional STEM demographics. The vast majority of research participants in Blueprint Earth's work are female and/or from a minority (non-white) background, and most are first-generation college students or from low-income, Pell grant-eligible households. Traditional field research programs for students often come at a high cost, creating barriers to access for field-based STEM opportunities. The nonprofit model employed by Blueprint Earth provides zero-cost access to opportunity for students that the STEM world is currently targeting for future professional development.

  7. Revisiting the chlorophyll biosynthesis pathway using genome scale metabolic model of Oryza sativa japonica

    Science.gov (United States)

    Chatterjee, Ankita; Kundu, Sudip

    2015-01-01

    Chlorophyll is one of the most important pigments present in green plants and rice is one of the major food crops consumed worldwide. We curated the existing genome scale metabolic model (GSM) of rice leaf by incorporating new compartment, reactions and transporters. We used this modified GSM to elucidate how the chlorophyll is synthesized in a leaf through a series of bio-chemical reactions spanned over different organelles using inorganic macronutrients and light energy. We predicted the essential reactions and the associated genes of chlorophyll synthesis and validated against the existing experimental evidences. Further, ammonia is known to be the preferred source of nitrogen in rice paddy fields. The ammonia entering into the plant is assimilated in the root and leaf. The focus of the present work is centered on rice leaf metabolism. We studied the relative importance of ammonia transporters through the chloroplast and the cytosol and their interlink with other intracellular transporters. Ammonia assimilation in the leaves takes place by the enzyme glutamine synthetase (GS) which is present in the cytosol (GS1) and chloroplast (GS2). Our results provided possible explanation why GS2 mutants show normal growth under minimum photorespiration and appear chlorotic when exposed to air. PMID:26443104

  8. Oxygen pathway modeling estimates high reactive oxygen species production above the highest permanent human habitation.

    Directory of Open Access Journals (Sweden)

    Isaac Cano

    Full Text Available The production of reactive oxygen species (ROS from the inner mitochondrial membrane is one of many fundamental processes governing the balance between health and disease. It is well known that ROS are necessary signaling molecules in gene expression, yet when expressed at high levels, ROS may cause oxidative stress and cell damage. Both hypoxia and hyperoxia may alter ROS production by changing mitochondrial Po2 (PmO2. Because PmO2 depends on the balance between O2 transport and utilization, we formulated an integrative mathematical model of O2 transport and utilization in skeletal muscle to predict conditions to cause abnormally high ROS generation. Simulations using data from healthy subjects during maximal exercise at sea level reveal little mitochondrial ROS production. However, altitude triggers high mitochondrial ROS production in muscle regions with high metabolic capacity but limited O2 delivery. This altitude roughly coincides with the highest location of permanent human habitation. Above 25,000 ft., more than 90% of exercising muscle is predicted to produce abnormally high levels of ROS, corresponding to the "death zone" in mountaineering.

  9. Galvanic microparticles increase migration of human dermal fibroblasts in a wound-healing model via reactive oxygen species pathway.

    Science.gov (United States)

    Tandon, Nina; Cimetta, Elisa; Villasante, Aranzazu; Kupferstein, Nicolette; Southall, Michael D; Fassih, Ali; Xie, Junxia; Sun, Ying; Vunjak-Novakovic, Gordana

    2014-01-01

    Electrical signals have been implied in many biological mechanisms, including wound healing, which has been associated with transient electrical currents not present in intact skin. One method to generate electrical signals similar to those naturally occurring in wounds is by supplementation of galvanic particles dispersed in a cream or gel. We constructed a three-layered model of skin consisting of human dermal fibroblasts in hydrogel (mimic of dermis), a hydrogel barrier layer (mimic of epidermis) and galvanic microparticles in hydrogel (mimic of a cream containing galvanic particles applied to skin). Using this model, we investigated the effects of the properties and amounts of Cu/Zn galvanic particles on adult human dermal fibroblasts in terms of the speed of wound closing and gene expression. The collected data suggest that the effects on wound closing are due to the ROS-mediated enhancement of fibroblast migration, which is in turn mediated by the BMP/SMAD signaling pathway. These results imply that topical low-grade electric currents via microparticles could enhance wound healing. © 2013 Elsevier Inc. All rights reserved.

  10. Testing a hierarchy-of-effects model: pathways from awareness to outcomes in the VERB campaign 2002-2003.

    Science.gov (United States)

    Bauman, Adrian; Bowles, Heather R; Huhman, Marian; Heitzler, Carrie D; Owen, Neville; Smith, Ben J; Reger-Nash, Bill

    2008-06-01

    The McGuire hierarchy-of-effects (HOE) model, used extensively in mass-media interventions to describe the mechanisms for understanding effects, has not been tested in physical activity campaigns. Data collected at baseline (2002) and follow-up (2003) surveys in the VERB evaluation were used in structural equation modeling to test pathways and hierarchies of campaign effects. Population-based cohort of youth aged 9-13 years (N=2364) for whom complete baseline and follow-up data were available. Awareness of the VERB campaign, understanding of the VERB message, attitude toward being active, outcome expectations, and physical activity participation. Among youth aged 9-13 years (tweens) in the study cohort, significant paths were identified between awareness and understanding (0.72, pmodel and suggest that increased awareness and understanding were the key proximal effects that led to behavior change. A distinct sequence of effects, which bypassed attitudes and outcome expectations, was found for these U.S. young people. The findings could inform the design of future campaigns to address youth physical activity.

  11. Updates to the Corn Ethanol Pathway and Development of an Integrated Corn and Corn Stover Ethanol Pathway in the GREET™ Model

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Zhichao [Argonne National Lab. (ANL), Argonne, IL (United States). Energy Systems Division; Dunn, Jennifer B. [Argonne National Lab. (ANL), Argonne, IL (United States). Energy Systems Division; Wang, Michael Q. [Argonne National Lab. (ANL), Argonne, IL (United States). Energy Systems Division

    2014-09-01

    Corn ethanol, a first-generation biofuel, is the predominant biofuel in the United States. In 2013, the total U.S. ethanol fuel production was 13.3 billion gallons, over 95% of which was produced from corn (RFA, 2014). The 2013 total renewable fuel mandate was 16.6 billion gallons according to the Energy Independence and Security Act (EISA) (U.S. Congress, 2007). Furthermore, until 2020, corn ethanol will make up a large portion of the renewable fuel volume mandated by Renewable Fuels Standard (RFS2). For the GREET1_2014 release, the corn ethanol pathway was subject to updates reflecting changes in corn agriculture and at corn ethanol plants. In the latter case, we especially focused on the incorporation of corn oil as a corn ethanol plant co-product. Section 2 covers these updates. In addition, GREET now includes options to integrate corn grain and corn stover ethanol production on the field and at the biorefinery. These changes are the focus of Section 3.

  12. Sensitization of trigeminal brainstem pathways in a model for tear deficient dry eye.

    Science.gov (United States)

    Rahman, Mostafeezur; Okamoto, Keiichiro; Thompson, Randall; Katagiri, Ayano; Bereiter, David A

    2015-05-01

    Chronic dry eye disease (DE) is associated with an unstable tear film and symptoms of ocular discomfort. The characteristics of symptoms suggest a key role for central neural processing; however, little is known about central neuroplasticity and DE. We used a model for tear deficient DE and assessed effects on eye blink behavior, orbicularis oculi muscle activity (OOemg), and trigeminal brainstem neural activity in male rats. Ocular-responsive neurons were recorded at the interpolaris/caudalis transition (Vi/Vc) and Vc/upper cervical cord (Vc/C1) regions under isoflurane, whereas OOemg activity was recorded under urethane. Spontaneous tear volume was reduced by ∼50% at 14 days after exorbital gland removal. Hypertonic saline-evoked eye blink behavior in awake rats was enhanced throughout the 14 days after surgery. Saline-evoked neural activity at the Vi/Vc transition and in superficial and deep laminae at the Vc/C1 region was greatly enhanced in DE rats. Neurons from DE rats classified as wide dynamic range displayed enlarged convergent periorbital receptive fields consistent with central sensitization. Saline-evoked OOemg activity was markedly enhanced in DE rats compared with controls. Synaptic blockade at the Vi/Vc transition or the Vc/C1 region greatly reduced hypertonic saline-evoked OOemg activity in DE and sham rats. These results indicated that persistent tear deficiency caused sensitization of ocular-responsive neurons at multiple regions of the caudal trigeminal brainstem and enhanced OOemg activity. Central sensitization of ocular-related brainstem circuits is a significant factor in DE and likely contributes to the apparent weak correlation between peripheral signs of tear dysfunction and symptoms of irritation.

  13. Assessment of the effect of visual impairment on mortality through multiple health pathways: structural equation modeling.

    Science.gov (United States)

    Christ, Sharon L; Lee, David J; Lam, Byron L; Zheng, D Diane; Arheart, Kristopher L

    2008-08-01

    To estimate the direct effects of self-reported visual impairment (VI) on health, disability, and mortality and to estimate the indirect effects of VI on mortality through health and disability mediators. The National Health Interview Survey (NHIS) is a population-based annual survey designed to be representative of the U.S. civilian noninstitutionalized population. The National Death Index of 135,581 NHIS adult participants, 18 years of age and older, from 1986 to 1996 provided the mortality linkage through 2002. A generalized linear structural equation model (GSEM) with latent variable was used to estimate the results of a system of equations with various outcomes. Standard errors and test statistics were corrected for weighting, clustering, and stratification. VI affects mortality, when direct adjustment was made for the covariates. Severe VI increases the hazard rate by a factor of 1.28 (95% CI: 1.07-1.53) compared with no VI, and some VI increases the hazard by a factor of 1.13 (95% CI: 1.07-1.20). VI also affects mortality indirectly through self-rated health and disability. The total effects (direct effects plus mediated effects) on the hazard of mortality of severe VI and some VI relative to no VI are hazard ratio (HR) 1.54 (95% CI: 1.28-1.86) and HR 1.23 (95% CI: 1.16-1.31), respectively. In addition to the direct link between VI and mortality, the effects of VI on general health and disability contribute to an increased risk of death. Ignoring the latter may lead to an underestimation of the substantive impact of VI on mortality.

  14. A simplified method for power-law modelling of metabolic pathways from time-course data and steady-state flux profiles

    OpenAIRE

    Kitayama, Tomoya; Kinoshita, Ayako; Sugimoto, Masahiro; Nakayama, Yoichi; Tomita, Masaru

    2006-01-01

    Abstract Background In order to improve understanding of metabolic systems there have been attempts to construct S-system models from time courses. Conventionally, non-linear curve-fitting algorithms have been used for modelling, because of the non-linear properties of parameter estimation from time series. However, the huge iterative calculations required have hindered the development of large-scale metabolic pathway models. To solve this problem we propose a novel method involving power-law...

  15. Pathways to nephron loss starting from glomerular diseases-insights from animal models.

    Science.gov (United States)

    Kriz, Wilhelm; LeHir, Michel

    2005-02-01

    Studies of glomerular diseases in animal models show that progression toward nephron loss starts with extracapillary lesions, whereby podocytes play the central role. If injuries remain bound within the endocapillary compartment, they will undergo recovery or be repaired by scaring. Degenerative, inflammatory and dysregulative mechanisms leading to nephron loss are distinguished. In addition to several other unique features, the dysregulative mechanisms leading to collapsing glomerulopathy are particular in that glomeruli and tubules are affected in parallel. In contrast, in degenerative and inflammatory diseases, tubular injury is secondary to glomerular lesions. In both of the latter groups of diseases, the progression starts in the glomerulus with the loss of the separation between the tuft and Bowman's capsule by forming cell bridges (parietal cells and/or podocytes) between the glomerular and the parietal basement membranes. Cell bridges develop into tuft adhesions to Bowman's capsule, which initiate the formation of crescents, either by misdirected filtration (proteinaceous crescents) or by epithelial cell proliferation (cellular crescents). Crescents may spread over the entire circumference of the glomerulus and, via the glomerulotubular junction, may extend onto the tubule. Two mechanisms concerning the transfer of a glomerular injury onto the tubulointerstitium are discussed: (1) direct encroachment of extracapillary lesions and (2) protein leakage into tubular urine, resulting in injury to the tubule and the interstitium. There is evidence that direct encroachment is the crucial mechanism. Progression of chronic renal disease is underlain by a vicious cycle which passes on the damage from lost and/or damaged nephrons to so far healthy nephrons. Presently, two mechanisms are discussed: (1) the loss of nephrons leads to compensatory mechanisms in the remaining nephrons (glomerular hypertension, hyperfiltration, hypertrophy) which increase their

  16. Replication and extension of the dual pathway model of disordered eating: The role of fear of negative evaluation, suggestibility, rumination, and self-compassion.

    Science.gov (United States)

    Maraldo, Toni M; Zhou, Wanni; Dowling, Jessica; Vander Wal, Jillon S

    2016-12-01

    The dual pathway model, a theoretical model of eating disorder development, suggests that thin ideal internalization leads to body dissatisfaction which leads to disordered eating via the dual pathways of negative affect and dietary restraint. While the dual pathway model has been a valuable guide for eating disorder prevention, greater knowledge of characteristics that predict thin ideal internalization is needed. The present study replicated and extended the dual pathway model by considering the addition of fear of negative evaluation, suggestibility, rumination, and self-compassion in a sample of community women and female university students. Results showed that fear of negative evaluation and suggestibility predicted thin ideal internalization whereas rumination and self-compassion (inversely) predicted body dissatisfaction. Negative affect was predicted by fear of negative evaluation, rumination, and self-compassion (inversely). The extended model fit the data well in both samples. Analogue and longitudinal study of these constructs is warranted in future research. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. Development of a model of dementia support and pathway for culturally and linguistically diverse communities using co-creation and participatory action research.

    Science.gov (United States)

    Goeman, Dianne; King, Jordan; Koch, Susan

    2016-12-07

    To develop an inclusive model of culturally sensitive support, using a specialist dementia nurse (SDN), to assist people with dementia from culturally and linguistically diverse (CALD) communities and their carers to overcome barriers to accessing health and social care services. Co-creation and participatory action research, based on reflection, data collection, interaction and feedback from participants and stakeholders. An SDN support model embedded within a home nursing service in Melbourne, Australia was implemented between October 2013 and October 2015. People experiencing memory loss or with a diagnosis of dementia from CALD backgrounds and their carers and family living in the community setting and expert stakeholders. Reflections from the SDN on interactions with participants and expert stakeholder opinion informed the CALD dementia support model and pathway. Interaction with 62 people living with memory loss or dementia from CALD backgrounds, carers or family members receiving support from the SDN and feedback from 13 expert stakeholders from community aged-care services, consumer advocacy organisations and ethnic community group representatives informed the development and refinement of the CALD dementia model of care and pathway. We delineate the three components of the 'SDN' model: the organisational support; a description of the role; and the competencies needed. Additionally, we provide an accompanying pathway for use by health professionals delivering care to consumers with dementia from CALD backgrounds. Our culturally sensitive model of dementia care and accompanying pathway allows for the tailoring of health and social support to assist people from CALD backgrounds, their carers and families to adjust to living with memory loss and remain living in the community as long as possible. The model and accompanying pathway also have the potential to be rolled out nationally for use by health professionals across a variety of health services. Published

  18. Cross-interference of two model peroxisome proliferators in peroxisomal and estrogenic pathways in brown trout hepatocytes.

    Science.gov (United States)

    Madureira, Tânia Vieira; Pinheiro, Ivone; Malhão, Fernanda; Lopes, Célia; Urbatzka, Ralph; Castro, L Filipe C; Rocha, Eduardo

    2017-06-01

    Peroxisome proliferators cause species-specific effects, which seem to be primarily transduced by peroxisome proliferator-activated receptor alpha (PPARα). Interestingly, PPARα has a close interrelationship with estrogenic signaling, and this latter has already been promptly activated in brown trout primary hepatocytes. Thus, and further exploring this model, we assess here the reactivity of two PPARα agonists in direct peroxisomal routes and, in parallel the cross-interferences in estrogen receptor (ER) mediated paths. To achieve these goals, three independent in vitro studies were performed using single exposures to clofibrate - CLF (50, 500 and 1000μM), Wy-14,643 - Wy (50 and 150μM), GW6471 - GW (1 and 10μM), and mixtures, including PPARα agonist or antagonist plus an ER agonist or antagonist. Endpoints included gene expression analysis of peroxisome/lipidic related genes (encoding apolipoprotein AI - ApoAI, fatty acid binding protein 1 - Fabp1, catalase - Cat, 17 beta-hydroxysteroid dehydrogenase 4 - 17β-HSD4, peroxin 11 alpha - Pex11α, PPARαBb, PPARαBa and urate oxidase - Uox) and those encoding estrogenic targets (ERα, ERβ-1 and vitellogenin A - VtgA). A quantitative morphological approach by using a pre-validated catalase immunofluorescence technique allowed checking possible changes in peroxisomes. Our results show a low responsiveness of trout hepatocytes to model PPARα agonists in direct target receptor pathways. Additionally, we unveiled interferences in estrogenic signaling caused by Wy, leading to an up-regulation VtgA and ERα at 150μM; these effects seem counteracted with a co-exposure to an ER antagonist. The present data stress the potential of this in vitro model for further exploring the physiological/toxicological implications related with this nuclear receptor cross-regulation. Copyright © 2017 Elsevier B.V. All rights reserved.

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

    Science.gov (United States)

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

    2016-12-01

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

  20. DYSFUNCTIONAL KYNURENINE PATHWAY METABOLISM IN THE R6/2 MOUSE MODEL OF HUNTINGTON’S DISEASE

    Science.gov (United States)

    Sathyasaikumar, Korrapati V.; Stachowski, Erin K.; Amori, Laura; Guidetti, Paolo; Muchowski, Paul J.; Schwarcz, Robert

    2013-01-01

    Elevated concentrations of neurotoxic metabolites of the kynurenine pathway (KP) of tryptophan degradation may play a causative role in Huntington’s disease (HD). The brain levels of one of these compounds, 3-hydroxykynurenine (3-HK), are increased in both HD and several mouse models of the disease. In the present study, we examined this impairment in greater detail using the R6/2 mouse, a well-established animal model of HD. Initially, mutant and age-matched wild-type mice received an intrastriatal injection of 3H-tryptophan to assess the acute, local de novo production of kynurenine, the immediate bioprecursor of 3-HK, in vivo. No effect of genotype was observed between 4 and 12 weeks of age. In contrast, intrastriatally applied 3H-kynurenine resulted in significantly increased neosynthesis of 3H-3-HK, but not other tritiated KP metabolites, in the R6/2 striatum. Subsequent ex vivo studies in striatal, cortical and cerebellar tissue revealed substantial increases in the activity of the biosynthetic enzyme of 3-HK, kynurenine 3-monooxygenase (KMO) and significant reductions in the activity of its degradative enzyme, kynureninase, in HD mice starting at 4 weeks of age. Decreased kynureninase activity was most evident in the cortex and preceded the increase in KMO activity. The activity of other KP enzymes showed no consistent brain abnormalities in the mutant mice. These findings suggest that impairments in its immediate metabolic enzymes jointly account for the abnormally high brain levels of 3-HK in the R6/2 model of HD. PMID:20236387

  1. Representative Agricultural Pathways: A Trans-Disciplinary Approach to Agricultural Model Inter-comparison, Improvement, Climate Impact Assessment and Stakeholder Engagement

    Science.gov (United States)

    Antle, J. M.; Valdivia, R. O.; Claessens, L.; Nelson, G. C.; Rosenzweig, C.; Ruane, A. C.; Vervoort, J.

    2013-12-01

    The global change research community has recognized that new pathway and scenario concepts are needed to implement impact and vulnerability assessment that is logically consistent across local, regional and global scales. For impact and vulnerability assessment, new socio-economic pathway and scenario concepts are being developed. Representative Agricultural Pathways (RAPs) are designed to extend global pathways to provide the detail needed for global and regional assessment of agricultural systems. In addition, research by the Agricultural Model Inter-comparison and Improvement Project (AgMIP) shows that RAPs provide a powerful way to engage stakeholders in climate-related research throughout the research process and in communication of research results. RAPs are based on the integrated assessment framework developed by AgMIP. This framework shows that both bio-physical and socio-economic drivers are essential components of agricultural pathways and logically precede the definition of adaptation and mitigation scenarios that embody associated capabilities and challenges. This approach is based on a trans-disciplinary process for designing pathways and then translating them into parameter sets for bio-physical and economic models that are components of agricultural integrated assessments of climate impact, adaptation and mitigation. RAPs must be designed to be part of a logically consistent set of drivers and outcomes from global to regional and local. Global RAPs are designed to be consistent with higher-level global socio-economic pathways, but add key agricultural drivers such as agricultural growth trends that are not specified in more general pathways, as illustrated in a recent inter-comparison of global agricultural models. To create pathways at regional or local scales, further detail is needed. At this level, teams of scientists and other experts with knowledge of the agricultural systems and regions work together through a step-wise process. Experiences

  2. Long-Term Impact of the Dutch Colorectal Cancer Screening Program on Cancer Incidence and Mortality-Model-Based Exploration of the Serrated Pathway

    NARCIS (Netherlands)

    Greuter, Marjolein J. E.; Demirel, Erhan; Lew, Jie-Bin; Berkhof, Johannes; Xu, Xiang-Ming; Canfell, Karen; Dekker, Evelien; Meijer, Gerrit A.; Coupé, Veerle M. H.

    2016-01-01

    We aimed to predict the long-term colorectal cancer incidence, mortality, and colonoscopy demand of the recently implemented Dutch colorectal cancer screening program. The Adenoma and Serrated pathway to Colorectal Cancer model was set up to simulate the Dutch screening program consisting of

  3. Pathways of change explaining the effect of smoke-free legislation on smoking cessation in the Netherlands: an application of the international tobacco control conceptual model

    NARCIS (Netherlands)

    Nagelhout, G.E.; de Vries, H.; Fong, G.T.; Candel, M.J.J.M.; Thrasher, J.F.; van den Putte, B.; Thompson, M.E.; Cummings, K.M.; Willemsen, M.C.

    2012-01-01

    Introduction: This study aims to test the pathways of change from individual exposure to smoke-free legislation on smoking cessation, as hypothesized in the International Tobacco Control (ITC) Conceptual Model. Methods: A nationally representative sample of Dutch smokers aged 15 years and older was

  4. Emodin Protects against Diabetic Cardiomyopathy by Regulating the AKT/GSK-3β Signaling Pathway in the Rat Model

    Directory of Open Access Journals (Sweden)

    Zhiqin Wu

    2014-09-01

    Full Text Available Diabetes mellitus (DM has been recognized as a major health problem. Emodin (Emo has been reported to exhibit protective effects against diabetic nephropathy. However, little has been known about the effect of Emo on diabetic cardiomyopathy (DCM. A type 2 DM model was induced in rats by low dose streptozotocin (STZ combined with high energy intake. We found that Emo-treated groups displayed significantly higher body weight (BW and lower heart weight (HW/BW. Furthermore, Emo could significantly decrease blood glucose, total cholesterol (TG levels, and triglyceride (TC levels in diabetic rats. Moreover, the Emo-treated group showed a marked increase in heart rate (HR and showed lower left ventricular end-diastolic diameter (LVEDD, left ventricular end-systolic diameter (LVESD, left ventricular posterior wall thickness (LWPWT, and interventricular septal diastolic wall thickness (IVSD. Emo induced a significant increase in phosphorylation of Akt and GSK-3β in myocardium. These results suggest that Emo may have great therapeutic potential in the treatment of DCM by Akt/GSK-3β signaling pathway.

  5. A model for the catabolism of rhizopine in Rhizobium leguminosarum involves a ferredoxin oxygenase complex and the inositol degradative pathway.

    Science.gov (United States)

    Bahar, M; de Majnik, J; Wexler, M; Fry, J; Poole, P S; Murphy, P J

    1998-11-01

    Rhizopines are nodule-specific compounds that confer an intraspecies competitive nodulation advantage to strains that can catabolize them. The rhizopine (3-O-methyl-scyllo-inosamine, 3-O-MSI) catabolic moc gene cluster mocCABRDE(F) in Rhizobium leguminosarum bv. viciae strain 1a is located on the Sym plasmid. MocCABR are homologous to the mocCABR gene products from Sinorhizobium meliloti. MocD and MocE contain motifs corresponding to a TOL-like oxygenase and a [2Fe-2S] Rieske-like ferredoxin, respectively. The mocF gene encodes a ferredoxin reductase that would complete the oxygenase system, but is not essential for rhizopine catabolism. We propose a rhizopine catabolic model whereby MocB transports rhizopine into the cell and MocDE and MocF (or a similar protein elsewhere in the genome), under the regulation of MocR, act in concert to form a ferredoxin oxygenase system that demethylates 3-O-MSI to form scyllo-inosamine (SI). MocA, an NAD(H)-dependent dehydrogenase, and MocC continue the catabolic process. Compounds formed then enter the inositol catabolic pathway.

  6. Modelling the interplay between childhood and adult adversity in pathways to psychosis: initial evidence from the AESOP study.

    Science.gov (United States)

    Morgan, C; Reininghaus, U; Fearon, P; Hutchinson, G; Morgan, K; Dazzan, P; Boydell, J; Kirkbride, J B; Doody, G A; Jones, P B; Murray, R M; Craig, T

    2014-01-01

    There is evidence that a range of socio-environmental exposures is associated with an increased risk of psychosis. However, despite the fact that such factors probably combine in complex ways to increase risk, the majority of studies have tended to consider each exposure separately. In light of this, we sought to extend previous analyses of data from the AESOP (Aetiology and Ethnicity in Schizophrenia and Other Psychoses) study on childhood and adult markers of disadvantage to examine how they combine to increase risk of psychosis, testing both mediation (path) models and synergistic effects. All patients with a first episode of psychosis who made contact with psychiatric services in defined catchment areas in London and Nottingham, UK (n = 390) and a series of community controls (n = 391) were included in the AESOP study. Data relating to clinical and social variables, including parental separation and loss, education and adult disadvantage, were collected from cases and controls. There was evidence that the effect of separation from, but not death of, a parent in childhood on risk of psychosis was partially mediated through subsequent poor educational attainment (no qualifications), adult social disadvantage and, to a lesser degree, low self-esteem. In addition, there was strong evidence that separation from, but not death of, a parent combined synergistically with subsequent disadvantage to increase risk. These effects held for all ethnic groups in the sample. Exposure to childhood and adult disadvantage may combine in complex ways to push some individuals along a predominantly sociodevelopmental pathway to psychosis.

  7. Increased Asics Expression via the Camkii-CREB Pathway in a Novel Mouse Model of Trigeminal Pain

    Directory of Open Access Journals (Sweden)

    Yan Wang

    2018-03-01

    Full Text Available Background/Aims: Migraine is a disabling condition that severely impacts socioeconomic function and quality of life. The focus of this study was to develop a mouse model of trigeminal pain that mimics migraine. Methods: After undergoing dural cannulation surgery, mice were treated with repeated dural doses of an acidic solution to induce trigeminal pain. Results: The method elicited intermittent, head-directed wiping and scratching as well as the expression of both the c-FOS gene in the spinal trigeminal nucleus caudalis and calcitonin gene related peptide (CGRP in the periaqueductal grey matter. Interestingly, the acid-induced trigeminal pain behaviour was inhibited by amiloride, an antagonist of acid-sensing ion channels (ASICs, but not by AMG-9810, an inhibitor of transient receptor potential cation channel V1(TRPV1. In addition, the relative mRNA and protein expression levels of ASIC1a and ASIC3 were increased in the acid-induced trigeminal nociceptive pathways. Furthermore, blocking CaMKII with KN-93 significantly reduced the acid-induced trigeminal pain behaviour and c-FOS gene expression. Conclusion: The data suggested that chronic intermittent administration of an acidic solution to mice resulted in trigeminal hypersensitivity and that dural acid-induced trigeminal pain behaviour in mice may mechanistically mimic migraine. The observations here identify an entirely novel treatment strategy for migraine.

  8. Kaempferol Attenuates Myocardial Ischemic Injury via Inhibition of MAPK Signaling Pathway in Experimental Model of Myocardial Ischemia-Reperfusion Injury

    Science.gov (United States)

    Suchal, Kapil; Malik, Salma; Gamad, Nanda; Malhotra, Rajiv Kumar; Goyal, Sameer N.; Chaudhary, Uma; Bhatia, Jagriti; Ojha, Shreesh; Arya, Dharamvir Singh

    2016-01-01

    Kaempferol (KMP), a dietary flavonoid, has antioxidant, anti-inflammatory, and antiapoptotic effects. Hence, we investigated the effect of KMP in ischemia-reperfusion (IR) model of myocardial injury in rats. We studied male albino Wistar rats that were divided into sham, IR-control, KMP-20 + IR, and KMP 20 per se groups. KMP (20 mg/kg; i.p.) was administered daily to rats for the period of 15 days, and, on the 15th day, ischemia was produced by one-stage ligation of left anterior descending coronary artery for 45 min followed by reperfusion for 60 min. After completion of surgery, rats were sacrificed; heart was removed and processed for biochemical, morphological, and molecular studies. KMP pretreatment significantly ameliorated IR injury by maintaining cardiac function, normalizing oxidative stress, and preserving morphological alterations. Furthermore, there was a decrease in the level of inflammatory markers (TNF-α, IL-6, and NFκB), inhibition of active JNK and p38 proteins, and activation of ERK1/ERK2, a prosurvival kinase. Additionally, it also attenuated apoptosis by reducing the expression of proapoptotic proteins (Bax and Caspase-3), TUNEL positive cells, and increased level of antiapoptotic proteins (Bcl-2). In conclusion, KMP protected against IR injury by attenuating inflammation and apoptosis through the modulation of MAPK pathway. PMID:27087891

  9. Kaempferol Attenuates Myocardial Ischemic Injury via Inhibition of MAPK Signaling Pathway in Experimental Model of Myocardial Ischemia-Reperfusion Injury

    Directory of Open Access Journals (Sweden)

    Kapil Suchal

    2016-01-01

    Full Text Available Kaempferol (KMP, a dietary flavonoid, has antioxidant, anti-inflammatory, and antiapoptotic effects. Hence, we investigated the effect of KMP in ischemia-reperfusion (IR model of myocardial injury in rats. We studied male albino Wistar rats that were divided into sham, IR-control, KMP-20 + IR, and KMP 20 per se groups. KMP (20 mg/kg; i.p. was administered daily to rats for the period of 15 days, and, on the 15th day, ischemia was produced by one-stage ligation of left anterior descending coronary artery for 45 min followed by reperfusion for 60 min. After completion of surgery, rats were sacrificed; heart was removed and processed for biochemical, morphological, and molecular studies. KMP pretreatment significantly ameliorated IR injury by maintaining cardiac function, normalizing oxidative stress, and preserving morphological alterations. Furthermore, there was a decrease in the level of inflammatory markers (TNF-α, IL-6, and NFκB, inhibition of active JNK and p38 proteins, and activation of ERK1/ERK2, a prosurvival kinase. Additionally, it also attenuated apoptosis by reducing the expression of proapoptotic proteins (Bax and Caspase-3, TUNEL positive cells, and increased level of antiapoptotic proteins (Bcl-2. In conclusion, KMP protected against IR injury by attenuating inflammation and apoptosis through the modulation of MAPK pathway.

  10. Glucose metabolism via the pentose phosphate pathway, glycolysis and Krebs cycle in an orthotopic mouse model of human brain tumors.

    Science.gov (United States)

    Marin-Valencia, Isaac; Cho, Steve K; Rakheja, Dinesh; Hatanpaa, Kimmo J; Kapur, Payal; Mashimo, Tomoyuki; Jindal, Ashish; Vemireddy, Vamsidhara; Good, Levi B; Raisanen, Jack; Sun, Xiankai; Mickey, Bruce; Choi, Changho; Takahashi, Masaya; Togao, Osamu; Pascual, Juan M; Deberardinis, Ralph J; Maher, Elizabeth A; Malloy, Craig R; Bachoo, Robert M

    2012-10-01

    It has been hypothesized that increased flux through the pentose phosphate pathway (PPP) is required to support the metabolic demands of rapid malignant cell growth. Using orthotopic mouse models of human glioblastoma (GBM) and renal cell carcinoma metastatic to brain, we estimated the activity of the PPP relative to glycolysis by infusing [1,2-(13) C(2) ]glucose. The [3-(13) C]lactate/[2,3-(13) C(2) ]lactate ratio was similar for both the GBM and brain metastasis and their respective surrounding brains (GBM, 0.197 ± 0.011 and 0.195 ± 0.033, respectively (p = 1); metastasis: 0.126 and 0.119 ± 0.033, respectively). This suggests that the rate of glycolysis is significantly greater than the PPP flux in these tumors, and that the PPP flux into the lactate pool is similar in both tumors. Remarkably, (13) C-(13) C coupling was observed in molecules derived from Krebs cycle intermediates in both tumor types, denoting glucose oxidation. In the renal cell carcinoma, in contrast with GBM, (13) C multiplets of γ-aminobutyric acid (GABA) differed from its precursor glutamate, suggesting that GABA did not derive from a common glutamate precursor pool. In addition, the orthotopic renal tumor, the patient's primary renal mass and brain metastasis were all strongly immunopositive for the 67-kDa isoform of glutamate decarboxylase, as were 84% of tumors on a renal cell carcinoma tissue microarray of the same histology, suggesting that GABA synthesis is cell autonomous in at least a subset of renal cell carcinomas. Taken together, these data demonstrate that (13) C-labeled glucose can be used in orthotopic mouse models to study tumor metabolism in vivo and to ascertain new metabolic targets for cancer diagnosis and therapy. Copyright © 2012 John Wiley & Sons, Ltd.

  11. Migration pathways in soils

    International Nuclear Information System (INIS)

    Gronow, J.R.

    1986-01-01

    This study looked at diffusive migration through three types of deformation; the projectile pathways, hydraulic fractures of the sediments and faults, and was divided into three experimental areas: autoradiography, the determination of diffusion coefficients and electron microscopy of model projectile pathways in clay. For the autoradiography, unstressed samples were exposed to two separate isotopes, Pm-147 (a possible model for Am behaviour) and the poorly sorbed iodide-125. The results indicated that there was no enhanced migration through deformed kaolin samples nor through fractured Great Meteor East (GME) sediment, although some was evident through the projectile pathways in GME and possibly through the GME sheared samples. The scanning electron microscopy of projectile pathways in clay showed that emplacement of a projectile appeared to have no effect on the orientation of particles at distances greater than two projectile radii from the centre of a projectile pathway. It showed that the particles were not simply aligned with the direction of motion of the projectile but that, the closer to the surface of a particular pathway, the closer the particles lay to their original orientation. This finding was of interest from two points of view: i) the ease of migration of a pollutant along the pathway, and ii) possible mechanisms of hole closure. It was concluded that, provided that there is no advective migration, the transport of radionuclides through sediments containing these defects would not be significantly more rapid than in undeformed sediments. (author)

  12. PathwayAccess: CellDesigner plugins for pathway databases.

    Science.gov (United States)

    Van Hemert, John L; Dickerson, Julie A

    2010-09-15

    CellDesigner provides a user-friendly interface for graphical biochemical pathway description. Many pathway databases are not directly exportable to CellDesigner models. PathwayAccess is an extensible suite of CellDesigner plugins, which connect CellDesigner directly to pathway databases using respective Java application programming interfaces. The process is streamlined for creating new PathwayAccess plugins for specific pathway databases. Three PathwayAccess plugins, MetNetAccess, BioCycAccess and ReactomeAccess, directly connect CellDesigner to the pathway databases MetNetDB, BioCyc and Reactome. PathwayAccess plugins enable CellDesigner users to expose pathway data to analytical CellDesigner functions, curate their pathway databases and visually integrate pathway data from different databases using standard Systems Biology Markup Language and Systems Biology Graphical Notation. Implemented in Java, PathwayAccess plugins run with CellDesigner version 4.0.1 and were tested on Ubuntu Linux, Windows XP and 7, and MacOSX. Source code, binaries, documentation and video walkthroughs are freely available at http://vrac.iastate.edu/~jlv.

  13. Activation of LILRB2 signal pathway in temporal lobe epilepsy patients and in a pilocarpine induced epilepsy model.

    Science.gov (United States)

    Yue, Jiong; Li, Wei; Liang, Chao; Chen, Bing; Chen, Xin; Wang, Lukang; Zang, Zhenle; Yu, Sixun; Liu, Shiyong; Li, Song; Yang, Hui

    2016-11-01

    Temporal lobe epilepsy (TLE) is a frequent form of focal intractable epilepsy in adults, but the specific mechanism underlying the epileptogenesis of TLE is still unknown. Human leukocyte immunoglobulin-like receptor B2 (LILRB2) (the murine homolog gene called paired immunoglobulin-like receptor B, or PirB), participates in the process of synaptic plasticity and neurite growth in the central nervous system (CNS), suggesting a potential role of LILRB2 in epilepsy. However, the expression pattern of LILRB2 and the downstream molecular signal in intractable TLE remains poorly understood. In the present study, western blotting and immunohistochemistry results showed that LILRB2 expression was upregulated in the temporal neocortex of patients with TLE. Moreover, protein levels of LILRB2 negatively correlated with the frequency of seizures in TLE patients. In the pilocarpine-induced C57BL/6 mouse model, PirB upregulation in the hippocampus began 12h after status epilepticus (SE), reached a peak at 7days and then maintained a significantly high level until day 60. Similarly, we found a remarkable increase in PirB expression at 1day, 7days and30days post-SE in the temporal cortex. Double-labeled immunofluorescence showed that LILRB2/PirB were highly expressed in neurons and astrocytes but not microglia. In addition, protein levels of POSH, SHROOM3, ROCK1 and ROCK2, the important downstream factors of the LILRB2 pathway, were significantly increased in the epileptic foci of TLE patients and located on the NeuN-positive neurons and GFAP-positive astrocytes. Taken together, our results indicate that LILRB2/PirB may be involved in the process of TLE. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. Hesperidin produces cardioprotective activity via PPAR-γ pathway in ischemic heart disease model in diabetic rats.

    Directory of Open Access Journals (Sweden)

    Yogeeta O Agrawal

    Full Text Available The present study investigated the effect of hesperidin, a natural flavonoid, in cardiac ischemia and reperfusion (I/R injury in diabetic rats. Male Wistar rats with diabetes were divided into five groups and were orally administered saline once daily (IR-sham and IR-control, Hesperidin (100 mg/kg/day; IR-Hesperidin, GW9962 (PPAR-γ receptor antagonist, or combination of both for 14 days. On the 15th day, in the IR-control and IR-treatment groups, rats were subjected to left anterior descending (LAD coronary artery occlusion for 45 minutes followed by a one-hour reperfusion. Haemodynamic parameters were recorded and rats were sacrificed; hearts were isolated for biochemical, histopathological, ultrastructural and immunohistochemistry. In the IR-control group, significant ventricular dysfunctions were observed along with enhanced expression of pro-apoptotic protein Bax. A decline in cardiac injury markers lactate dehydrogenase activity, CK-MB and increased content of thiobarbituric acid reactive substances, a marker of lipid peroxidation, and TNF-α were observed. Hesperidin pretreatment significantly improved mean arterial pressure, reduced left ventricular end-diastolic pressure, and improved both inotropic and lusitropic function of the heart (+LVdP/dt and -LVdP/dt as compared to IR-control. Furthermore, hesperidin treatment significantly decreased the level of thiobarbituric acid reactive substances and reversed the activity of lactate dehydrogenase towards normal value. Hesperidin showed anti-apoptotic effects by upregulating Bcl-2 protein and decreasing Bax protein expression. Additionally, histopathological and ultrastructural studies reconfirmed the protective action of hesperidin. On the other hand, GW9662, selective PPAR-γ receptor antagonist, produced opposite effects and attenuated the hesperidin induced improvements. The study for the first time evidence the involvement of PPAR-γ pathway in the cardioprotective activity of

  15. Mars Atmospheric Conversion to Methane and Water: An Engineering Model of the Sabatier Reactor with Characterization of Ru/Al2O3 for Long Duration Use on Mars

    Science.gov (United States)

    Meier, Anne J.; Shah, Malay; Petersen, Elspeth; Hintze, Paul; Muscatello, Tony

    2017-01-01

    The Atmospheric Processing Module (APM) is a Mars In-Situ Resource Utilization (ISRU) technology designed to demonstrate conversion of the Martian atmosphere into methane and water. The Martian atmosphere consists of approximately 95 carbon dioxide (CO2) and residual argon and nitrogen. APM utilizes cryocoolers for CO2 acquisition from a simulated Martian atmosphere and pressure. The captured CO2 is sublimated and pressurized as a feedstock into the Sabatier reactor, which converts CO2 and hydrogen to methane and water. The Sabatier reaction occurs over a packed bed reactor filled with Ru/Al2O3 pellets. The long duration use of the APM system and catalyst was investigated for future scaling and failure limits. Failure of the catalyst was detected by gas chromatography and temperature sensors on the system. Following this, characterization and experimentation with the catalyst was carried out with analysis including x-ray photoelectron spectroscopy and scanning electron microscopy with elemental dispersive spectroscopy. This paper will discuss results of the catalyst performance, the overall APM Sabatier approach, as well as intrinsic catalyst considerations of the Sabatier reactor performance incorporated into a chemical model.

  16. Climate change forecasting in a mountainous data scarce watershed using CMIP5 models under representative concentration pathways

    Science.gov (United States)

    Aghakhani Afshar, A.; Hasanzadeh, Y.; Besalatpour, A. A.; Pourreza-Bilondi, M.

    2017-07-01

    Hydrology cycle of river basins and available water resources in arid and semi-arid regions are highly affected by climate changes. In recent years, the increment of temperature due to excessive increased emission of greenhouse gases has led to an abnormality in the climate system of the earth. The main objective of this study is to survey the future climate changes in one of the biggest mountainous watersheds in northeast of Iran (i.e., Kashafrood). In this research, by considering the precipitation and temperature as two important climatic parameters in watersheds, 14 models evolved in the general circulation models (GCMs) of the newest generation in the Coupled Model Intercomparison Project Phase 5 (CMIP5) were used to forecast the future climate changes in the study area. For the historical period of 1992-2005, four evaluation criteria including Nash-Sutcliffe (NS), percent of bias (PBIAS), coefficient of determination ( R 2) and the ratio of the root-mean-square-error to the standard deviation of measured data (RSR) were used to compare the simulated observed data for assessing goodness-of-fit of the models. In the primary results, four climate models namely GFDL-ESM2G, IPSL-CM5A-MR, MIROC-ESM, and NorESM1-M were selected among the abovementioned 14 models due to their more prediction accuracies to the investigated evaluation criteria. Thereafter, climate changes of the future periods (near-century, 2006-2037; mid-century, 2037-2070; and late-century, 2070-2100) were investigated and compared by four representative concentration pathways (RCPs) of new emission scenarios of RCP2.6, RCP4.5, RCP6.0, and RCP8.5. In order to assess the trend of annual and seasonal changes of climatic components, Mann-Kendall non-parametric test (MK) was also employed. The results of Mann-Kendall test revealed that the precipitation has significant variable trends of both positive and negative alterations. Furthermore, the mean, maximum, and minimum temperature values had

  17. Systems Biology Model of Interactions between Tissue Growth Factors and DNA Damage Pathways: Low Dose Response and Cross-Talk in TGFβ and ATM Signaling

    International Nuclear Information System (INIS)

    Cucinotta, Francis A

    2016-01-01

    The etiology of radiation carcinogenesis has been described in terms of aberrant changes that span several levels of biological organization. Growth factors regulate many important cellular and tissue functions including apoptosis, differentiation and proliferation. A variety of genetic and epigenetic changes of growth factors have been shown to contribute to cancer initiation and progression. It is known that cellular and tissue damage to ionizing radiation is in part initiated by the production of reactive oxygen species, which can activate cytokine signaling, and the DNA damage response pathways, most notably the ATM signaling pathway. Recently, the transforming growth factor β (TGFβ) pathway has been shown to regulate or directly interact with the ATM pathway in the response to radiation. The relevance of this interaction with the ATM pathway is not known although p53 becomes phosphorylated and DNA damage responses are involved. However, growth factor interactions with DNA damage responses have not been elucidated particularly at low doses, and further characterization of their relationship to cancer processes is warranted. Our goal will be to use a systems biology approach to mathematically and experimentally describe the low-dose responses and cross-talk between the ATM and TGFβ pathways initiated by low- and high-LET radiation. We will characterize ATM and TGFβ signaling in epithelial and fibroblast cells using 2D models and ultimately extending to 3D organotypic cell culture models to begin to elucidate possible differences that may occur for different cell types and/or inter-cellular communication. We will investigate the roles of the Smad and Activating transcription factor 2 (ATF2) proteins as the potential major contributors to crosstalk between the TGFβ and ATM pathways, and links to cell cycle control and/or the DNA damage response, and potential differences in their responses at low and high doses. We have developed various experimental

  18. Systems Biology Model of Interactions Between Tissue Growth Factors and DNA Damage Pathways: Low Dose Response and Cross-Talk in TGFbeta and ATM Signaling

    Energy Technology Data Exchange (ETDEWEB)

    O' Neill, Peter [University of Oxford; Anderson, Jennifer [University of Oxford

    2014-10-02

    The etiology of radiation carcinogenesis has been described in terms of aberrant changes that span several levels of biological organization. Growth factors regulate many important cellular and tissue functions including apoptosis, differentiation and proliferation. A variety of genetic and epigenetic changes of growth factors have been shown to contribute to cancer initiation and progression. It is known that cellular and tissue damage to ionizing radiation is in part initiated by the production of reactive oxygen species, which can activate cytokine signaling, and the DNA damage response pathways, most notably the ATM signaling pathway. Recently the transforming growth factor β (TGFβ) pathway has been shown to regulate or directly interact with the ATM pathway in the response to radiation. The relevance of this interaction with the ATM pathway is not known although p53 becomes phosphorylated and DNA damage responses are involved. However, growth factor interactions with DNA damage responses have not been elucidated particularly at low doses and further characterization of their relationship to cancer processes is warranted. Our goal will be to use a systems biology approach to mathematically and experimentally describe the low dose responses and cross-talk between the ATM and TGFβ pathways initiated by low and high LET radiation. We will characterize ATM and TGFβ signaling in epithelial and fibroblast cells using 2D models and ultimately extending to 3D organotypic cell culture models to begin to elucidate possible differences that may occur for different cell types and/or inter-cellular communication. We will investigate the roles of the Smad and Activating transcription factor 2 (ATF2) proteins as the potential major contributors to cross- talk between the TGFβ and ATM pathways, and links to cell cycle control and/or the DNA damage response, and potential differences in their responses at low and high doses. We have developed various experimental

  19. Systems Biology Model of Interactions between Tissue Growth Factors and DNA Damage Pathways: Low Dose Response and Cross-Talk in TGFβ and ATM Signaling

    Energy Technology Data Exchange (ETDEWEB)

    Cucinotta, Francis A [Univ. of Nevada, Las Vegas, NV (United States)

    2016-09-01

    The etiology of radiation carcinogenesis has been described in terms of aberrant changes that span several levels of biological organization. Growth factors regulate many important cellular and tissue functions including apoptosis, differentiation and proliferation. A variety of genetic and epigenetic changes of growth factors have been shown to contribute to cancer initiation and progression. It is known that cellular and tissue damage to ionizing radiation is in part initiated by the production of reactive oxygen species, which can activate cytokine signaling, and the DNA damage response pathways, most notably the ATM signaling pathway. Recently, the transforming growth factor β (TGFβ) pathway has been shown to regulate or directly interact with the ATM pathway in the response to radiation. The relevance of this interaction with the ATM pathway is not known although p53 becomes phosphorylated and DNA damage responses are involved. However, growth factor interactions with DNA damage responses have not been elucidated particularly at low doses, and further characterization of their relationship to cancer processes is warranted. Our goal will be to use a systems biology approach to mathematically and experimentally describe the low-dose responses and cross-talk between the ATM and TGFβ pathways initiated by low- and high-LET radiation. We will characterize ATM and TGFβ signaling in epithelial and fibroblast cells using 2D models and ultimately extending to 3D organotypic cell culture models to begin to elucidate possible differences that may occur for different cell types and/or inter-cellular communication. We will investigate the roles of the Smad and Activating transcription factor 2 (ATF2) proteins as the potential major contributors to crosstalk between the TGFβ and ATM pathways, and links to cell cycle control and/or the DNA damage response, and potential differences in their responses at low and high doses. We have developed various experimental

  20. New insights into the complex regulation of the glycolytic pathway in Lactococcus lactis. I. Construction and diagnosis of a comprehensive dynamic model.

    Science.gov (United States)

    Dolatshahi, Sepideh; Fonseca, Luis L; Voit, Eberhard O

    2016-01-01

    This article and the companion paper use computational systems modeling to decipher the complex coordination of regulatory signals controlling the glycolytic pathway in the dairy bacterium Lactococcus lactis. In this first article, the development of a comprehensive kinetic dynamic model is described. The model is based on in vivo NMR data that consist of concentration trends in key glycolytic metabolites and cofactors. The model structure and parameter values are identified with a customized optimization strategy that uses as its core the method of dynamic flux estimation. For the first time, a dynamic model with a single parameter set fits all available glycolytic time course data under anaerobic operation. The model captures observations that had not been addressed so far and suggests the existence of regulatory effects that had been observed in other species, but not in L. lactis. The companion paper uses this model to analyze details of the dynamic control of glycolysis under aerobic and anaerobic conditions.

  1. Using a Novel Transgenic Mouse Model to Study c-Myc Oncogenic Pathway in Castration Resistance and Chemoresistance of Prostate Cancer

    Science.gov (United States)

    2017-12-01

    AWARD NUMBER: W81XWH-13-1-0162 TITLE: Using a Novel Transgenic Mouse Model to Study c -Myc Oncogenic Pathway in Castration Resistance and...DATES COVERED 15Sept2013 - 14Sept2017 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Using a Novel Transgenic Mouse Model to Study c -Myc Oncogenic...ABSTRACT We previously made a PB-Cre4/Ai-Myc model for Cre-induced and androgen-independent expression of c -Myc and Luc2 in prostate. This is designed

  2. Summary of the BIOMOVS A4 scenario: Testing models of the air-pasture-cow milk pathway using Chernobyl fallout data

    International Nuclear Information System (INIS)

    Peterson, S.R.; Hoffman, F.O.; Koehler, H.

    1996-01-01

    A unique opportunity to test dose assessment models arose after the Chernobyl reactor accident. During the passage of the contaminated plume, concentrations of 131 I and 137 Cs in air, pasture, and cow's milk were collected at various sites in the northern hemisphere. Afterwards, contaminated pasture and milk samples were analyzed over time. Under the auspices of the Biospheric Model Validation Study (BIOMOVS), data from 13 sites for 131 I and 10 sites for 137 Cs were used to test model predictions for the air-pasture-cow milk pathway. Calculations were submitted for 23 models, 10 of which were quasi-steady state. The others were time-dependent. Daily predictions and predictions of time-integrated concentration of 131 I and 137 Cs in pasture grass and milk for six months post-accident were calculated and compared with observed data. Testing against data from several locations over time for several steps in the air-to-milk pathway resulted in a better understanding of important processes and how they should be modeled. This model testing exercise showed both the strengths and weaknesses of the models and revealed the importance of testing all parts of dose assessment models whenever possible. 19 refs., 14 figs., 4 tabs

  3. Estimating the per-capita contribution of habitats and pathways in a migratory network: A modelling approach

    Science.gov (United States)

    Wiederholt, Ruscena; Mattsson, Brady J.; Thogmartin, Wayne E.; Runge, Michael C.; Diffendorfer, Jay E.; Erickson, Richard A.; Federico, Paula; Lopez-Hoffman, Laura; Fryxell, John; Norris, D. Ryan; Sample, Christine

    2018-01-01

    Every year, migratory species undertake seasonal movements along different pathways between discrete regions and habitats. The ability to assess the relative demographic contributions of these different habitats and pathways to the species’ overall population dynamics is critical for understanding the ecology of migratory species, and also has practical applications for management and conservation. Metrics for assessing habitat contributions have been well-developed for metapopulations, but an equivalent metric is not currently available for migratory populations. Here, we develop a framework for estimating the demographic contributions of the discrete habitats and pathways used by migratory species throughout the annual cycle by estimating the per capita contribution of cohorts using these locations. Our framework accounts for seasonal movements between multiple breeding and non-breeding habitats and for both resident and migratory cohorts. We illustrate our framework using a hypothetical migratory network of four habitats, which allows us to better understand how variations in habitat quality affect per capita contributions. Results indicate that per capita contributions for any habitat or pathway are dependent on habitat-specific survival probabilities in all other areas used as part of the migratory circuit, and that contribution metrics are spatially linked (e.g. reduced survival in one habitat also decreases the contribution metric for other habitats). Our framework expands existing theory on the dynamics of spatiotemporally structured populations by developing a generalized approach to estimate the habitat- and pathway-specific contributions of species migrating between multiple breeding and multiple non-breeding habitats for a range of life histories or migratory strategies. Most importantly, it provides a means of prioritizing conservation efforts towards those migratory pathways and habitats that are most critical for the population viability of

  4. Hippocampal proteomics defines pathways associated with memory decline and resilience in normal aging and Alzheimer's disease mouse models.

    Science.gov (United States)

    Neuner, Sarah M; Wilmott, Lynda A; Hoffmann, Brian R; Mozhui, Khyobeni; Kaczorowski, Catherine C

    2017-03-30

    Alzheimer's disease (AD), the most common form of dementia in the elderly, has no cure. Thus, the identification of key molecular mediators of cognitive decline in AD remains a top priority. As aging is the most significant risk factor for AD, the goal of this study was to identify altered proteins and pathways associated with the development of normal aging and AD memory deficits, and identify unique proteins and pathways that may contribute to AD-specific symptoms. We used contextual fear conditioning to diagnose 8-month-old 5XFAD and non-transgenic (Ntg) mice as having either intact or impaired memory, followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) to quantify hippocampal membrane proteins across groups. Subsequent analysis detected 113 proteins differentially expressed relative to memory status (intact vs impaired) in Ntg mice and 103 proteins in 5XFAD mice. Thirty-six proteins, including several involved in neuronal excitability and synaptic plasticity (e.g., GRIA1, GRM3, and SYN1), were altered in both normal aging and AD. Pathway analysis highlighted HDAC4 as a regulator of observed protein changes in both genotypes and identified the REST epigenetic regulatory pathway and G i intracellular signaling as AD-specific pathways involved in regulating the onset of memory deficits. Comparing the hippocampal membrane proteome of Ntg versus AD, regardless of cognitive status, identified 138 differentially expressed proteins, including confirmatory proteins APOE and CLU. Overall, we provide a novel list of putative targets and pathways with therapeutic potential, including a set of proteins associated with cognitive status in normal aging mice or gene mutations that cause AD. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  5. The use of comparative 137Cs body burden estimates from environmental data/models and whole body counting to evaluate diet models for the ingestion pathway

    International Nuclear Information System (INIS)

    Robison, W.L.; Sun, C.

    1997-01-01

    Rongelap and Utirik Atolls were contaminated on 1 March 1954, by a U.S. nuclear test at Bikini Atoll code named BRAVO. The people at both atolls were removed from their atolls in the first few days after the detonation and were returned to their atolls at different times. Detailed studies have been carried out over the years by Lawrence Livermore National Laboratory (LLNL) to determine the radiological conditions at the atolls and estimate the doses to the populations. The contribution of each exposure pathway and radionuclide have been evaluated. All dose assessments show that the major potential contribution to the estimated dose is 137 Cs uptake via the terrestrial food chain. Brookhaven National Laboratory (BNL) has carried out an extensive whole body counting program at both atolls over several years to directly measure the 137 Cs body burden. Here we compare the estimates of the body burdens from the LLNL environmental method with body burdens measured by the BNL whole body counting method. The combination of the results from both methods is used to evaluate proposed diet models to establish more realistic dose assessments. Very good agreement is achieved between the two methods with a diet model that includes both local and imported foods. Other diet models greatly overestimate the body burdens (i.e., dose) observed by whole body counting. The upper 95% confidence limit of interindividual variability around the population mean value based on the environmental method is similar to that calculated from direct measurement by whole body counting. Moreover, the uncertainty in the population mean value based on the environmental method is in very good agreement with the whole body counting data. This provides additional confidence in extrapolating the estimated doses calculated by the environmental method to other islands and atolls. 46 refs., 8 figs., 5 tabs

  6. Independent component and pathway-based analysis of miRNA-regulated gene expression in a model of type 1 diabetes

    DEFF Research Database (Denmark)

    Bang-Berthelsen, Claus Heiner; Pedersen, Lykke; Fløyel, Tina

    2011-01-01

    enrichment of sequence predicted targets, compared to only four miRNAs when using simple negative correlation. The ICs were enriched for miRNA targets that function in diabetes-relevant pathways e.g. type 1 and type 2 diabetes and maturity onset diabetes of the young (MODY). CONCLUSIONS: In this study, ICA...... (ICA). Here, we developed a novel target prediction method based on ICA that incorporates both seed matching and expression profiling of miRNA and mRNA expressions. The method was applied on a cellular model of type 1 diabetes. RESULTS: Microrray profiling identified eight miRNAs (miR-124...... between the predicted miRNA targets. Applying the method on a model of type 1 diabetes resulted in identification of eight miRNAs that appear to affect pathways of relevance to disease mechanisms in diabetes....

  7. Integrative analyses of miRNA and proteomics identify potential biological pathways associated with onset of pulmonary fibrosis in the bleomycin rat model

    International Nuclear Information System (INIS)

    Fukunaga, Satoki; Kakehashi, Anna; Sumida, Kayo; Kushida, Masahiko; Asano, Hiroyuki; Gi, Min; Wanibuchi, Hideki

    2015-01-01

    To determine miRNAs and their predicted target proteins regulatory networks which are potentially involved in onset of pulmonary fibrosis in the bleomycin rat model, we conducted integrative miRNA microarray and iTRAQ-coupled LC-MS/MS proteomic analyses, and evaluated the significance of altered biological functions and pathways. We observed that alterations of miRNAs and proteins are associated with the early phase of bleomycin-induced pulmonary fibrosis, and identified potential target pairs by using ingenuity pathway analysis. Using the data set of these alterations, it was demonstrated that those miRNAs, in association with their predicted target proteins, are potentially involved in canonical pathways reflective of initial epithelial injury and fibrogenic processes, and biofunctions related to induction of cellular development, movement, growth, and proliferation. Prediction of activated functions suggested that lung cells acquire proliferative, migratory, and invasive capabilities, and resistance to cell death especially in the very early phase of bleomycin-induced pulmonary fibrosis. The present study will provide new insights for understanding the molecular pathogenesis of idiopathic pulmonary fibrosis. - Highlights: • We analyzed bleomycin-induced pulmonary fibrosis in the rat. • Integrative analyses of miRNA microarray and proteomics were conducted. • We determined the alterations of miRNAs and their potential target proteins. • The alterations may control biological functions and pathways in pulmonary fibrosis. • Our result may provide new insights of pulmonary fibrosis

  8. Integrative analyses of miRNA and proteomics identify potential biological pathways associated with onset of pulmonary fibrosis in the bleomycin rat model

    Energy Technology Data Exchange (ETDEWEB)

    Fukunaga, Satoki [Department of Molecular Pathology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585 (Japan); Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd., 3-1-98 Kasugade-Naka, Konohana-ku, Osaka 554-8558 (Japan); Kakehashi, Anna [Department of Molecular Pathology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585 (Japan); Sumida, Kayo; Kushida, Masahiko; Asano, Hiroyuki [Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd., 3-1-98 Kasugade-Naka, Konohana-ku, Osaka 554-8558 (Japan); Gi, Min [Department of Molecular Pathology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585 (Japan); Wanibuchi, Hideki, E-mail: wani@med.osaka-cu.ac.jp [Department of Molecular Pathology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585 (Japan)

    2015-08-01

    To determine miRNAs and their predicted target proteins regulatory networks which are potentially involved in onset of pulmonary fibrosis in the bleomycin rat model, we conducted integrative miRNA microarray and iTRAQ-coupled LC-MS/MS proteomic analyses, and evaluated the significance of altered biological functions and pathways. We observed that alterations of miRNAs and proteins are associated with the early phase of bleomycin-induced pulmonary fibrosis, and identified potential target pairs by using ingenuity pathway analysis. Using the data set of these alterations, it was demonstrated that those miRNAs, in association with their predicted target proteins, are potentially involved in canonical pathways reflective of initial epithelial injury and fibrogenic processes, and biofunctions related to induction of cellular development, movement, growth, and proliferation. Prediction of activated functions suggested that lung cells acquire proliferative, migratory, and invasive capabilities, and resistance to cell death especially in the very early phase of bleomycin-induced pulmonary fibrosis. The present study will provide new insights for understanding the molecular pathogenesis of idiopathic pulmonary fibrosis. - Highlights: • We analyzed bleomycin-induced pulmonary fibrosis in the rat. • Integrative analyses of miRNA microarray and proteomics were conducted. • We determined the alterations of miRNAs and their potential target proteins. • The alterations may control biological functions and pathways in pulmonary fibrosis. • Our result may provide new insights of pulmonary fibrosis.

  9. MUSICA MetOp/IASI {H2O,δD} pair retrieval simulations for validating tropospheric moisture pathways in atmospheric models

    Science.gov (United States)

    Schneider, Matthias; Borger, Christian; Wiegele, Andreas; Hase, Frank; García, Omaira E.; Sepúlveda, Eliezer; Werner, Martin

    2017-02-01

    The project MUSICA (MUlti-platform remote Sensing of Isotopologues for investigating the Cycle of Atmospheric water) has shown that the sensor IASI aboard the satellite MetOp can measure the free tropospheric {H2O,δD} pair distribution twice per day on a quasi-global scale. Such data are very promising for investigating tropospheric moisture pathways, however, the complex data characteristics compromise their usage in the context of model evaluation studies. Here we present a tool that allows for simulating MUSICA MetOp/IASI {H2O,δD} pair remote sensing data for a given model atmosphere, thereby creating model data that have the remote sensing data characteristics assimilated. This model data can then be compared to the MUSICA data. The retrieval simulation method is based on the physical principles of radiative transfer and we show that the uncertainty of the simulations is within the uncertainty of the MUSICA MetOp/IASI products, i.e. the retrieval simulations are reliable enough. We demonstrate the working principle of the simulator by applying it to ECHAM5-wiso model data. The few case studies clearly reveal the large potential of the MUSICA MetOp/IASI {H2O,δD} data pairs for evaluating modelled moisture pathways. The tool is made freely available in form of MATLAB and Python routines and can be easily connected to any atmospheric water vapour isotopologue model.

  10. Modelling the structure of a ceRNA-theoretical, bipartite microRNA-mRNA interaction network regulating intestinal epithelial cellular pathways using R programming.

    Science.gov (United States)

    Robinson, J M; Henderson, W A

    2018-01-12

    We report a method using functional-molecular databases and network modelling to identify hypothetical mRNA-miRNA interaction networks regulating intestinal epithelial barrier function. The model forms a data-analysis component of our cell culture experiments, which produce RNA expression data from Nanostring Technologies nCounter ® system. The epithelial tight-junction (TJ) and actin cytoskeleton interact as molecular components of the intestinal epithelial barrier. Upstream regulation of TJ-cytoskeleton interaction is effected by the Rac/Rock/Rho signaling pathway and other associated pathways which may be activated or suppressed by extracellular signaling from growth factors, hormones, and immune receptors. Pathway activations affect epithelial homeostasis, contributing to degradation of the epithelial barrier associated with osmotic dysregulation, inflammation, and tumor development. The complexity underlying miRNA-mRNA interaction networks represents a roadblock for prediction and validation of competing-endogenous RNA network function. We developed a network model to identify hypothetical co-regulatory motifs in a miRNA-mRNA interaction network related to epithelial function. A mRNA-miRNA interaction list was generated using KEGG and miRWalk2.0 databases. R-code was developed to quantify and visualize inherent network structures. We identified a sub-network with a high number of shared, targeting miRNAs, of genes associated with cellular proliferation and cancer, including c-MYC and Cyclin D.

  11. Chemical Conversion Pathways and Kinetic Modeling for the OH-Initiated Reaction of Triclosan in Gas-Phase

    Directory of Open Access Journals (Sweden)

    Xue Zhang

    2015-04-01

    Full Text Available As a widely used antimicrobial additive in daily consumption, attention has been paid to the degradation and conversion of triclosan for a long time. The quantum chemistry calculation and the canonical variational transition state theory are employed to investigate the mechanism and kinetic property. Besides addition and abstraction, oxidation pathways and further conversion pathways are also considered. The OH radicals could degrade triclosan to phenols, aldehydes, and other easily degradable substances. The conversion mechanisms of triclosan to the polychlorinated dibenzopdioxin and furan (PCDD/Fs and polychlorinated biphenyls (PCBs are clearly illustrated and the toxicity would be strengthened in such pathways. Single radical and diradical pathways are compared to study the conversion mechanism of dichlorodibenzo dioxin (DCDD. Furthermore, thermochemistry is discussed in detail. Kinetic property is calculated and the consequent ratio of kadd/ktotal and kabs/ktotal at 298.15 K are 0.955 and 0.045, respectively. Thus, the OH radical addition reactions are predominant, the substitute position of OH radical on triclosan is very important to generate PCDD and furan, and biradical is also a vital intermediate to produce dioxin.

  12. Chemical conversion pathways and kinetic modeling for the OH-initiated reaction of triclosan in gas-phase.

    Science.gov (United States)

    Zhang, Xue; Zhang, Chenxi; Sun, Xiaomin; Kang, Lingyan; Zhao, Yan

    2015-04-10

    As a widely used antimicrobial additive in daily consumption, attention has been paid to the degradation and conversion of triclosan for a long time. The quantum chemistry calculation and the canonical variational transition state theory are employed to investigate the mechanism and kinetic property. Besides addition and abstraction, oxidation pathways and further conversion pathways are also considered. The OH radicals could degrade triclosan to phenols, aldehydes, and other easily degradable substances. The conversion mechanisms of triclosan to the polychlorinated dibenzopdioxin and furan (PCDD/Fs) and polychlorinated biphenyls (PCBs) are clearly illustrated and the toxicity would be strengthened in such pathways. Single radical and diradical pathways are compared to study the conversion mechanism of dichlorodibenzo dioxin (DCDD). Furthermore, thermochemistry is discussed in detail. Kinetic property is calculated and the consequent ratio of k add/k total and k abs/k total at 298.15 K are 0.955 and 0.045, respectively. Thus, the OH radical addition reactions are predominant, the substitute position of OH radical on triclosan is very important to generate PCDD and furan, and biradical is also a vital intermediate to produce dioxin.

  13. Leucine Modulation of the mTOR Pathway for Cognition Modulation: Kinetic and In Vitro Studies and Model Development

    Science.gov (United States)

    2015-09-30

    ultimately at regional levels. In other words , the arrival of free leucine at a tissue site and taken up by the cells would impart a signal for...immunohistochemical techniques and immortalized rat hippocampal cells. Figure 2. Schematic of the Impact of Leucine on the mTOR Protein Synthesis Pathway

  14. Differential [